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Classifications

IUIS Category

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Inheritance

1

Autosomal recessive inheritance HP:0000007

The index patient is homozygous for a loss-of-function TBX21 variant, described by the reporting group as autosomal recessive, complete T-bet deficiency. Consistent with the rest of the MSMD gene set, in which most etiologies are autosomal recessive complete deficiencies, heterozygous carriage is not reported to cause mycobacterial disease. The patient was ascertained in a Moroccan MSMD cohort in which 64% of patients were born to consanguineous parents — the demographic context in which autosomal recessive MSMD etiologies are found, and the reason BCG-vaccinating, TB-endemic, high-consanguinity populations are where further TBX21 cases would be looked for.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:38341181 SUPPORT Human Clinical

"showed that homozygosity for a T-box transcription factor-21 (TBX21) variant could result in MSMD"

States that the reported TBX21 genotype underlying MSMD is homozygous, the basis for recording autosomal recessive inheritance.

PMID:34160550 SUPPORT Human Clinical

"We have described a child suffering from Mendelian susceptibility to mycobacterial disease (MSMD) due to autosomal recessive, complete T-bet deficiency"

States the inheritance mode and the completeness of the deficiency explicitly.

PMID:36630059 SUPPORT Human Clinical

"Fourteen patients (64%) were born to consanguineous parents."

Gives the consanguinity rate in the cohort from which this patient was ascertained, the demographic context for an autosomal recessive etiology.

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Discussions and Knowledge Gaps

4

Does the Tbx21-null mouse predict human T-bet deficiency in the B cell compartment, given that the mouse has impaired humoral immunity and the patient does not?

HUMAN MODEL MISMATCH tbet_mouse_human_humoral_mismatch

Attached to

pathophysiology#Loss of T-bet-Dependent B Cell Subset Development and Class-Switch Skewing

The two disagree, and the disagreement is documented on both sides. T-bet-deficient mice have reduced age-associated B cells and impaired humoral immunity; the T-bet-deficient patient has largely normal humoral immunity, with intact somatic hypermutation, affinity maturation, memory B cell formation and vaccine-specific antibody titres. What survives the species jump is narrower than the mouse suggested: a requirement for one CD11c-high CD21-low subset and a bias in immunoglobulin class switching, not a humoral deficit. The mismatch matters because the mouse literature is the reason T-bet was expected to be broadly required for antibody responses, and it is not — in humans it is largely redundant for long-lived protective humoral immunity. Note this is one patient, so the human side of the comparison rests on a single individual. The same caution applies to the type-2 arm, though more weakly, because there the human side is a gap rather than a contrary finding. The mouse develops lower-airway asthma spontaneously; the patient's reported type-2 disease is described as upper airway inflammation with eosinophilia, and lower-airway involvement is neither reported nor excluded. Whether any real difference exists — and whether it would be a species difference, a difference between a null allele and a DNA-binding-deficient one, or simply the range of one patient — cannot be settled with the evidence available.

Proposed experiments

Assess the CD11c-high CD21-low compartment and class-switch profile in additional TBX21-deficient individuals

tbx21_additional_patients_bcell_profile

The human side of every claim here rests on one person. Identifying further TBX21-deficient individuals — through MSMD cohort sequencing in BCG-vaccinating, consanguineous populations, where this patient was found — and repeating the B cell immunophenotyping and serum immunoglobulin subclass measurement would establish whether the spared humoral immunity is a property of human T-bet deficiency or of this patient's particular allele.

Would support

pathophysiology#Loss of T-bet-Dependent B Cell Subset Development and Class-Switch Skewing

Supporting outcome

Additional TBX21-deficient individuals show absent CD11c-high CD21-low B cells and the same IgG1/IgG4/IgE-skewed, IgG2-reduced profile, with normal vaccine responses.

Refuting outcome

Additional individuals show a frank humoral deficit resembling the mouse, which would place this patient's spared humoral immunity down to his specific allele rather than to a human-versus-mouse difference.

Does the mycobacterial susceptibility in human T-bet deficiency arise from the absence of the innate and innate-like lineages themselves, or from the reduced per-cell IFN-gamma output of the cells that remain?

KNOWLEDGE GAP tbet_lineage_vs_percell_ifng

Attached to

pathophysiology#Deficient Mycobacterium-Reactive IFN-gamma Production

The reported patient has both defects at once — the Mycobacterium-reactive NK, iNKT, MAIT and Vdelta2+ gamma-delta compartments are largely absent, and the residual cells are individually hypofunctional for IFN-gamma. The two are not separable in a single natural genotype, so the entry records them as one node with two components rather than asserting a dominant contribution. The distinction matters therapeutically: a per-cell secretion defect would be expected to respond to exogenous IFN-gamma, whereas a purely developmental lesion might also require reconstitution of the missing lineages.

Is recombinant IFN-gamma clinically effective in TBX21 deficiency specifically?

KNOWLEDGE GAP tbx21_ifng_therapy_untested

Attached to

treatments#Recombinant Interferon Gamma

The indication recorded in this entry is mechanistic and generalised from the IFN-gamma-production arm of MSMD, not observed in TBX21-deficient patients. Human T-bet deficiency is reported in a very small number of individuals, and no treated series exists. TBX21 is not itself a component of the IFN-gamma receptor or the JAK-STAT1 module, so the structural argument for the indication holds, but no source directly assays this patient's response to IFN-gamma. There is a concrete mechanistic reason for caution beyond the absence of a direct assay. T-bet is itself induced downstream of the IFN-gamma receptor through the JAK-STAT1 pathway in NK and T cells (PMID:34675939), so a feedback loop links T-bet to the response side of IFN-gamma signalling as well as to its production. In principle, losing T-bet could blunt that loop's contribution to the cellular response to IFN-gamma, not only IFN-gamma output. That loop is documented specifically in the NK/T-lymphocyte compartment - the same compartment T-bet deficiency already depletes and that this entry already models as failing - and no cached source places T-bet in the macrophage response to IFN-gamma, which is the compartment recombinant IFN-gamma is intended to activate. So the concern bears on an arm of the disease that has already failed rather than on the treatment's target cell, which bounds it without eliminating it, and the entry should not be read as reporting a demonstrated response.

Would a type-2-targeting biologic (anti-IL-5, anti-IL-4Ralpha, or anti-IgE) help the type-2 arm of TBX21 deficiency specifically?

KNOWLEDGE GAP tbx21_type2_biologics_untested

Attached to

treatments#Mepolizumab treatments#Dupilumab treatments#Omalizumab

All three indications recorded here are mechanistic and generalised from the general eosinophilic-asthma and allergic-asthma populations in which each drug was trialled, not observed in a TBX21-deficient patient. No case report or series of a TBX21-deficient individual receiving one has been published, and the index patient's report does not describe type-2-directed treatment either way — an absence of reporting, not a reported absence — so the indications rest entirely on the patient's measured cytokine and immunoglobulin profile (elevated plasma IL-5 and IL-13, elevated circulating IgE) rather than on a treated response. A further open question is whether the disease's upper-airway-predominant presentation would respond the way the pivotal trials' lower-airway (asthma-predominant) populations did. Mepolizumab and dupilumab's efficacy evidence comes from severe asthma cohorts selected on exacerbation history and lung function; the reported TBX21-deficient patient's type-2 disease is described as upper airway inflammation with eosinophilia, and whether the same cytokine blockade transfers to that clinical picture is not established by these trials.

Proposed experiments

N-of-1 type-2 biologic trial in TBX21 deficiency with cytokine and eosinophil readouts

exp_tbx21_type2_biologic_n_of_1_with_cytokine_readout

TBX21 deficiency is vanishingly rare, so a powered randomised trial is not the realistic design and proposing one would be idle. What is feasible is a prospectively registered n-of-1 or small case series: treat a TBX21-deficient patient who has active type-2 disease with a single type-2-targeting biologic, with pre-specified outcomes and pre-treatment baselines, and publish the result whichever way it goes. Anti-IL-5 is the cleanest first choice, because its target and its pharmacodynamic readout lie on the same axis. Because the type-2 disease here is described as upper-airway-predominant, upper-airway outcomes must be measured directly rather than substituting the spirometric endpoints the pivotal asthma trials used — that substitution is the specific transfer this gap doubts. The mycobacterial arm has to be monitored in parallel: suppressing type-2 immunity in a patient whose type-1 immunity is already defective is a risk the mechanism-based rationale does not address.

Readouts

Blood eosinophil count

phenotypes#Increased total eosinophil count

Direction: DECREASED

Interpretation: Direct pharmacodynamic marker of target engagement for anti-IL-5. A fall here without clinical improvement is the informative negative result, which is why it is measured separately from the airway outcome rather than standing in for it.

Plasma IL-5 and IL-13 concentration

pathophysiology#Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells

Direction: DECREASED

Interpretation: The two cytokines recorded at markedly elevated concentration in the index patient, and the quantities the mechanism-based rationale rests on.

Upper airway inflammation, measured directly

phenotypes#Chronic upper airway inflammation

Direction: DECREASED

Interpretation: The clinical outcome that matters here, and the one the pivotal trials do not supply, since they selected on exacerbation history and lung function in lower-airway disease.

Would support

pathophysiology#Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells

Supporting outcome

Symptomatic and objective improvement in the upper-airway type-2 disease, together with a fall in blood eosinophil count and in the plasma IL-5 and IL-13 concentrations that are elevated at baseline, would show the Th2 cytokine excess is the operative driver of the type-2 arm and is druggable downstream of the T-bet lesion.

Refuting outcome

No clinical improvement despite documented target engagement — eosinophils falling on anti-IL-5 while the airway disease is unchanged — would indicate the type-2 manifestations are not driven by the cytokine axis alone, and would point back at the T-bet lesion's other consequences, including the class-switch skew, as contributors these biologics do not reach.

Recorded as the feasible design rather than the ideal one. A single well-reported treated patient would move this gap further than any amount of further extrapolation from the asthma trials.

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Pathophysiology

10

TBX21 Loss of Function

The initiating lesion is biallelic loss of function of TBX21, abolishing functional T-bet. T-bet is a sequence-specific DNA-binding transcription factor of the T-box family and is the master regulator of the type 1 immune program; its loss removes the transcriptional instruction that specifies the IFN-gamma-producing lineages rather than any component of the IL-12/IFN-gamma signalling circuit itself.

Genetic context allele_type: INDEL variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

T-bet sequence-specific transcriptional activation GO:0000981 ⇓ LOSS OF FUNCTION

Downstream

Failed Development of Innate and Innate-like Lymphocyte Lineages Loss of the T-bet transcriptional program removes the lineage-specification signal for the NK, iNKT, MAIT and Vdelta2+ gamma-delta T compartments.

Loss of T-bet Repression of the Th2 Program T-bet has a second, repressive function that is lost at the same time: the wild-type protein restrains the type 2 program, and the patient's mutant protein does not.

Loss of T-bet-Dependent Chromatin Accessibility at Lineage-Defining Loci The same loss of T-bet also removes a B-cell-intrinsic requirement, and it acts there through chromatin: the lineage-defining loci of the CD11c-high CD21-low program do not become accessible.

Show evidence (2 references)

PMID:33296702 SUPPORT Human Clinical

"We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet."

Establishes inherited T-bet deficiency as the initiating molecular lesion.

PMID:34675939 SUPPORT Other

"T box domain of T box proteins might bind the target sequence as a dimer, interacting with both the major and the minor grooves of the DNA"

Supports the molecular-function annotation of T-bet as a sequence-specific DNA-binding transcription factor.

Failed Development of Innate and Innate-like Lymphocyte Lineages

Without T-bet, the innate (NK) and innate-like adaptive (iNKT, MAIT, Vdelta2+ gamma-delta T) lymphocyte lineages fail to develop, and circulating counts of the Mycobacterium-reactive members of these populations are extremely low. Classic TH1 lymphocytes, which are Mycobacterium-non-reactive, are also severely depleted. This is a developmental rather than a signalling defect, which is what distinguishes IMD88 from the receptor and JAK-STAT etiologies of MSMD.

Mycobacterium-reactive natural killer cell CL:0000623 invariant NKT cell CL:0000921 mucosal-associated invariant T cell CL:0000940 Vdelta2+ gamma-delta T cell CL:0000798 classic TH1 lymphocyte CL:0000545

natural killer cell development GO:0001779 ↓ DECREASED TH1 lineage commitment GO:0045063 ↓ DECREASED

Animal models

T-bet knockout mouse (Tbx21-/-), NK and NKT development Mouse recapitulates Demonstrates that loss of T-bet blocks generation of mature NK and invariant NKT cells at the stem-cell level, supplying the developmental interpretation of the patient's depleted counts.

Downstream

Reduced natural killer cell count

Decreased mucosal-associated invariant T cell proportion

Decreased gamma-delta T cell proportion

Decreased Th1 T cell proportion

Deficient Mycobacterium-Reactive IFN-gamma Production The depleted lineages are the ones that supply IFN-gamma against mycobacteria, so their absence is the proximate cause of the IFN-gamma deficit.

Show evidence (2 references)

PMID:33296702 SUPPORT Human Clinical

"The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of Mycobacterium-non reactive classic TH1 lymphocytes"

Direct enumeration of the depleted lineages in the patient.

PMID:34675939 SUPPORT Model Organism

"Deficiency of T-bet leads to significantly reduced NK cell numbers"

Mouse genetic data independently support T-bet as a requirement for the NK compartment, corroborating the human developmental defect.

Failure of Purely Adaptive IFN-gamma Compensation

CD8+ alpha-beta T and non-classic CD4+ alpha-beta TH1* lymphocytes are spared by the T-bet lesion and produce IFN-gamma normally in response to mycobacterial antigens. They nonetheless fail to compensate for the missing innate and innate-like output. This negative result is the disease's central mechanistic finding: it establishes that the innate and innate-like IFN-gamma compartments are non-redundant for anti-mycobacterial immunity in humans, and it is why the residual adaptive response does not rescue the phenotype.

mycobacterium-specific CD8+ alpha-beta T cell CL:0000625 non-classic CD4+ alpha-beta TH1-star cell CL:0000624

Animal models

T-bet knockout mouse (Tbx21-/-), CD4 and NK IFN-gamma production Mouse recapitulates The mouse independently establishes that the CD8 compartment's IFN-gamma production is T-bet-independent, which is precisely why the spared human CD8+ compartment is functionally intact and why its failure to compensate is a substantive finding rather than a second deficit.

Downstream

Deficient Mycobacterium-Reactive IFN-gamma Production Because the spared adaptive compartment cannot substitute, the IFN-gamma deficit created by the lineage failure persists rather than being corrected.

Show evidence (1 reference)

PMID:33296702 SUPPORT Human Clinical

"Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αβ T and non-classic CD4+ αβ TH1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens."

Establishes that this compartment is functionally intact, which is what makes its failure to compensate a substantive finding rather than a second deficit.

Deficient Mycobacterium-Reactive IFN-gamma Production

The net result is insufficient IFN-gamma at the site of mycobacterial challenge. The deficit is quantitative and has two components: the cells that would normally supply the cytokine are largely absent, and the residual members of those populations each secrete abnormally small amounts. Human IFN-gamma level behaves as a quantitative trait determining the outcome of mycobacterial infection, so a partial deficit is sufficient to produce disease.

IFN-gamma production by mycobacterium-reactive lymphocytes GO:0032609 ↓ DECREASED

Downstream

Failed IFN-gamma-Dependent Macrophage Activation IFN-gamma is the macrophage-activating signal; too little of it leaves the macrophage compartment unactivated.

Show evidence (1 reference)

PMID:33296702 SUPPORT Human Clinical

"with the residual populations of these cells also producing abnormally small amounts of IFN-γ"

Establishes the second component of the deficit: the surviving cells are themselves hypofunctional for IFN-gamma.

Failed IFN-gamma-Dependent Macrophage Activation

IFN-gamma is the signal that licenses macrophages to kill ingested mycobacteria. With the cytokine in short supply, the macrophage antimicrobial program is not engaged. This is the step at which every MSMD etiology converges, whether the upstream lesion impairs IFN-gamma production - documented for TBX21 - or the response to it, or, as in some etiologies, both; whether TBX21 deficiency also blunts the response to IFN-gamma has not been tested.

macrophage CL:0000235

IFN-gamma-dependent macrophage activation GO:0042116 ↓ DECREASED

Downstream

Uncontrolled Replication of Weakly Virulent Mycobacteria An unactivated macrophage is a permissive niche, so ingested mycobacteria are not killed.

Show evidence (1 reference)

PMID:38025345 SUPPORT Human Clinical

"almost all genetic etiologies of MSMD alter the interferon-gamma (IFN-γ)- mediated immunity by impairing or abolishing IFN-γ production or the response to this cytokine"

Establishes IFN-gamma-mediated immunity as the common convergence point of MSMD, of which macrophage activation is the effector arm.

Uncontrolled Replication of Weakly Virulent Mycobacteria

Mycobacteria that a competent host clears without difficulty — the M. bovis BCG vaccine strain and environmental non-tuberculous species — replicate unchecked and disseminate. The susceptibility is selective: these patients are not broadly vulnerable to all pathogens, which is the clinical signature that distinguishes MSMD from combined immunodeficiency.

macrophage-mediated killing of intracellular mycobacteria GO:0042742 ↓ DECREASED

Animal models

T-bet knockout mouse (Tbx21-/-), Mycobacterium tuberculosis susceptibility Mouse recapitulates Reproduces the organism-level outcome — failure to contain mycobacterial replication — and ties it to the same proximate cause, diminished IFN-gamma.

Downstream

Fever The second most common presenting manifestation across the MSMD patient population, after lymphadenopathy, and the systemic response to uncontrolled mycobacterial replication.

Hepatosplenomegaly Organomegaly from mycobacterial dissemination to liver and spleen — the third most common manifestation in the MSMD cohort, bound to the combined term because the reports split across splenomegaly, hepatomegaly and both.

Disseminated BCG disease

Non-tuberculous mycobacterial infection

Tuberculosis infection

Non-typhoidal salmonellosis

Lymphadenopathy

Show evidence (1 reference)

PMID:38025345 SUPPORT Human Clinical

"MSMD confers a selective susceptibility to infections with weakly virulent mycobacteria, including the M. bovis Bacille Calmette-Guerin (BCG) vaccines and various environmental mycobacteria in patients, primarily children, without classical immune defects."

Describes the organism-level outcome and its selectivity, which is the content of this node.

Loss of T-bet Repression of the Th2 Program

T-bet is not only the activator of the type 1 program; it is also a repressor of the type 2 one. The patient's mutant T-bet, unlike the wild-type protein, fails to inhibit production of the Th2 cytokines IL-4, IL-5, IL-9 and IL-13 when overexpressed in Th2 cells. A single transcription-factor lesion therefore produces two opposite-signed defects at once, and this repressive arm is what gives IMD88 an allergic phenotype on top of its infectious one.

T-helper 2 cell CL:0000546

T-bet repression of Th2 lineage commitment GO:0045629 ⇓ LOSS OF FUNCTION

Downstream

Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells With the repressor gone, the CD4+ alpha-beta T compartment produces Th2 cytokines without restraint.

Show evidence (1 reference)

PMID:34160550 SUPPORT In Vitro

"Unlike wild-type (WT) T-bet, the mutant form of T-bet from this patient did not inhibit the production of Th2 cytokines, including IL-4, IL-5, IL-9, and IL-13, when overexpressed in T helper 2 (Th2) cells."

Establishes loss of the Th2-repressive function of T-bet as a distinct molecular consequence of the same variant.

Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells

The patient's CD4+ alpha-beta T lymphocytes produce most of the Th2 cytokines on chronic stimulation, and do so regardless of antigen specificity — the defect is a loss of restraint on the program rather than an antigen-directed response. Note the compartment: this is the same purely adaptive CD4+ alpha-beta population that is spared by, and cannot compensate for, the type 1 arm of the disease. One compartment thus carries both the disease's failure to help and its excess.

CD4-positive, alpha-beta T cell CL:0000624

Th2 cytokine production GO:0035745 ↑ INCREASED

Animal models

T-bet knockout mouse (Tbx21-/-), airway type 2 phenotype Mouse partially recapitulates The mouse reproduces the central claim of this node — that losing T-bet releases a CD4+ T-cell-intrinsic type 2 program in the absence of any allergen — and the CD4+ adoptive transfer localises it to the same compartment as in the patient.

Downstream

Increased total eosinophil count

Chronic upper airway inflammation

Asthma

Show evidence (3 references)

PMID:34160550 SUPPORT In Vitro

"Herpesvirus saimiri-immortalized T cells from the patient produced abnormally large amounts of Th2 cytokines"

Documents the Th2 cytokine overproduction in patient-derived cells.

PMID:34160550 SUPPORT Human Clinical

"the patient had markedly high plasma IL-5 and IL-13 concentrations"

Gives the systemic in vivo correlate of the cellular overproduction. Quoted separately from the in vitro finding in the same sentence because the two are different kinds of evidence.

PMID:34160550 SUPPORT Human Clinical

"T-bet deficiency thus underlies the excessive production of Th2 cytokines, particularly IL-5 and IL-13, by CD4+ αβ T cells, causing blood eosinophilia and UAI."

States the causal chain from T-bet loss through CD4+ Th2 cytokine excess to the two clinical consequences recorded as downstream phenotypes.

Loss of T-bet-Dependent Chromatin Accessibility at Lineage-Defining Loci

The molecular step between the transcription-factor lesion and the B cell outcome. T-bet governs the CD11c-high CD21-low differentiation program by controlling chromatin accessibility at a defined set of lineage-defining genes — FAS, IL21R, SEC61B, DUSP4, DAPP1, SOX5, CD79B and CXCR4. Without T-bet those loci do not open: 89% of the 2478 loci differentially regulated in stimulated healthy B cells remained unaltered in the patient's. This is what makes the requirement structural rather than a matter of transcriptional tuning, and it is the reason the subset fails to form at all rather than forming at reduced numbers.

B cell CL:0000236

T-bet-dependent chromatin opening at lineage-defining loci GO:0006338 ↓ DECREASED

Downstream

Loss of T-bet-Dependent B Cell Subset Development and Class-Switch Skewing Failure to open the lineage-defining loci is what prevents the CD11c-high CD21-low differentiation program from running.

Show evidence (1 reference)

PMID:35867801 SUPPORT In Vitro

"89% (2208) of these 2478 differentially regulated loci remained unaltered in CpG/αIg/IFN-γ-stimulated T-bet-deficient B cells"

Quantifies the accessibility defect in the patient's B cells: the great majority of loci that normally change on stimulation do not.

Loss of T-bet-Dependent B Cell Subset Development and Class-Switch Skewing

A third consequence of the same lesion, in a third compartment. T-bet is dispensable for the bulk of humoral immunity in humans — somatic hypermutation, affinity maturation, memory and plasmablast formation, and vaccine-specific antibody titres are all intact — but it is required for one specific B cell subset (CD11c-high CD21-low) and it biases immunoglobulin class switching. The patient's isotype profile is skewed toward IgG1, IgG4 and IgE and away from IgG2. The IgE limb is not incidental: it runs in the same type-2 direction as the Th2 excess, which is consistent with a common loss of T-bet restraint on type 2 responses.

CD11c-high CD21-low B cell CL:0000236

Downstream

Increased circulating IgE concentration

Decreased circulating IgG2 concentration

Show evidence (2 references)

PMID:35867801 SUPPORT Human Clinical

"Thus, human T-bet is largely redundant for long-lived protective humoral immunity but is essential for the development of a distinct subset of human CD11chiCD21lo B cells."

States both halves of this node: humoral immunity is broadly spared, and one specific B cell subset is T-bet-dependent.

PMID:35867801 SUPPORT Human Clinical

"Nevertheless, the patient exhibited skewed class switching to IgG1, IgG4, and IgE, along with reduced IgG2, both in vivo and in vitro."

Documents the class-switch skewing that produces the immunoglobulin phenotypes recorded downstream of this node.

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Pathograph

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Phenotypes

16

Blood 7

Reduced natural killer cell count Reduced total natural killer cell count HP:0040218

Show evidence (1 reference)

PMID:33296702 SUPPORT Human Clinical

"The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes"

Reports the reduced NK count directly in the affected patient.

Decreased mucosal-associated invariant T cell proportion HP:4000039

Show evidence (1 reference)

PMID:33296702 SUPPORT Human Clinical

"The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes"

Reports the reduced MAIT count directly in the affected patient.

Decreased gamma-delta T cell proportion HP:0500271

Show evidence (1 reference)

PMID:33296702 SUPPORT Human Clinical

"The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes"

Reports the reduced Vdelta2+ gamma-delta T cell count directly in the affected patient.

Decreased Th1 T cell proportion HP:0025829

Show evidence (1 reference)

PMID:33296702 SUPPORT Human Clinical

"and of Mycobacterium-non reactive classic TH1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ"

Reports depletion of classic TH1 lymphocytes alongside the innate-like lineages.

Increased total eosinophil count HP:0001880

Show evidence (1 reference)

PMID:34160550 SUPPORT Human Clinical

"T-bet deficiency thus underlies the excessive production of Th2 cytokines, particularly IL-5 and IL-13, by CD4+ αβ T cells, causing blood eosinophilia and UAI."

Attributes the patient's blood eosinophilia to the Th2 cytokine excess caused by T-bet deficiency.

Increased circulating IgE concentration HP:0003212

Show evidence (1 reference)

PMID:35867801 SUPPORT Human Clinical

"Plasma IgA and IgM levels in P were normal, while IgE was elevated"

Reports the elevated plasma IgE alongside normal IgA and IgM, which localises the defect to class switching rather than to antibody production generally.

Decreased circulating IgG2 concentration HP:0008348

Recorded as a laboratory finding, not as a clinically consequential antibody deficiency: vaccine-specific IgG titres against tetanus, diphtheria, Haemophilus influenzae b and pneumococcus were all normal in this patient.

Show evidence (1 reference)

PMID:35867801 SUPPORT Human Clinical

"Plasma total IgG levels were also higher in P, predominantly due to increased IgG1, and a modest increase in IgG4 (Fig. 1D). By contrast, IgG2 was reduced"

Reports the full immunoglobulin subclass profile in the patient: total IgG and IgG1 up, IgG4 modestly up, IgG2 down.

Cardiovascular 2

Lymphadenopathy HP:0002716

Show evidence (1 reference)

PMID:38341181 SUPPORT Human Clinical

"Lymphadenopathy was the most common clinical manifestation of MSMD, reported in 378 (45.5%) cases and multifocal in 35.1%."

Cohort-level frequency of lymphadenopathy in MSMD; applied here as the syndromic context for this etiology, not as a TBX21-specific rate.

Hepatosplenomegaly HP:0001433

Show evidence (1 reference)

PMID:38341181 SUPPORT Human Clinical

"Organomegaly was reported in 206 patients (24.8%)"

Cohort-level frequency of organomegaly in MSMD; applied here as syndromic context, not as a TBX21-specific rate.

Immune 5

Disseminated BCG disease BCGosis HP:0020087

Show evidence (1 reference)

PMID:38025345 SUPPORT Human Clinical

"MSMD confers a selective susceptibility to infections with weakly virulent mycobacteria, including the M. bovis Bacille Calmette-Guerin (BCG) vaccines"

Establishes BCG disease as a defining clinical manifestation of MSMD, the syndrome this TBX21 etiology produces.

Non-tuberculous mycobacterial infection HP:5210115

Show evidence (2 references)

PMID:38025345 SUPPORT Human Clinical

"MSMD confers a selective susceptibility to infections with weakly virulent mycobacteria, including the M. bovis Bacille Calmette-Guerin (BCG) vaccines and various environmental mycobacteria in patients, primarily children, without classical immune defects."

Establishes susceptibility to environmental mycobacteria as a defining feature of MSMD, the syndrome this TBX21 etiology produces.

PMID:35867801 NO_EVIDENCE Human Clinical

"he has been in remission and free of mycobacterial infection for several years"

Does not bear on whether the susceptibility exists — it reports the outcome of the one treated episode. Recorded here so a reader does not infer a recurrent or relapsing course from the class-level susceptibility above; the sentence is cited as evidence of course under `progression`, where that is the claim being made.

Tuberculosis infection HP:5210111

Show evidence (1 reference)

PMID:38025345 SUPPORT Human Clinical

"These patients may also present severe forms of tuberculosis, and about half of them might develop non-typhoidal salmonellosis."

Extends the MSMD infectious spectrum to severe tuberculosis. Quoted for the tuberculosis clause; the salmonellosis clause is curated as its own phenotype.

Non-typhoidal salmonellosis Unusual Salmonella infection HP:5210093

Show evidence (1 reference)

PMID:38025345 SUPPORT Human Clinical

"These patients may also present severe forms of tuberculosis, and about half of them might develop non-typhoidal salmonellosis."

Cohort-level frequency of non-typhoidal salmonellosis in MSMD; applied here as syndromic context, not as a TBX21-specific finding.

Asthma HP:0002099

Show evidence (1 reference)

PMID:41209815 SUPPORT Human Clinical

"In patients with MSMD, 39% reported left axillary lymphadenopathy, 13% had proven tuberculosis, 13% reported salmonellosis, 13% reported bilateral necrotic cervical lymphadenopathy with fistula, and 13% reported asthma."

Gives an MSMD-population frequency for asthma, which is what allows it to be curated without resting on the single patient's airway phenotype.

Metabolism 1

Fever HP:0001945

Show evidence (1 reference)

PMID:38341181 SUPPORT Human Clinical

"Fever was described in 251 (30.2%) patients"

Cohort-level frequency of fever in MSMD; applied here as syndromic context, not as a TBX21-specific rate.

Other 1

Chronic upper airway inflammation

Temporal: CHRONIC

Deliberately left unbound. The nearest HPO term is HP:0002257 Chronic rhinitis, defined as chronic inflammation of the *nasal mucosa*; the source says only "upper airway inflammation" and its abstract contains no instance of nasal, rhinitis or sinus. Binding it would manufacture an anatomical claim the source does not make, and HPO has no broader upper-airway-inflammation term (the nearest alternatives, HP:0002781 and HP:0005945, are obstruction rather than inflammation). Recorded so a later curator does not repeat the search; an HPO new-term request is the real fix.

Show evidence (1 reference)

PMID:34160550 SUPPORT Human Clinical

"Here, we explore the persistent upper airway inflammation (UAI) and blood eosinophilia of this patient."

Documents persistent upper airway inflammation as a clinical feature of the reported T-bet-deficient patient.

🧬

Genetic Associations

1

TBX21 (CAUSATIVE)

Gene: TBX21 hgnc:11599 variant_origin: GERMLINE

Show evidence (6 references)

PMID:38341181 SUPPORT Human Clinical

"showed that homozygosity for a T-box transcription factor-21 (TBX21) variant could result in MSMD"

Establishes a homozygous TBX21 variant as a genetic cause of Mendelian susceptibility to mycobacterial disease.

PMID:33296702 SUPPORT Human Clinical

"We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet."

Attributes the patient's mycobacterial disease to inherited deficiency of T-bet, the TBX21 gene product.

PMID:33296702 SUPPORT Human Clinical

"Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αβ T and non-classic CD4+ αβ TH1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens."

Documents that the TBX21 lesion is lineage-selective rather than a global lymphocyte defect, which is what distinguishes it from other MSMD etiologies.

+ 3 more references

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Medical Actions

7

Recombinant Interferon Gamma

Action: Pharmacotherapy NCIT:C15986

Agent: interferon gamma-1b NCIT:C100089

Platform: Protein replacement

Subcutaneous recombinant IFN-gamma is the mechanistically indicated therapy for this etiology. TBX21 is not itself a component of the IFN-gamma receptor or the downstream JAK-STAT1 module, so those are not mutated in this patient; whether the patient's cells respond normally to IFN-gamma has not been directly assayed. This is the therapeutic dividing line within MSMD: production defects are candidates for recombinant IFN-gamma, whereas defects abolishing the response to the cytokine are not, and are managed with transplantation or gene therapy instead. Note that this is a mechanism-based indication for the production arm of MSMD generally; no trial or case series of recombinant IFN-gamma in TBX21-deficient patients has been reported.

Mechanism Target:

ACTIVATES Failed IFN-gamma-Dependent Macrophage Activation — Exogenous recombinant IFN-gamma supplies the cytokine that the T-bet-deficient lymphocyte compartment cannot make, to a receptor and JAK-STAT1 module that TBX21 does not itself lesion, with the aim of restoring the macrophage-activating signal; whether the patient's macrophages actually respond has not been tested.

Show evidence (1 reference)

PMID:38025345 SUPPORT Human Clinical

"MSMD patients with impaired production of IFN-γ may benefit from injections of human recombinant IFN-γ, while for patients with abolished response to this cytokine, hematopoietic stem cell transplantation (HSCT) and promising gene therapy are the only current therapeutic options."

States the production-versus-response therapeutic split that places TBX21 deficiency, a production defect, on the recombinant IFN-gamma side.

Show evidence (4 references)

PMID:38025345 SUPPORT Human Clinical

"MSMD patients with impaired production of IFN-γ may benefit from injections of human recombinant IFN-γ"

Supports recombinant IFN-gamma as the therapy indicated for the IFN-gamma production arm of MSMD, to which TBX21 deficiency belongs.

PMID:36630059 SUPPORT Human Clinical

"Patients with defects in IFN-γ production may benefit from treatment with recombinant human IFN-γ, in addition to antibiotics."

Independent statement of the same indication, and specifies that it is an adjunct to antibiotics rather than a replacement for them.

PMID:36630059 SUPPORT Human Clinical

"All identified mutations/variants altered production or response to IFN-γ or both."

This cohort's own etiology-level summary leaves both the production and the response arm open for every gene it reports, including TBX21; it does not classify TBX21 on either side, so it cannot be read as settling whether this patient's IFN-gamma responsiveness is preserved.

+ 1 more reference

Antimycobacterial Therapy

Action: multidrug antimycobacterial chemotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: antitubercular agent NCIT:C280 rifampicin CHEBI:28077 isoniazid CHEBI:6030 pyrazinamide CHEBI:45285 ethambutol CHEBI:4877

Platform: Small molecule

Prolonged multidrug antimycobacterial chemotherapy is the mainstay of managing the mycobacterial disease itself, and is required regardless of which MSMD gene is involved. It treats the infection rather than the underlying immune defect, so relapse on withdrawal would be expected while the IFN-gamma deficit persists, though the index patient has in fact remained in remission off therapy. The agents listed are the drugs used across the Moroccan MSMD cohort from which this patient was ascertained; regimen composition should follow species identification and susceptibility testing rather than being applied as a fixed block, and this entry does not assert a specific regimen or duration for this disease.

Mechanism Target:

INHIBITS Uncontrolled Replication of Weakly Virulent Mycobacteria — Antimycobacterial drugs act directly on the organism, substituting pharmacological killing for the macrophage-mediated killing the host cannot perform.

Show evidence (2 references)

PMID:38341181 SUPPORT Human Clinical

"MSMD is associated with a high mortality rate, mostly due to impaired control of infection."

Establishes uncontrolled mycobacterial infection as the dominant cause of death in MSMD, which is what antimycobacterial therapy is directed at.

PMID:36630059 SUPPORT Human Clinical

"Patients with defects in IFN-γ production may benefit from treatment with recombinant human IFN-γ, in addition to antibiotics."

Establishes antibiotics as the baseline treatment in MSMD, on which recombinant IFN-gamma is an adjunct rather than a substitute.

Avoidance of BCG Vaccination

Action: avoidance of live BCG vaccination Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Live BCG vaccine is the commonest trigger of disease in MSMD, so it is contraindicated in an affected child and in at-risk siblings pending genetic testing. Because in endemic countries BCG is given at birth, the vaccine is frequently administered before any diagnosis is possible, which is why changes to vaccination policy in endemic areas are proposed as a pre-exposure prevention strategy at the population level rather than as an individual clinical decision.

Mechanism Target:

INHIBITS Uncontrolled Replication of Weakly Virulent Mycobacteria — Withholding the live vaccine removes the mycobacterial challenge that the IFN-gamma-deficient host cannot contain.

Show evidence (2 references)

PMID:38341181 SUPPORT Human Clinical

"Preexposure strategies, such as changes in vaccination policy in endemic areas, the establishment of a worldwide registry of patients with MSMD, and precise follow-up over generations in affected families, appear to be vital to decrease MSMD-related mortality."

Supports pre-exposure avoidance of BCG as a recommended strategy for reducing MSMD mortality.

PMID:36630059 SUPPORT Human Clinical

"BCG vaccination is contraindicated in MSMD patients and should be delayed in newborn siblings until the exclusion of a genetic predisposition to mycobacteria."

States the contraindication and extends it to at-risk newborn siblings pending genetic testing, which is the actionable content of this entry.

Inhaled Corticosteroid Controller Therapy

Action: inhaled corticosteroid therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: inhaled corticosteroid CHEBI:24261

Platform: Small molecule

Standard step-1-to-4 asthma controller therapy, and the first-line management of the asthma this patient's type-2 arm produces. GINA recommends inhaled corticosteroids for every asthma patient, daily or as needed, including mild disease. Curated ahead of the type-2 biologics below because it is the therapy that would actually be given: the biologics are step-5 options reserved for disease uncontrolled on this, and none has been given to a TBX21-deficient patient. Like them, this is extrapolated from the general asthma literature — nothing IMD88-specific has been published — but it is the less speculative extrapolation of the two, and treating the asthma arm as though only biologics were available would invert the usual evidence gradient. Symptomatic control of airway inflammation only. It does not touch the T-bet lesion, the Th2 skew that drives it, or the mycobacterial-susceptibility arm of the disease, and carries the usual caveat that corticosteroid use in a patient with impaired mycobacterial control is a risk-benefit judgement rather than a free intervention.

Mechanism Target:

INHIBITS Asthma — Inhaled corticosteroids suppress the airway inflammation that produces the asthma phenotype, without acting on the Th2 cytokine overproduction upstream of it or on the transcriptional lesion upstream of that.

Show evidence (1 reference)

PMID:32868307 SUPPORT Human Clinical

"The 2019 Global Initiative for Asthma (GINA) guidelines recommend that all asthma patients be treated with inhaled corticosteroids taken daily or as needed; this improves symptoms and outcomes, even in those with mild disease."

Establishes inhaled corticosteroids as the guideline-recommended controller for all asthma severities, which is the general indication this mechanism-based use is extrapolated from. It reports symptom and outcome improvement, not an effect on any upstream mechanism.

Show evidence (1 reference)

PMID:32868307 SUPPORT Human Clinical

"Further, asthma management requires a stepwise approach, escalating and de-escalating treatment based on symptom control."

Sources the stepwise framework that places inhaled corticosteroids before the type-2 biologics curated below, which is why this treatment is recorded first.

Mepolizumab

Action: Pharmacotherapy NCIT:C15986

Agent: mepolizumab NCIT:C157376

Platform: Monoclonal antibody

Mepolizumab is a humanized monoclonal antibody against IL-5, one of the two cytokines (with IL-13) measured at markedly elevated plasma concentration in this patient. It is approved for severe eosinophilic asthma, where it substantially reduces exacerbations by neutralizing the cytokine that drives eosinophil production and survival. The resemblance to this arm is partial rather than exact: the eosinophilia is directly recorded, but the index patient's type-2 disease is described as upper airway inflammation, and lower-airway involvement is neither reported nor excluded — the same hedge the Asthma phenotype node carries. This is a mechanism-based indication only: no TBX21-deficient patient has been treated with mepolizumab or any other type-2-targeting biologic. The index-patient report does not describe type-2-directed treatment either way, so its silence is an absence of reporting rather than a reported absence.

Mechanism Target:

INHIBITS Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells — Mepolizumab neutralizes circulating IL-5, one of the Th2 cytokines this patient's T-bet-deficient CD4+ alpha-beta T cells overproduce without restraint, without correcting the transcriptional lesion that causes the overproduction.

Show evidence (1 reference)

PMID:25199059 SUPPORT Human Clinical

"Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5"

Establishes the mechanism (neutralizing IL-5) that this edge attributes to the drug.

Show evidence (1 reference)

PMID:25199059 SUPPORT Human Clinical

"The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo"

Supports mepolizumab's efficacy in the general severe eosinophilic asthma population that this patient's type-2 arm resembles.

Dupilumab

Action: Pharmacotherapy NCIT:C15986

Agent: dupilumab NCIT:C162455

Platform: Monoclonal antibody

Dupilumab blocks IL-4 receptor alpha, the shared receptor subunit through which both IL-4 and IL-13 signal — two of the four Th2 cytokines this patient's T-bet-deficient CD4+ alpha-beta T cells overproduce. It is approved for uncontrolled moderate-to-severe asthma, with the largest benefit in patients with elevated blood eosinophils, the same laboratory picture recorded in this entry. As with mepolizumab, this is a mechanism-based indication only: no TBX21-deficient patient has been treated with dupilumab.

Mechanism Target:

INHIBITS Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells — Dupilumab blocks IL-4Ralpha, preventing signalling by both IL-4 and IL-13 downstream of, rather than correcting, the T-bet lesion that causes this patient's T cells to overproduce them.

Show evidence (1 reference)

PMID:29782217 SUPPORT BACKGROUND Human Clinical

"Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling."

Establishes the mechanism (blocking IL-4Ralpha, and so both IL-4 and IL-13 signalling) that this edge attributes to the drug. The sentence sits in QUEST's BACKGROUND paragraph, restating established pharmacology rather than reporting the trial's own result, which is what quote_role records; the trial itself is a human RCT, so evidence_source is unchanged.

Show evidence (2 references)

PMID:29782217 SUPPORT Human Clinical

"patients who received dupilumab had significantly lower rates of severe asthma exacerbation than those who received placebo, as well as better lung function and asthma control. Greater benefits were seen in patients with higher baseline levels of eosinophils."

Supports dupilumab's efficacy in the general uncontrolled-asthma-with-eosinophilia population that this patient's type-2 arm resembles, and that the benefit tracks eosinophil count, the same marker elevated in this entry.

PMID:29782217 SUPPORT Human Clinical

"Blood eosinophilia occurred after the start of the intervention in 52 patients (4.1%) who received dupilumab as compared with 4 patients (0.6%) who received placebo"

A caveat specific to this entry rather than a generic safety note. Dupilumab raised blood eosinophils in a minority of QUEST participants, and this patient already carries an elevated eosinophil count as a curated phenotype. Of the three biologics here it is the one that does not target eosinophils directly, so it could worsen the marker it is partly being proposed for. Recorded so the trade-off is visible at the point of the proposal.

Omalizumab

Action: Pharmacotherapy NCIT:C15986

Agent: omalizumab NCIT:C29299

Platform: Monoclonal antibody

Omalizumab neutralizes free circulating IgE. It is approved for severe persistent allergic asthma and is a mechanism-based candidate here because this patient's class-switch skew, driven by the same T-bet lesion as the Th2 cytokine excess, produces elevated circulating IgE in addition to eosinophilia and Th2 cytokine overproduction. Unlike mepolizumab and dupilumab, its target is not a Th2 cytokine but the class-switch product downstream of it, so it is wired to the IgE phenotype node rather than to the Th2 cytokine production node. As with the other two biologics, no TBX21-deficient patient has been treated with omalizumab.

Mechanism Target:

INHIBITS Increased circulating IgE concentration — Omalizumab binds free circulating IgE, the class-switch product this patient's T-bet-deficient B cell compartment overproduces, preventing it from engaging its receptors without correcting the class-switch skew itself.

Show evidence (2 references)

PMID:31576204 SUPPORT BACKGROUND Other

"Omalizumab works to block the binding of free IgE to its corresponding FcεRI receptor on basophils and mast cells consequently inhibiting their activation by allergens"

Sources the anti-IgE binding mechanism this edge asserts, which the INNOVATE efficacy citation below does not state. Graded OTHER and marked BACKGROUND because the sentence is the citing paper's restatement of omalizumab's established pharmacology, not a result of the case report it appears in.

PMID:15679715 SUPPORT Human Clinical

"Omalizumab is effective and should be considered as add-on therapy for patients with inadequately controlled severe persistent asthma who have a significant unmet need despite best available therapy."

Supports omalizumab as an effective add-on therapy in the severe persistent allergic asthma population, the general indication this mechanism-based use is extrapolated from. It is an exacerbation-rate efficacy result and does not itself state the anti-IgE mechanism; the item above carries that.

Show evidence (1 reference)

PMID:15679715 SUPPORT Human Clinical

"Omalizumab significantly reduced severe asthma exacerbation rate (0.24 vs 0.48, P = 0.002) and emergency visit rate (0.24 vs 0.43, P = 0.038)."

Supports omalizumab's efficacy in the general severe allergic asthma population, which this patient's IgE-skewed type-2 arm resembles.

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Environmental Factors

1

Bacille Calmette-Guerin (BCG) vaccination

The binding is deliberately broader than the exposure. ECTO has no BCG-, Calmette- or M. bovis-specific exposure class: `runoak -i sqlite:obo:ecto search "l~BCG"`, `"l~Calmette"` and `"l~bacille"` each return nothing, and `"l~mycobacter"` returns only pathogen exposure classes for M. tuberculosis and M. avium and exposures to antimycobacterial drugs, none of which is a vaccine. ECTO:2000129 exposure to vaccination is the most specific true class available, and preferred_term carries the vaccine identity.

Routine BCG immunisation is the sentinel environmental exposure in this disorder. The attenuated Mycobacterium bovis BCG strain is harmless to immunocompetent infants but disseminates in a host that cannot mount IFN-gamma-dependent macrophage activation, which is how MSMD patients typically come to attention. In endemic countries the vaccine is given at birth, so the exposure almost always precedes any possibility of diagnosis.

Show evidence (1 reference)

PMID:38025345 SUPPORT Human Clinical

"MSMD confers a selective susceptibility to infections with weakly virulent mycobacteria, including the M. bovis Bacille Calmette-Guerin (BCG) vaccines"

Establishes BCG vaccine exposure as a defining trigger of clinical disease in this disease family.

Mechanism Target:

TRIGGERS Uncontrolled Replication of Weakly Virulent Mycobacteria — BCG vaccination introduces the live attenuated mycobacterium that then replicates unchecked in macrophages the T-bet-deficient host cannot activate.

Show evidence (1 reference)

PMID:38025345 SUPPORT Human Clinical

"MSMD confers a selective susceptibility to infections with weakly virulent mycobacteria, including the M. bovis Bacille Calmette-Guerin (BCG) vaccines"

Links the BCG exposure to the failure of mycobacterial containment modelled by this node.

🔬

Biochemical Markers

1

Plasma IL-5 and IL-13 (INCREASED)

Pathograph Readouts

Readout Of Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells

The systemic readout of the CD4+ alpha-beta Th2 excess, and the proximate cause of the eosinophilia through IL-5. `direction` is deliberately omitted: the enum on this slot takes association-style values (POSITIVE / NEGATIVE / PRESENT_ABSENT / THRESHOLD_DEPENDENT), and none of them expresses "the analyte is elevated", which is already carried by `presence: INCREASED` on the biomarker itself.

Show evidence (1 reference)

PMID:34160550 SUPPORT Human Clinical

"the patient had markedly high plasma IL-5 and IL-13 concentrations"

Reports the elevated plasma IL-5 and IL-13 concentrations directly.

🔬

Diagnosis

4

Whole blood IL-12 / IFN-gamma activation test

The functional screening assay for MSMD. Whole blood is stimulated and both the production of IL-12 and IFN-gamma and the response to those cytokines are measured, which localises the lesion to the production or the response arm of the circuit before any gene is named. In TBX21 deficiency the expected pattern is impaired IFN-gamma production with an intact response — the distinction that determines whether recombinant IFN-gamma is a rational therapy.

Show evidence (1 reference)

PMID:36630059 SUPPORT Human Clinical

"Whole blood activation test was performed to assess both the production of IL-12 and IFN-γ and the response to these two cytokines"

Describes the assay and, importantly, that it reads production and response separately — which is what makes it discriminating within MSMD.

Extended innate and innate-like lymphocyte immunophenotyping

Routine immunological testing is unremarkable in MSMD, which is precisely why the syndrome is missed. What distinguishes TBX21 deficiency is an extended flow panel covering the innate and innate-like compartments — NK, invariant NKT, MAIT and Vdelta2+ gamma-delta T cells — all of which are present at extremely low counts here. That combined pattern is close to specific for this etiology: no other MSMD gene removes all four lineages, since the others break the cytokine circuit rather than the developmental program that builds it. A standard lymphocyte subset panel does not include these populations and will look normal.

Show evidence (1 reference)

PMID:33296702 SUPPORT Human Clinical

"The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes"

Enumerates the four compartments an extended panel must cover to detect this etiology.

Whole exome sequencing with Sanger confirmation

Genetic confirmation is what assigns the etiology, and it is not optional in MSMD: the functional assay narrows the arm of the circuit but not the gene, and the therapeutic split between production and response defects turns on which gene it is. This is how the index patient's TBX21 genotype was established.

Show evidence (2 references)

PMID:36630059 SUPPORT Human Clinical

"WES was performed for all patients and Sanger sequencing was used to confirm the mutations in the patients and their relatives"

Describes the genetic workup applied to the cohort that includes the TBX21 patient.

PMID:38535546 SUPPORT Human Clinical

"In most suspected MSMD cases, patients are treated empirically without confirming a microbiological and molecular diagnosis."

Records the gap this step addresses: molecular diagnosis is frequently not obtained in practice, which is why it is called out here rather than assumed.

Exclusion of chronic granulomatous disease (ABSENT)

NBT and DHR testing is the standard discriminator against chronic granulomatous disease, the other inborn error that presents with BCG complications and granulomas. Neutrophil oxidative burst is normal in MSMD, and CGD was among the initial misdiagnoses recorded in the MSMD literature.

Show evidence (1 reference)

PMID:36630059 SUPPORT Human Clinical

"NBT and/or DHR tests were performed for 12 symptomatic patients and showed normal phagocytic activity of neutrophils in all of them"

Establishes normal neutrophil oxidative burst in MSMD patients, which is what separates them from chronic granulomatous disease.

📈

Progression

1

Reported course of the index patient

The only published disease course in this genotype, and a single patient's course rather than a natural history for the disorder. Disease presented as mycobacterial disease in childhood and was treated; he has since remained in remission and free of mycobacterial infection for several years. The specific regimen and its duration are deliberately not stated here: they appear in a deep-research summary but in none of the cited sources, and an uncited treatment duration is exactly the kind of detail that should not be promoted to entry fact. Two features of the course are worth separating. First, if an affected child is ascertained through BCG disease, the age at onset is a property of the vaccination schedule rather than of the genotype — an affected child in a country that does not give BCG would be expected to present later, on exposure to an environmental mycobacterium. Do not read an infantile onset as an intrinsic disease property. Second, the type-2 arm did not follow the infection's trajectory: the upper airway inflammation and eosinophilia were reported independently of the mycobacterial episode, which is consistent with the two arms being mechanistically separate.

Show evidence (2 references)

PMID:35867801 SUPPORT Human Clinical

"The patient also developed upper airway inflammation and peripheral eosinophilia due to TH2-skewing of T-bet-deficient CD4+ T cells"

Records the type-2 arm as a separate development in the same patient, reported after and independently of the mycobacterial episode.

PMID:35867801 SUPPORT Human Clinical

"he has been in remission and free of mycobacterial infection for several years"

Records the outcome of the mycobacterial episode: sustained remission, not a relapsing course.

📊

Prevalence

2

Worldwide

Point Prevalence

Deliberately carries no `rate_per_100000` and no `prevalence_class`. The published figures are for MSMD as a syndrome across all 20-plus causal genes, not for the TBX21 etiology, and putting them in machine-queryable slots would assert a population rate for a disease with one reported patient — a claim the surrounding prose disclaims but the exported fields would not. The two available syndrome-level estimates also disagree five-fold and are quoted here side by side rather than reconciled: about 1 in 10,000 (PMID:36630059) and about 1 in 50,000 (PMID:36326697), both 2022-2023 papers from overlapping author groups.

Show evidence (2 references)

PMID:36630059 SUPPORT Human Clinical

"This condition affects about 1/10,000 individuals worldwide"

One of the two worldwide prevalence estimates for MSMD, the syndrome of which this disease is one genetic etiology.

PMID:36326697 SUPPORT Human Clinical

"selectively predisposes ∼1/50,000 individuals to severe disease caused by weakly virulent mycobacteria"

The competing worldwide estimate for MSMD, five-fold lower than the other. Recorded alongside it rather than averaged or chosen between.

TBX21 etiology specifically

Cases In Literature Unknown

TBX21 is among the rarest MSMD etiologies. In the 22-patient Moroccan MSMD series it accounted for a single patient, against 8 for IL12RB1 and 7 for STAT1; that patient is the index case of this disease. No prevalence rate can be derived from a single reported individual, which is why the class is UNKNOWN rather than an ultra-rare band.

Show evidence (1 reference)

PMID:36630059 SUPPORT Human Clinical

"Genetic mutations were identified on the following genes: IL12RB1 in 8 patients, STAT1 in 7 patients; SPPL2A, IFNGR1, and TYK2 in two patients each; and TBX21 in one patient, with different modes of inheritance."

Gives the relative rarity of the TBX21 etiology within a genetically characterised MSMD cohort.

📊

Related Datasets

1

Ex vivo scRNA-Seq of CD4+ cells in T-bet deficiency and wild type geo:GSE174804

human SINGLE CELL RNA SEQ

PMID:34160550

Single-cell transcriptomes of CD4+ T cells from the T-bet-deficient patient and wild-type controls, generated for the Th2/upper-airway-inflammation study. Relevance was triaged manually: the candidate was surfaced by a TBX21 gene-only search, which returned mostly mouse and cancer datasets about unrelated T-bet biology, but this accession is from the companion study of this disease's index patient.

🐁

Animal Models

4

T-bet knockout mouse (Tbx21-/-), CD4 and NK IFN-gamma production

The original Tbx21-null characterisation, and the model that anticipated the compartment-selectivity of the human disease. It reports that T-bet is required for IFN-gamma production in CD4 and NK cells but not in CD8 cells — the same asymmetry later found in the patient, whose CD8+ alpha-beta T cells produce IFN-gamma normally while the innate and innate-like compartments do not.

Species

Mouse

Genotype

Tbx21 targeted deletion (homozygous null)

Publication

PMID:11786644

Pathograph links

Failure of Purely Adaptive IFN-gamma Compensation recapitulates fidelity: moderate The mouse independently establishes that the CD8 compartment's IFN-gamma production is T-bet-independent, which is precisely why the spared human CD8+ compartment is functionally intact and why its failure to compensate is a substantive finding rather than a second deficit.

Limitations: The mouse is a clean null; the patient's allele abolishes DNA binding with protein still expressed at reduced levels. The mouse also lacks the MAIT and Vdelta2+ gamma-delta compartment structure of humans, so it cannot model the innate-like arm of the human deficit.

Show evidence (1 reference)

PMID:11786644 SUPPORT Model Organism

"it is required for control of IFN-gamma production in CD4 and NK cells, but not in CD8 cells"

States the CD4/NK-versus-CD8 asymmetry that the human disease reproduces.

T-bet knockout mouse (Tbx21-/-), NK and NKT development

Establishes that the NK and invariant NKT deficit in T-bet deficiency is a developmental, stem-cell-intrinsic defect rather than a defect of mature-cell function. This is the mechanistic claim the human entry's lineage-failure node makes, and the mouse is where it was demonstrated — the human evidence is a single patient's cell counts, which cannot on their own distinguish failed development from peripheral loss.

Species

Mouse

Genotype

Tbx21 targeted deletion (homozygous null)

Publication

PMID:15084276

Pathograph links

Failed Development of Innate and Innate-like Lymphocyte Lineages recapitulates fidelity: moderate Demonstrates that loss of T-bet blocks generation of mature NK and invariant NKT cells at the stem-cell level, supplying the developmental interpretation of the patient's depleted counts.

Limitations: Mice have no MAIT compartment and no Vdelta2+ gamma-delta subset comparable to the human one, so two of the four lineages depleted in the patient have no counterpart in this model. The mouse is also a null allele rather than the patient's DNA-binding-deficient one.

Show evidence (1 reference)

PMID:15084276 SUPPORT Model Organism

"a profound, stem cell-intrinsic defect in their ability to generate mature NK and Valpha14i NKT cells"

Localises the deficit to development rather than to maintenance of mature cells, which is the claim of the node this link targets.

T-bet knockout mouse (Tbx21-/-), Mycobacterium tuberculosis susceptibility

The only model evidence in this entry for the infectious outcome itself rather than for a cellular step. Tbx21-null mice are susceptible to virulent M. tuberculosis, with increased systemic bacterial burden and diminished IFN-gamma production — the mouse counterpart of the severe-tuberculosis susceptibility recorded as a class-level MSMD phenotype here.

Species

Mouse

Genotype

Tbx21 targeted deletion (homozygous null)

Publication

PMID:16177104

Pathograph links

Uncontrolled Replication of Weakly Virulent Mycobacteria recapitulates fidelity: moderate Reproduces the organism-level outcome — failure to contain mycobacterial replication — and ties it to the same proximate cause, diminished IFN-gamma.

Limitations: Uses virulent M. tuberculosis, whereas the defining human phenotype is disease from weakly virulent mycobacteria including BCG. The mouse also accumulates eosinophilic macrophages and multinucleated giant cells and shows selective IL-10 elevation rather than a fully polarized Th2 response, so its pulmonary pathology is not a straightforward model of the human lesion.

Readouts

Systemic mycobacterial burden

Direction: INCREASED

Interpretation: Direct measure of failed containment, the claim this node makes.

Show evidence (1 reference)

PMID:16177104 SUPPORT Model Organism

"Susceptibility of T-bet-deficient mice is associated with increased systemic bacterial burden, diminished IFN-gamma production"

Reports the measured bacterial burden and the IFN-gamma deficit together.

Show evidence (1 reference)

PMID:16177104 SUPPORT Model Organism

"Mice lacking T-bet are susceptible to virulent M. tuberculosis infection."

Supports treating the Tbx21-null mouse as informative for mycobacterial containment failure.

T-bet knockout mouse (Tbx21-/-), airway type 2 phenotype

Mice with a targeted deletion of Tbx21 spontaneously develop the physiological and inflammatory features of asthma without any allergen exposure, and the phenotype transfers with CD4+ cells into SCID recipients. The model predates the human disease by eighteen years and predicted its type-2 arm: it is the reason the allergic phenotype in the T-bet-deficient patient was recognised as part of the disease rather than as a coincidence.

Species

Mouse

Genotype

Tbx21 targeted deletion (homozygous null)

Publication

PMID:11786643

Pathograph links

Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells partially recapitulates fidelity: moderate The mouse reproduces the central claim of this node — that losing T-bet releases a CD4+ T-cell-intrinsic type 2 program in the absence of any allergen — and the CD4+ adoptive transfer localises it to the same compartment as in the patient.

Limitations: The murine phenotype is lower-airway asthma; the reported human type-2 phenotype is described as upper airway inflammation with blood eosinophilia, and whether lower-airway disease is present in the patient has not been reported either way. Do not read this as an established difference in anatomical level — it is a gap in what has been published. The mouse is also a clean null, while the patient's variant abolishes DNA binding with protein still expressed at reduced levels, so the two are not the same molecular lesion. Only one human patient has been described, so the extent of any species difference cannot be assessed.

Readouts

Spontaneous asthma-like airway physiology and inflammation

Direction: INCREASED

Interpretation: Airway inflammation arising without allergen challenge is the model's evidence that loss of T-bet is itself sufficient to drive the type 2 program.

Show evidence (1 reference)

PMID:11786643 SUPPORT Model Organism

"Mice with a targeted deletion of the T-bet gene and severe combined immunodeficient mice receiving CD4+ cells from T-bet knockout mice spontaneously demonstrated multiple physiological and inflammatory features characteristic of asthma."

Reports the measured airway phenotype and its transfer by CD4+ cells.

Show evidence (1 reference)

PMID:11786643 SUPPORT Model Organism

"Thus, T-bet deficiency, in the absence of allergen exposure, induces a murine phenotype reminiscent of both acute and chronic human asthma."

Supports treating the Tbx21-null mouse as informative for the type-2 arm of human T-bet deficiency.

Show evidence (1 reference)

PMID:11786643 SUPPORT Human Clinical

"We observed reduced expression of the TH1 transcription factor, T-bet, in T cells from airways of patients with asthma compared with that in T cells from airways of nonasthmatic patients"

The human airway observation that motivated the knockout, establishing that the T-bet/asthma link was not purely a mouse finding.

{ }

Source YAML

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name: Immunodeficiency 88
creation_date: "2026-09-01T00:00:00Z"
category: Mendelian
synonyms:
- IMD88
- Mendelian susceptibility to mycobacterial diseases due to TBX21 deficiency
- T-bet deficiency
- TBX21 deficiency
- Human T-bet deficiency
description: >
  Immunodeficiency 88 is an autosomal recessive inborn error of immunity caused by
  biallelic loss-of-function variants in TBX21, the gene encoding the T-box
  transcription factor T-bet. It presents as Mendelian susceptibility to mycobacterial
  disease (MSMD): a selective predisposition to clinical disease caused by weakly
  virulent mycobacteria, in particular the Bacille Calmette-Guerin (BCG) vaccine strain
  and environmental non-tuberculous mycobacteria, in individuals with no overt
  abnormality on routine haematological and immunological testing.

  Almost every genetic etiology of MSMD converges on interferon gamma (IFN-gamma):
  each either impairs the production of the cytokine or the cellular response to it.
  TBX21 deficiency, reported by Yang and colleagues in 2020, belongs to the
  production arm, but it is mechanistically distinctive within that arm. T-bet is not
  a component of the IL-12/IFN-gamma signalling circuit; it is the master
  transcription factor of type 1 immunity, required for the *development* of the
  lymphocyte lineages that supply IFN-gamma rapidly at the site of mycobacterial
  challenge. Human T-bet deficiency therefore removes the cells rather than the
  signalling step.

  The consequence is a lineage-selective lesion. Circulating
  Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT),
  mucosal-associated invariant T (MAIT) and Vdelta2+ gamma-delta T lymphocytes are
  present at extremely low counts, as are Mycobacterium-non-reactive classic TH1
  lymphocytes, and the cells that do remain produce abnormally small amounts of
  IFN-gamma. Critically, the compartment that is spared cannot substitute: CD8+
  alpha-beta T and non-classic CD4+ alpha-beta TH1* lymphocytes produce IFN-gamma
  normally in response to mycobacterial antigens and still fail to compensate. That
  dissociation is the central finding of the disease and is what makes it informative
  about protective anti-mycobacterial immunity in humans generally — it shows that
  purely adaptive IFN-gamma is not sufficient, and that the innate and innate-like
  compartments are non-redundant.

  The disease has a second, opposite-signed arm. T-bet both drives the type 1 program
  and represses the type 2 one, and the patient's mutant protein does neither. The
  spared CD4+ alpha-beta T compartment therefore overproduces Th2 cytokines on chronic
  stimulation regardless of antigen specificity — a phenotype reversed by restoring
  wild-type T-bet — giving markedly high plasma IL-5 and IL-13, blood eosinophilia and
  persistent upper airway inflammation. One transcription-factor lesion thus yields an
  infectious phenotype from too little type 1 immunity and an allergic one from too
  much type 2, in different lymphocyte compartments. The same purely adaptive CD4+
  alpha-beta population carries both the failure to compensate and the excess.
disease_term:
  preferred_term: immunodeficiency 88
  term:
    id: MONDO:0030483
    label: immunodeficiency 88
parents:
- Primary immunodeficiency
- Mendelian susceptibility to mycobacterial disease
references:
- reference: PMID:33296702
  title: "Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria."
- reference: PMID:36630059
  title: "Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds."
- reference: PMID:35867801
  title: "Human T-bet governs the generation of a distinct subset of CD11c(high)CD21(low) B cells."
- reference: PMID:16177104
  title: "Increased susceptibility of mice lacking T-bet to infection with Mycobacterium tuberculosis correlates with increased IL-10 and decreased IFN-gamma production."
- reference: PMID:11786644
  title: "Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells."
- reference: PMID:15084276
  title: "T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells."
- reference: PMID:11786643
  title: "Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet."
- reference: PMID:34160550
  title: "High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency."
- reference: PMID:38341181
  title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
- reference: PMID:38025345
  title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
- reference: PMID:30264912
  title: "Mendelian susceptibility to mycobacterial disease: 2014-2018 update."
- reference: PMID:34675939
  title: "Expression Regulation and Function of T-Bet in NK Cells."
classifications:
  iuis_category:
    classification_value: innate immunity defect
    notes: >-
      IUIS phenotypic classification of inborn errors of immunity, Mendelian
      susceptibility to mycobacterial disease (MSMD) table. Immunodeficiency 88 is the
      TBX21 (T-bet) etiology of MSMD.
    evidence:
    - reference: PMID:38341181
      reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Twenty-one genes are now known to be associated with MSMD: 18 autosomal genes
        (IL12B, IL12RB1, IL12RB2, IL23R, JAK1, RORC, ISG15, USP18, TYK2, IRF8, SPPL2A,
        IFNGR1, IFNGR2, IRF1, STAT1, TBX21, IFNG and ZNFX1) and three X-linked genes
        (CYBB, MCTS1 and NEMO)
      explanation: >-
        Places TBX21 in the established gene set of Mendelian susceptibility to
        mycobacterial disease, the syndrome under which this entry is classified.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  notes: >-
    Deliberately carries no `rate_per_100000` and no `prevalence_class`. The published
    figures are for MSMD as a syndrome across all 20-plus causal genes, not for the
    TBX21 etiology, and putting them in machine-queryable slots would assert a
    population rate for a disease with one reported patient — a claim the surrounding
    prose disclaims but the exported fields would not. The two available syndrome-level
    estimates also disagree five-fold and are quoted here side by side rather than
    reconciled: about 1 in 10,000 (PMID:36630059) and about 1 in 50,000
    (PMID:36326697), both 2022-2023 papers from overlapping author groups.
  evidence:
  - reference: PMID:36630059
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This condition affects about 1/10,000 individuals worldwide
    explanation: >-
      One of the two worldwide prevalence estimates for MSMD, the syndrome of which this
      disease is one genetic etiology.
  - reference: PMID:36326697
    reference_title: "Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      selectively predisposes ∼1/50,000 individuals to severe disease caused by weakly
      virulent mycobacteria
    explanation: >-
      The competing worldwide estimate for MSMD, five-fold lower than the other. Recorded
      alongside it rather than averaged or chosen between.
- population: TBX21 etiology specifically
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    TBX21 is among the rarest MSMD etiologies. In the 22-patient Moroccan MSMD series it
    accounted for a single patient, against 8 for IL12RB1 and 7 for STAT1; that patient
    is the index case of this disease. No prevalence rate can be derived from a single
    reported individual, which is why the class is UNKNOWN rather than an ultra-rare
    band.
  evidence:
  - reference: PMID:36630059
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic mutations were identified on the following genes: IL12RB1 in 8 patients,
      STAT1 in 7 patients; SPPL2A, IFNGR1, and TYK2 in two patients each; and TBX21 in
      one patient, with different modes of inheritance.
    explanation: >-
      Gives the relative rarity of the TBX21 etiology within a genetically characterised
      MSMD cohort.
diagnosis:
- name: Whole blood IL-12 / IFN-gamma activation test
  description: >
    The functional screening assay for MSMD. Whole blood is stimulated and both the
    production of IL-12 and IFN-gamma and the response to those cytokines are measured,
    which localises the lesion to the production or the response arm of the circuit
    before any gene is named. In TBX21 deficiency the expected pattern is impaired
    IFN-gamma production with an intact response — the distinction that determines
    whether recombinant IFN-gamma is a rational therapy.
  evidence:
  - reference: PMID:36630059
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole blood activation test was performed to assess both the production of IL-12
      and IFN-γ and the response to these two cytokines
    explanation: >-
      Describes the assay and, importantly, that it reads production and response
      separately — which is what makes it discriminating within MSMD.
- name: Extended innate and innate-like lymphocyte immunophenotyping
  description: >
    Routine immunological testing is unremarkable in MSMD, which is precisely why the
    syndrome is missed. What distinguishes TBX21 deficiency is an extended flow panel
    covering the innate and innate-like compartments — NK, invariant NKT, MAIT and
    Vdelta2+ gamma-delta T cells — all of which are present at extremely low counts here.
    That combined pattern is close to specific for this etiology: no other MSMD gene
    removes all four lineages, since the others break the cytokine circuit rather than
    the developmental program that builds it. A standard lymphocyte subset panel does not
    include these populations and will look normal.
  evidence:
  - reference: PMID:33296702
    reference_title: "Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient has extremely low counts of circulating Mycobacterium-reactive natural
      killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+
      γδ T lymphocytes
    explanation: >-
      Enumerates the four compartments an extended panel must cover to detect this
      etiology.
- name: Whole exome sequencing with Sanger confirmation
  description: >
    Genetic confirmation is what assigns the etiology, and it is not optional in MSMD:
    the functional assay narrows the arm of the circuit but not the gene, and the
    therapeutic split between production and response defects turns on which gene it is.
    This is how the index patient's TBX21 genotype was established.
  evidence:
  - reference: PMID:36630059
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES was performed for all patients and Sanger sequencing was used to confirm the
      mutations in the patients and their relatives
    explanation: >-
      Describes the genetic workup applied to the cohort that includes the TBX21 patient.
  - reference: PMID:38535546
    reference_title: "Diagnosis and Management of Infections in Patients with Mendelian Susceptibility to Mycobacterial Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In most suspected MSMD cases, patients are treated empirically without confirming a
      microbiological and molecular diagnosis.
    explanation: >-
      Records the gap this step addresses: molecular diagnosis is frequently not obtained
      in practice, which is why it is called out here rather than assumed.
- name: Exclusion of chronic granulomatous disease
  description: >
    NBT and DHR testing is the standard discriminator against chronic granulomatous
    disease, the other inborn error that presents with BCG complications and granulomas.
    Neutrophil oxidative burst is normal in MSMD, and CGD was among the initial
    misdiagnoses recorded in the MSMD literature.
  presence: ABSENT
  evidence:
  - reference: PMID:36630059
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NBT and/or DHR tests were performed for 12 symptomatic patients and showed normal
      phagocytic activity of neutrophils in all of them
    explanation: >-
      Establishes normal neutrophil oxidative burst in MSMD patients, which is what
      separates them from chronic granulomatous disease.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    The index patient is homozygous for a loss-of-function TBX21 variant, described by
    the reporting group as autosomal recessive, complete T-bet deficiency. Consistent
    with the rest of the MSMD gene set, in which most etiologies are autosomal
    recessive complete deficiencies, heterozygous carriage is not reported to cause
    mycobacterial disease. The patient was ascertained in a Moroccan MSMD cohort in
    which 64% of patients were born to consanguineous parents — the demographic context
    in which autosomal recessive MSMD etiologies are found, and the reason
    BCG-vaccinating, TB-endemic, high-consanguinity populations are where further TBX21
    cases would be looked for.
  evidence:
  - reference: PMID:38341181
    reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      showed that homozygosity for a T-box transcription factor-21 (TBX21) variant
      could result in MSMD
    explanation: >-
      States that the reported TBX21 genotype underlying MSMD is homozygous, the basis
      for recording autosomal recessive inheritance.
  - reference: PMID:34160550
    reference_title: "High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have described a child suffering from Mendelian susceptibility to mycobacterial
      disease (MSMD) due to autosomal recessive, complete T-bet deficiency
    explanation: >-
      States the inheritance mode and the completeness of the deficiency explicitly.
  - reference: PMID:36630059
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fourteen patients (64%) were born to consanguineous parents.
    explanation: >-
      Gives the consanguinity rate in the cohort from which this patient was ascertained,
      the demographic context for an autosomal recessive etiology.
genetic:
- name: TBX21
  gene_term:
    preferred_term: TBX21
    term:
      id: hgnc:11599
      label: TBX21
  association: CAUSATIVE
  variant_origin: GERMLINE
  features: >
    TBX21 encodes T-bet, the T-box transcription factor that specifies type 1 immunity.
    The reported disease genotype is homozygosity for an in-del variant in exon 1 that
    abolishes DNA-binding activity. Protein expression is reduced but not abolished —
    TBX21 RNA is normal while protein is diminished — so the defect is functional rather
    than a clean null, which matters when comparing the patient with Tbx21-null mouse
    models. The resulting cellular phenotype is lineage-selective
    rather than global: the developmental programs for NK, iNKT, MAIT and Vdelta2+
    gamma-delta T lymphocytes fail, while other lymphocyte subsets develop normally and
    are impaired only in the amount of IFN-gamma they produce.
  evidence:
  - reference: PMID:38341181
    reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      showed that homozygosity for a T-box transcription factor-21 (TBX21) variant
      could result in MSMD
    explanation: >-
      Establishes a homozygous TBX21 variant as a genetic cause of Mendelian
      susceptibility to mycobacterial disease.
  - reference: PMID:33296702
    reference_title: "Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a patient with mycobacterial disease due to inherited deficiency of the
      transcription factor T-bet.
    explanation: >-
      Attributes the patient's mycobacterial disease to inherited deficiency of T-bet,
      the TBX21 gene product.
  - reference: PMID:33296702
    reference_title: "Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with
      the exception of CD8+ αβ T and non-classic CD4+ αβ TH1∗ lymphocytes, which produce
      IFN-γ normally in response to mycobacterial antigens.
    explanation: >-
      Documents that the TBX21 lesion is lineage-selective rather than a global
      lymphocyte defect, which is what distinguishes it from other MSMD etiologies.
  - reference: PMID:35867801
    reference_title: "Human T-bet governs the generation of a distinct subset of CD11c(high)CD21(low) B cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This patient carries a homozygous in-del mutation in TBX21 that abolishes
      DNA-binding activity without abrogating protein expression
    explanation: >-
      Specifies the variant class and its functional consequence: loss of DNA binding
      with protein still expressed, not a null allele.
  - reference: PMID:36630059
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a patient (P22) has a homozygous indel (insertion and/or deletion) mutation in exon
      1 of the TBX21 gene
    explanation: >-
      Localises the variant to exon 1 and independently confirms the homozygous indel
      genotype.
  - reference: PMID:36630059
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient expressed normal amounts of TBX21 RNA but protein expression was
      diminished
    explanation: >-
      Quantifies the expression defect: transcript normal, protein reduced. This is why
      the allele is described as functional rather than a null.
pathophysiology:
- name: TBX21 Loss of Function
  biological_scale: MOLECULAR
  genetic_context:
    allele_type: INDEL
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  description: >
    The initiating lesion is biallelic loss of function of TBX21, abolishing functional
    T-bet. T-bet is a sequence-specific DNA-binding transcription factor of the T-box
    family and is the master regulator of the type 1 immune program; its loss removes
    the transcriptional instruction that specifies the IFN-gamma-producing lineages
    rather than any component of the IL-12/IFN-gamma signalling circuit itself.
  molecular_functions:
  - preferred_term: T-bet sequence-specific transcriptional activation
    term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
    modifier: LOSS_OF_FUNCTION
  downstream:
  - target: Failed Development of Innate and Innate-like Lymphocyte Lineages
    causal_link_type: DIRECT
    description: >-
      Loss of the T-bet transcriptional program removes the lineage-specification
      signal for the NK, iNKT, MAIT and Vdelta2+ gamma-delta T compartments.
    evidence:
    - reference: PMID:33296702
      reference_title: "Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Human T-bet deficiency thus underlies mycobacterial disease by preventing the
        development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and
        Vδ2+ γδ T cells)
      explanation: >-
        States the causal step directly: T-bet deficiency prevents the development of
        these lineages.
  - target: Loss of T-bet Repression of the Th2 Program
    causal_link_type: DIRECT
    description: >-
      T-bet has a second, repressive function that is lost at the same time: the
      wild-type protein restrains the type 2 program, and the patient's mutant protein
      does not.
    evidence:
    - reference: PMID:34160550
      reference_title: "High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Unlike wild-type (WT) T-bet, the mutant form of T-bet from this patient did not
        inhibit the production of Th2 cytokines, including IL-4, IL-5, IL-9, and IL-13,
        when overexpressed in T helper 2 (Th2) cells.
      explanation: >-
        Direct comparison of wild-type and patient-mutant T-bet establishes that the
        variant specifically abolishes Th2 repression, which is this causal edge.
  - target: Loss of T-bet-Dependent Chromatin Accessibility at Lineage-Defining Loci
    causal_link_type: DIRECT
    description: >-
      The same loss of T-bet also removes a B-cell-intrinsic requirement, and it acts
      there through chromatin: the lineage-defining loci of the CD11c-high CD21-low
      program do not become accessible.
    evidence:
    - reference: PMID:35867801
      reference_title: "Human T-bet governs the generation of a distinct subset of CD11c(high)CD21(low) B cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Mechanistically, human T-bet governed CD21loCD11chi B cell differentiation by
        controlling the chromatin accessibility of lineage-defining genes in these cells:
        FAS, IL21R, SEC61B, DUSP4, DAPP1, SOX5, CD79B, and CXCR4.
      explanation: >-
        States that T-bet acts on this B-cell program through chromatin accessibility,
        which is what this edge claims.
  evidence:
  - reference: PMID:33296702
    reference_title: "Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a patient with mycobacterial disease due to inherited deficiency of the
      transcription factor T-bet.
    explanation: >-
      Establishes inherited T-bet deficiency as the initiating molecular lesion.
  - reference: PMID:34675939
    reference_title: "Expression Regulation and Function of T-Bet in NK Cells."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      T box domain of T box proteins might bind the target sequence as a dimer,
      interacting with both the major and the minor grooves of the DNA
    explanation: >-
      Supports the molecular-function annotation of T-bet as a sequence-specific
      DNA-binding transcription factor.
- name: Failed Development of Innate and Innate-like Lymphocyte Lineages
  biological_scale: CELLULAR
  description: >
    Without T-bet, the innate (NK) and innate-like adaptive (iNKT, MAIT, Vdelta2+
    gamma-delta T) lymphocyte lineages fail to develop, and circulating counts of the
    Mycobacterium-reactive members of these populations are extremely low. Classic TH1
    lymphocytes, which are Mycobacterium-non-reactive, are also severely depleted. This
    is a developmental rather than a signalling defect, which is what distinguishes
    IMD88 from the receptor and JAK-STAT etiologies of MSMD.
  cell_types:
  - preferred_term: Mycobacterium-reactive natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  - preferred_term: invariant NKT cell
    term:
      id: CL:0000921
      label: type I NK T cell
  - preferred_term: mucosal-associated invariant T cell
    term:
      id: CL:0000940
      label: mucosal-associated invariant T cell
  - preferred_term: Vdelta2+ gamma-delta T cell
    term:
      id: CL:0000798
      label: gamma-delta T cell
  - preferred_term: classic TH1 lymphocyte
    term:
      id: CL:0000545
      label: T-helper 1 cell
  biological_processes:
  - preferred_term: natural killer cell development
    term:
      id: GO:0001779
      label: natural killer cell differentiation
    modifier: DECREASED
  - preferred_term: TH1 lineage commitment
    term:
      id: GO:0045063
      label: T-helper 1 cell differentiation
    modifier: DECREASED
  downstream:
  - target: Reduced natural killer cell count
  - target: Decreased mucosal-associated invariant T cell proportion
  - target: Decreased gamma-delta T cell proportion
  - target: Decreased Th1 T cell proportion
  - target: Deficient Mycobacterium-Reactive IFN-gamma Production
    causal_link_type: DIRECT
    description: >-
      The depleted lineages are the ones that supply IFN-gamma against mycobacteria, so
      their absence is the proximate cause of the IFN-gamma deficit.
    evidence:
    - reference: PMID:33296702
      reference_title: "Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Human T-bet deficiency thus underlies mycobacterial disease by preventing the
        development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and
        Vδ2+ γδ T cells) and IFN-γ production by them
      explanation: >-
        Links the developmental failure of these lineages to the loss of IFN-gamma
        production by them, which is exactly this edge.
  evidence:
  - reference: PMID:33296702
    reference_title: "Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient has extremely low counts of circulating Mycobacterium-reactive natural
      killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+
      γδ T lymphocytes, and of Mycobacterium-non reactive classic TH1 lymphocytes
    explanation: >-
      Direct enumeration of the depleted lineages in the patient.
  - reference: PMID:34675939
    reference_title: "Expression Regulation and Function of T-Bet in NK Cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Deficiency of T-bet leads to significantly reduced NK cell numbers
    explanation: >-
      Mouse genetic data independently support T-bet as a requirement for the NK
      compartment, corroborating the human developmental defect.
- name: Failure of Purely Adaptive IFN-gamma Compensation
  biological_scale: CELLULAR
  description: >
    CD8+ alpha-beta T and non-classic CD4+ alpha-beta TH1* lymphocytes are spared by
    the T-bet lesion and produce IFN-gamma normally in response to mycobacterial
    antigens. They nonetheless fail to compensate for the missing innate and
    innate-like output. This negative result is the disease's central mechanistic
    finding: it establishes that the innate and innate-like IFN-gamma compartments are
    non-redundant for anti-mycobacterial immunity in humans, and it is why the residual
    adaptive response does not rescue the phenotype.
  cell_types:
  - preferred_term: mycobacterium-specific CD8+ alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  - preferred_term: non-classic CD4+ alpha-beta TH1-star cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  downstream:
  - target: Deficient Mycobacterium-Reactive IFN-gamma Production
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Because the spared adaptive compartment cannot substitute, the IFN-gamma deficit
      created by the lineage failure persists rather than being corrected.
    evidence:
    - reference: PMID:33296702
      reference_title: "Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8+ αβ T, and
        CD4+ αβ TH1∗ cells unable to compensate for this deficit
      explanation: >-
        States explicitly that the spared adaptive compartment does not compensate for
        the IFN-gamma deficit.
  evidence:
  - reference: PMID:33296702
    reference_title: "Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with
      the exception of CD8+ αβ T and non-classic CD4+ αβ TH1∗ lymphocytes, which produce
      IFN-γ normally in response to mycobacterial antigens.
    explanation: >-
      Establishes that this compartment is functionally intact, which is what makes its
      failure to compensate a substantive finding rather than a second deficit.
- name: Deficient Mycobacterium-Reactive IFN-gamma Production
  biological_scale: ORGANISM
  description: >
    The net result is insufficient IFN-gamma at the site of mycobacterial challenge.
    The deficit is quantitative and has two components: the cells that would normally
    supply the cytokine are largely absent, and the residual members of those
    populations each secrete abnormally small amounts. Human IFN-gamma level behaves as
    a quantitative trait determining the outcome of mycobacterial infection, so a
    partial deficit is sufficient to produce disease.
  biological_processes:
  - preferred_term: IFN-gamma production by mycobacterium-reactive lymphocytes
    term:
      id: GO:0032609
      label: type II interferon production
    modifier: DECREASED
  downstream:
  - target: Failed IFN-gamma-Dependent Macrophage Activation
    causal_link_type: DIRECT
    description: >-
      IFN-gamma is the macrophage-activating signal; too little of it leaves the
      macrophage compartment unactivated.
    evidence:
    - reference: PMID:38025345
      reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        It was proven that the human IFN-γ level is a quantitative trait that defines
        the outcome of mycobacterial infection.
      explanation: >-
        Supports the dose-dependent step from a reduced IFN-gamma level to failure of
        mycobacterial control.
  evidence:
  - reference: PMID:33296702
    reference_title: "Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with the residual populations of these cells also producing abnormally small
      amounts of IFN-γ
    explanation: >-
      Establishes the second component of the deficit: the surviving cells are
      themselves hypofunctional for IFN-gamma.
- name: Failed IFN-gamma-Dependent Macrophage Activation
  biological_scale: CELLULAR
  conforms_to: "granuloma_formation#Th1 and TNF-Driven Macrophage Recruitment and Activation"
  description: >
    IFN-gamma is the signal that licenses macrophages to kill ingested mycobacteria.
    With the cytokine in short supply, the macrophage antimicrobial program is not
    engaged. This is the step at which every MSMD etiology converges, whether the
    upstream lesion impairs IFN-gamma production - documented for TBX21 - or the
    response to it, or, as in some etiologies, both; whether TBX21 deficiency also
    blunts the response to IFN-gamma has not been tested.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: IFN-gamma-dependent macrophage activation
    term:
      id: GO:0042116
      label: macrophage activation
    modifier: DECREASED
  downstream:
  - target: Uncontrolled Replication of Weakly Virulent Mycobacteria
    causal_link_type: DIRECT
    description: >-
      An unactivated macrophage is a permissive niche, so ingested mycobacteria are not
      killed.
  evidence:
  - reference: PMID:38025345
    reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      almost all genetic etiologies of MSMD alter the interferon-gamma (IFN-γ)- mediated
      immunity by impairing or abolishing IFN-γ production or the response to this
      cytokine
    explanation: >-
      Establishes IFN-gamma-mediated immunity as the common convergence point of MSMD,
      of which macrophage activation is the effector arm.
- name: Uncontrolled Replication of Weakly Virulent Mycobacteria
  biological_scale: ORGANISM
  description: >
    Mycobacteria that a competent host clears without difficulty — the M. bovis BCG
    vaccine strain and environmental non-tuberculous species — replicate unchecked and
    disseminate. The susceptibility is selective: these patients are not broadly
    vulnerable to all pathogens, which is the clinical signature that distinguishes
    MSMD from combined immunodeficiency.
  biological_processes:
  - preferred_term: macrophage-mediated killing of intracellular mycobacteria
    term:
      id: GO:0042742
      label: defense response to bacterium
    modifier: DECREASED
  downstream:
  - target: Fever
    causal_link_type: DIRECT
    description: >-
      The second most common presenting manifestation across the MSMD patient population, after lymphadenopathy, and the systemic response to uncontrolled mycobacterial replication.
  - target: Hepatosplenomegaly
    causal_link_type: DIRECT
    description: >-
      Organomegaly from mycobacterial dissemination to liver and spleen — the third most common manifestation in the MSMD cohort, bound to the combined term because the reports split across splenomegaly, hepatomegaly and both.
  - target: Disseminated BCG disease
  - target: Non-tuberculous mycobacterial infection
  - target: Tuberculosis infection
  - target: Non-typhoidal salmonellosis
  - target: Lymphadenopathy
  evidence:
  - reference: PMID:38025345
    reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MSMD confers a selective susceptibility to infections with weakly virulent
      mycobacteria, including the M. bovis Bacille Calmette-Guerin (BCG) vaccines and
      various environmental mycobacteria in patients, primarily children, without
      classical immune defects.
    explanation: >-
      Describes the organism-level outcome and its selectivity, which is the content of
      this node.
- name: Loss of T-bet Repression of the Th2 Program
  biological_scale: MOLECULAR
  description: >
    T-bet is not only the activator of the type 1 program; it is also a repressor of
    the type 2 one. The patient's mutant T-bet, unlike the wild-type protein, fails to
    inhibit production of the Th2 cytokines IL-4, IL-5, IL-9 and IL-13 when
    overexpressed in Th2 cells. A single transcription-factor lesion therefore produces
    two opposite-signed defects at once, and this repressive arm is what gives IMD88 an
    allergic phenotype on top of its infectious one.
  cell_types:
  - preferred_term: T-helper 2 cell
    term:
      id: CL:0000546
      label: T-helper 2 cell
  biological_processes:
  - preferred_term: T-bet repression of Th2 lineage commitment
    term:
      id: GO:0045629
      label: negative regulation of T-helper 2 cell differentiation
    modifier: LOSS_OF_FUNCTION
  downstream:
  - target: Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells
    causal_link_type: DIRECT
    description: >-
      With the repressor gone, the CD4+ alpha-beta T compartment produces Th2 cytokines
      without restraint.
    evidence:
    - reference: PMID:34160550
      reference_title: "High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Finally, the patient's CD4+ αβ T cells produced most of the Th2 cytokines in
        response to chronic stimulation, regardless of their antigen specificities, a
        phenotype reversed by the expression of WT T-bet.
      explanation: >-
        Restoration of wild-type T-bet reverses the overproduction, establishing that
        loss of T-bet repression causes it rather than merely accompanying it.
  evidence:
  - reference: PMID:34160550
    reference_title: "High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Unlike wild-type (WT) T-bet, the mutant form of T-bet from this patient did not
      inhibit the production of Th2 cytokines, including IL-4, IL-5, IL-9, and IL-13,
      when overexpressed in T helper 2 (Th2) cells.
    explanation: >-
      Establishes loss of the Th2-repressive function of T-bet as a distinct molecular
      consequence of the same variant.
- name: Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells
  biological_scale: CELLULAR
  description: >
    The patient's CD4+ alpha-beta T lymphocytes produce most of the Th2 cytokines on
    chronic stimulation, and do so regardless of antigen specificity — the defect is a
    loss of restraint on the program rather than an antigen-directed response. Note the
    compartment: this is the same purely adaptive CD4+ alpha-beta population that is
    spared by, and cannot compensate for, the type 1 arm of the disease. One
    compartment thus carries both the disease's failure to help and its excess.
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: Th2 cytokine production
    term:
      id: GO:0035745
      label: T-helper 2 cell cytokine production
    modifier: INCREASED
  downstream:
  - target: Increased total eosinophil count
  - target: Chronic upper airway inflammation
  - target: Asthma
  evidence:
  - reference: PMID:34160550
    reference_title: "High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Herpesvirus saimiri-immortalized T cells from the patient produced abnormally
      large amounts of Th2 cytokines
    explanation: >-
      Documents the Th2 cytokine overproduction in patient-derived cells.
  - reference: PMID:34160550
    reference_title: "High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the patient had markedly high plasma IL-5 and IL-13 concentrations
    explanation: >-
      Gives the systemic in vivo correlate of the cellular overproduction. Quoted
      separately from the in vitro finding in the same sentence because the two are
      different kinds of evidence.
  - reference: PMID:34160550
    reference_title: "High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      T-bet deficiency thus underlies the excessive production of Th2 cytokines,
      particularly IL-5 and IL-13, by CD4+ αβ T cells, causing blood eosinophilia and
      UAI.
    explanation: >-
      States the causal chain from T-bet loss through CD4+ Th2 cytokine excess to the
      two clinical consequences recorded as downstream phenotypes.
- name: Loss of T-bet-Dependent Chromatin Accessibility at Lineage-Defining Loci
  biological_scale: MOLECULAR
  description: >
    The molecular step between the transcription-factor lesion and the B cell outcome.
    T-bet governs the CD11c-high CD21-low differentiation program by controlling
    chromatin accessibility at a defined set of lineage-defining genes — FAS, IL21R,
    SEC61B, DUSP4, DAPP1, SOX5, CD79B and CXCR4. Without T-bet those loci do not open:
    89% of the 2478 loci differentially regulated in stimulated healthy B cells remained
    unaltered in the patient's. This is what makes the requirement structural rather than
    a matter of transcriptional tuning, and it is the reason the subset fails to form at
    all rather than forming at reduced numbers.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: T-bet-dependent chromatin opening at lineage-defining loci
    term:
      id: GO:0006338
      label: chromatin remodeling
    modifier: DECREASED
  downstream:
  - target: Loss of T-bet-Dependent B Cell Subset Development and Class-Switch Skewing
    causal_link_type: DIRECT
    description: >-
      Failure to open the lineage-defining loci is what prevents the CD11c-high
      CD21-low differentiation program from running.
    evidence:
    - reference: PMID:35867801
      reference_title: "Human T-bet governs the generation of a distinct subset of CD11c(high)CD21(low) B cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Mechanistically, human T-bet governed CD21loCD11chi B cell differentiation by
        controlling the chromatin accessibility of lineage-defining genes in these cells:
        FAS, IL21R, SEC61B, DUSP4, DAPP1, SOX5, CD79B, and CXCR4.
      explanation: >-
        States the causal mechanism explicitly — chromatin accessibility is the step
        through which T-bet governs the differentiation this edge points at.
  evidence:
  - reference: PMID:35867801
    reference_title: "Human T-bet governs the generation of a distinct subset of CD11c(high)CD21(low) B cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      89% (2208) of these 2478 differentially regulated loci remained unaltered in
      CpG/αIg/IFN-γ-stimulated T-bet-deficient B cells
    explanation: >-
      Quantifies the accessibility defect in the patient's B cells: the great majority of
      loci that normally change on stimulation do not.
- name: Loss of T-bet-Dependent B Cell Subset Development and Class-Switch Skewing
  biological_scale: CELLULAR
  description: >
    A third consequence of the same lesion, in a third compartment. T-bet is dispensable
    for the bulk of humoral immunity in humans — somatic hypermutation, affinity
    maturation, memory and plasmablast formation, and vaccine-specific antibody titres
    are all intact — but it is required for one specific B cell subset (CD11c-high
    CD21-low) and it biases immunoglobulin class switching. The patient's isotype
    profile is skewed toward IgG1, IgG4 and IgE and away from IgG2. The IgE limb is not
    incidental: it runs in the same type-2 direction as the Th2 excess, which is
    consistent with a common loss of T-bet restraint on type 2 responses.
  cell_types:
  - preferred_term: CD11c-high CD21-low B cell
    term:
      id: CL:0000236
      label: B cell
  downstream:
  - target: Increased circulating IgE concentration
  - target: Decreased circulating IgG2 concentration
  evidence:
  - reference: PMID:35867801
    reference_title: "Human T-bet governs the generation of a distinct subset of CD11c(high)CD21(low) B cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, human T-bet is largely redundant for long-lived protective humoral immunity
      but is essential for the development of a distinct subset of human
      CD11chiCD21lo B cells.
    explanation: >-
      States both halves of this node: humoral immunity is broadly spared, and one
      specific B cell subset is T-bet-dependent.
  - reference: PMID:35867801
    reference_title: "Human T-bet governs the generation of a distinct subset of CD11c(high)CD21(low) B cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nevertheless, the patient exhibited skewed class switching to IgG1, IgG4, and IgE,
      along with reduced IgG2, both in vivo and in vitro.
    explanation: >-
      Documents the class-switch skewing that produces the immunoglobulin phenotypes
      recorded downstream of this node.
phenotypes:
- category: Infectious
  name: Disseminated BCG disease
  description: >
    Disseminated disease caused by the M. bovis BCG vaccine strain following routine
    vaccination. In countries with universal BCG programmes this is typically the
    presenting event of MSMD, since it is the first mycobacterial challenge an infant
    meets.
  phenotype_term:
    preferred_term: BCGosis
    term:
      id: HP:0020087
      label: BCGosis
  evidence:
  - reference: PMID:38025345
    reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MSMD confers a selective susceptibility to infections with weakly virulent
      mycobacteria, including the M. bovis Bacille Calmette-Guerin (BCG) vaccines
    explanation: >-
      Establishes BCG disease as a defining clinical manifestation of MSMD, the syndrome
      this TBX21 etiology produces.
- category: Infectious
  name: Non-tuberculous mycobacterial infection
  description: >
    Susceptibility to weakly virulent environmental non-tuberculous mycobacteria. In
    countries that do not vaccinate with BCG these organisms, rather than the vaccine
    strain, are the usual precipitant of MSMD. Recorded as the class-level susceptibility
    of the syndrome: the index patient was ascertained through BCG disease, was cured,
    and has remained free of mycobacterial infection for several years, so he is not an
    example of a recurrent or NTM course. HP:0011274 Recurrent mycobacterial infections
    is deliberately not bound anywhere in this entry for that reason.
  phenotype_term:
    preferred_term: Non-tuberculous mycobacterial infection
    term:
      id: HP:5210115
      label: Non-tuberculous mycobacterial infection
  evidence:
  - reference: PMID:38025345
    reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MSMD confers a selective susceptibility to infections with weakly virulent
      mycobacteria, including the M. bovis Bacille Calmette-Guerin (BCG) vaccines and
      various environmental mycobacteria in patients, primarily children, without
      classical immune defects.
    explanation: >-
      Establishes susceptibility to environmental mycobacteria as a defining feature of
      MSMD, the syndrome this TBX21 etiology produces.
  - reference: PMID:35867801
    reference_title: "Human T-bet governs the generation of a distinct subset of CD11c(high)CD21(low) B cells."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      he has been in remission and free of mycobacterial infection for several years
    explanation: >-
      Does not bear on whether the susceptibility exists — it reports the outcome of the
      one treated episode. Recorded here so a reader does not infer a recurrent or
      relapsing course from the class-level susceptibility above; the sentence is cited
      as evidence of course under `progression`, where that is the claim being made.
- category: Infectious
  name: Tuberculosis infection
  description: >
    Susceptibility to severe forms of tuberculosis, over and above the susceptibility to
    weakly virulent mycobacteria. Recorded as the MSMD-wide spectrum, not as an observed
    event in the index patient. The HPO term's own definition names MSMD as one of the
    inborn errors in which disseminated tuberculosis is characteristic.
  phenotype_term:
    preferred_term: Severe tuberculosis
    term:
      id: HP:5210111
      label: Tuberculosis infection
  evidence:
  - reference: PMID:38025345
    reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients may also present severe forms of tuberculosis, and about half of
      them might develop non-typhoidal salmonellosis.
    explanation: >-
      Extends the MSMD infectious spectrum to severe tuberculosis. Quoted for the
      tuberculosis clause; the salmonellosis clause is curated as its own phenotype.
- category: Infectious
  name: Non-typhoidal salmonellosis
  description: >
    About half of MSMD patients develop non-typhoidal salmonellosis, reflecting the same
    dependence on IFN-gamma-activated macrophages for control of intracellular bacteria.
    As with lymphadenopathy, this is the MSMD-wide figure and is recorded as the expected
    syndromic spectrum; it is not reported in the TBX21-deficient patient, whose only
    documented infection was the BCG episode.
  phenotype_term:
    preferred_term: Non-typhoidal salmonellosis
    term:
      id: HP:5210093
      label: Unusual Salmonella infection
  evidence:
  - reference: PMID:38025345
    reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients may also present severe forms of tuberculosis, and about half of
      them might develop non-typhoidal salmonellosis.
    explanation: >-
      Cohort-level frequency of non-typhoidal salmonellosis in MSMD; applied here as
      syndromic context, not as a TBX21-specific finding.
- category: Immunologic
  name: Reduced natural killer cell count
  description: >
    Circulating Mycobacterium-reactive NK lymphocytes are present at extremely low
    counts, reflecting the failure of the T-bet-dependent NK developmental program.
  phenotype_term:
    preferred_term: Reduced total natural killer cell count
    term:
      id: HP:0040218
      label: Reduced total natural killer cell count
  evidence:
  - reference: PMID:33296702
    reference_title: "Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient has extremely low counts of circulating Mycobacterium-reactive natural
      killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+
      γδ T lymphocytes
    explanation: >-
      Reports the reduced NK count directly in the affected patient.
- category: Immunologic
  name: Decreased mucosal-associated invariant T cell proportion
  description: >
    MAIT lymphocytes are among the innate-like adaptive lineages that fail to develop
    without T-bet, and circulating Mycobacterium-reactive MAIT counts are extremely low.
  phenotype_term:
    preferred_term: Decreased mucosal-associated invariant T cell proportion
    term:
      id: HP:4000039
      label: Decreased mucosal-associated invariant T cell proportion
  evidence:
  - reference: PMID:33296702
    reference_title: "Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient has extremely low counts of circulating Mycobacterium-reactive natural
      killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+
      γδ T lymphocytes
    explanation: >-
      Reports the reduced MAIT count directly in the affected patient.
- category: Immunologic
  name: Decreased gamma-delta T cell proportion
  description: >
    Vdelta2+ gamma-delta T lymphocytes, the innate-like gamma-delta subset that responds
    to mycobacterial phosphoantigens, are present at extremely low counts.
  phenotype_term:
    preferred_term: Decreased Vdelta2+ gamma-delta T cell proportion
    term:
      id: HP:0500271
      label: Decreased gamma-delta T cell proportion
  evidence:
  - reference: PMID:33296702
    reference_title: "Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient has extremely low counts of circulating Mycobacterium-reactive natural
      killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+
      γδ T lymphocytes
    explanation: >-
      Reports the reduced Vdelta2+ gamma-delta T cell count directly in the affected
      patient.
- category: Immunologic
  name: Decreased Th1 T cell proportion
  description: >
    Classic TH1 lymphocytes are severely depleted, consistent with T-bet's canonical
    role as the TH1 lineage-specifying transcription factor. Note that these cells are
    Mycobacterium-non-reactive in this patient, so their loss is a marker of the
    transcriptional lesion rather than the direct cause of the mycobacterial
    susceptibility.
  phenotype_term:
    preferred_term: Decreased classic TH1 lymphocyte count
    term:
      id: HP:0025829
      label: Decreased Th1 T cell proportion
  evidence:
  - reference: PMID:33296702
    reference_title: "Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and of Mycobacterium-non reactive classic TH1 lymphocytes, with the residual
      populations of these cells also producing abnormally small amounts of IFN-γ
    explanation: >-
      Reports depletion of classic TH1 lymphocytes alongside the innate-like lineages.
- category: Immunologic
  name: Lymphadenopathy
  description: >
    Lymphadenopathy, frequently multifocal, is the single most common clinical
    manifestation across the MSMD patient population. The frequency figure below is for
    MSMD as a whole rather than for the TBX21 etiology specifically, which has too few
    reported patients to support an etiology-specific estimate; it is recorded here as
    the expected syndromic presentation.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:38341181
    reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymphadenopathy was the most common clinical manifestation of MSMD, reported in
      378 (45.5%) cases and multifocal in 35.1%.
    explanation: >-
      Cohort-level frequency of lymphadenopathy in MSMD; applied here as the syndromic
      context for this etiology, not as a TBX21-specific rate.
- category: Hematologic
  name: Increased total eosinophil count
  description: >
    Blood eosinophilia in the reported patient, driven by the IL-5 excess that follows
    loss of T-bet repression of the Th2 program. This is a consequence of the same
    variant as the mycobacterial susceptibility but reaches the clinic by an entirely
    separate route, so it is not a marker of infection severity.
  phenotype_term:
    preferred_term: Blood eosinophilia
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  evidence:
  - reference: PMID:34160550
    reference_title: "High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      T-bet deficiency thus underlies the excessive production of Th2 cytokines,
      particularly IL-5 and IL-13, by CD4+ αβ T cells, causing blood eosinophilia and
      UAI.
    explanation: >-
      Attributes the patient's blood eosinophilia to the Th2 cytokine excess caused by
      T-bet deficiency.
- category: Respiratory
  name: Chronic upper airway inflammation
  description: >
    Persistent upper airway inflammation in the reported patient, described alongside
    the blood eosinophilia as the allergic arm of the disease and attributed to the same
    Th2 cytokine excess.
  phenotype_term:
    preferred_term: Persistent upper airway inflammation
    temporality: CHRONIC
  evidence:
  - reference: PMID:34160550
    reference_title: "High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we explore the persistent upper airway inflammation (UAI) and blood
      eosinophilia of this patient.
    explanation: >-
      Documents persistent upper airway inflammation as a clinical feature of the
      reported T-bet-deficient patient.
  notes: >-
    Deliberately left unbound. The nearest HPO term is HP:0002257 Chronic rhinitis,
    defined as chronic inflammation of the *nasal mucosa*; the source says only "upper
    airway inflammation" and its abstract contains no instance of nasal, rhinitis or
    sinus. Binding it would manufacture an anatomical claim the source does not make,
    and HPO has no broader upper-airway-inflammation term (the nearest alternatives,
    HP:0002781 and HP:0005945, are obstruction rather than inflammation). Recorded so a
    later curator does not repeat the search; an HPO new-term request is the real fix.
- category: Immunologic
  name: Increased circulating IgE concentration
  description: >
    Elevated plasma IgE, part of the class-switch skew toward IgG1, IgG4 and IgE that
    follows loss of T-bet. It sits on the same type-2 axis as the Th2 cytokine excess
    and the eosinophilia.
  phenotype_term:
    preferred_term: Increased circulating IgE concentration
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  evidence:
  - reference: PMID:35867801
    reference_title: "Human T-bet governs the generation of a distinct subset of CD11c(high)CD21(low) B cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plasma IgA and IgM levels in P were normal, while IgE was elevated
    explanation: >-
      Reports the elevated plasma IgE alongside normal IgA and IgM, which localises the
      defect to class switching rather than to antibody production generally.
- category: Immunologic
  name: Decreased circulating IgG2 concentration
  description: >
    Reduced plasma IgG2, the opposite limb of the same class-switch skew, present both
    in vivo and in vitro and mirrored by fewer IgG2+ memory B cells.
  phenotype_term:
    preferred_term: Decreased circulating IgG2 concentration
    term:
      id: HP:0008348
      label: Decreased circulating IgG2 concentration
  evidence:
  - reference: PMID:35867801
    reference_title: "Human T-bet governs the generation of a distinct subset of CD11c(high)CD21(low) B cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plasma total IgG levels were also higher in P, predominantly due to increased IgG1,
      and a modest increase in IgG4 (Fig. 1D). By contrast, IgG2 was reduced
    explanation: >-
      Reports the full immunoglobulin subclass profile in the patient: total IgG and
      IgG1 up, IgG4 modestly up, IgG2 down.
  notes: >-
    Recorded as a laboratory finding, not as a clinically consequential antibody
    deficiency: vaccine-specific IgG titres against tetanus, diphtheria, Haemophilus
    influenzae b and pneumococcus were all normal in this patient.
- category: Constitutional
  name: Fever
  description: >
    Fever is the second most common presenting manifestation across the MSMD patient
    population, after lymphadenopathy. As with lymphadenopathy, the frequency below is
    for MSMD as a whole rather than for the TBX21 etiology, and is recorded as the
    expected syndromic presentation.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:38341181
    reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fever was described in 251 (30.2%) patients
    explanation: >-
      Cohort-level frequency of fever in MSMD; applied here as syndromic context, not as
      a TBX21-specific rate.
- category: Constitutional
  name: Hepatosplenomegaly
  description: >
    Organomegaly is the third most common manifestation in the MSMD cohort, split across
    splenomegaly, hepatomegaly and hepatosplenomegaly. Bound to the combined term because
    the entry records the organomegaly finding as a whole rather than one organ; the
    per-organ breakdown is in the cited source. MSMD-wide figure, not TBX21-specific.
  phenotype_term:
    preferred_term: Organomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:38341181
    reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Organomegaly was reported in 206 patients (24.8%)
    explanation: >-
      Cohort-level frequency of organomegaly in MSMD; applied here as syndromic context,
      not as a TBX21-specific rate.
- category: Respiratory
  name: Asthma
  description: >
    Asthma is reported in 13% of a Moroccan MSMD cohort. It is curated here as MSMD-wide
    syndromic context, on the same footing as lymphadenopathy and fever, which sidesteps
    the question the single index patient cannot settle — his type-2 disease is described
    as upper airway inflammation, and lower-airway involvement is neither reported nor
    excluded. This phenotype is the HPO-bound distal terminus of the Th2 de-repression
    branch, which otherwise ends in an unbound free-text phenotype.
  phenotype_term:
    preferred_term: Asthma
    term:
      id: HP:0002099
      label: Asthma
  evidence:
  - reference: PMID:41209815
    reference_title: "Defects in Innate and Intrinsic Immunity in Morocco: A Retrospective Analysis of the Genetic Landscape and Clinical Correlations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with MSMD, 39% reported left axillary lymphadenopathy, 13% had proven
      tuberculosis, 13% reported salmonellosis, 13% reported bilateral necrotic cervical
      lymphadenopathy with fistula, and 13% reported asthma.
    explanation: >-
      Gives an MSMD-population frequency for asthma, which is what allows it to be
      curated without resting on the single patient's airway phenotype.
biochemical:
- name: Plasma IL-5 and IL-13
  presence: INCREASED
  readouts:
  - target: Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells
    relationship: READOUT_OF
    interpretation: >-
      The systemic readout of the CD4+ alpha-beta Th2 excess, and the proximate cause of
      the eosinophilia through IL-5. `direction` is deliberately omitted: the enum on
      this slot takes association-style values (POSITIVE / NEGATIVE / PRESENT_ABSENT /
      THRESHOLD_DEPENDENT), and none of them expresses "the analyte is elevated", which
      is already carried by `presence: INCREASED` on the biomarker itself.
  notes: >-
    Markedly elevated plasma concentrations of the type 2 cytokines IL-5 and IL-13, the
    systemic correlate of the CD4+ alpha-beta T cell Th2 excess. IL-5 is the
    eosinophilopoietic signal that accounts for the blood eosinophilia.
  evidence:
  - reference: PMID:34160550
    reference_title: "High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the patient had markedly high plasma IL-5 and IL-13 concentrations
    explanation: >-
      Reports the elevated plasma IL-5 and IL-13 concentrations directly.
datasets:
- accession: geo:GSE174804
  title: Ex vivo scRNA-Seq of CD4+ cells in T-bet deficiency and wild type
  data_type: SINGLE_CELL_RNA_SEQ
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:34160550
  notes: >-
    Single-cell transcriptomes of CD4+ T cells from the T-bet-deficient patient and
    wild-type controls, generated for the Th2/upper-airway-inflammation study. Relevance
    was triaged manually: the candidate was surfaced by a TBX21 gene-only search, which
    returned mostly mouse and cancer datasets about unrelated T-bet biology, but this
    accession is from the companion study of this disease's index patient.
animal_models:
- name: T-bet knockout mouse (Tbx21-/-), CD4 and NK IFN-gamma production
  species: Mouse
  genotype: Tbx21 targeted deletion (homozygous null)
  publication: PMID:11786644
  description: >
    The original Tbx21-null characterisation, and the model that anticipated the
    compartment-selectivity of the human disease. It reports that T-bet is required for
    IFN-gamma production in CD4 and NK cells but not in CD8 cells — the same asymmetry
    later found in the patient, whose CD8+ alpha-beta T cells produce IFN-gamma normally
    while the innate and innate-like compartments do not.
  modeled_mechanisms:
  - target: Failure of Purely Adaptive IFN-gamma Compensation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The mouse independently establishes that the CD8 compartment's IFN-gamma
      production is T-bet-independent, which is precisely why the spared human CD8+
      compartment is functionally intact and why its failure to compensate is a
      substantive finding rather than a second deficit.
    limitations: >-
      The mouse is a clean null; the patient's allele abolishes DNA binding with protein
      still expressed at reduced levels. The mouse also lacks the MAIT and Vdelta2+
      gamma-delta compartment structure of humans, so it cannot model the innate-like
      arm of the human deficit.
    evidence:
    - reference: PMID:11786644
      reference_title: "Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        it is required for control of IFN-gamma production in CD4 and NK cells, but not
        in CD8 cells
      explanation: >-
        States the CD4/NK-versus-CD8 asymmetry that the human disease reproduces.
- name: T-bet knockout mouse (Tbx21-/-), NK and NKT development
  species: Mouse
  genotype: Tbx21 targeted deletion (homozygous null)
  publication: PMID:15084276
  description: >
    Establishes that the NK and invariant NKT deficit in T-bet deficiency is a
    developmental, stem-cell-intrinsic defect rather than a defect of mature-cell
    function. This is the mechanistic claim the human entry's lineage-failure node makes,
    and the mouse is where it was demonstrated — the human evidence is a single patient's
    cell counts, which cannot on their own distinguish failed development from
    peripheral loss.
  modeled_mechanisms:
  - target: Failed Development of Innate and Innate-like Lymphocyte Lineages
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Demonstrates that loss of T-bet blocks generation of mature NK and invariant NKT
      cells at the stem-cell level, supplying the developmental interpretation of the
      patient's depleted counts.
    limitations: >-
      Mice have no MAIT compartment and no Vdelta2+ gamma-delta subset comparable to the
      human one, so two of the four lineages depleted in the patient have no counterpart
      in this model. The mouse is also a null allele rather than the patient's
      DNA-binding-deficient one.
    evidence:
    - reference: PMID:15084276
      reference_title: "T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        a profound, stem cell-intrinsic defect in their ability to generate mature NK and
        Valpha14i NKT cells
      explanation: >-
        Localises the deficit to development rather than to maintenance of mature cells,
        which is the claim of the node this link targets.
- name: T-bet knockout mouse (Tbx21-/-), Mycobacterium tuberculosis susceptibility
  species: Mouse
  genotype: Tbx21 targeted deletion (homozygous null)
  publication: PMID:16177104
  description: >
    The only model evidence in this entry for the infectious outcome itself rather than
    for a cellular step. Tbx21-null mice are susceptible to virulent M. tuberculosis,
    with increased systemic bacterial burden and diminished IFN-gamma production —
    the mouse counterpart of the severe-tuberculosis susceptibility recorded as a
    class-level MSMD phenotype here.
  modeled_mechanisms:
  - target: Uncontrolled Replication of Weakly Virulent Mycobacteria
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the organism-level outcome — failure to contain mycobacterial
      replication — and ties it to the same proximate cause, diminished IFN-gamma.
    limitations: >-
      Uses virulent M. tuberculosis, whereas the defining human phenotype is disease from
      weakly virulent mycobacteria including BCG. The mouse also accumulates eosinophilic
      macrophages and multinucleated giant cells and shows selective IL-10 elevation
      rather than a fully polarized Th2 response, so its pulmonary pathology is not a
      straightforward model of the human lesion.
    readouts:
    - name: Systemic mycobacterial burden
      target: Uncontrolled Replication of Weakly Virulent Mycobacteria
      direction: INCREASED
      interpretation: >-
        Direct measure of failed containment, the claim this node makes.
      evidence:
      - reference: PMID:16177104
        reference_title: "Increased susceptibility of mice lacking T-bet to infection with Mycobacterium tuberculosis correlates with increased IL-10 and decreased IFN-gamma production."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Susceptibility of T-bet-deficient mice is associated with increased systemic
          bacterial burden, diminished IFN-gamma production
        explanation: >-
          Reports the measured bacterial burden and the IFN-gamma deficit together.
    evidence:
    - reference: PMID:16177104
      reference_title: "Increased susceptibility of mice lacking T-bet to infection with Mycobacterium tuberculosis correlates with increased IL-10 and decreased IFN-gamma production."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mice lacking T-bet are susceptible to virulent M. tuberculosis infection.
      explanation: >-
        Supports treating the Tbx21-null mouse as informative for mycobacterial
        containment failure.
- name: T-bet knockout mouse (Tbx21-/-), airway type 2 phenotype
  species: Mouse
  genotype: Tbx21 targeted deletion (homozygous null)
  publication: PMID:11786643
  description: >
    Mice with a targeted deletion of Tbx21 spontaneously develop the physiological and
    inflammatory features of asthma without any allergen exposure, and the phenotype
    transfers with CD4+ cells into SCID recipients. The model predates the human disease
    by eighteen years and predicted its type-2 arm: it is the reason the allergic
    phenotype in the T-bet-deficient patient was recognised as part of the disease
    rather than as a coincidence.
  modeled_mechanisms:
  - target: Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The mouse reproduces the central claim of this node — that losing T-bet releases a
      CD4+ T-cell-intrinsic type 2 program in the absence of any allergen — and the
      CD4+ adoptive transfer localises it to the same compartment as in the patient.
    limitations: >-
      The murine phenotype is lower-airway asthma; the reported human type-2 phenotype is
      described as upper airway inflammation with blood eosinophilia, and whether
      lower-airway disease is present in the patient has not been reported either way.
      Do not read this as an established difference in anatomical level — it is a gap in
      what has been published. The mouse is also a clean null, while the patient's
      variant abolishes DNA binding with protein still expressed at reduced levels, so
      the two are not the same molecular lesion. Only one human patient has been
      described, so the extent of any species difference cannot be assessed.
    readouts:
    - name: Spontaneous asthma-like airway physiology and inflammation
      target: Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells
      direction: INCREASED
      interpretation: >-
        Airway inflammation arising without allergen challenge is the model's evidence
        that loss of T-bet is itself sufficient to drive the type 2 program.
      evidence:
      - reference: PMID:11786643
        reference_title: "Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Mice with a targeted deletion of the T-bet gene and severe combined
          immunodeficient mice receiving CD4+ cells from T-bet knockout mice
          spontaneously demonstrated multiple physiological and inflammatory features
          characteristic of asthma.
        explanation: >-
          Reports the measured airway phenotype and its transfer by CD4+ cells.
    evidence:
    - reference: PMID:11786643
      reference_title: "Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Thus, T-bet deficiency, in the absence of allergen exposure, induces a murine
        phenotype reminiscent of both acute and chronic human asthma.
      explanation: >-
        Supports treating the Tbx21-null mouse as informative for the type-2 arm of
        human T-bet deficiency.
  evidence:
  - reference: PMID:11786643
    reference_title: "Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We observed reduced expression of the TH1 transcription factor, T-bet, in T cells
      from airways of patients with asthma compared with that in T cells from airways of
      nonasthmatic patients
    explanation: >-
      The human airway observation that motivated the knockout, establishing that the
      T-bet/asthma link was not purely a mouse finding.
treatments:
- name: Recombinant Interferon Gamma
  description: >
    Subcutaneous recombinant IFN-gamma is the mechanistically indicated therapy for this
    etiology. TBX21 is not itself a component of the IFN-gamma receptor or the
    downstream JAK-STAT1 module, so those are not mutated in this patient; whether the
    patient's cells respond normally to IFN-gamma has not been directly assayed. This is
    the therapeutic dividing line within MSMD: production defects are candidates for
    recombinant IFN-gamma, whereas defects abolishing the response to the cytokine are
    not, and are managed with transplantation or gene therapy instead. Note that this is
    a mechanism-based indication for the production arm of MSMD generally; no trial or
    case series of recombinant IFN-gamma in TBX21-deficient patients has been reported.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: interferon gamma-1b
      term:
        id: NCIT:C100089
        label: Interferon Gamma-1b
  target_mechanisms:
  - target: Failed IFN-gamma-Dependent Macrophage Activation
    treatment_effect: ACTIVATES
    description: >-
      Exogenous recombinant IFN-gamma supplies the cytokine that the T-bet-deficient
      lymphocyte compartment cannot make, to a receptor and JAK-STAT1 module that TBX21
      does not itself lesion, with the aim of restoring the macrophage-activating
      signal; whether the patient's macrophages actually respond has not been tested.
    evidence:
    - reference: PMID:38025345
      reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        MSMD patients with impaired production of IFN-γ may benefit from injections of
        human recombinant IFN-γ, while for patients with abolished response to this
        cytokine, hematopoietic stem cell transplantation (HSCT) and promising gene
        therapy are the only current therapeutic options.
      explanation: >-
        States the production-versus-response therapeutic split that places TBX21
        deficiency, a production defect, on the recombinant IFN-gamma side.
  evidence:
  - reference: PMID:38025345
    reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MSMD patients with impaired production of IFN-γ may benefit from injections of
      human recombinant IFN-γ
    explanation: >-
      Supports recombinant IFN-gamma as the therapy indicated for the IFN-gamma
      production arm of MSMD, to which TBX21 deficiency belongs.
  - reference: PMID:36630059
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with defects in IFN-γ production may benefit from treatment with
      recombinant human IFN-γ, in addition to antibiotics.
    explanation: >-
      Independent statement of the same indication, and specifies that it is an adjunct
      to antibiotics rather than a replacement for them.
  - reference: PMID:36630059
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All identified mutations/variants altered production or response to IFN-γ or
      both.
    explanation: >-
      This cohort's own etiology-level summary leaves both the production and the
      response arm open for every gene it reports, including TBX21; it does not
      classify TBX21 on either side, so it cannot be read as settling whether this
      patient's IFN-gamma responsiveness is preserved.
  - reference: PMID:36630059
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hematopoietic stem cell transplantation (HSCT) is the only medical option to date
      for patients with completely defective responses to IFN-γ
    explanation: >-
      Supports the general MSMD therapeutic dividing line between production and
      response defects as a principle, without asserting which side TBX21 falls on.
  notes: >-
    Recorded as a class-level indication, not as an administered treatment. The
    published TBX21-deficient patient was treated with antimycobacterial drugs alone and
    responded; recombinant IFN-gamma is not reported to have been given to him or to any
    other TBX21-deficient individual.
- name: Antimycobacterial Therapy
  description: >
    Prolonged multidrug antimycobacterial chemotherapy is the mainstay of managing the
    mycobacterial disease itself, and is required regardless of which MSMD gene is
    involved. It treats the infection rather than the underlying immune defect, so
    relapse on withdrawal would be expected while the IFN-gamma deficit persists, though
    the index patient has in fact remained in remission off therapy. The agents listed
    are the drugs used across the Moroccan MSMD cohort from which this patient was
    ascertained; regimen composition should follow species identification and
    susceptibility testing rather than being applied as a fixed block, and this entry
    does not assert a specific regimen or duration for this disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: multidrug antimycobacterial chemotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antitubercular agent
      term:
        id: NCIT:C280
        label: Antitubercular Agent
    - preferred_term: rifampicin
      term:
        id: CHEBI:28077
        label: rifampicin
    - preferred_term: isoniazid
      term:
        id: CHEBI:6030
        label: isoniazide
    - preferred_term: pyrazinamide
      term:
        id: CHEBI:45285
        label: pyrazinecarboxamide
    - preferred_term: ethambutol
      term:
        id: CHEBI:4877
        label: ethambutol
  target_mechanisms:
  - target: Uncontrolled Replication of Weakly Virulent Mycobacteria
    treatment_effect: INHIBITS
    description: >-
      Antimycobacterial drugs act directly on the organism, substituting pharmacological
      killing for the macrophage-mediated killing the host cannot perform.
  evidence:
  - reference: PMID:38341181
    reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MSMD is associated with a high mortality rate, mostly due to impaired control of
      infection.
    explanation: >-
      Establishes uncontrolled mycobacterial infection as the dominant cause of death in
      MSMD, which is what antimycobacterial therapy is directed at.
  - reference: PMID:36630059
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with defects in IFN-γ production may benefit from treatment with
      recombinant human IFN-γ, in addition to antibiotics.
    explanation: >-
      Establishes antibiotics as the baseline treatment in MSMD, on which recombinant
      IFN-gamma is an adjunct rather than a substitute.
- name: Avoidance of BCG Vaccination
  description: >
    Live BCG vaccine is the commonest trigger of disease in MSMD, so it is
    contraindicated in an affected child and in at-risk siblings pending genetic
    testing. Because in endemic countries BCG is given at birth, the vaccine is
    frequently administered before any diagnosis is possible, which is why changes to
    vaccination policy in endemic areas are proposed as a pre-exposure prevention
    strategy at the population level rather than as an individual clinical decision.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: avoidance of live BCG vaccination
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Uncontrolled Replication of Weakly Virulent Mycobacteria
    treatment_effect: INHIBITS
    description: >-
      Withholding the live vaccine removes the mycobacterial challenge that the
      IFN-gamma-deficient host cannot contain.
  evidence:
  - reference: PMID:38341181
    reference_title: "Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Preexposure strategies, such as changes in vaccination policy in endemic areas,
      the establishment of a worldwide registry of patients with MSMD, and precise
      follow-up over generations in affected families, appear to be vital to decrease
      MSMD-related mortality.
    explanation: >-
      Supports pre-exposure avoidance of BCG as a recommended strategy for reducing
      MSMD mortality.
  - reference: PMID:36630059
    reference_title: "Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BCG vaccination is contraindicated in MSMD patients and should be delayed in
      newborn siblings until the exclusion of a genetic predisposition to mycobacteria.
    explanation: >-
      States the contraindication and extends it to at-risk newborn siblings pending
      genetic testing, which is the actionable content of this entry.
- name: Inhaled Corticosteroid Controller Therapy
  description: >
    Standard step-1-to-4 asthma controller therapy, and the first-line management of
    the asthma this patient's type-2 arm produces. GINA recommends inhaled
    corticosteroids for every asthma patient, daily or as needed, including mild
    disease. Curated ahead of the type-2 biologics below because it is the therapy
    that would actually be given: the biologics are step-5 options reserved for
    disease uncontrolled on this, and none has been given to a TBX21-deficient
    patient. Like them, this is extrapolated from the general asthma literature —
    nothing IMD88-specific has been published — but it is the less speculative
    extrapolation of the two, and treating the asthma arm as though only biologics
    were available would invert the usual evidence gradient.

    Symptomatic control of airway inflammation only. It does not touch the T-bet
    lesion, the Th2 skew that drives it, or the mycobacterial-susceptibility arm of
    the disease, and carries the usual caveat that corticosteroid use in a patient
    with impaired mycobacterial control is a risk-benefit judgement rather than a
    free intervention.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: inhaled corticosteroid therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: inhaled corticosteroid
      term:
        id: CHEBI:24261
        label: glucocorticoid
  target_mechanisms:
  - target: Asthma
    treatment_effect: INHIBITS
    description: >-
      Inhaled corticosteroids suppress the airway inflammation that produces the
      asthma phenotype, without acting on the Th2 cytokine overproduction upstream
      of it or on the transcriptional lesion upstream of that.
    evidence:
    - reference: PMID:32868307
      reference_title: "Managing adult asthma: The 2019 GINA guidelines."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The 2019 Global Initiative for Asthma (GINA) guidelines recommend that all
        asthma patients be treated with inhaled corticosteroids taken daily or as
        needed; this improves symptoms and outcomes, even in those with mild disease.
      explanation: >-
        Establishes inhaled corticosteroids as the guideline-recommended controller
        for all asthma severities, which is the general indication this
        mechanism-based use is extrapolated from. It reports symptom and outcome
        improvement, not an effect on any upstream mechanism.
  evidence:
  - reference: PMID:32868307
    reference_title: "Managing adult asthma: The 2019 GINA guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further, asthma management requires a stepwise approach, escalating and
      de-escalating treatment based on symptom control.
    explanation: >-
      Sources the stepwise framework that places inhaled corticosteroids before the
      type-2 biologics curated below, which is why this treatment is recorded first.
- name: Mepolizumab
  description: >
    Mepolizumab is a humanized monoclonal antibody against IL-5, one of the two
    cytokines (with IL-13) measured at markedly elevated plasma concentration in this
    patient. It is approved for severe eosinophilic asthma, where it substantially
    reduces exacerbations by neutralizing the cytokine that drives eosinophil
    production and survival. The resemblance to this arm is partial rather than exact:
    the eosinophilia is directly recorded, but the index patient's type-2 disease is
    described as upper airway inflammation, and lower-airway involvement is neither
    reported nor excluded — the same hedge the Asthma phenotype node carries. This is
    a mechanism-based indication only: no TBX21-deficient patient has been treated with
    mepolizumab or any other type-2-targeting biologic. The index-patient report does
    not describe type-2-directed treatment either way, so its silence is an absence of
    reporting rather than a reported absence.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mepolizumab
      term:
        id: NCIT:C157376
        label: Mepolizumab
  target_mechanisms:
  - target: Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells
    treatment_effect: INHIBITS
    description: >-
      Mepolizumab neutralizes circulating IL-5, one of the Th2 cytokines this
      patient's T-bet-deficient CD4+ alpha-beta T cells overproduce without
      restraint, without correcting the transcriptional lesion that causes the
      overproduction.
    evidence:
    - reference: PMID:25199059
      reference_title: "Mepolizumab treatment in patients with severe eosinophilic asthma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients were assigned to receive mepolizumab, a humanized monoclonal
        antibody against interleukin-5
      explanation: >-
        Establishes the mechanism (neutralizing IL-5) that this edge attributes to
        the drug.
  evidence:
  - reference: PMID:25199059
    reference_title: "Mepolizumab treatment in patients with severe eosinophilic asthma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29
      to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37
      to 65) among those receiving subcutaneous mepolizumab, as compared with those
      receiving placebo
    explanation: >-
      Supports mepolizumab's efficacy in the general severe eosinophilic asthma
      population that this patient's type-2 arm resembles.
  notes: >-
    Recorded as a class-level, mechanism-based indication extrapolated from the general
    eosinophilic asthma population, not as an administered treatment. No case report or
    series of a TBX21-deficient patient receiving mepolizumab, or any other type-2
    biologic, has been published.
- name: Dupilumab
  description: >
    Dupilumab blocks IL-4 receptor alpha, the shared receptor subunit through which
    both IL-4 and IL-13 signal — two of the four Th2 cytokines this patient's
    T-bet-deficient CD4+ alpha-beta T cells overproduce. It is approved for
    uncontrolled moderate-to-severe asthma, with the largest benefit in patients with
    elevated blood eosinophils, the same laboratory picture recorded in this entry.
    As with mepolizumab, this is a mechanism-based indication only: no TBX21-deficient
    patient has been treated with dupilumab.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dupilumab
      term:
        id: NCIT:C162455
        label: Dupilumab
  target_mechanisms:
  - target: Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells
    treatment_effect: INHIBITS
    description: >-
      Dupilumab blocks IL-4Ralpha, preventing signalling by both IL-4 and IL-13
      downstream of, rather than correcting, the T-bet lesion that causes this
      patient's T cells to overproduce them.
    evidence:
    - reference: PMID:29782217
      reference_title: "Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma."
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody
        that blocks both interleukin-4 and interleukin-13 signaling.
      explanation: >-
        Establishes the mechanism (blocking IL-4Ralpha, and so both IL-4 and IL-13
        signalling) that this edge attributes to the drug. The sentence sits in
        QUEST's BACKGROUND paragraph, restating established pharmacology rather
        than reporting the trial's own result, which is what quote_role records;
        the trial itself is a human RCT, so evidence_source is unchanged.
  evidence:
  - reference: PMID:29782217
    reference_title: "Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients who received dupilumab had significantly lower rates of severe asthma
      exacerbation than those who received placebo, as well as better lung function
      and asthma control. Greater benefits were seen in patients with higher baseline
      levels of eosinophils.
    explanation: >-
      Supports dupilumab's efficacy in the general uncontrolled-asthma-with-eosinophilia
      population that this patient's type-2 arm resembles, and that the benefit tracks
      eosinophil count, the same marker elevated in this entry.
  - reference: PMID:29782217
    reference_title: "Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Blood eosinophilia occurred after the start of the intervention in 52 patients (4.1%) who received dupilumab as compared with 4 patients (0.6%) who received placebo
    explanation: >-
      A caveat specific to this entry rather than a generic safety note. Dupilumab
      raised blood eosinophils in a minority of QUEST participants, and this patient
      already carries an elevated eosinophil count as a curated phenotype. Of the
      three biologics here it is the one that does not target eosinophils directly,
      so it could worsen the marker it is partly being proposed for. Recorded so the
      trade-off is visible at the point of the proposal.
  notes: >-
    Recorded as a class-level, mechanism-based indication extrapolated from the general
    eosinophilic asthma population, not as an administered treatment. No case report or
    series of a TBX21-deficient patient receiving dupilumab has been published.

    Benralizumab (anti-IL-5-receptor-alpha) is deliberately not curated, although the
    openscientist deep-research artifact names it alongside mepolizumab. Mepolizumab
    already represents the anti-IL-5 axis in this entry, and adding a second agent
    against the same axis would multiply mechanism-based extrapolations without adding
    a distinct mechanism. Noted so the omission reads as a scoping decision rather than
    an oversight.
- name: Omalizumab
  description: >
    Omalizumab neutralizes free circulating IgE. It is approved for severe persistent
    allergic asthma and is a mechanism-based candidate here because this patient's
    class-switch skew, driven by the same T-bet lesion as the Th2 cytokine excess,
    produces elevated circulating IgE in addition to eosinophilia and Th2 cytokine
    overproduction. Unlike mepolizumab and dupilumab, its target is not a Th2 cytokine
    but the class-switch product downstream of it, so it is wired to the IgE
    phenotype node rather than to the Th2 cytokine production node. As with the other
    two biologics, no TBX21-deficient patient has been treated with omalizumab.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: omalizumab
      term:
        id: NCIT:C29299
        label: Omalizumab
  target_mechanisms:
  - target: Increased circulating IgE concentration
    treatment_effect: INHIBITS
    description: >-
      Omalizumab binds free circulating IgE, the class-switch product this patient's
      T-bet-deficient B cell compartment overproduces, preventing it from engaging
      its receptors without correcting the class-switch skew itself.
    evidence:
    - reference: PMID:31576204
      reference_title: Successful treatment of idiopathic mast cell activation syndrome with low-dose Omalizumab.
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: OTHER
      snippet: >-
        Omalizumab works to block the binding of free IgE to its corresponding FcεRI receptor on basophils and mast cells consequently inhibiting their activation by allergens
      explanation: >-
        Sources the anti-IgE binding mechanism this edge asserts, which the
        INNOVATE efficacy citation below does not state. Graded OTHER and marked
        BACKGROUND because the sentence is the citing paper's restatement of
        omalizumab's established pharmacology, not a result of the case report it
        appears in.
    - reference: PMID:15679715
      reference_title: "Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Omalizumab is effective and should be considered as add-on therapy for
        patients with inadequately controlled severe persistent asthma who have a
        significant unmet need despite best available therapy.
      explanation: >-
        Supports omalizumab as an effective add-on therapy in the severe persistent
        allergic asthma population, the general indication this mechanism-based use
        is extrapolated from. It is an exacerbation-rate efficacy result and does
        not itself state the anti-IgE mechanism; the item above carries that.
  evidence:
  - reference: PMID:15679715
    reference_title: "Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Omalizumab significantly reduced severe asthma exacerbation rate (0.24 vs 0.48,
      P = 0.002) and emergency visit rate (0.24 vs 0.43, P = 0.038).
    explanation: >-
      Supports omalizumab's efficacy in the general severe allergic asthma population,
      which this patient's IgE-skewed type-2 arm resembles.
  notes: >-
    Recorded as a class-level, mechanism-based indication extrapolated from the general
    severe allergic asthma population, not as an administered treatment. No case report
    or series of a TBX21-deficient patient receiving omalizumab has been published.
progression:
- phase: Reported course of the index patient
  notes: >-
    The only published disease course in this genotype, and a single patient's course
    rather than a natural history for the disorder. Disease presented as mycobacterial
    disease in childhood and was treated; he has since remained in remission and free of
    mycobacterial infection for several years. The specific regimen and its duration are
    deliberately not stated here: they appear in a deep-research summary but in none of
    the cited sources, and an uncited treatment duration is exactly the kind of detail
    that should not be promoted to entry fact.

    Two features of the course are worth separating. First, if an affected child is
    ascertained through BCG disease, the age at onset is a property of the vaccination
    schedule rather than of the genotype — an affected child in a country that does not
    give BCG would be expected to present later, on exposure to an environmental
    mycobacterium. Do not read an infantile onset as an intrinsic disease property.
    Second, the type-2 arm did not follow the infection's trajectory: the upper airway
    inflammation and eosinophilia were reported independently of the mycobacterial
    episode, which is consistent with the two arms being mechanistically separate.
  evidence:
  - reference: PMID:35867801
    reference_title: "Human T-bet governs the generation of a distinct subset of CD11c(high)CD21(low) B cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient also developed upper airway inflammation and peripheral eosinophilia
      due to TH2-skewing of T-bet-deficient CD4+ T cells
    explanation: >-
      Records the type-2 arm as a separate development in the same patient, reported
      after and independently of the mycobacterial episode.
  - reference: PMID:35867801
    reference_title: "Human T-bet governs the generation of a distinct subset of CD11c(high)CD21(low) B cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      he has been in remission and free of mycobacterial infection for several years
    explanation: >-
      Records the outcome of the mycobacterial episode: sustained remission, not a
      relapsing course.
environmental:
- name: Bacille Calmette-Guerin (BCG) vaccination
  description: >
    Routine BCG immunisation is the sentinel environmental exposure in this disorder.
    The attenuated Mycobacterium bovis BCG strain is harmless to immunocompetent
    infants but disseminates in a host that cannot mount IFN-gamma-dependent macrophage
    activation, which is how MSMD patients typically come to attention. In endemic
    countries the vaccine is given at birth, so the exposure almost always precedes any
    possibility of diagnosis.
  exposure_term:
    preferred_term: exposure to Bacille Calmette-Guerin vaccine
    term:
      id: ECTO:2000129
      label: exposure to vaccination
  effect: Triggers disseminated mycobacterial disease in an IFN-gamma-deficient host.
  notes: >-
    The binding is deliberately broader than the exposure. ECTO has no BCG-, Calmette- or
    M. bovis-specific exposure class: `runoak -i sqlite:obo:ecto search "l~BCG"`,
    `"l~Calmette"` and `"l~bacille"` each return nothing, and `"l~mycobacter"` returns
    only pathogen exposure classes for M. tuberculosis and M. avium and exposures to
    antimycobacterial drugs, none of which is a vaccine. ECTO:2000129 exposure to
    vaccination is the most specific true class available, and preferred_term carries the
    vaccine identity.
  evidence:
  - reference: PMID:38025345
    reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MSMD confers a selective susceptibility to infections with weakly virulent
      mycobacteria, including the M. bovis Bacille Calmette-Guerin (BCG) vaccines
    explanation: >-
      Establishes BCG vaccine exposure as a defining trigger of clinical disease in this
      disease family.
  influences_mechanisms:
  - target: Uncontrolled Replication of Weakly Virulent Mycobacteria
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      BCG vaccination introduces the live attenuated mycobacterium that then replicates
      unchecked in macrophages the T-bet-deficient host cannot activate.
    evidence:
    - reference: PMID:38025345
      reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        MSMD confers a selective susceptibility to infections with weakly virulent
        mycobacteria, including the M. bovis Bacille Calmette-Guerin (BCG) vaccines
      explanation: >-
        Links the BCG exposure to the failure of mycobacterial containment modelled by
        this node.
discussions:
- discussion_id: tbet_mouse_human_humoral_mismatch
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Does the Tbx21-null mouse predict human T-bet deficiency in the B cell compartment,
    given that the mouse has impaired humoral immunity and the patient does not?
  attaches_to:
  - pathophysiology#Loss of T-bet-Dependent B Cell Subset Development and Class-Switch Skewing
  rationale: >-
    The two disagree, and the disagreement is documented on both sides. T-bet-deficient
    mice have reduced age-associated B cells and impaired humoral immunity; the
    T-bet-deficient patient has largely normal humoral immunity, with intact somatic
    hypermutation, affinity maturation, memory B cell formation and vaccine-specific
    antibody titres. What survives the species jump is narrower than the mouse
    suggested: a requirement for one CD11c-high CD21-low subset and a bias in
    immunoglobulin class switching, not a humoral deficit. The mismatch matters because
    the mouse literature is the reason T-bet was expected to be broadly required for
    antibody responses, and it is not — in humans it is largely redundant for
    long-lived protective humoral immunity. Note this is one patient, so the human side
    of the comparison rests on a single individual.

    The same caution applies to the type-2 arm, though more weakly, because there the
    human side is a gap rather than a contrary finding. The mouse develops lower-airway
    asthma spontaneously; the patient's reported type-2 disease is described as upper
    airway inflammation with eosinophilia, and lower-airway involvement is neither
    reported nor excluded. Whether any real difference exists — and whether it would be
    a species difference, a difference between a null allele and a DNA-binding-deficient
    one, or simply the range of one patient — cannot be settled with the evidence
    available.
  proposed_experiments:
  - experiment_id: tbx21_additional_patients_bcell_profile
    name: Assess the CD11c-high CD21-low compartment and class-switch profile in additional TBX21-deficient individuals
    description: >-
      The human side of every claim here rests on one person. Identifying further
      TBX21-deficient individuals — through MSMD cohort sequencing in BCG-vaccinating,
      consanguineous populations, where this patient was found — and repeating the B cell
      immunophenotyping and serum immunoglobulin subclass measurement would establish
      whether the spared humoral immunity is a property of human T-bet deficiency or of
      this patient's particular allele.
    would_support:
    - pathophysiology#Loss of T-bet-Dependent B Cell Subset Development and Class-Switch Skewing
    supporting_outcome:
    - >-
      Additional TBX21-deficient individuals show absent CD11c-high CD21-low B cells and
      the same IgG1/IgG4/IgE-skewed, IgG2-reduced profile, with normal vaccine responses.
    refuting_outcome:
    - >-
      Additional individuals show a frank humoral deficit resembling the mouse, which
      would place this patient's spared humoral immunity down to his specific allele
      rather than to a human-versus-mouse difference.
- discussion_id: tbet_lineage_vs_percell_ifng
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does the mycobacterial susceptibility in human T-bet deficiency arise from the
    absence of the innate and innate-like lineages themselves, or from the reduced
    per-cell IFN-gamma output of the cells that remain?
  attaches_to:
  - pathophysiology#Deficient Mycobacterium-Reactive IFN-gamma Production
  rationale: >-
    The reported patient has both defects at once — the Mycobacterium-reactive NK, iNKT,
    MAIT and Vdelta2+ gamma-delta compartments are largely absent, and the residual
    cells are individually hypofunctional for IFN-gamma. The two are not separable in a
    single natural genotype, so the entry records them as one node with two components
    rather than asserting a dominant contribution. The distinction matters
    therapeutically: a per-cell secretion defect would be expected to respond to
    exogenous IFN-gamma, whereas a purely developmental lesion might also require
    reconstitution of the missing lineages.
- discussion_id: tbx21_ifng_therapy_untested
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is recombinant IFN-gamma clinically effective in TBX21 deficiency specifically?
  attaches_to:
  - treatments#Recombinant Interferon Gamma
  rationale: >-
    The indication recorded in this entry is mechanistic and generalised from the
    IFN-gamma-production arm of MSMD, not observed in TBX21-deficient patients. Human
    T-bet deficiency is reported in a very small number of individuals, and no treated
    series exists. TBX21 is not itself a component of the IFN-gamma receptor or the
    JAK-STAT1 module, so the structural argument for the indication holds, but no
    source directly assays this patient's response to IFN-gamma.

    There is a concrete mechanistic reason for caution beyond the absence of a direct
    assay. T-bet is itself induced downstream of the IFN-gamma receptor through the
    JAK-STAT1 pathway in NK and T cells (PMID:34675939), so a feedback loop links T-bet
    to the response side of IFN-gamma signalling as well as to its production. In
    principle, losing T-bet could blunt that loop's contribution to the cellular
    response to IFN-gamma, not only IFN-gamma output. That loop is documented
    specifically in the NK/T-lymphocyte compartment - the same compartment T-bet
    deficiency already depletes and that this entry already models as failing - and no
    cached source places T-bet in the macrophage response to IFN-gamma, which is the
    compartment recombinant IFN-gamma is intended to activate. So the concern bears on
    an arm of the disease that has already failed rather than on the treatment's target
    cell, which bounds it without eliminating it, and the entry should not be read as
    reporting a demonstrated response.
- discussion_id: tbx21_type2_biologics_untested
  kind: KNOWLEDGE_GAP
  prompt: >-
    Would a type-2-targeting biologic (anti-IL-5, anti-IL-4Ralpha, or anti-IgE) help
    the type-2 arm of TBX21 deficiency specifically?
  attaches_to:
  - treatments#Mepolizumab
  - treatments#Dupilumab
  - treatments#Omalizumab
  rationale: >-
    All three indications recorded here are mechanistic and generalised from the
    general eosinophilic-asthma and allergic-asthma populations in which each drug
    was trialled, not observed in a TBX21-deficient patient. No case report or series
    of a TBX21-deficient individual receiving one has been published, and the index
    patient's report does not describe type-2-directed treatment either way — an
    absence of reporting, not a reported absence — so the indications rest entirely on the
    patient's measured cytokine and immunoglobulin profile (elevated plasma IL-5 and
    IL-13, elevated circulating IgE) rather than on a treated response.

    A further open question is whether the disease's upper-airway-predominant
    presentation would respond the way the pivotal trials' lower-airway
    (asthma-predominant) populations did. Mepolizumab and dupilumab's efficacy
    evidence comes from severe asthma cohorts selected on exacerbation history and
    lung function; the reported TBX21-deficient patient's type-2 disease is described
    as upper airway inflammation with eosinophilia, and whether the same cytokine
    blockade transfers to that clinical picture is not established by these trials.
  proposed_experiments:
  - experiment_id: exp_tbx21_type2_biologic_n_of_1_with_cytokine_readout
    name: N-of-1 type-2 biologic trial in TBX21 deficiency with cytokine and eosinophil readouts
    description: >-
      TBX21 deficiency is vanishingly rare, so a powered randomised trial is not the
      realistic design and proposing one would be idle. What is feasible is a
      prospectively registered n-of-1 or small case series: treat a TBX21-deficient
      patient who has active type-2 disease with a single type-2-targeting biologic,
      with pre-specified outcomes and pre-treatment baselines, and publish the result
      whichever way it goes. Anti-IL-5 is the cleanest first choice, because its target
      and its pharmacodynamic readout lie on the same axis. Because the type-2 disease
      here is described as upper-airway-predominant, upper-airway outcomes must be
      measured directly rather than substituting the spirometric endpoints the pivotal
      asthma trials used — that substitution is the specific transfer this gap doubts.
      The mycobacterial arm has to be monitored in parallel: suppressing type-2
      immunity in a patient whose type-1 immunity is already defective is a risk the
      mechanism-based rationale does not address.
    would_support:
    - pathophysiology#Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells
    supporting_outcome:
    - >-
      Symptomatic and objective improvement in the upper-airway type-2 disease,
      together with a fall in blood eosinophil count and in the plasma IL-5 and IL-13
      concentrations that are elevated at baseline, would show the Th2 cytokine excess
      is the operative driver of the type-2 arm and is druggable downstream of the
      T-bet lesion.
    refuting_outcome:
    - >-
      No clinical improvement despite documented target engagement — eosinophils
      falling on anti-IL-5 while the airway disease is unchanged — would indicate the
      type-2 manifestations are not driven by the cytokine axis alone, and would point
      back at the T-bet lesion's other consequences, including the class-switch skew,
      as contributors these biologics do not reach.
    readouts:
    - name: Blood eosinophil count
      target: phenotypes#Increased total eosinophil count
      direction: DECREASED
      interpretation: >-
        Direct pharmacodynamic marker of target engagement for anti-IL-5. A fall here
        without clinical improvement is the informative negative result, which is why
        it is measured separately from the airway outcome rather than standing in for it.
    - name: Plasma IL-5 and IL-13 concentration
      target: pathophysiology#Excessive Th2 Cytokine Production by Adaptive CD4+ Alpha-Beta T Cells
      direction: DECREASED
      interpretation: >-
        The two cytokines recorded at markedly elevated concentration in the index
        patient, and the quantities the mechanism-based rationale rests on.
    - name: Upper airway inflammation, measured directly
      target: phenotypes#Chronic upper airway inflammation
      direction: DECREASED
      interpretation: >-
        The clinical outcome that matters here, and the one the pivotal trials do not
        supply, since they selected on exacerbation history and lung function in
        lower-airway disease.
    notes: >-
      Recorded as the feasible design rather than the ideal one. A single
      well-reported treated patient would move this gap further than any amount of
      further extrapolation from the asthma trials.
notes: >-
  OMIM records this disease as 619630 (IMMUNODEFICIENCY 88; IMD88), and the causal gene
  as TBX21 (*604895, 17q21.32). There is no `omim_mappings` slot in the schema —
  `DiseaseMappings` covers ICD-10-CM, ICD-11, MONDO and NCIT only — so the OMIM
  identifier is recorded here rather than as a structured mapping. Orphanet has no
  dedicated code for TBX21 deficiency; the parent concept is ORPHA:748 (Mendelian
  susceptibility to mycobacterial diseases).

  Two of the cached references are republications rather than independent reports.
  PMID:35909394 (Qatar Med J) is a near-verbatim republication of the PMID:34160550 JEM
  abstract on the same patient; the JEM paper is cited here as the primary source, and
  the two must not be read as two studies.

  One caution for future curators on patient counts. `PMID:36630059` reports TBX21 in one
  patient of a 22-patient Moroccan MSMD cohort, and a later Moroccan registry survey
  (`PMID:41209815`) also reports a TBX21 patient. These are almost certainly the same
  individual, ascertained through the same centre, rather than two cases. Do not read
  the two reports as independent patients when revising the prevalence or penetrance
  statements here.

  Human T-bet deficiency is one of the most recently described MSMD etiologies, reported
  by Yang et al. in 2020, and is known from a very small number of patients. Frequencies,
  natural history, and treatment response are therefore not established at the level of
  detail available for the older etiologies such as IL12RB1 and IFNGR1 deficiency, which
  between them account for 61% of reported MSMD patients. Claims in this entry that
  derive from the MSMD population rather than from TBX21-deficient patients are marked as
  such in the relevant explanation or description.

  A caution on `PMID:36630059` and the TBX21 patient's IFN-gamma response. That paper
  did run a functional IFN-gamma response assay (whole blood stimulated with BCG plus
  recombinant IFN-gamma, scored on IL-12p40 output) and reports that most of the
  patients tested had a normal response. But the assay was performed on only 12 of the
  22 patients, enumerated by genotype (the IL12RB1, SPPL2A, AD STAT1, and TYK2 patients),
  and the TBX21 patient is not among them. The paper's own patient numbering is
  internally inconsistent for this individual - called "P15" in the immunological-assays
  paragraph (where "P15" elsewhere labels one of the AD STAT1 patients) and "P22"
  everywhere else, including the Discussion. The "other patients showed a normal
  response to IFN-γ" sentence describing that 12-patient assay must not be cited as
  evidence that TBX21-deficient patients respond normally to IFN-gamma.

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References & Deep Research