Immunodeficiency 88 (IMD88) — Comprehensive Disease Research Report

Prepared: 2026-09-01 · Target: Immunodeficiency 88 / T-bet (TBX21) deficiency · MONDO:0030483 · Category: Mendelian

Critical framing caveat for the whole report. As of this writing, IMD88 rests on a single reported patient, from one consanguineous Moroccan kindred, described in one index paper (PMID:33296702, Yang et al., Cell, 23 Dec 2020) and three follow-up studies of the same individual (PMID:35909394, PMID:35867801, PMID:36630059). Every "frequency," "penetrance," "prognosis," and "natural history" statement below is therefore n = 1 unless it is explicitly borrowed from the broader MSMD literature or from mouse models. I flag n = 1 claims throughout. Do not curate them as population frequencies.

1. Disease Information

Overview

Immunodeficiency-88 is an autosomal recessive inborn error of immunity caused by biallelic loss-of-function variants in TBX21, encoding the T-box transcription factor T-bet. It is one of the genetic etiologies of Mendelian susceptibility to mycobacterial disease (MSMD) — the group of monogenic disorders that selectively predispose otherwise healthy individuals to disease from weakly virulent mycobacteria (BCG vaccine substrains, environmental mycobacteria) and, more variably, to M. tuberculosis and non-typhoidal Salmonella.

What distinguishes IMD88 mechanistically from the rest of MSMD is where in the IFN-γ circuit the lesion sits. Most MSMD genes break IFN-γ signalling (IFNGR1/2, STAT1, JAK1) or the IL-12/IL-23→IFN-γ induction axis (IL12B, IL12RB1, IL12RB2, IL23R, TYK2). T-bet deficiency instead breaks the developmental program of the IFN-γ-producing innate and innate-like lymphocyte compartment itself — NK, iNKT, MAIT, and Vδ2⁺ γδ T cells fail to develop, and the residual cells underproduce IFN-γ. Purely adaptive CD8⁺ αβ T cells and non-classic CD4⁺ TH1* cells retain normal mycobacterium-specific IFN-γ production and do not compensate.

A second, mechanistically separable phenotype accompanies the immunodeficiency: because T-bet normally represses the Th2 program, its loss produces Th2 cytokine excess (IL-4/IL-5/IL-9/IL-13), blood eosinophilia, and chronic upper airway inflammation/asthma — the human counterpart of the spontaneous asthma-like phenotype of Tbx21⁻/⁻ mice.

Key identifiers

Synonyms

• IMD88
• T-bet deficiency / human T-bet deficiency
• TBX21 deficiency
• Autosomal recessive complete T-bet deficiency
• Mendelian susceptibility to mycobacterial disease due to TBX21 deficiency
• Immunodeficiency 88, mycobacteriosis, autosomal recessive (MedGen synonym)

Provenance of the evidence

Aggregated disease-level resources (OMIM, MONDO, MedGen, HPO) all trace to a single primary case report. The HPO annotation set for OMIM:619630 is sourced entirely from PMID:33296702 and consists of five terms, all with frequency 1/1. There is no registry, no EHR-derived cohort, and no natural-history study for IMD88. Population-level statements must be borrowed from MSMD as a whole.

2. Etiology

2a. Disease causal factors

Primary cause: monogenic, germline, autosomal recessive. Homozygous loss-of-function variation in TBX21.

The index (and only) patient carries the homozygous indel:

• cDNA: NM_013351.2:c.466_471delGAGATGinsAGTTTA
• Protein: p.Glu156_Met157delinsSerLeu (E156→S, M157→L)
• Consequence: in-frame two-residue substitution within/adjacent to the T-box DNA-binding domain (UniProt Q9UL17, T-box domain residues 141–326)

"The rare indel variant c.466_471delGAGATGinsAGTTTA of TBX21 is MSMD-causing." — derived from PMID:33296702

UniProt Q9UL17 annotates the IMD88 variant's functional effect as "loss of binding to DNA; loss of transcriptional activity." OMIM 619630 adds that in vitro expression in HEK293T cells showed the mutation "impaired protein production and nuclear translocation, as well as interfered with the ability of TBX21 to bind to target DNA." Notably, TBX21 mRNA levels are normal in the patient's cells while endogenous T-bet protein is low — implying a post-transcriptional/protein-destabilization component layered on top of the DNA-binding defect. This is a triple hit on one allele product: reduced protein, impaired nuclear entry, and abolished DNA binding.

Required environmental co-factor: mycobacterial exposure. IMD88 is not a spontaneously symptomatic disorder. The immunodeficiency is only revealed by encounter with a mycobacterium — in this case, live attenuated BCG vaccine given at 3 months of age under Morocco's mandatory national immunization schedule. This is the archetypal gene–environment interaction of MSMD: the genotype is necessary but the live vaccine (or environmental mycobacterium) is the precipitant.

2b. Risk factors

Genetic - Biallelic TBX21 LoF — causal, not merely a risk factor. n = 1 variant known; no allelic series exists. - Consanguinity — the index patient's parents were first cousins (PMID:33296702). In the Moroccan MSMD series, 64% of 22 patients were born to consanguineous parents (PMID:36630059); in the broader Moroccan innate/intrinsic immunity cohort, 51.1% (PMID:41209815, Pathog Immun, Nov 2025). - Ancestry/founder effects — none demonstrated. The single variant is private; there is no evidence of a founder haplotype. - Modifier loci — none identified. With n = 1 there is no basis for a modifier claim.

Environmental / exposure - BCG vaccination — the dominant precipitant in BCG-vaccinating countries. Errami et al. state plainly: "BCG vaccination is contraindicated in MSMD patients and should be delayed in newborn siblings until the exclusion of a genetic predisposition to mycobacteria." (PMID:36630059) - Environmental (non-tuberculous) mycobacteria — the dominant precipitant in non-BCG-vaccinating countries (PMID:38535546, Pathogens 2024). - Tuberculosis endemicity — Morocco is TB-endemic; Errami et al. name the combination of "the mandatory use of the BCG vaccine, the endemicity of tuberculosis (TB), and the high rate of consanguinity" as the triggering context for MSMD in that population. - Age — infantile onset; the vaccine is given in the first months of life, so exposure timing sets onset timing. - Sex — no evidence of sex effect (autosomal recessive; n = 1, male). - Suggested ECTO/exposure concepts: BCG vaccination is a clinical intervention rather than an environmental toxicant; ECTO has no clean term. Consider modelling as environmental with environmental_effect: TRIGGERS and a free-text preferred_term ("BCG vaccination"), leaving term: unbound with a notes: line recording the ECTO search — per the repo's no term beats a bad one rule.

2c. Protective factors

• Heterozygous carriage is asymptomatic. The patient's mother is heterozygous and healthy; his wild-type brother is healthy (PMID:35867801, Methods). Consistent with fully recessive inheritance.
• Avoidance of live mycobacterial vaccines is the single most effective protective intervention (see §13).
• No protective genetic modifier has been identified. gnomAD-level protective allele analysis is not informative at n = 1.

2d. Gene–environment interaction

The causal architecture is cleanly two-factor:

biallelic TBX21 LoF (necessary, non-sufficient) × live/weakly virulent mycobacterial exposure (necessary, non-sufficient) → disseminated mycobacterial disease

A second, exposure-independent branch also exists: the Th2/eosinophilic airway phenotype developed and persisted independently of the mycobacterial episode and independently of documented allergen sensitization, mirroring the mouse phenotype in which "T-bet deficiency, in the absence of allergen exposure, induces a murine phenotype reminiscent of both acute and chronic human asthma" (PMID:11786643, Finotto et al., Science 2002).

3. Phenotypes

All frequencies below are 1/1 (single patient) unless attributed to the wider MSMD literature. HPO annotations for OMIM:619630 (source: PMID:33296702) comprise exactly five terms.

3a. Curated HPO annotation set (authoritative, from HPO/ontology.jax.org)

3b. Clinical signs and infectious manifestations

OMIM 619630: "The single patient described did not develop other clinical infectious diseases, although serology documented exposure to various viruses and bacteria."

This selectivity is the diagnostic signature of MSMD and is a positive discriminating feature — it separates IMD88 from combined immunodeficiencies.

3c. Allergic / type-2 inflammatory manifestations

Verbatim, from PMID:35909394 (Benhsaien et al., Qatar Med J 2022): "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."

Critically, the same paper draws the two-branch dissociation explicitly: "The MSMD of this patient results from defective IFN-γ production by innate and innate-like adaptive lymphocytes, whereas the UAI and eosinophilia result from excessive Th2 cytokine production by adaptive CD4+ αβ T lymphocytes." These are two mechanistically distinct arms of one lesion and should be curated as two separate causal chains from the same root node.

3d. Laboratory / immunophenotypic abnormalities

From PMID:35867801 (Yang et al., Sci Immunol 2022): "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 CD11c^hi CD21^lo B cells."

3e. Quality-of-life impact

No formal QoL instrument (EQ-5D, PROMIS, SF-36, PedsQL) has been applied to any IMD88 patient. Inference only, and should be curated as such:

• The acute BCG-osis episode required hospitalization and 18 months of four-drug therapy — substantial short-term burden, then resolution.
• The persistent asthma/upper-airway phenotype is the ongoing QoL determinant, not the immunodeficiency. It is chronic and long-outlasted the infection.
• BCG contraindication for siblings and lifelong avoidance of live mycobacterial vaccines carry a family-level counselling burden.
• The patient "has been in remission and free of mycobacterial infection for several years" (PMID:35867801) — a favourable trajectory relative to MSMD as a class.

4. Genetic / Molecular Information

4a. Causal gene

TBX21 (T-box transcription factor 21; T-bet; alias TBLYM), hgnc:11599, OMIM *604895, chromosome 17q21.32, NCBI Gene 30009, Ensembl ENSG00000073861, UniProt Q9UL17 (535 aa).

Normal function (UniProt Q9UL17): a lineage-defining transcription factor that "initiates Th1 lineage development from naive Th precursor cells both by activating Th1 genetic programs and by repressing the opposing Th2 and Th17 genetic programs." It transactivates IFNG and CXCR3. Domain: T-box DNA-binding domain, residues 141–326. Subcellular localization: nucleus (GO:0005634).

4b. Pathogenic variant

Functional-consequence classification for the dismech schema:

genetic:
- name: TBX21
  gene_term: {preferred_term: TBX21, term: {id: hgnc:11599, label: TBX21}}
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION   # variant-level claim
    allele_type: INDEL
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS

Do not put LOSS_OF_FUNCTION on the pathway descriptors as well unless you are making a separate activity-state claim — see the repo's GOF/LOF slot decision table. The downstream node "TH1 program transcriptional output" is best described with modifier: LOSS_OF_FUNCTION (qualitative: the program is not merely reduced, it is not initiated), while "IFN-γ production" is modifier: DECREASED (quantitative, PATO-bound PATO:0002301).

4c. Gene-level constraint and selection

TBX21, like other genes underlying autosomal recessive inborn errors of immunity, is not under strong negative selection at the gene level. The related analysis in PMID:36326697 (Ogishi et al., J Exp Med 2023) makes the general point for AR IEI genes: "Like other genes with mutations underlying AR IEI, ITK is not under negative selection, as shown by CoNeS." The same logic applies to TBX21: recessive, exposure-contingent phenotypes are poorly purged. Verify the specific CoNeS/pLI values in gnomAD before curating a numeric constraint claim — I did not retrieve gene-specific gnomAD constraint metrics for TBX21.

4d. Modifier genes

None identified. With one patient, modifier inference is impossible. The obvious candidate class — genes governing residual IFN-γ output (e.g. EOMES, which partially overlaps T-bet function in NK/CD8 cells; see PMID:38740922, Cell Mol Immunol 2024) — remains untested in human T-bet deficiency.

4e. Epigenetic information — this is unusually well characterized and mechanistically central

T-bet's disease mechanism in IMD88 is substantially epigenetic: it acts as a pioneer-like factor establishing chromatin accessibility at lineage-defining loci.

From PMID:35867801 (Omni-ATAC-seq on patient vs. control naïve B cells):

• Under CpG/αIg/IFN-γ stimulation, chromatin accessibility differed at 2,391 loci between patient and healthy-donor B cells; under CpG/αIg/IL-27, at 139 loci, 50 overlapping.
• 89% of the 2,478 loci normally remodelled by CpG/αIg/IFN-γ in healthy donors "remained unaltered in CpG/αIg/IFN-γ-stimulated T-bet-deficient B cells." The same 89% figure held for IL-27.
• 902 loci were shared T-bet-dependent targets of both stimuli. DNA-binding motifs for IRF1, JUNB, and RUNX1 were the most significantly enriched in these — suggesting "T-bet provides permissive environment for binding of IRF1 to IFN-γ- and IL-27-dependent targets in human B cells."
• Specific loci: chromatin opened in a T-bet-dependent manner at FAS, IL21R, SEC61B, DUSP4, DAPP1, SOX5, plus IRF4 (3 loci) and GFI1 (3 loci); closed at CD79B, CXCR4, plus SEMA4B, CCR6, CD37.
• CCL3L1 (3 loci) and CCL4L1 were in a closed configuration in T-bet deficiency even unstimulated — interpreted as leaving "T-bet-deficient B cells... less poised to secrete chemokines required for T-cell recruitment."
• The index paper (PMID:33296702) likewise reports CpG-island DNA methylation and chromatin analyses in the patient's cells (MeSH indexing includes DNA Methylation/genetics, CpG Islands/genetics, Chromatin/metabolism, Epigenesis, Genetic).
• T-bet also autoregulates: "T-bet-deficient B cells had lower levels of T-bet than naïve B cells from most healthy donors... suggesting T-bet promotes its own expression."

Suggested GO terms: GO:0045893 positive regulation of DNA-templated transcription; GO:0006338 chromatin remodeling; GO:0043565 sequence-specific DNA binding; GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding.

4f. Chromosomal abnormalities

None. IMD88 is a single-nucleotide-scale indel disorder. No aneuploidy, translocation, CNV, or structural variant is implicated. Chromosomal microarray, karyotype, and FISH are not indicated for IMD88 diagnosis.

5. Environmental Information

5a. Environmental factors

The disorder has no toxicological, radiological, or pollution-related component. CTD/TOXNET/EPA searches are not applicable. The only relevant "environmental" exposures are microbiological and iatrogenic:

5b. Lifestyle factors

Not applicable. Smoking, diet, alcohol, and exercise have no established role. The patient is a young child.

5c. Infectious agents

6. Mechanism / Pathophysiology

6a. Ordered causal chain

Root lesion

1. Homozygous TBX21 c.466_471delinsAGTTTA (p.E156_M157delinsSL) → leads to a T-bet protein that is expressed at reduced steady-state levels (normal mRNA, low protein — post-transcriptional destabilization), translocates poorly to the nucleus, and cannot bind its T-box DNA motif.
2. Loss of T-box DNA binding → results in complete loss of T-bet transactivation function (GO:0003700 DNA-binding transcription factor activity, modifier: LOSS_OF_FUNCTION).
3. Loss of T-bet transactivation → results in failure to establish the T-bet-dependent permissive chromatin landscape at lineage-defining loci — ~89% of the normal IFN-γ/IL-27-induced accessibility changes fail to occur, with loss of an IRF1/JUNB/RUNX1-motif-enriched enhancer program (GO:0006338 chromatin remodeling). Demonstrated by ATAC-seq in B cells (PMID:35867801); inferred by extension to other T-bet-dependent lineages.

Branch A — the immunodeficiency arm (innate/innate-like IFN-γ collapse)

1. Failure of the T-bet chromatin/transcription program in lymphoid progenitors → leads to a block in terminal maturation of NK cells (CL:0000623), invariant NKT cells (CL:0000921), MAIT cells (CL:0000940), and Vδ2⁺ γδ T cells (CL:0000798). Directly demonstrated in the human patient (PMID:33296702); mechanistically anchored by the mouse stem-cell-intrinsic maturation defect (PMID:15084276).
2. In parallel, failure of the T-bet program in naïve CD4⁺ T cells → results in failure of classic TH1 lineage commitment (CL:0000545 T-helper 1 cell; GO:0045063 T-helper 1 cell differentiation, modifier: LOSS_OF_FUNCTION), so classic TH1 cells are numerically reduced.
3. Steps 4 and 5 together → result in "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" (PMID:33296702).
4. Independently, loss of direct T-bet transactivation of IFNG → results in the residual cells of those populations "also producing abnormally small amounts of IFN-γ" (GO:0032609 interferon-gamma production, modifier: DECREASED). This is a second, additive hit: the cells are both fewer and worse.
5. Steps 6 + 7 → result in a profound deficit in early, antigen-independent IFN-γ available at the site of mycobacterial encounter.

Branch point / failed rescue. 8a. CD8⁺ αβ T cells and non-classic CD4⁺ αβ TH1* cells produce IFN-γ normally in response to mycobacterial antigens — but do not compensate. This is not an incidental observation; it is the paper's central claim, and it is predicted by mouse genetics: Szabo et al. showed T-bet "is required for control of IFN-γ production in CD4 and NK cells, but not in CD8 cells" (PMID:11786644, Science 2002). The human and mouse data converge exactly.

1. Insufficient early IFN-γ → results in failure of macrophage (CL:0000235) classical activation and killing of intracellular mycobacteria (GO:0006952 defense response; GO:0071346 cellular response to interferon-gamma, modifier: DECREASED).
2. Failure of macrophage mycobactericidal activity → leads to uncontrolled intracellular replication of BCG and dissemination beyond the vaccination site.
3. Dissemination → results in the clinical phenotype: fever, ipsilateral axillary lymphadenopathy, cutaneous eruption, then hepatosplenomegaly, abdominal adenopathy, and weight loss — i.e. BCG-osis (HP:0020087).

Branch B — the type-2 immunopathology arm (de-repression)

1. Loss of T-bet's repressive function on the Th2 program → results in failure to inhibit Th2 cytokine transcription. Demonstrated by gain-of-function rescue: unlike WT T-bet, "the mutant form of T-bet from this patient did not inhibit the production of T helper 2 (Th2) cytokines, including IL-4, IL-5, IL-9, and IL-13, when overexpressed in Th2 cells" (PMID:35909394).
2. De-repression → leads to CD4⁺ αβ T cells (CL:0000624) producing excess IL-4 (CHEBI n/a; protein), IL-5, IL-9, and IL-13 "in response to chronic stimulation, regardless of their antigen specificities" — i.e. an antigen-nonspecific, cell-intrinsic skew (GO:0042092 type 2 immune response, modifier: INCREASED).
3. Excess IL-5 → results in eosinophil (CL:0000771) expansion → blood eosinophilia (HP:0001880).
4. Excess IL-13 (plus IL-4/IL-9) → results in airway type-2 inflammation → chronic upper airway inflammation and asthma/reactive airway disease (HP:0002099).
5. Rescue confirms causality: the Th2-skewed phenotype was "reversed by the expression of WT T-bet." This is a bona fide complementation experiment and should be curated as SUPPORT / directness: DIRECT.

Branch C — the B-cell arm (a lineage lost, but clinically quiet)

1. Loss of T-bet-dependent chromatin opening at FAS, IL21R, SEC61B, DUSP4, DAPP1, SOX5 and closing at CD79B, CXCR4 in activated B cells → results in complete absence of the CD21^lo CD11c^hi CD19^hi CD20^hi FCRL5^hi T-bet^hi B-cell subset (CL:0000236 B cell), the human counterpart of murine age-associated B cells. Confirmed by 29-colour spectral flow (FlowSOM clusters 9, 10, 13, 14 all depleted) and by CITE-seq ("the T-bet-deficient patient was completely devoid of cluster 3").
2. Loss of T-bet-dependent constraint on class-switch recombination, plus the Branch-B Th2 cytokine excess acting on B cells → results in skewing to IgG1, IgG4, and IgE with reduced IgG2. The authors explicitly attribute part of this to Branch B: "increased serum IgG1, IgG4 and IgE in T-bet deficiency are consistent with skewing of T-bet deficient CD4+ T cells to a TH2-type effector function." This is a cross-branch interaction and should be drawn as such in the pathograph.
3. Branch C does not reach clinical disease. Somatic hypermutation, affinity maturation, memory B-cell formation, plasmablast differentiation, and vaccine-specific antibody titres (tetanus, diphtheria, Hib, pneumococcus) were all normal, and "he has not presented any clinical disease due to infections with, for example, S. pneumoniae." Curate as a Cellular/Laboratory phenotype, not as an infection-susceptibility phenotype.

6b. Molecular pathways

Suggested GO biological processes: GO:0045063 T-helper 1 cell differentiation · GO:0032609 interferon-gamma production · GO:0032729 positive regulation of type II interferon production · GO:0045064 T-helper 2 cell differentiation · GO:0042092 type 2 immune response · GO:0001780 neutrophil homeostasis (n/a) · GO:0030101 natural killer cell activation · GO:0001782 B cell homeostasis · GO:0045190 isotype switching · GO:0006338 chromatin remodeling · GO:0071346 cellular response to interferon-gamma · GO:0050830 defense response to Gram-positive bacterium

Suggested GO molecular functions: GO:0003700 DNA-binding transcription factor activity · GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific · GO:0043565 sequence-specific DNA binding

6c. Cellular processes

• Terminal maturation arrest of NK and iNKT lineages — mouse data establish this is stem-cell-intrinsic: "mice with a targeted deletion of T-bet... have a profound, stem cell-intrinsic defect in their ability to generate mature NK and Valpha14i NKT cells. Both cell types fail to complete normal terminal maturation and are present in decreased numbers in peripheral lymphoid organs" (PMID:15084276, Townsend et al., Immunity 2004).
• Lineage-commitment failure in naïve CD4⁺ T cells (TH1) and in activated B cells (CD21^lo CD11c^hi subset).
• Impaired macrophage classical activation — inferred from the IFN-γ deficit, not directly measured in the patient. Flag as inferred.
• Granuloma formation — not characterized in the human patient. In Tbx21⁻/⁻ mice infected with M. tuberculosis, there is "the striking accumulation of eosinophilic macrophages and multinucleated giant cells in the lung" (PMID:16177104) — an abnormal, type-2-flavoured granulomatous response rather than an absent one. Extrapolation to human; do not curate as a human histopathology finding.

6d. Protein dysfunction

Three concurrent defects in one mutant protein: 1. Reduced steady-state protein despite normal mRNA → post-transcriptional degradation. 2. Impaired nuclear translocation → less of the residual protein reaches its site of action (GO:0005634 nucleus). 3. Abolished sequence-specific DNA binding at the T-box motif → the fraction that does reach the nucleus is non-functional.

The p.E156/M157 residues lie at the N-terminal margin of the T-box domain (141–326). No experimental structure of the mutant is available; AlphaFold/PDB modelling of this indel has not been reported — this is an open structural question.

6e. Metabolic changes

None reported. No evidence of altered energy, lipid, or amino-acid metabolism in IMD88. Immunometabolic profiling of T-bet-deficient human lymphocytes has not been performed. This is a genuine data gap, not an absence.

6f. Immune system involvement

This is the disease. Two axes, both intrinsic: - Immunodeficiency — selective, narrow, mycobacterial. Not a combined immunodeficiency; not a humoral immunodeficiency. - Immune dysregulation (allergic/type-2) — asthma, upper airway inflammation, eosinophilia, IgE elevation. - No autoimmunity. Despite enrichment of putatively autoreactive IGHV4-34-expressing IgG⁺ memory B cells (20.2% of IgG1 clones vs 8.5% in controls), "there was no clinical or serological evidence of autoantibodies in the patient." This is notable given that CD21^lo T-bet⁺ B cells are expanded in SLE and RA — the patient is a natural experiment for whether that expansion is causal, and so far argues against a requirement.

6g. Tissue damage mechanisms

• Infectious/granulomatous tissue injury from disseminated BCG in lymph nodes, liver, spleen, and skin.
• Type-2 inflammatory airway remodelling. In mice: "increased type III collagen deposition below the bronchial epithelium basement membrane" — i.e. subepithelial fibrosis (PMID:11786643). Not documented histologically in the human patient; treat as a model-organism finding with evidence_source: MODEL_ORGANISM and consider a HUMAN_MODEL_MISMATCH discussion node.
• No oxidative-stress, ischemic, or necrotic mechanism is implicated.

6h. Biochemical abnormalities

Not an enzymopathy, receptoropathy, or channelopathy. The biochemical lesion is a transcription-factor DNA-binding defect. Downstream measurable biochemistry: reduced IFN-γ, elevated IL-5 and IL-13, elevated IgE/IgG1/IgG4, reduced IgG2, elevated eosinophil count.

6i. Molecular profiling

Dataset curation note. I did not locate a public GEO/SRA/ArrayExpress accession for the CITE-seq or ATAC-seq data in a form I could verify. Do not curate a datasets: accession for IMD88 without running just verify-datasets first — and be aware that a TBX21-gene search will surface asthma and lymphoma datasets that have nothing to do with this disease (the Named Entity Confusion trap the repo's dataset-curation guidance warns about; TBX21 is far more famous for asthma-association GWAS than for IMD88).

7. Anatomical Structures Affected

Organ level

Primary (site of immune lesion — the "organ" is the immune system itself):

Secondary (sites of disseminated infection, n = 1):

Secondary (type-2 inflammation):

Body systems involved: hematopoietic/lymphoid, respiratory, integumentary, hepatobiliary (secondary), reticuloendothelial.

Notably spared: central and peripheral nervous system, cardiovascular system, musculoskeletal system, kidney, endocrine organs. No dysmorphology, no developmental anomaly, no neurocognitive involvement. IMD88 is an isolated (non-syndromic) MSMD.

Tissue and cell level

Subcellular level

No mitochondrial, lysosomal, peroxisomal, or ER pathology.

8. Temporal Development

Onset

• Age: Infantile (HP:0003593). Symptoms began at 3 months of age, within weeks of BCG vaccination.
• Pattern: Acute onset of the infectious episode (fever, regional lymphadenopathy, rash), progressing subacutely over ~3 months to disseminated disease by 6 months.
• Onset is exposure-timed, not age-timed. In a country that does not give BCG, an IMD88 patient would be expected to present later, on environmental-mycobacterium exposure. The 3-month figure is a property of Morocco's immunization schedule, not of the genotype. Curate accordingly — do not assert "onset at 3 months" as a disease property.
• The asthma/upper-airway phenotype onset is less precisely dated ("early childhood") and appears independent of the infectious timeline.

onset:
  onset_category: INFANTILE_ONSET
  # HP:0003593

Progression

Stages (n = 1 trajectory):

• Progression rate of the infection: rapid (weeks–months) if untreated; arrested by therapy.
• Course of the immunodeficiency: lifelong and non-progressive — the underlying genetic defect does not worsen; risk is exposure-contingent.
• Course of the airway disease: chronic, persistent (clinical_course: PROGRESSIVE is not supported; use temporality: CHRONIC).
• Disease duration: chronic lifelong susceptibility; individual infectious episodes are self-limited with treatment.

Patterns

• Remission: treatment-induced, sustained. No spontaneous remission reported. No relapse reported over several years off antibiotics.
• Critical periods:
• Neonatal/early infancy — the highest-value intervention window. Withholding or deferring BCG in an at-risk newborn prevents the entire Branch-A clinical phenotype. This is the strongest actionable statement in the whole disease.
• Errami et al.: BCG "should be delayed in newborn siblings until the exclusion of a genetic predisposition to mycobacteria."
• Early recognition of BCG-itis — the regional phase (3 months) precedes dissemination (6 months) by a treatable interval.

9. Inheritance and Population

Epidemiology

IMD88 specifically: - Reported cases: 1 (one). Prevalence is therefore best recorded as prevalence_class: CASES_IN_LITERATURE / ULTRA_RARE, measure_type: CASES_IN_LITERATURE, count = 1. - OMIM notes only one patient reported as of 2021, and I found no subsequent independent case in literature through September 2026. The 2025 Moroccan cohort (PMID:41209815) reports "TBX21 in 1 patient" among 23 genetically diagnosed MSMD — almost certainly the same individual, since it is the same centre (Casablanca) and same collaborating group. Do not double-count.

MSMD as a class — and note the sources disagree:

A five-fold discrepancy between two 2023 papers from overlapping author groups. Report both; do not average them. If curating a single Prevalence record for the MSMD parent concept, curate two records with distinct evidence, or pick the more conservative and record the other in notes.

• Within MSMD, TBX21 accounts for 1 of 23 genetically diagnosed Moroccan MSMD patients (~4%) and 1 of 22 in the earlier kindred series — i.e. the rarest identified etiology in that cohort. AR complete IL-12Rβ1 deficiency is "found in about 60% of diagnosed patients as the most common genetic cause of MSMD."
• ~50% of all MSMD patients remain genetically unexplained: "no genetic disorder has yet been identified for about half of all MSMD patients." Additional TBX21 patients plausibly sit in that unexplained fraction.

Genetic parameters

Population demographics

• Affected populations: one Moroccan (North African/Maghrebi) kindred. No basis for an ethnic predisposition claim — ascertainment is entirely explained by BCG mandate + TB endemicity + high consanguinity + an active reference immunology centre in Casablanca collaborating with the Casanova/Bustamante laboratories.
• Geographic distribution: Morocco (single kindred). Variant-specific geography: not applicable.
• Sex ratio: the index patient is male. AR inheritance predicts 1:1. Do not curate 1:0.
• Age distribution: infantile onset; the patient was born in 2015 and was ~3–7 years old across the published studies. No adult IMD88 patient has been described.
• Diagnostic delay (regional context): median 35 months (IQR 6–80) across the Moroccan innate/intrinsic IEI cohort (PMID:41209815); mean age at MSMD diagnosis 87 months vs mean onset 47 months in the same cohort.

10. Diagnostics

10a. Clinical / laboratory tests

First-line, non-genetic:

Microbiology (essential and often the rate-limiting step): - Mycobacterial culture from blood, bone marrow, lymph node aspirate/biopsy - Ziehl–Neelsen / auramine acid-fast staining - BCG substrain-specific PCR to distinguish vaccine strain from M. tuberculosis / M. bovis — this distinction changed management in the ITK cohort and is directly relevant here - Species-level identification (MALDI-TOF, line probe assay, sequencing)

PMID:38535546 is candid about this: "Isolating these organisms presents a significant challenge, and treatment is often initiated without confirming the specific species."

Imaging: chest radiograph and CT (pulmonary infiltrates, mediastinal adenopathy, tree-in-bud); abdominal ultrasound/CT (hepatosplenomegaly, mesenteric adenopathy); consider MRI for suspected CNS involvement.

Functional respiratory: spirometry with bronchodilator reversibility and/or methacholine challenge for the asthma component; FeNO for type-2 airway inflammation.

Biopsy/histopathology: lymph node biopsy showing granulomatous inflammation with acid-fast bacilli. Human IMD88 granuloma histopathology has not been characterized in the published literature — an explicit gap. The mouse phenotype (eosinophilic macrophages, multinucleated giant cells) is not transferable as a human claim.

Electrophysiology: not indicated.

10b. Genetic testing

Recommended approach — WES/WGS first. The index case was solved by whole-exome sequencing combined with genome-wide linkage analysis, confirmed by Sanger. Errami et al. used "WES for all index cases and Sanger sequencing for relatives or to confirm mutations."

The Moroccan authors argue for cost-adapted strategies: because six of their patients shared one IL12RB1 variant, "cost-effective diagnostic methods, such as PCR, could be used for early detection in this population." That logic does not extend to TBX21, whose single known variant is private.

Functional confirmation is expected for a novel TBX21 variant and was performed for the index variant: HEK293T overexpression assays for protein level, nuclear translocation, and DNA binding; EMSA/reporter transactivation; IFN-γ induction in NK/CD4⁺ T cells; and — decisively — WT T-bet complementation reversing the Th2 phenotype.

10c. Omics-based diagnostics

None validated for clinical use. RNA-seq, ATAC-seq, CITE-seq, and BCR repertoire sequencing were research tools here, not diagnostics. Liquid biopsy, proteomics, metabolomics: not applicable.

Deep immunophenotyping is, however, effectively diagnostic — the combined pattern of reduced NK + iNKT + MAIT + Vδ2⁺ γδ T with preserved CD8⁺ IFN-γ is not produced by any other known MSMD genotype and should be treated as a strong genotype-predictive signature.

10d. Clinical criteria

No IMD88-specific criteria exist. Diagnosis proceeds via MSMD criteria + molecular confirmation.

MSMD entry criteria as operationalized by Errami et al.: "complicated local/regional (BCG-itis) or systemic, disseminated reactions (BCG-osis) to BCG vaccination, unusually severe, persistent, and/or recurrent infections with mycobacteria, and/or tuberculosis (TB), and/or salmonella and/or CMC."

ESID criteria are used for disseminated BCG disease. Operational definitions (Errami et al.): - Local BCG-itis: local abscess at the injection site ≥10 mm × 10 mm and/or severe BCG scar ulceration - Regional BCG-itis: involvement of regional lymph nodes or lesions beyond the injection site (axillary, supraclavicular, cervical, ipsilateral) - BCG-osis: confirmed in more than one remote site beyond the vaccination site, and/or at least one positive blood or bone marrow culture

The index patient meets BCG-osis criteria (hepatosplenomegaly + abdominal adenopathy + axillary node).

10e. Differential diagnosis

10f. Screening

• Newborn screening: not available. TREC-based SCID screening will not detect IMD88 (T-cell numbers are normal).
• Carrier screening: not available; the variant is private.
• Cascade screening: the highest-value screening action. Once a familial TBX21 variant is known, test siblings by Sanger before administering BCG. This is the actionable recommendation and Errami et al. state it directly.
• Risk stratification: consanguineous families with a BCG-complication history in TB-endemic, BCG-mandating countries.

11. Outcome / Prognosis

All prognostic statements for IMD88 are n = 1. Curate them as case-level observations, never as survival statistics.

Survival and mortality

• Survival: the single reported patient survived. Alive and in remission at last report (~2022, age ~7).
• 5-/10-year survival, life expectancy, mortality rate, disease-specific mortality: NOT ESTABLISHED. No data exist. Do not populate these fields.
• MSMD-class context: mortality is highly genotype-dependent. AR complete IFN-γR1/R2 deficiency carries the worst prognosis (often fatal without HSCT); IL-12Rβ1 deficiency is substantially better. T-bet deficiency's residual CD8⁺/TH1* IFN-γ capacity predicts a milder position on this spectrum — but this is inference from one favourable case plus mechanistic reasoning, not evidence.

Morbidity and function

• Acute morbidity: hospitalization, disseminated infection, 18 months of four-drug therapy.
• Chronic morbidity: persistent asthma and upper-airway inflammation — the durable functional burden, unaffected by antimycobacterial cure.
• Disability outcomes: no reported permanent organ damage, no neurological sequelae, no growth failure after recovery.
• QoL measures: none applied. No EQ-5D, PedsQL, SF-36, PROMIS, or ACT/ACQ asthma-control score has been reported.

Disease course and complications

• Complications observed: dissemination to liver, spleen, abdominal nodes; weight loss; chronic airway disease.
• Complications predicted but not observed: recurrent mycobacterial disease, TB, non-typhoidal salmonellosis, NTM infection.
• Notable non-complications: no bacterial sepsis, no pneumococcal disease despite documented exposure and reduced IgG2, no EBV disease, no autoimmunity, no malignancy.
• Recovery potential: excellent with treatment in this case — complete clinical remission sustained for years off antibiotics.
• Without treatment: disseminated BCG disease is expected to be life-threatening (general MSMD principle).

Prognostic factors

Prognostic biomarkers: none validated. Plausible candidates requiring study: whole-blood IFN-γ output on BCG stimulation; NK/iNKT/MAIT/Vδ2 absolute counts; plasma IL-5/IL-13 for the type-2 arm.

12. Treatment

No IMD88-specific trial or guideline exists. Management follows MSMD principles plus standard asthma care. All treatment content below is class-level MSMD evidence or single-case experience.

12a. Antimycobacterial pharmacotherapy — the definitive treatment of the acute episode

What the patient received: "Treated with four antimycobacterial drugs for 18 months with good response" — the standard MSMD regimen. Errami et al. name the agents: rifampin, isoniazid, pyrazinamide, ethambutol.

Note: BCG substrains are intrinsically pyrazinamide-resistant; regimen composition should follow species/susceptibility once identified.

treatments:
- name: Multidrug Antimycobacterial Therapy
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antimycobacterial pharmacotherapy
    term: {id: NCIT:C15986, label: Pharmacotherapy}
    therapeutic_agent:
    - preferred_term: rifampicin
      term: {id: CHEBI:28077, label: rifampicin}
    - preferred_term: isoniazid
      term: {id: CHEBI:6030, label: isoniazid}
    - preferred_term: pyrazinamide
      term: {id: CHEBI:45285, label: pyrazinamide}
    - preferred_term: ethambutol
      term: {id: CHEBI:4877, label: ethambutol}

Verify every CHEBI ID above with runoak before curating — I am supplying these from general knowledge, not from a validated lookup in this session.

12b. Recombinant human IFN-γ — the mechanistically indicated adjunct

"Patients with defects in IFN-γ production may benefit from treatment with recombinant human IFN-γ, in addition to antibiotics." — PMID:36630059

IMD88 sits squarely in the "defects in IFN-γ production" category, so IFN-γ replacement is the rational adjunct — the receptor and its signalling are intact. Efficacy of rhIFN-γ in the same laboratory's ITK-deficiency patients is instructive: subcutaneous rhIFN-γ plus four-drug therapy produced "complete remission" in P1 (healthy at 28 years); P2 "recovered on standard anti-TB therapy plus subcutaneous IFN-γ injections" and remains on biweekly IFN-γ (PMID:36326697).

However — the published IMD88 case does not report rhIFN-γ use. He responded to antibiotics alone. Do not curate rhIFN-γ as an administered treatment for this patient; curate it as an indicated class-level therapy with evidence_source: HUMAN_CLINICAL citing the MSMD literature, and record the distinction in notes.

- name: Recombinant Interferon Gamma Therapy
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: interferon gamma therapy
    term: {id: NCIT:C15986, label: Pharmacotherapy}
    therapeutic_agent:
    - preferred_term: interferon gamma-1b
      term: {id: NCIT:C1471, label: Interferon Gamma}   # VERIFY with runoak
  notes: >-
    Indicated in MSMD due to impaired IFN-gamma production; not reported as
    administered to the single published IMD88 patient.

12c. Hematopoietic stem cell transplantation

"Hematopoietic stem cell transplantation (HSCT) is the only medical option to date for patients with completely defective responses to IFN-γ." — PMID:36630059

HSCT is indicated for defects in IFN-γ response — which IMD88 is not. IMD88 is a production/development defect with intact receptor signalling. HSCT would nonetheless be curative in principle, since the defect is hematopoietic and stem-cell-intrinsic for the NK/iNKT compartment (PMID:15084276). No IMD88 patient has undergone HSCT. Curate as a theoretical/reserve option, explicitly not as standard of care.

NCIT:C15431 Hematopoietic Cell Transplantation → therapeutic_modality: CELL_THERAPY

12d. Management of the type-2 / asthma arm

Standard asthma therapy is indicated; nothing IMD88-specific has been published.

• Inhaled corticosteroids — NCIT:C15986 + CHEBI agent; therapeutic_modality: SMALL_MOLECULE
• Inhaled β2-agonists (bronchodilators)
• Leukotriene receptor antagonists (montelukast)
• Anti-IL-5 (mepolizumab, benralizumab) or anti-IL-4Rα (dupilumab) — mechanistically the most interesting untried option. The patient has "markedly high plasma IL-5 and IL-13 concentrations"; dupilumab blocks IL-4Rα (IL-4 and IL-13 signalling) and anti-IL-5 targets the eosinophil driver directly. therapeutic_modality: MONOCLONAL_ANTIBODY, NCIT:C20401 Monoclonal Antibody. No IMD88 patient has received biologic therapy; this is a hypothesis, and should be curated as a discussions entry with kind: KNOWLEDGE_GAP and a proposed_experiments block, not as a treatment.

12e. Advanced therapeutics

12f. Surgical and interventional

• Lymph node excision/drainage for suppurative or fistulizing BCG lymphadenitis — supportive, adjunct to chemotherapy. NCIT:C15329 Surgical Procedure, therapeutic_modality: SURGERY
• Diagnostic biopsy for microbiological confirmation

12g. Supportive and rehabilitative

• Nutritional support during the wasting phase of disseminated disease (NCIT:C15433 Nutritional Support — do not auto-tag this as BEHAVIORAL, per the repo's explicit backfill caveat)
• Antipyretics, symptom management
• Genetic counselling — NCIT:C15240 Genetic Counseling, therapeutic_modality: BEHAVIORAL
• No rehabilitation need reported

12h. Experimental treatments / clinical trials

No clinical trial has ever enrolled an IMD88 patient. No NCT identifier is associated with IMD88, TBX21 deficiency, or T-bet deficiency. Broader MSMD trials (rhIFN-γ, HSCT registries) may be relevant but do not name this genotype. Do not curate a clinical_trials block for IMD88 without a verified, disease-specific NCT.

12i. Treatment outcomes

• Response rate: 1/1 responded to four-drug therapy with sustained remission.
• Adverse events: none reported for this patient. Class AEs of the regimen (hepatotoxicity from isoniazid/rifampin/pyrazinamide; ethambutol optic neuritis; rhIFN-γ flu-like syndrome) apply but are not IMD88-specific.

12j. Treatment strategy / algorithm

1. Recognize BCG complication or unexplained mycobacterial disease in a child → suspect MSMD
2. Exclude HIV; exclude CGD (DHR/NBT)
3. Culture and speciate (BCG substrain PCR)
4. Start empiric multidrug antimycobacterial therapy — do not wait for species confirmation
5. Whole-blood IL-12/IFN-γ functional assay → localize the defect to production vs response
6. WES (or a current-generation MSMD panel that includes TBX21)
7. Extended immunophenotyping (NK, iNKT, MAIT, Vδ2⁺ γδ T) — for IMD88 this is near-pathognomonic
8. If IFN-γ production defect confirmed → add recombinant human IFN-γ
9. Contraindicate all live mycobacterial vaccines; test and defer BCG in siblings
10. Genetic counselling for the consanguineous kindred
11. Manage the type-2 airway phenotype separately and indefinitely — it will not remit with antimycobacterial cure
12. Reserve HSCT for refractory disease (no IMD88 precedent)

12k. Pharmacogenomics

No IMD88-specific pharmacogenomics. Generic and important: NAT2 acetylator status governs isoniazid metabolism and hepatotoxicity/neuropathy risk (PharmGKB/CPIC); relevant to any patient on prolonged isoniazid, not to IMD88 specifically.

13. Prevention

Primary prevention

The single highest-impact intervention in this disease is negative: do not give BCG.

"BCG vaccination is contraindicated in MSMD patients and should be delayed in newborn siblings until the exclusion of a genetic predisposition to mycobacteria." — PMID:36630059

• All live mycobacterial and attenuated-organism vaccines are contraindicated in confirmed IMD88.
• Deferral of BCG in newborn siblings of a known MSMD proband, pending genetic exclusion, prevents the entire Branch-A phenotype.
• Reduce environmental mycobacterial exposure where practicable (aerosolized water sources, soil) — plausible but unevidenced for IMD88 specifically.
• The disease itself is not primarily preventable — it is inherited. Prevention targets the precipitant, not the genotype.

Secondary prevention

• Cascade genetic testing of siblings and at-risk relatives once the familial variant is known.
• Early recognition of BCG-itis — the regional phase precedes dissemination by ~3 months in the index case, a real treatment window.
• Prompt evaluation of any febrile illness with mycobacterial cultures.

Tertiary prevention

• Complete the full antimycobacterial course (18 months in the index case) to prevent relapse.
• Ongoing surveillance for TB, NTM, and salmonellosis.
• Long-term asthma control to prevent airway remodelling — supported mechanistically by the mouse subepithelial collagen deposition finding (PMID:11786643), though unproven in humans.

Immunization

This is an unusually clean and clinically useful result: IMD88 patients respond normally to routine non-live vaccines.

Screening, counselling, and public health

• Newborn screening: unavailable and not feasible with current TREC-based platforms.
• Prenatal / PGT: technically feasible for a known familial variant; not reported. Appropriate to discuss with a consanguineous kindred.
• Genetic counselling: 25% recurrence risk per pregnancy; carrier testing for parents and relatives; discussion of consanguinity risk more broadly.
• Public health: in high-consanguinity, TB-endemic, BCG-mandating settings, a family history of BCG complications should trigger deferral of BCG in subsequent newborns pending evaluation. PMID:41209815 makes the broader system-level point — median 35-month diagnostic delay driven by "the lack of awareness of emerging diseases unfamiliar to clinicians and the lack of diagnostic facilities due to the high cost of required molecular tests."
• Prophylaxis: no established antimicrobial prophylaxis regimen for IMD88. Prophylactic macrolides/rifamycins are used in some severe MSMD genotypes; no IMD88 precedent.

14. Other Species / Natural Disease

Taxonomy and orthologs

Verify all non-human Gene IDs before curating — I supply these from general knowledge, not from a validated NCBI Gene lookup in this session.

Natural disease in other species

No naturally occurring TBX21-deficiency disease has been described in any animal species. OMIA contains no entry for T-bet deficiency. There is no veterinary counterpart, no companion-animal or wildlife natural model.

However, mycobacterial disease susceptibility is a major veterinary problem in its own right, and T-bet biology is implicated: "Preferential differential gene expression within the WC1.1+ γδ T cell compartment in cattle naturally infected with Mycobacterium bovis" (PMID:37942326, Front Immunol 2023) — bovine γδ T cells, the veterinary analog of the Vδ2⁺ compartment lost in IMD88. This is a comparative-immunology parallel, not a natural disease model of IMD88.

Comparative biology

• Evolutionary conservation is strong. T-bet's role as the TH1/type-1 master regulator is conserved from birds through mammals.
• Key conserved function: T-bet-dependent NK and NKT terminal maturation, demonstrated in mouse (PMID:15084276) and mirrored in human (PMID:33296702).
• Key conserved dissociation: T-bet is required for IFN-γ control in CD4 and NK cells but not CD8 cells in mouse (PMID:11786644) — and the human patient's CD8⁺ αβ T cells likewise produce IFN-γ normally. This cross-species concordance is the strongest translational validation in the disease.
• Key conserved reciprocal repression: T-bet loss produces spontaneous asthma-like airway disease in mice (PMID:11786643) and asthma + eosinophilia + Th2 cytokine excess in the human patient (PMID:35909394).
• Key divergence — curate as a HUMAN_MODEL_MISMATCH: "T-bet-deficient mice have reduced ABCs and impaired humoral immunity", yet the human patient has "largely normal humoral immunity including intact somatic hypermutation, affinity maturation and memory B cell formation in vivo" (PMID:35867801). The murine humoral phenotype does not translate. This is a textbook case for the HUMAN_MODEL_MISMATCH discussion kind rather than a generic knowledge gap: evidence exists in the model, and its translational validity is the open question — and here it has been answered negatively.

Transmission

No zoonotic potential. IMD88 is a non-transmissible inherited disorder. The pathogens it predisposes to (M. bovis BCG, M. tuberculosis, M. bovis, NTM, Salmonella) have their own transmission biology, but the host disorder does not.

15. Model Organisms

Available models

Phenotype recapitulation — Tbx21⁻/⁻ mouse

Model limitations (curate these as limitations on ModelMechanismLink)

1. Mice have no Vδ2⁺ γδ T cell lineage, so the model cannot address one of the four human innate-like compartments lost in IMD88.
2. The humoral phenotype does not translate. Reduced ABCs + impaired humoral immunity in mouse vs. absent CD21^lo CD11c^hi B cells + intact humoral immunity in human. This is a genuine FAILS_TO_RECAPITULATE claim and — per the repo's rules — requires both limitations and evidence, both of which are available (PMID:35867801).
3. The mycobacterial immunopathology diverges: IL-10 elevation without full Th2 polarization in mouse vs. full Th2 skew in human.
4. The mouse is a complete null; the human variant is an in-frame indel with residual (mislocalized, non-DNA-binding) protein. Any residual non-DNA-binding function of T-bet — protein–protein interactions, for instance — would be present in the patient and absent in the KO. Untested.
5. No model carries the human variant. All mouse data are null-allele data.
6. Mouse infection studies use virulent M. tuberculosis; the human presentation was with attenuated BCG.

Research applications

• Mechanism of NK/iNKT terminal maturation (mouse)
• TH1/TH2 reciprocal regulation (mouse + patient cells)
• T-bet-dependent chromatin programs (patient primary B cells + Omni-ATAC-seq — the human system is superior here)
• Preclinical testing of rhIFN-γ or type-2 biologics — not yet done in any Tbx21⁻/⁻ mycobacterial model

Model databases

MGI (mouse; Tbx21 MGI:1888984 — verify), IMPC, IMSR, JAX, KOMP/EuMMCR/MMRRC, Alliance of Genome Resources, RGD (rat), Cellosaurus (HEK293T, HVS-immortalized lines).

Summary of Ontology Term Suggestions

Disease: MONDO:0030483 immunodeficiency 88

Gene: hgnc:11599 TBX21 (lowercase prefix, per repo convention)

Phenotypes (HP): HP:0020087 BCGosis · HP:0002099 Asthma · HP:0001880 Increased total eosinophil count · HP:0003593 Infantile onset · HP:0000007 Autosomal recessive inheritance · HP:0040218 Reduced total natural killer cell count · HP:0003212 Increased circulating IgE concentration · HP:0008348 Decreased circulating IgG2 concentration · HP:0001433 Hepatosplenomegaly · HP:0002716 Lymphadenopathy · HP:0001945 Fever · HP:0001824 Weight loss · HP:0002257 Chronic rhinitis · HP:0011274 Recurrent mycobacterial infections (negative in this patient)

Cell types (CL): CL:0000623 natural killer cell · CL:0000921 type I NK T cell · CL:0000940 mucosal invariant T cell · CL:0000798 gamma-delta T cell · CL:0000545 T-helper 1 cell · CL:0000624 CD4-positive, alpha-beta T cell · CL:0000625 CD8-positive, alpha-beta T cell · CL:0000236 B cell · CL:0000771 eosinophil · CL:0000235 macrophage · CL:0000037 hematopoietic stem cell

Biological processes (GO): GO:0045063 T-helper 1 cell differentiation · GO:0032609 interferon-gamma production · GO:0032729 positive regulation of type II interferon production · GO:0045064 T-helper 2 cell differentiation · GO:0042092 type 2 immune response · GO:0030101 natural killer cell activation · GO:0045190 isotype switching · GO:0006338 chromatin remodeling · GO:0071346 cellular response to interferon-gamma

Molecular functions (GO): GO:0003700 DNA-binding transcription factor activity · GO:0043565 sequence-specific DNA binding

Cellular components (GO): GO:0005634 nucleus · GO:0000785 chromatin

Anatomy (UBERON): UBERON:0002390 hematopoietic system · UBERON:0002371 bone marrow · UBERON:0002370 thymus · UBERON:0000029 lymph node · UBERON:0002439 axillary lymph node · UBERON:0002106 spleen · UBERON:0002107 liver · UBERON:0002097 skin · UBERON:0001557 upper respiratory tract · UBERON:0002185 bronchus

Organisms (NCBITaxon): NCBITaxon:9606 Homo sapiens · NCBITaxon:1765 Mycobacterium bovis · NCBITaxon:1773 Mycobacterium tuberculosis · NCBITaxon:10090 Mus musculus

Treatments (NCIT): NCIT:C15986 Pharmacotherapy · NCIT:C15431 Hematopoietic Cell Transplantation · NCIT:C15329 Surgical Procedure · NCIT:C15240 Genetic Counseling · NCIT:C15747 Supportive Care · NCIT:C20401 Monoclonal Antibody

Every ontology ID above must be validated with just validate-terms before curation. The HP, MONDO, and HGNC identifiers were resolved against authoritative APIs during this research; the CL, GO, UBERON, NCBITaxon, NCIT, and CHEBI suggestions are drawn from general knowledge and are leads, not verified bindings.

Reference List (all PMIDs verified against PubMed; cached where noted)

Non-PMID sources: OMIM #619630 · OMIM *604895 · MedGen 1794236 · UniProt Q9UL17 · HGNC:11599 · HPO annotations for OMIM:619630 · Orphanet ORPHA:748 · GTR: Immunodeficiency 88

Curation Notes and Open Gaps

Highest-value things this report establishes for the KB entry:

1. Two mechanistically independent causal branches from one root node — the IFN-γ/innate-lymphocyte collapse and the Th2 de-repression. PMID:35909394 states the dissociation in one sentence. Model them as separate downstream chains, not one.
2. A genuine FAILS_TO_RECAPITULATE animal-model link — the murine humoral phenotype does not translate. This requires limitations + evidence, both available.
3. A textbook HUMAN_MODEL_MISMATCH discussion on the mouse-vs-human B-cell/humoral divergence and the IL-10-vs-Th2 divergence in mycobacterial challenge.
4. A complementation-rescue evidence item (WT T-bet reverses the Th2 skew) — directness: DIRECT.

Genuine gaps to record as discussions with kind: KNOWLEDGE_GAP: - Human IMD88 granuloma histopathology is uncharacterized. - No proteomic, metabolomic, or immunometabolic profiling exists. - rhIFN-γ has never been given to an IMD88 patient despite being the mechanistically indicated adjunct. - Anti-IL-5/anti-IL-4Rα biologics are untried despite documented IL-5/IL-13 elevation. - Penetrance is unestimable at n = 1; the "residual IFN-γ ⇒ incomplete penetrance" prediction is untested. - No knock-in mouse carrying the human p.E156_M157delinsSL allele.

One housekeeping item: while chasing the mouse-model references I fetched two PMIDs that turned out to be misidentified (PMID:11934957 is a rheumatology sonography paper; PMID:15308104 is an IL-22 paper) — both irrelevant to this disease. The correct references are PMID:11786644 and PMID:15084276, both now cached and cited above. My attempt to delete the two stray cache files was blocked by the sandbox, so references_cache/PMID_11934957.md and references_cache/PMID_15308104.md are sitting untracked in the worktree. Delete them before staging, or they will end up in the PR.

Next step: if you want, I can turn this into the expanded kb/disorders/Immunodeficiency_88.yaml — the current stub has one pathophysiology node and one phenotype, and the full causal chain in §6a plus the phenotype table in §3 would populate it properly. Say the word and I'll draft it against the schema and run the validation loop.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• UBERON:0002439 (2 mentions) - the report calls it "Axillary lymph node"; UBERON calls it myenteric nerve plexus
• UBERON:0003950 (1 mention) - the report calls it "Abdominal/mesenteric lymph nodes"; UBERON calls it inner ear canal

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• HP:0020087 (4 mentions) - the report calls it "BCGosis", "BCG-osis"; HP calls it BCGosis
• HP:0003593 (5 mentions) - the report calls it "Infantile onset", "Infantile", "Age: Infantile"; HP calls it Infantile onset
• HP:0002099 (4 mentions) - the report calls it "Asthma", "chronic upper airway inflammation and asthma/reactive airway disease"; HP calls it Asthma, and lists "Reactive airway disease" among its other names
• HP:0001880 (5 mentions) - the report calls it "Increased total eosinophil count", "blood eosinophilia", "Eosinophilia"; HP calls it Increased total eosinophil count, and lists "Eosinophilia" among its other names
• HP:0000007 (3 mentions) - the report calls it "Autosomal recessive inheritance", "Autosomal recessive"; HP calls it Autosomal recessive inheritance, and lists "Autosomal recessive" among its other names
• NCBITaxon:1763 (1 mention) - the report calls it "Mycobacterium genus"; NCBITaxon calls it Mycobacterium*
• NCBITaxon:28901 (1 mention) - the report calls it "Non-typhoidal Salmonella enterica"; NCBITaxon calls it Salmonella enterica*
• CL:0000545 (3 mentions) - the report calls it "T-helper 1 cell (classic)"; CL calls it T-helper 1 cell
• GO:0045063 (4 mentions) - the report calls it "TH1 differentiation program"; GO calls it T-helper 1 cell differentiation
• CL:0000624 (3 mentions) - the report calls it "CD4⁺ αβ T cell"; CL calls it CD4-positive, alpha-beta T cell
• GO:0045064 (3 mentions) - the report calls it "TH2 differentiation program"; GO calls it T-helper 2 cell differentiation
• UBERON:0002097 (2 mentions) - the report calls it "Skin"; UBERON calls it skin of body, and lists "skin" among its other names
• CL:0000824 (1 mention) - the report calls it "Mature NK cell"; CL calls it mature natural killer cell, and lists "mature NK cell" among its other names
• CL:0000625 (2 mentions) - the report calls it "CD8⁺ αβ T cell"; CL calls it CD8-positive, alpha-beta T cell
• NCBITaxon:9913 (1 mention) - the report calls it "Cattle"; NCBITaxon calls it Bos taurus, and lists "domestic cattle" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

• HP:0020087 - called "BCGosis", "BCG-osis"
• HP:0003593 - called "Infantile onset", "Infantile", "Age: Infantile"
• HP:0002099 - called "Asthma", "chronic upper airway inflammation and asthma/reactive airway disease"
• HP:0001880 - called "Increased total eosinophil count", "blood eosinophilia", "Eosinophilia"
• HP:0000007 - called "Autosomal recessive inheritance", "Autosomal recessive"
• GO:0005634 - called "nucleus", "Nucleus"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, OMIM, LOINC, MGI.