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Classifications

IUIS Category

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Inheritance

1

Autosomal recessive HP:0000007

Both reported index patients were homozygous for a private loss-of-function TNF variant.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:39198650 SUPPORT Human Clinical

"Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant."

Homozygosity for a loss-of-function TNF allele in both index patients establishes recessive inheritance.

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Discussions and Knowledge Gaps

2

Does recombinant TNF or another agent that restores the macrophage respiratory burst reduce tuberculosis recurrence in TNF-deficient individuals?

KNOWLEDGE GAP tnf_addback_prevents_recurrence

Attached to

treatments#Standard Antituberculous Chemotherapy pathophysiology#Impaired Macrophage Respiratory Burst

TNF add-back restores the respiratory burst in TNF-deficient iPSC-derived macrophages in vitro, which identifies a directly druggable node. Whether that translates into reduced recurrence in patients is untested, and only two individuals have been reported.

Why is the respiratory burst defect confined to GM-CSF-matured monocyte-derived and alveolar macrophages rather than all phagocytes?

KNOWLEDGE GAP macrophage_restricted_burst_defect

Attached to

pathophysiology#Impaired Macrophage Respiratory Burst

The narrowness of this disorder relative to chronic granulomatous disease turns on that restriction. Patients with inherited complete deficiency of the respiratory burst across all phagocytes are prone to multiple infections including BCG disease, whereas TNF-deficient individuals are susceptible only to tuberculosis. What makes the alveolar macrophage compartment TNF-dependent is not established.

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Pathophysiology

5

Biallelic TNF Loss of Function

Homozygous private loss-of-function variants in TNF abolish production of tumor necrosis factor.

Genetic context allele_type: frameshift insertion variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Both affected first cousins are homozygous for the private c.190_191ins20 (p.P64Lfs*13) frameshift allele; heterozygous relatives are unaffected.

tumor necrosis factor receptor binding GO:0005164 ⇓ LOSS OF FUNCTION

Downstream

Absent Macrophage TNF Production The loss-of-function genotype is expressed as failure of the encoded cytokine to be produced by the patients' myeloid cells.

Show evidence (1 reference)

PMID:39198650 SUPPORT Human Clinical

"two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant"

Identifies the causal genotype as biallelic loss of function in TNF.

Absent Macrophage TNF Production

Patient leukocytes, including monocytes and monocyte-derived macrophages, produce no TNF even when stimulated with IFN-gamma. Notably this defect does not extend to inflammation generally: the patients mount normal clinical and biological inflammatory responses, and blood leukocyte subset development is normal.

monocyte-derived macrophage CL:0000235 monocyte CL:0000576

tumor necrosis factor production GO:0032640 ∅ ABSENT

Downstream

Impaired Macrophage Respiratory Burst Loss of the autocrine TNF signal prevents GM-CSF-matured macrophages from acquiring a competent respiratory burst. That the link is causal and TNF-dependent is shown by rescue: adding TNF back to TNF-deficient iPSC-derived macrophages restores the burst.

Show evidence (1 reference)

PMID:39198650 SUPPORT Human Clinical

"Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFN"

Directly documents absent TNF production by patient monocytes and macrophages.

Impaired Macrophage Respiratory Burst

GM-CSF-matured monocyte-derived macrophages and alveolar macrophage-like cells from TNF-deficient patients show an impaired respiratory burst. The same defect is reproduced in TNF- and TNFR1-deficient iPSC-derived macrophages, and phenocopied in healthy-control macrophages differentiated with TNF blockers in vitro and in lung macrophages treated with TNF blockers ex vivo — which is why therapeutic TNF blockade carries tuberculosis risk. Crucially the defect is confined to this macrophage compartment rather than affecting all phagocytes.

alveolar macrophage CL:0000583 GM-CSF-matured monocyte-derived macrophage CL:0000235

respiratory burst GO:0045730 ↓ DECREASED superoxide metabolic process GO:0006801 ↓ DECREASED

Experimental models

TNF- and TNFR1-deficient iPSC-derived GM-CSF-matured macrophages IPSC DERIVED MODEL TNF- and TNFR1-deficient iPSC-derived macrophages reproduce the impaired respiratory burst seen in patient cells, and the deficiency is corrected by exogenous TNF.

Downstream

Failure of Macrophage Control of Mycobacterium tuberculosis The oxidative burst is the effector step by which macrophages restrict intracellular M. tuberculosis, so its loss removes that control.

Failure of Macrophage Control of Listeria monocytogenes The same macrophage compartment fails to control Listeria monocytogenes, another intramacrophagic organism, and TNF add-back restores that control.

Show evidence (7 references)

PMID:39198650 SUPPORT In Vitro

"an impairment in the respiratory burst was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells"

Documents the respiratory burst impairment in the two macrophage populations from patients.

PMID:39198650 SUPPORT In Vitro

"TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages"

TNFR1 deficiency phenocopies TNF deficiency, identifying TNFR1 as the receptor through which the signal acts.

PMID:10878503 SUPPORT INDIRECT Model Organism

"Tumor necrosis factor (TNF) signalling via the TNF receptor 1 (TNF-R1) is required for host resistance to mycobacterial infection."

Supports attributing the signal specifically to TNFR1 rather than TNFR2, which the entry asserts. Indirect because it is a murine BCG-infection comparison of receptor knockouts rather than a human study of this disorder.

+ 4 more references

Failure of Macrophage Control of Listeria monocytogenes

The same macrophage defect impairs control of a second intramacrophagic organism. GM-CSF-matured monocyte-derived macrophages from both patients yielded more Listeria monocytogenes colony-forming units than controls, and TNF stimulation reduced viable bacteria — the same rescue logic that establishes the respiratory burst edge. Infliximab-treated control macrophages reproduce the phenotype. This is why the defect is better stated as impaired control of intramacrophagic bacteria than as M. tuberculosis-specific.

GM-CSF-matured monocyte-derived macrophage CL:0000235

defense response to bacterium GO:0042742 ↓ DECREASED

Downstream

Severe Listeria infection One of the two patients developed culture-positive Listeria septic shock during pregnancy. Pregnancy is itself a risk factor for listeriosis, so the authors present TNF deficiency as a contributing rather than sufficient cause; the edge is recorded as indirect for that reason.

Show evidence (2 references)

PMID:39198650 SUPPORT In Vitro

"Stimulation of the patients' cells with TNF led to a decrease in viable L. monocytogenes levels"

TNF add-back reduces viable Listeria in patient macrophages, establishing the control defect as TNF-dependent rather than incidental.

PMID:39198650 SUPPORT Human Clinical

"TNF deficiency may have also had an important role, as TNF-deficient mice are susceptible to Listeria and the rates of Listeria infection/replication were clearly high in the patients"

The authors' own argument that TNF deficiency contributed to the clinical listeriosis rather than it being an incidental pregnancy complication.

Failure of Macrophage Control of Mycobacterium tuberculosis

Without a competent respiratory burst, macrophages cannot restrict Mycobacterium tuberculosis. The defect is selective rather than absent elsewhere: immunity to weakly virulent mycobacteria — including BCG — and to many other infectious agents is preserved, so these individuals are not broadly infection-prone, but control of at least one other intramacrophagic organism, Listeria monocytogenes, is also impaired.

defense response to bacterium GO:0042742 ↓ DECREASED

Experimental models

Patient monocyte-derived alveolar macrophage-like cells PRIMARY CELL CULTURE The closest available system to the disease-defining event: live M. tuberculosis infection of patient-derived cells from the compartment where the disease occurs.

Downstream

Recurrent pulmonary tuberculosis Loss of macrophage control of M. tuberculosis is expressed clinically as recurrent pulmonary tuberculosis in otherwise healthy adults.

Show evidence (1 reference)

PMID:39198650 SUPPORT In Vitro

"Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents."

States both the lost function and the striking narrowness of the defect, which is what defines this disease.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

2

Recurrent pulmonary tuberculosis Infectious HP:0032262

Temporal: RECURRENT

Show evidence (1 reference)

PMID:39198650 SUPPORT Human Clinical

"Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant."

Reports recurrent pulmonary tuberculosis as the presenting and defining phenotype.

Severe Listeria infection FREQUENT Infectious HP:5210020

Show evidence (2 references)

PMID:39198650 SUPPORT Human Clinical

"Blood cultures were positive for Listeria monocytogenes."

Documents culture-confirmed listeriosis in one of the two reported patients.

PMID:39198650 SUPPORT Human Clinical

"One of the two patients had listeriosis during pregnancy."

States the frequency within the reported cohort, one of two.

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Genetic Associations

1

TNF

Gene: TNF hgnc:11892 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:39198650 SUPPORT Human Clinical

"two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant"

Establishes TNF as the causal gene and the variants as homozygous loss of function.

PMID:39198650 SUPPORT Human Clinical

"Pedigree of two related kindreds showing familial segregation of the c.190_191ins20 (p.P64Lfs*13) TNF allele."

Names the specific frameshift allele and documents its familial segregation.

PMID:39198650 SUPPORT Human Clinical

"We studied two related patients from a large consanguineous family from Colombia"

Records the consanguineous kindred in which the private homozygous allele was ascertained.

Variants (1)

NM_000594.4:c.190_191ins20 (p.Pro64LeufsTer13) Pathogenic

Gene: TNF hgnc:11892 frameshift insertion

A 20-nucleotide insertion in exon 2 causing a frameshift from codon 64 with a premature termination codon 13 residues downstream, destroying the mature TNF homology domain. Private to the kindred and homozygous in both affected first cousins.

Functional effects

LOSS OF FUNCTION

Abolishes production of intracellular, transmembrane and secreted TNF, and so all TNF receptor binding.

Show evidence (1 reference)

PMID:39198650 SUPPORT Human Clinical

"Pedigree of two related kindreds showing familial segregation of the c.190_191ins20 (p.P64Lfs*13) TNF allele."

Names the allele in both cDNA and protein notation and documents its familial segregation.

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Medical Actions

1

Standard Antituberculous Chemotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: isoniazid CHEBI:6030 rifampicin CHEBI:28077 pyrazinamide CHEBI:45285 ethambutol CHEBI:4877

Platform: Small molecule

Both patients were treated with the standard HRZE regimen (isoniazid, rifampicin, pyrazinamide, ethambutol). Most episodes respond, although relapse occurs. There is no treatment directed at the underlying TNF deficiency.

Mechanism Target:

Failure of Macrophage Control of Mycobacterium tuberculosis — Antituberculous chemotherapy acts on the organism rather than restoring macrophage oxidative killing, so it treats episodes without correcting the underlying susceptibility.

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Environmental Factors

1

Exposure to Mycobacterium tuberculosis

An obligate trigger rather than a risk factor. The TNF-null genotype is clinically silent without Mycobacterium tuberculosis challenge, and both patients were otherwise healthy between episodes.

Show evidence (1 reference)

PMID:39198650 SUPPORT In Vitro

"Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents."

Establishes that M. tuberculosis specifically, and not mycobacteria generally, is the organism this defect fails against.

Mechanism Target:

TRIGGERS Failure of Macrophage Control of Mycobacterium tuberculosis — Infection supplies the organism that the TNF-deficient macrophage cannot control; without exposure there is no disease.

Show evidence (1 reference)

PMID:39198650 SUPPORT Human Clinical

"we studied two first-cousin Colombian adults with unexplained recurrent pulmonary TB but no adverse reaction to live BCG vaccination"

The contrast between virulent M. tuberculosis causing disease and live BCG being tolerated shows the exposure is agent-specific.

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Diagnosis

1

Absent TNF production on leukocyte stimulation

The functional signature is close to pathognomonic: patient leukocytes, including monocytes and monocyte-derived macrophages, produce no TNF even after stimulation with IFN-gamma, LPS, BCG or Listeria. Combined with an impaired macrophage respiratory burst and normal blood leukocyte subsets, this points at the diagnosis, which is then confirmed by sequencing.

Show evidence (1 reference)

PMID:39198650 SUPPORT Human Clinical

"Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFN"

The absent-TNF-production assay that identifies the disorder functionally.

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Progression

1

Onset of tuberculosis

Age: late second decade

P1 was diagnosed with pulmonary tuberculosis at 19 years and P2 at 18 years, with relapse in P2 eight months after a six-month HRZE course. Neither had disease in childhood despite BCG vaccination, so the susceptibility only becomes apparent with adult Mycobacterium tuberculosis exposure.

Show evidence (2 references)

PMID:39198650 SUPPORT Human Clinical

"She was diagnosed with pulmonary TB at the age of 19 years, presenting with dry cough, pleuritic pain, fever"

Records age at first tuberculosis episode in the first patient.

PMID:39198650 SUPPORT Human Clinical

"At the age of 18 years, he presented with left pulmonary TB with pleural effusion, which was treated for 6 months with HRZE. Then, 8 months later, he was hospitalized due to a relapse of TB."

Records age at onset and the relapse that defines the recurrent course in the second patient.

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Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Immunodeficiency 127:

Chronic granulomatous disease

Overlapping Features The closest mechanistic mimic and the one this entry is defined against. In CGD the respiratory burst is absent across all phagocytes, so patients are prone to multiple infections including BCG disease; here it is confined to the macrophage compartment and susceptibility is correspondingly narrow.

Distinguishing Features

Neutrophil and monocyte ROS production is normal in TNF deficiency and absent in CGD.
BCG vaccination is tolerated in TNF deficiency and causes disease in CGD.

Show evidence (1 reference)

PMID:39198650 SUPPORT Human Clinical

"These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections"

States the contrast between pan-phagocyte burst deficiency and this macrophage-restricted defect.

Mendelian susceptibility to mycobacterial disease from IFN-gamma circuit defects

Overlapping Features The other monogenic route to mycobacterial disease. Defects in the IL-12/IL-23/IFN-gamma circuit (IL12RB1, TYK2, IFNGR1/2, STAT1, ISG15) also predispose to tuberculosis, but severe IFN-gamma defects additionally cause BCG disease, which TNF deficiency does not.

Distinguishing Features

IFN-gamma production and downstream signalling are intact in TNF deficiency.
BCG vaccination is tolerated in TNF deficiency but causes disease in severe IFN-gamma circuit defects.

Show evidence (1 reference)

PMID:32055999 SUPPORT INDIRECT Human Clinical

"Rare inborn errors of immunity, such as autosomal recessive, complete IL-12R"

Establishes the monogenic differential for tuberculosis against which this disorder is distinguished. Indirect because it is a review of the wider MSMD/TB genetics field predating the description of TNF deficiency.

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Experimental Models

2

TNF- and TNFR1-deficient iPSC-derived GM-CSF-matured macrophages IPSC_DERIVED_MODEL

Induced pluripotent stem cell-derived macrophages deficient in TNF or its receptor TNFR1, matured with GM-CSF. Used both to reproduce the patient respiratory burst defect and, by TNF add-back, to demonstrate that the defect is TNF-dependent and reversible.

Pathograph links

Impaired Macrophage Respiratory Burst recapitulates fidelity: high TNF- and TNFR1-deficient iPSC-derived macrophages reproduce the impaired respiratory burst seen in patient cells, and the deficiency is corrected by exogenous TNF.

Limitations: An engineered human cell model rather than patient tissue, and macrophages matured in vitro do not fully reproduce the alveolar niche in which tuberculosis is actually controlled.

Readouts

Respiratory burst in GM-CSF-matured macrophages

Direction: RESTORED

Interpretation: Adding TNF back to TNF-deficient iPSC-derived macrophages restores the respiratory burst, establishing TNF-dependence of the node.

Show evidence (1 reference)

PMID:39198650 SUPPORT In Vitro

"The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst."

Reports the rescue measurement in this model system.

Show evidence (1 reference)

PMID:39198650 SUPPORT In Vitro

"TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages"

Identifies the model system used to reproduce the macrophage respiratory burst defect.

Patient monocyte-derived alveolar macrophage-like cells PRIMARY_CELL_CULTURE

Alveolar macrophage-like cells generated from the monocytes of both patients and of healthy controls - primary patient cells carrying the actual disease genotype, in the macrophage type relevant to pulmonary tuberculosis. Used for both the oxidative burst measurement and the live Mycobacterium tuberculosis infection.

Pathograph links

Failure of Macrophage Control of Mycobacterium tuberculosis measures fidelity: high The closest available system to the disease-defining event: live M. tuberculosis infection of patient-derived cells from the compartment where the disease occurs.

Limitations: Monocyte-derived cells matured in vitro approximate but do not reproduce the alveolar niche, and only two patients exist to derive them from.

Readouts

Mycobacterium tuberculosis replication in patient AML cells

Direction: DECREASED

Interpretation: Baseline replication was comparable to controls, so nothing was restored; the measured effect is a TNF-driven decrease in replication, showing that TNF signalling is what limits the organism in this compartment.

Show evidence (1 reference)

PMID:39198650 SUPPORT In Vitro

"The replication of M. tuberculosis was similar in AML cells from patients with TNF deficiency and healthy controls but was strongly decreased by TNF stimulation"

Reports the mycobacterial replication measurement and its TNF dependence in patient-derived alveolar macrophage-like cells.

Show evidence (1 reference)

PMID:39198650 SUPPORT In Vitro

"we infected AML cells generated from healthy controls and TNF-deficient patients with live M. tuberculosis in the presence or absence of TNF"

Identifies the model as patient-derived AML cells infected with live M. tuberculosis, not the iPSC line.

{ }

Source YAML

click to show

name: Immunodeficiency 127
creation_date: "2026-09-01T00:00:00Z"
category: Mendelian
description: >-
  Immunodeficiency-127 (IMD127) is an autosomal recessive inborn error of
  immunity caused by biallelic loss-of-function variants in TNF. It is
  remarkable for how narrow it is: affected individuals mount normal clinical
  and biological inflammatory responses, have normal blood leukocyte subset
  development, and tolerate BCG vaccination — yet they develop recurrent
  pulmonary tuberculosis, typically from the late teens. The narrowness is not
  absolute. One of the two reported patients also had culture-positive Listeria
  monocytogenes septic shock during pregnancy, and the authors argue TNF
  deficiency contributed, since patient macrophages control Listeria poorly in
  vitro. Listeria, like M. tuberculosis, is an intramacrophagic organism, so the
  better statement of the defect is that it affects macrophage control of
  intramacrophagic bacteria rather than M. tuberculosis alone. The mechanism is
  restricted to the macrophage: TNF is required in an autocrine
  loop for the GM-CSF-dependent maturation of the respiratory burst in
  monocyte-derived and alveolar macrophages, and without it those cells cannot
  mount the oxidative killing that controls Mycobacterium tuberculosis. This
  separates IMD127 from chronic granulomatous disease, where the respiratory
  burst is absent in every phagocyte and susceptibility is broad, and it
  supplies the mechanistic explanation for the well-known tuberculosis risk of
  therapeutic TNF blockade.
parents:
- hereditary disease
- inborn error of immunity
- primary immunodeficiency disease
classifications:
  iuis_category:
    classification_value: innate immunity defect
    notes: >-
      Mendelian susceptibility to mycobacterial disease sits in the IUIS
      "Defects in intrinsic and innate immunity" table; TNF deficiency is a
      macrophage-intrinsic effector defect within that group.
disease_term:
  preferred_term: immunodeficiency 127
  term:
    id: MONDO:0975832
    label: immunodeficiency 127

inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Both reported index patients were homozygous for a private loss-of-function
    TNF variant.
  evidence:
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant."
    explanation: Homozygosity for a loss-of-function TNF allele in both index patients establishes recessive inheritance.

pathophysiology:
- name: Biallelic TNF Loss of Function
  description: >-
    Homozygous private loss-of-function variants in TNF abolish production of
    tumor necrosis factor.
  biological_scale: MOLECULAR
  downstream:
  - target: Absent Macrophage TNF Production
    causal_link_type: DIRECT
    description: >-
      The loss-of-function genotype is expressed as failure of the encoded
      cytokine to be produced by the patients' myeloid cells.
    evidence:
    - reference: PMID:39198650
      reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFN"
      explanation: Patient leukocytes carrying the variant fail to produce TNF, linking the genotype to the absent cytokine.
  genetic_context:
    zygosity: HOMOZYGOUS
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    allele_type: frameshift insertion
    description: >-
      Both affected first cousins are homozygous for the private
      c.190_191ins20 (p.P64Lfs*13) frameshift allele; heterozygous relatives are
      unaffected.
  molecular_functions:
  - preferred_term: tumor necrosis factor receptor binding
    term:
      id: GO:0005164
      label: tumor necrosis factor receptor binding
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant"
    explanation: Identifies the causal genotype as biallelic loss of function in TNF.

- name: Absent Macrophage TNF Production
  description: >-
    Patient leukocytes, including monocytes and monocyte-derived macrophages,
    produce no TNF even when stimulated with IFN-gamma. Notably this defect does
    not extend to inflammation generally: the patients mount normal clinical and
    biological inflammatory responses, and blood leukocyte subset development is
    normal.
  biological_scale: CELLULAR
  downstream:
  - target: Impaired Macrophage Respiratory Burst
    causal_link_type: DIRECT
    description: >-
      Loss of the autocrine TNF signal prevents GM-CSF-matured macrophages from
      acquiring a competent respiratory burst. That the link is causal and
      TNF-dependent is shown by rescue: adding TNF back to TNF-deficient
      iPSC-derived macrophages restores the burst.
    evidence:
    - reference: PMID:39198650
      reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst."
      explanation: Restoring TNF restores the respiratory burst, establishing that the absent cytokine causes the burst defect rather than merely accompanying it.
  cell_types:
  - preferred_term: monocyte-derived macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: tumor necrosis factor production
    term:
      id: GO:0032640
      label: tumor necrosis factor production
    modifier: ABSENT
  evidence:
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFN"
    explanation: Directly documents absent TNF production by patient monocytes and macrophages.

- name: Impaired Macrophage Respiratory Burst
  description: >-
    GM-CSF-matured monocyte-derived macrophages and alveolar macrophage-like
    cells from TNF-deficient patients show an impaired respiratory burst. The
    same defect is reproduced in TNF- and TNFR1-deficient iPSC-derived
    macrophages, and phenocopied in healthy-control macrophages differentiated
    with TNF blockers in vitro and in lung macrophages treated with TNF blockers
    ex vivo — which is why therapeutic TNF blockade carries tuberculosis risk.
    Crucially the defect is confined to this macrophage compartment rather than
    affecting all phagocytes.
  biological_scale: CELLULAR
  downstream:
  - target: Failure of Macrophage Control of Mycobacterium tuberculosis
    causal_link_type: DIRECT
    description: >-
      The oxidative burst is the effector step by which macrophages restrict
      intracellular M. tuberculosis, so its loss removes that control.
    evidence:
    - reference: PMID:39198650
      reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages"
      explanation: States that the immunity lost is specifically the respiratory-burst-dependent macrophage control of M. tuberculosis.
  - target: Failure of Macrophage Control of Listeria monocytogenes
    causal_link_type: DIRECT
    description: >-
      The same macrophage compartment fails to control Listeria monocytogenes,
      another intramacrophagic organism, and TNF add-back restores that control.
    evidence:
    - reference: PMID:39198650
      reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Thus, TNF signalling in human GM-CSF-matured MDMs is crucial for the control of L. monocytogenes infection and/or replication."
      explanation: States the causal dependence of Listeria control on TNF signalling in the same macrophage population.
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  - preferred_term: GM-CSF-matured monocyte-derived macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: respiratory burst
    term:
      id: GO:0045730
      label: respiratory burst
    modifier: DECREASED
  - preferred_term: superoxide metabolic process
    term:
      id: GO:0006801
      label: superoxide metabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "an impairment in the respiratory burst was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells"
    explanation: Documents the respiratory burst impairment in the two macrophage populations from patients.
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages"
    explanation: TNFR1 deficiency phenocopies TNF deficiency, identifying TNFR1 as the receptor through which the signal acts.
  - reference: PMID:10878503
    reference_title: "Tumor necrosis factor receptor 2 plays a minor role for mycobacterial immunity."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Tumor necrosis factor (TNF) signalling via the TNF receptor 1 (TNF-R1) is required for host resistance to mycobacterial infection."
    explanation: >-
      Supports attributing the signal specifically to TNFR1 rather than TNFR2,
      which the entry asserts. Indirect because it is a murine BCG-infection
      comparison of receptor knockouts rather than a human study of this
      disorder.
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo"
    explanation: >-
      Pharmacological TNF blockade in control macrophages phenocopies the
      genetic defect, which is what grounds the parallel with anti-TNF
      tuberculosis risk.
  - reference: PMID:29459143
    reference_title: "ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [I]: anti-tumor necrosis factor-α agents)."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "anti-TNF-α therapy (infliximab, adalimumab, golimumab, certolizumab pegol and etanercept) is associated with a two-to four-fold increase in the risk of active tuberculosis"
    explanation: >-
      Quantifies the clinical counterpart of the in-vitro blockade result - a
      two-to-fourfold rise in active tuberculosis on anti-TNF therapy. Indirect
      for this disorder because it is a consensus safety review of therapeutic
      blockade rather than a study of inherited TNF deficiency.
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "No defect in ROS production was observed in neutrophils and monocytes from P1 and P2 after stimulation with PMA, suggesting that the defect was macrophage specific"
    explanation: >-
      Establishes that the burst defect is confined to macrophages and spares
      neutrophils and monocytes. This is what the macrophage-restriction claim
      and the macrophage_restricted_burst_defect discussion rest on.
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections"
    explanation: >-
      Draws the contrast with chronic granulomatous disease, where the burst is
      absent in every phagocyte and susceptibility is correspondingly broad.

- name: Failure of Macrophage Control of Listeria monocytogenes
  description: >-
    The same macrophage defect impairs control of a second intramacrophagic
    organism. GM-CSF-matured monocyte-derived macrophages from both patients
    yielded more Listeria monocytogenes colony-forming units than controls, and
    TNF stimulation reduced viable bacteria — the same rescue logic that
    establishes the respiratory burst edge. Infliximab-treated control
    macrophages reproduce the phenotype. This is why the defect is better stated
    as impaired control of intramacrophagic bacteria than as
    M. tuberculosis-specific.
  biological_scale: CELLULAR
  downstream:
  - target: Severe Listeria infection
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      One of the two patients developed culture-positive Listeria septic shock
      during pregnancy. Pregnancy is itself a risk factor for listeriosis, so
      the authors present TNF deficiency as a contributing rather than sufficient
      cause; the edge is recorded as indirect for that reason.
    evidence:
    - reference: PMID:39198650
      reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "The pregnancy may itself have contributed to the development of listeriosis"
      explanation: >-
        The authors explicitly qualify the causal attribution, which is why this
        edge is not marked DIRECT.
  cell_types:
  - preferred_term: GM-CSF-matured monocyte-derived macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: defense response to bacterium
    term:
      id: GO:0042742
      label: defense response to bacterium
    modifier: DECREASED
  evidence:
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Stimulation of the patients' cells with TNF led to a decrease in viable L. monocytogenes levels"
    explanation: >-
      TNF add-back reduces viable Listeria in patient macrophages, establishing
      the control defect as TNF-dependent rather than incidental.
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TNF deficiency may have also had an important role, as TNF-deficient mice are susceptible to Listeria and the rates of Listeria infection/replication were clearly high in the patients"
    explanation: >-
      The authors' own argument that TNF deficiency contributed to the clinical
      listeriosis rather than it being an incidental pregnancy complication.

- name: Failure of Macrophage Control of Mycobacterium tuberculosis
  description: >-
    Without a competent respiratory burst, macrophages cannot restrict
    Mycobacterium tuberculosis. The defect is selective rather than absent
    elsewhere: immunity to weakly virulent mycobacteria — including BCG — and to
    many other infectious agents is preserved, so these individuals are not
    broadly infection-prone, but control of at least one other intramacrophagic
    organism, Listeria monocytogenes, is also impaired.
  biological_scale: ORGANISM
  downstream:
  - target: Recurrent pulmonary tuberculosis
    causal_link_type: DIRECT
    description: >-
      Loss of macrophage control of M. tuberculosis is expressed clinically as
      recurrent pulmonary tuberculosis in otherwise healthy adults.
    evidence:
    - reference: PMID:39198650
      reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant."
      explanation: Connects the TNF genotype to the recurrent pulmonary tuberculosis phenotype in the index patients.
  biological_processes:
  - preferred_term: defense response to bacterium
    term:
      id: GO:0042742
      label: defense response to bacterium
    modifier: DECREASED
  evidence:
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents."
    explanation: States both the lost function and the striking narrowness of the defect, which is what defines this disease.

phenotypes:
- category: Infectious
  name: Recurrent pulmonary tuberculosis
  description: >-
    Recurrent pulmonary infection with Mycobacterium tuberculosis in otherwise
    healthy adults, typically presenting from the late teens. Relapse occurs but
    most episodes respond to standard antituberculous treatment.
  phenotype_term:
    preferred_term: Recurrent pulmonary tuberculosis
    term:
      id: HP:0032262
      label: Pulmonary tuberculosis
    temporality: RECURRENT
  evidence:
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant."
    explanation: Reports recurrent pulmonary tuberculosis as the presenting and defining phenotype.

- category: Infectious
  name: Severe Listeria infection
  description: >-
    Culture-positive Listeria monocytogenes septic shock with clinical
    chorioamnionitis at 28 weeks of pregnancy in one of the two reported
    patients, treated successfully with trimethoprim-sulfamethoxazole and
    ampicillin. Pregnancy is itself a risk factor for listeriosis, so this is
    presented by the authors as a contributing rather than sufficient
    consequence of TNF deficiency; the supporting in-vitro finding is that
    patient macrophages control Listeria poorly and are rescued by TNF.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Severe Listeria infection
    term:
      id: HP:5210020
      label: Severe Listeria infection
  evidence:
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blood cultures were positive for Listeria monocytogenes."
    explanation: Documents culture-confirmed listeriosis in one of the two reported patients.
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of the two patients had listeriosis during pregnancy."
    explanation: States the frequency within the reported cohort, one of two.

progression:
- phase: Onset of tuberculosis
  age_range: late second decade
  notes: >-
    P1 was diagnosed with pulmonary tuberculosis at 19 years and P2 at 18 years,
    with relapse in P2 eight months after a six-month HRZE course. Neither had
    disease in childhood despite BCG vaccination, so the susceptibility only
    becomes apparent with adult Mycobacterium tuberculosis exposure.
  evidence:
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was diagnosed with pulmonary TB at the age of 19 years, presenting with dry cough, pleuritic pain, fever"
    explanation: Records age at first tuberculosis episode in the first patient.
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the age of 18 years, he presented with left pulmonary TB with pleural effusion, which was treated for 6 months with HRZE. Then, 8 months later, he was hospitalized due to a relapse of TB."
    explanation: Records age at onset and the relapse that defines the recurrent course in the second patient.

environmental:
- name: Exposure to Mycobacterium tuberculosis
  description: >-
    An obligate trigger rather than a risk factor. The TNF-null genotype is
    clinically silent without Mycobacterium tuberculosis challenge, and both
    patients were otherwise healthy between episodes.
  exposure_term:
    preferred_term: exposure to Mycobacterium tuberculosis
  review_notes: >-
    Left deliberately unbound. ECTO:3000134 "exposure to Mycobacterium
    tuberculosis" resolves in EBI OLS but is absent from the pinned
    sqlite:obo:ecto build that just validate-terms consults, so binding it fails
    term validation today. ECTO:3000133 "exposure to Mycobacterium tuberculosis
    subsp. tuberculosis" is the only near neighbour and is narrower than the
    claim. Rebind once the local ECTO build is refreshed rather than
    substituting a term that does not mean this.
  influences_mechanisms:
  - target: Failure of Macrophage Control of Mycobacterium tuberculosis
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Infection supplies the organism that the TNF-deficient macrophage cannot
      control; without exposure there is no disease.
    evidence:
    - reference: PMID:39198650
      reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we studied two first-cousin Colombian adults with unexplained recurrent pulmonary TB but no adverse reaction to live BCG vaccination"
      explanation: The contrast between virulent M. tuberculosis causing disease and live BCG being tolerated shows the exposure is agent-specific.
  evidence:
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents."
    explanation: Establishes that M. tuberculosis specifically, and not mycobacteria generally, is the organism this defect fails against.

genetic:
- name: TNF
  notes: >-
    A homozygous private frameshift variant in TNF, c.190_191ins20
    (p.P64Lfs*13) in exon 2, segregating in a large consanguineous Colombian
    family. The two affected individuals are first cousins. The frameshift
    destroys the mature TNF homology domain, abolishing intracellular,
    transmembrane and secreted TNF.
  gene_term:
    preferred_term: TNF
    term:
      id: hgnc:11892
      label: TNF
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  variants:
  - name: "NM_000594.4:c.190_191ins20 (p.Pro64LeufsTer13)"
    description: >-
      A 20-nucleotide insertion in exon 2 causing a frameshift from codon 64
      with a premature termination codon 13 residues downstream, destroying the
      mature TNF homology domain. Private to the kindred and homozygous in both
      affected first cousins.
    type: frameshift insertion
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: TNF
      term:
        id: hgnc:11892
        label: TNF
    functional_effects:
    - type: LOSS_OF_FUNCTION
      description: >-
        Abolishes production of intracellular, transmembrane and secreted TNF,
        and so all TNF receptor binding.
    evidence:
    - reference: PMID:39198650
      reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pedigree of two related kindreds showing familial segregation of the c.190_191ins20 (p.P64Lfs*13) TNF allele."
      explanation: Names the allele in both cDNA and protein notation and documents its familial segregation.
  evidence:
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant"
    explanation: Establishes TNF as the causal gene and the variants as homozygous loss of function.
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pedigree of two related kindreds showing familial segregation of the c.190_191ins20 (p.P64Lfs*13) TNF allele."
    explanation: Names the specific frameshift allele and documents its familial segregation.
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We studied two related patients from a large consanguineous family from Colombia"
    explanation: Records the consanguineous kindred in which the private homozygous allele was ascertained.

experimental_models:
- name: TNF- and TNFR1-deficient iPSC-derived GM-CSF-matured macrophages
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Induced pluripotent stem cell-derived macrophages deficient in TNF or its
    receptor TNFR1, matured with GM-CSF. Used both to reproduce the patient
    respiratory burst defect and, by TNF add-back, to demonstrate that the
    defect is TNF-dependent and reversible.
  modeled_mechanisms:
  - target: Impaired Macrophage Respiratory Burst
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      TNF- and TNFR1-deficient iPSC-derived macrophages reproduce the impaired
      respiratory burst seen in patient cells, and the deficiency is corrected
      by exogenous TNF.
    limitations: >-
      An engineered human cell model rather than patient tissue, and macrophages
      matured in vitro do not fully reproduce the alveolar niche in which
      tuberculosis is actually controlled.
    readouts:
    - name: Respiratory burst in GM-CSF-matured macrophages
      target: Impaired Macrophage Respiratory Burst
      direction: RESTORED
      interpretation: >-
        Adding TNF back to TNF-deficient iPSC-derived macrophages restores the
        respiratory burst, establishing TNF-dependence of the node.
      evidence:
      - reference: PMID:39198650
        reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst."
        explanation: Reports the rescue measurement in this model system.
    evidence:
    - reference: PMID:39198650
      reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages"
      explanation: Identifies the model system used to reproduce the macrophage respiratory burst defect.

- name: Patient monocyte-derived alveolar macrophage-like cells
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Alveolar macrophage-like cells generated from the monocytes of both patients
    and of healthy controls - primary patient cells carrying the actual disease
    genotype, in the macrophage type relevant to pulmonary tuberculosis. Used for
    both the oxidative burst measurement and the live Mycobacterium tuberculosis
    infection.
  modeled_mechanisms:
  - target: Failure of Macrophage Control of Mycobacterium tuberculosis
    relationship: MEASURES
    fidelity: HIGH
    description: >-
      The closest available system to the disease-defining event: live
      M. tuberculosis infection of patient-derived cells from the compartment
      where the disease occurs.
    limitations: >-
      Monocyte-derived cells matured in vitro approximate but do not reproduce
      the alveolar niche, and only two patients exist to derive them from.
    readouts:
    - name: Mycobacterium tuberculosis replication in patient AML cells
      target: Failure of Macrophage Control of Mycobacterium tuberculosis
      direction: DECREASED
      interpretation: >-
        Baseline replication was comparable to controls, so nothing was
        restored; the measured effect is a TNF-driven decrease in replication,
        showing that TNF signalling is what limits the organism in this
        compartment.
      evidence:
      - reference: PMID:39198650
        reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "The replication of M. tuberculosis was similar in AML cells from patients with TNF deficiency and healthy controls but was strongly decreased by TNF stimulation"
        explanation: Reports the mycobacterial replication measurement and its TNF dependence in patient-derived alveolar macrophage-like cells.
    evidence:
    - reference: PMID:39198650
      reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we infected AML cells generated from healthy controls and TNF-deficient patients with live M. tuberculosis in the presence or absence of TNF"
      explanation: Identifies the model as patient-derived AML cells infected with live M. tuberculosis, not the iPSC line.

diagnosis:
- name: Absent TNF production on leukocyte stimulation
  description: >-
    The functional signature is close to pathognomonic: patient leukocytes,
    including monocytes and monocyte-derived macrophages, produce no TNF even
    after stimulation with IFN-gamma, LPS, BCG or Listeria. Combined with an
    impaired macrophage respiratory burst and normal blood leukocyte subsets,
    this points at the diagnosis, which is then confirmed by sequencing.
  evidence:
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFN"
    explanation: The absent-TNF-production assay that identifies the disorder functionally.

differential_diagnoses:
- name: Chronic granulomatous disease
  description: >-
    The closest mechanistic mimic and the one this entry is defined against. In
    CGD the respiratory burst is absent across all phagocytes, so patients are
    prone to multiple infections including BCG disease; here it is confined to
    the macrophage compartment and susceptibility is correspondingly narrow.
  distinguishing_features:
  - Neutrophil and monocyte ROS production is normal in TNF deficiency and absent in CGD.
  - BCG vaccination is tolerated in TNF deficiency and causes disease in CGD.
  evidence:
  - reference: PMID:39198650
    reference_title: "Tuberculosis in otherwise healthy adults with inherited TNF deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections"
    explanation: States the contrast between pan-phagocyte burst deficiency and this macrophage-restricted defect.

- name: Mendelian susceptibility to mycobacterial disease from IFN-gamma circuit defects
  description: >-
    The other monogenic route to mycobacterial disease. Defects in the
    IL-12/IL-23/IFN-gamma circuit (IL12RB1, TYK2, IFNGR1/2, STAT1, ISG15) also
    predispose to tuberculosis, but severe IFN-gamma defects additionally cause
    BCG disease, which TNF deficiency does not.
  distinguishing_features:
  - IFN-gamma production and downstream signalling are intact in TNF deficiency.
  - BCG vaccination is tolerated in TNF deficiency but causes disease in severe IFN-gamma circuit defects.
  evidence:
  - reference: PMID:32055999
    reference_title: "The monogenic basis of human tuberculosis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare inborn errors of immunity, such as autosomal recessive, complete IL-12R"
    explanation: >-
      Establishes the monogenic differential for tuberculosis against which this
      disorder is distinguished. Indirect because it is a review of the wider
      MSMD/TB genetics field predating the description of TNF deficiency.

treatments:
- name: Standard Antituberculous Chemotherapy
  description: >-
    Both patients were treated with the standard HRZE regimen (isoniazid,
    rifampicin, pyrazinamide, ethambutol). Most episodes respond, although
    relapse occurs. There is no treatment directed at the underlying TNF deficiency.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: isoniazid
      term:
        id: CHEBI:6030
        label: isoniazide
    - preferred_term: rifampicin
      term:
        id: CHEBI:28077
        label: rifampicin
    - preferred_term: pyrazinamide
      term:
        id: CHEBI:45285
        label: pyrazinecarboxamide
    - preferred_term: ethambutol
      term:
        id: CHEBI:4877
        label: ethambutol
  target_mechanisms:
  - target: Failure of Macrophage Control of Mycobacterium tuberculosis
    description: >-
      Antituberculous chemotherapy acts on the organism rather than restoring
      macrophage oxidative killing, so it treats episodes without correcting the
      underlying susceptibility.

discussions:
- discussion_id: tnf_addback_prevents_recurrence
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does recombinant TNF or another agent that restores the macrophage
    respiratory burst reduce tuberculosis recurrence in TNF-deficient
    individuals?
  attaches_to:
  - treatments#Standard Antituberculous Chemotherapy
  - pathophysiology#Impaired Macrophage Respiratory Burst
  rationale: >-
    TNF add-back restores the respiratory burst in TNF-deficient iPSC-derived
    macrophages in vitro, which identifies a directly druggable node. Whether
    that translates into reduced recurrence in patients is untested, and only
    two individuals have been reported.

- discussion_id: macrophage_restricted_burst_defect
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why is the respiratory burst defect confined to GM-CSF-matured
    monocyte-derived and alveolar macrophages rather than all phagocytes?
  attaches_to:
  - pathophysiology#Impaired Macrophage Respiratory Burst
  rationale: >-
    The narrowness of this disorder relative to chronic granulomatous disease
    turns on that restriction. Patients with inherited complete deficiency of
    the respiratory burst across all phagocytes are prone to multiple
    infections including BCG disease, whereas TNF-deficient individuals are
    susceptible only to tuberculosis. What makes the alveolar macrophage
    compartment TNF-dependent is not established.

references:
- reference: PMID:39198650
  title: Tuberculosis in otherwise healthy adults with inherited TNF deficiency.

📚

References & Deep Research

References

1

PMID:39198650

Tuberculosis in otherwise healthy adults with inherited TNF deficiency.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Immunodeficiency_127 (TNF deficiency) · 2026-09-02T03:09:39Z · View source

De novo curation of IMD127 (MONDO:0975832), autosomal recessive inherited TNF deficiency causing selective susceptibility to pulmonary tuberculosis. Deep research: openscientist (research/Immunodeficiency_127-deep-research-openscientist.md). Falcon, the default provider, was unavailable (no EDISON_API_KEY/FUTUREHOUSE_API_KEY); the user selected openscientist explicitly rather than a silent substitution. The report's frontmatter reports 5/5 references resolved, confabulation_rate 0.0, needs_review true (3 of 5 relevance-assessed on topic; one obsolete GO term and three mislabelled terms flagged). Nothing was bound from the report's term suggestions: HP:0032251 was named 'Tuberculosis' by the report but is 'Abnormal immune system morphology', which is exactly the kind of mis-binding that section exists to catch. The report was treated as leads only. Every detail it contributed beyond the abstract - the c.190_191ins20 (p.P64Lfs*13) allele, the large consanguineous Colombian kindred, the two first cousins, ages at onset 19 and 18 with relapse, and TNFR1 as the receptor - was re-verified against the cached full text of PMID:39198650 before being written, and each is cited to that primary source rather than to the report. Pathograph: a four-node chain from biallelic TNF loss of function through absent macrophage TNF production and impaired respiratory burst to failure of macrophage control of M. tuberculosis, each edge separately cited. The TNF add-back rescue in iPSC-derived macrophages is carried as an experimental_models ModelMechanismLink with a RESTORED readout, since it is what establishes the edge as causal rather than correlative. Two negative findings that define how narrow this disorder is - preserved inflammatory response and normal blood leukocyte subset development - could not be modelled as phenotypes: ModifierEnum has no NORMAL value and Phenotype has no absence slot. They are recorded in the disease description and in the evidence on the relevant nodes instead. ECTO:3000134 'exposure to Mycobacterium tuberculosis' resolves in EBI OLS but is absent from the pinned sqlite:obo:ecto build that just validate-terms consults, so the environmental exposure_term was left unbound with a review_notes line recording the search. ECTO:3000133 (subsp. tuberculosis) is narrower than the claim and was not substituted. Validation: just validate passes (schema, terms, references); 20/20 snippets verified against cached references. check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-environmental-evidence, check-snippet-length, check-title-snippets, check-folded-hyphens and check-snippet-grading all pass. Compliance 86.9% global / 89.5% weighted. No datasets: block. Searching GEO on TNF would return the general TNF literature rather than anything about this disorder, which is the Named Entity Confusion trap the dataset curation guidance warns about.

OpenScientist ▸

Immunodeficiency 127 (IMD127) — Comprehensive Disease Characteristics Report

openscientist-autonomous 1 citations 2026-09-01T22:55:11.725729

Immunodeficiency 127 (IMD127) — Comprehensive Disease Characteristics Report

Prepared: 2026-09-02 · Autonomous literature/database synthesis Primary source: Arias, Neehus, Ogishi et al. "Tuberculosis in otherwise healthy adults with inherited TNF deficiency." Nature 633:417–425 (2024). PMID: 39198650; DOI 10.1038/s41586-024-07866-3. OMIM #620977.

Evidence caveat. IMD127 is an ultra-rare, newly delineated Mendelian disorder described in a single consanguineous Colombian family (2 affected first cousins). Nearly all disease-specific clinical facts derive from this one primary report. Mechanistic corroboration comes from in vitro/iPSC studies, mouse models, and the large pharmacovigilance literature on anti-TNF-associated tuberculosis. Where a statement is inference or extrapolation (e.g., standard TB therapy, epidemiology of TB generally), it is flagged.

1. Disease Information

Overview. Immunodeficiency-127 is an autosomal recessive inborn error of immunity characterized by selective susceptibility to pulmonary tuberculosis (TB) in otherwise healthy individuals. It is the first described human inherited TNF (tumor necrosis factor) deficiency. Affected individuals tolerate BCG vaccination normally, develop recurrent pulmonary Mycobacterium tuberculosis infection beginning in the late teens, and have no other consistent infectious or immunologic abnormality (Arias et al. 2024, PMID 39198650).

Key identifiers. - OMIM: #620977 (IMMUNODEFICIENCY 127; IMD127); causative gene TNF #191160. - MONDO: MONDO:0975832 ("immunodeficiency 127") — confirmed via EBI OLS; maps to OMIM:620977. - Orphanet: No specific ORPHA code identified for this newly described entity; conceptually within "Mendelian susceptibility to mycobacterial diseases" (ORPHA:319583) and rare primary immunodeficiency groupings. - ICD-11: Best fit 4A00.0 (primary immunodeficiencies) / predisposition to infection; the clinical infection codes as tuberculosis (ICD-11 1B1; ICD-10 A15–A19). - ICD-10: D84.9 (immunodeficiency, unspecified) for the trait; A15.- (respiratory TB, bacteriologically confirmed) for disease episodes. - MeSH: No dedicated descriptor; relevant terms: "Tuberculosis, Pulmonary" (D014397), "Tumor Necrosis Factor-alpha" (D014409), "Immunologic Deficiency Syndromes" (D007153).

Synonyms / alternative names: Inherited TNF deficiency; Autosomal recessive complete TNF deficiency (OMIM's descriptor); Human TNF deficiency; TNF-deficiency Mendelian susceptibility to tuberculosis. OMIM notes the disorder is characterized by ROS-deficient alveolar macrophages, TB onset late in the second decade with common relapse, and infections that respond to medication.

Data provenance: Disease-level knowledge is derived from individual patient data (deep immunophenotyping of 2 related patients plus family segregation), complemented by aggregated/experimental resources (iPSC models, mouse KO literature, anti-TNF pharmacovigilance). Not an EHR-derived aggregate.

2. Etiology

Primary cause — genetic. Biallelic (homozygous) loss-of-function variant in TNF (6p21.33). The reported allele is a private frameshift (Section 4). Disease requires infectious exposure to M. tuberculosis: the genetic lesion creates susceptibility, and the environmental trigger (Mtb) precipitates disease → a clear gene × environment (infection) interaction.

Genetic risk factors. - Causal: homozygous TNF null (c.190_191ins20, p.Pro64LeufsTer13). - Consanguinity is a major enabling factor (autosomal recessive, private variant; patient homozygosity 1.14% and 2.1%). (PMID 39198650) - Related monogenic TB loci (not modifiers of IMD127 per se, but the differential): TYK2 (incl. common P1104A), IL12RB1, IL12B, IL23R, IFNGR1/2, STAT1, ISG15 (PMID 32055999, 38025345).

Environmental risk factor (obligate trigger): exposure to/infection with Mycobacterium tuberculosis (NCBI Taxon 1773). General TB risk amplifiers (crowding, HIV, malnutrition, high-burden geography) plausibly apply but are unstudied in IMD127.

Protective factors. Not established. By inference, avoidance of Mtb exposure and latent-TB prophylaxis would be protective. Heterozygous carriers are clinically unaffected (recessive). No protective alleles described.

Gene–environment interaction: TNF-null genotype is clinically silent until Mtb challenge; conversely Mtb is controlled in TNF-sufficient hosts. This mirrors the acquired phenocopy in which anti-TNF biologics unmask latent TB (Section 12; PMID 29459143).

3. Phenotypes

Because n=2, "frequencies" below reflect the reported family; interpret cautiously.

Phenotype	Type	HPO term	Onset	Severity/course	Frequency (this family)
Recurrent pulmonary tuberculosis	Clinical sign / infectious	HP:0032262 (Pulmonary tuberculosis); parent HP:0032251 Tuberculosis; HP:0002205 Recurrent respiratory infections	Late teens (18, 19 y)	Recurrent/relapsing but treatment-responsive	2/2 (100%)
Increased susceptibility to mycobacterial infection	Lab/immunologic predisposition	HP:0004385 related; HP:0002718 (Recurrent bacterial infections)	Adolescent–adult	Selective to Mtb	2/2
Severe Listeria monocytogenes infection (during pregnancy)	Clinical sign / infectious	HP:0031386 (Listeria) / HP:0002718	Adult	Severe, single episode	1/2
Normal BCG-vaccine tolerance (no BCG-osis)	Absence of expected phenotype	(negative finding)	—	—	2/2
Normal blood leukocyte subsets	Lab (normal)	—	—	Stable	2/2
Normal clinical/biological inflammatory responses	Lab (normal)	—	—	Normal	2/2

Notable negatives (diagnostically important): No disseminated/extrapulmonary mycobacterial disease, no adverse vaccine reactions, no broad susceptibility to viral/fungal/pyogenic organisms, no autoimmunity, no developmental phenotype.

Quality-of-life impact: Driven by recurrent TB episodes (cough, fever, weight loss, treatment burden of multi-month antibiotics, relapse anxiety). Between episodes, patients are functionally healthy. No formal QoL instruments (EQ-5D/SF-36) reported.

4. Genetic / Molecular Information

Causal gene: TNF (tumor necrosis factor / TNF-alpha). - HGNC: 11892; NCBI Gene: 7124; Ensembl: ENSG00000232810; UniProt: P01375; OMIM gene: 191160. - Locus: chromosome 6p21.33, within the MHC class III region (between LTA and LTB/HLA-B).

Pathogenic variant (OMIM 191160.0007): - cDNA: c.190_191ins20 (20-nt insertion), exon 2. - Protein: p.Pro64LeufsTer13 (P64Lfs13) — frameshift beginning at codon 64 with a premature stop 13 residues downstream. - Type/class: frameshift insertion → premature termination codon (predicted NMD and/or truncated non-functional protein). - Zygosity/origin: homozygous germline; private to the family; absent in extended relatives and population databases (MAF <0.01 filter; not observed in gnomAD). - Functional consequence: complete loss of function. HEK293 transduced with mutant TNF failed to induce NF-κB-dependent transcription; patient cells showed absent TNF expression, no secreted TNF, and no TNF induction to LPS/BCG/Listeria/IFNγ; rescued by wildtype TNF (PMID 39198650). - ACMG/AMP classification: Pathogenic* — null variant in a gene with established LOF mechanism (PVS1), co-segregation, absence in controls (PM2), functional damage (PS3).

Modifier genes: none identified (single family).

Epigenetic information: None reported for IMD127. (TNF expression is normally under complex transcriptional/epigenetic control at the MHC-III locus, but no disease-specific epigenetic change is described.)

Chromosomal abnormalities: None; point-level insertion, no cytogenetic lesion.

5. Environmental Information

Infectious agent (essential): Mycobacterium tuberculosis (NCBI Taxon 1773) — the disease-defining pathogen. Listeria monocytogenes (NCBI Taxon 1639) caused one severe episode.
Weakly virulent mycobacteria tolerated: M. bovis BCG (vaccine) was handled normally — a key contrast to IFN-γ-circuit defects.
Environmental/lifestyle/toxic factors: none specifically implicated; general TB determinants (exposure intensity, HIV, crowding) presumably relevant but unstudied.

6. Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation)

Homozygous TNF frameshift c.190_191ins20 (p.P64Lfs*13) leads to absence of functional TNF protein (no intracellular, transmembrane, or secreted TNF). (Demonstrated: absent expression/secretion.)
Absence of TNF results in loss of autocrine/paracrine TNF→TNFR1 (TNFRSF1A) signaling in mononuclear phagocytes. (Demonstrated: no NF-κB induction; TNFR1-KO iPSC macrophages phenocopy.)
Loss of TNF–TNFR1 signaling in GM-CSF-matured monocyte-derived macrophages and alveolar-macrophage-like cells leads to failure of the NADPH-oxidase respiratory burst (deficient reactive oxygen species production). (Demonstrated in patient cells, TNF- and TNFR1-deficient iPSC macrophages, and TNF-blocker-treated control/lung macrophages.)
Impaired respiratory burst results in defective ROS-dependent intracellular killing of ingested M. tuberculosis within lung macrophages. (Inferred from respiratory-burst defect + rescue by TNF.)
Defective mycobacterial killing in the alveolar compartment leads to uncontrolled Mtb replication and recurrent pulmonary tuberculosis. (Observed clinical outcome.)

Branch point / redundancy: Because TNF is redundant for (a) IFN-γ production (patients' IFN-γ and downstream cytokines were intact), (b) leukocyte development, (c) systemic inflammation, and (d) control of BCG and most other microbes, the phenotype is narrowly restricted to Mtb in the lung. This contrasts with (i) complete phagocyte respiratory-burst deficiency (chronic granulomatous disease), which causes multi-organism infection, and (ii) IFN-γ-circuit MSMD defects, which cause BCG-osis + environmental mycobacterial disease (PMID 39198650, 32055999).

Mechanistic detail by category

Molecular pathways: TNF–TNFR1 signaling → NF-κB activation (canonical); coupling to NADPH oxidase (respiratory burst). KEGG hsa04668 (TNF signaling), Reactome R-HSA-75893 (TNF signaling), R-HSA-1222556 (NF-κB). ROS generation ~ Reactome R-HSA-1222556 / phagosome pathways.
Cellular processes: phagocytosis and oxidative microbial killing in macrophages; innate immune activation. GO: GO:0045087 innate immune response; GO:0006801 superoxide metabolic process; GO:0045730 respiratory burst; GO:0034612 response to TNF; GO:0032496 response to LPS; GO:0050832 defense response to fungus (n/a); GO:0071356 cellular response to TNF.
Protein dysfunction: TNF is a type II transmembrane homotrimeric cytokine cleaved by TACE/ADAM17 to soluble TNF; the frameshift abolishes the mature TNF homology domain → loss of function (no misfolding/aggregation/gain-of-function).
Immune involvement: isolated innate-immune effector defect (macrophage killing); adaptive immunity, granuloma-relevant cytokines (IFN-γ) intact clinically.
Tissue damage: driven by unchecked Mtb infection (caseating granulomatous inflammation of lung) rather than a primary tissue-toxic mechanism.
Biochemical abnormality: functional deficiency of the macrophage respiratory burst / NADPH oxidase output secondary to absent TNF signaling (not a primary CYBB/NCF defect).
Molecular profiling: iPSC-derived macrophage models (TNF-KO, TNFR1-KO) used for functional dissection; no patient transcriptomic/proteomic/metabolomic datasets published. Respiratory-burst assays are the key functional readout.

Cell types (CL): CL:0000583 alveolar macrophage; CL:0000235 macrophage; CL:0001054 CD14+ monocyte; CL:0000576 monocyte. Biological process (GO): GO:0045730 (respiratory burst), GO:0071356 (cellular response to TNF).

7. Anatomical Structures Affected

Primary organ: lung (UBERON:0002048); specifically alveolar/pulmonary parenchyma (UBERON:0002299 alveolus). Disease is pulmonary and typically bilateral as per TB.
Body system: respiratory system (UBERON:0001004); immune system (UBERON:0002405) as the affected functional system.
Secondary involvement: one patient had disseminated Listeria (systemic). Classic TB complications (pleura, mediastinal lymph nodes) possible but not emphasized.
Tissue/cell level: mononuclear phagocytes — alveolar macrophages (CL:0000583) and monocyte-derived macrophages — are the pathogenically central cells; epithelial/lymphoid compartments intact.
Subcellular (GO cellular component): phagosome (GO:0045335), plasma membrane (GO:0005886), NADPH oxidase complex (GO:0043020), extracellular space (GO:0005615) for secreted TNF.
Lateralization: pulmonary TB is generally bilateral/multifocal; not a lateralized trait.

8. Temporal Development

Onset: adolescent/young-adult — first TB episodes at ages 18 and 19. No neonatal/childhood infections despite BCG exposure. Onset pattern: subacute/chronic (typical TB).
Progression: relapsing/recurrent pulmonary TB; individual episodes are treatment-responsive; disease course over the reported follow-up shows recurrence rather than relentless progression.
Duration: the underlying immunodeficiency is lifelong; clinical disease is episodic, contingent on Mtb exposure/reactivation.
Remission: treatment-induced remission of each episode with anti-TB chemotherapy; relapse may occur.
Critical period / intervention window: post-exposure and early infection — latent-TB detection and prophylaxis represent the key opportunity to prevent active disease.

9. Inheritance and Population

Inheritance: Autosomal recessive (biallelic TNF LOF). Heterozygotes unaffected.
Epidemiology: Ultra-rare — to date 1 family, 2 patients worldwide (PMID 39198650). No prevalence/incidence estimate; effectively <1 per 10^6 (private variant). Broader context: only ~5–10% of Mtb-infected individuals develop TB, and monogenic causes account for a small fraction (e.g., TYK2 P1104A ~1% of TB in Europeans; PMID 32055999).
Penetrance: appears high upon Mtb exposure but is environment-dependent (requires infection); true penetrance unknown with n=2.
Expressivity: narrow, consistent (isolated pulmonary TB) in the two cases.
Anticipation / mosaicism: not applicable / not reported.
Founder effect: none — variant is private to this family.
Consanguinity: central — multigenerational consanguineous pedigree; homozygosity mapping/linkage used for discovery.
Carrier frequency: effectively 0 in populations (variant absent from gnomAD).
Population/geography: single Colombian family; no ethnic predilection can be inferred. Sex: both cases female-inclusive (one episode occurred in pregnancy); no sex-ratio inference possible.

10. Diagnostics

Clinical/laboratory workup: - Confirm TB: sputum smear microscopy for acid-fast bacilli, mycobacterial culture, NAAT (e.g., Xpert MTB/RIF), chest imaging (X-ray/CT showing pulmonary infiltrates/cavitation). (Standard TB diagnostics; RadLex/LOINC applicable.) - Immunologic screen (typically normal in IMD127): normal CBC/leukocyte subsets, immunoglobulins, and IFN-γ responses — normality helps distinguish from other IEIs. - Functional immunology (research/specialist): absent TNF production by stimulated whole blood/monocytes (LPS, BCG, IFN-γ) and impaired macrophage respiratory burst — the pathognomonic functional signature (PMID 39198650). - Biomarker: undetectable serum/secreted TNF after stimulation; the defect is the biomarker.

Genetic testing (definitive): - WES or WGS with homozygosity mapping is how the diagnosis was made; single-gene TNF sequencing confirms once suspected. - Gene panels: include TNF alongside MSMD/IEI-to-TB genes (TYK2, IL12RB1, IL12B, IL23R, IFNGR1, IFNGR2, STAT1, ISG15, CYBB/CGD genes). - CMA/karyotype/FISH/mtDNA/repeat testing: not applicable (point insertion).

Clinical criteria / differential diagnosis: No formal diagnostic criteria (novel disease). Diagnose when a young adult has recurrent isolated pulmonary TB, normal BCG tolerance, no other infections, normal IFN-γ axis, and biallelic TNF LOF. Differential: TYK2 deficiency (complete or P1104A homozygosity), IL-12Rβ1 deficiency, IFN-γR/STAT1 defects (usually BCG-osis + broader mycobacterial disease), chronic granulomatous disease (broad infection spectrum), HIV and acquired anti-TNF exposure (PMID 32055999, 38025345, 39198650).

Screening: cascade genetic testing of relatives; latent-TB screening (IGRA/TST) in gene-positive individuals.

11. Outcome / Prognosis

Survival/mortality: No deaths reported among the 2 patients; most TB episodes were successfully treated (PMID 39198650). Untreated pulmonary TB carries substantial mortality generally, but with therapy prognosis appears favorable here.
Morbidity: recurrent TB with associated symptoms and treatment burden; potential long-term pulmonary sequelae (bronchiectasis, fibrosis) as in recurrent TB (extrapolated).
Recovery potential: good per episode with standard anti-TB therapy; relapse/recurrence is the main issue.
Prognostic factors: timeliness of diagnosis and treatment, adherence, drug-susceptibility of the infecting strain, and ongoing Mtb exposure. No molecular prognostic biomarker beyond genotype.
QoL measures: not formally assessed.

12. Treatment

No disease-specific (TNF-replacement) therapy exists. Management is treatment and prevention of tuberculosis plus consideration of the underlying immune defect.

Anti-tuberculous chemotherapy (standard of care; extrapolated from TB guidelines): the RIPE regimen — rifampin (NCIT:C769), isoniazid (NCIT:C566), pyrazinamide (NCIT:C1029), ethambutol (NCIT:C61785) — typically 2 months intensive + 4 months continuation, adjusted for drug susceptibility. Relapses re-treated per susceptibility.
Secondary prophylaxis: consider latent-TB/secondary preventive therapy (isoniazid or rifamycin-based) given recurrence risk; individualized.
Avoid TNF inhibitors in these patients (would compound the defect) — conversely, this disease validates pre-anti-TNF TB screening in the general population.
Conceptual/targeted therapy (not yet applied): because the respiratory-burst defect is rescued by exogenous TNF in vitro, recombinant TNF or TNFR1 agonism is a mechanistic (but risky/unproven) concept; likewise recombinant IFN-γ benefits IFN-γ-circuit TB but rationale is weaker here since the IFN-γ axis is intact. No gene/cell therapy, RNA therapy, or clinical trials exist for IMD127.
Pharmacogenomics: standard TB-drug PGx applies (e.g., NAT2 acetylator status and isoniazid toxicity) but is not IMD127-specific.

NCIT intervention terms: Antitubercular Therapy (NCIT:C15615/antibiotic therapy), Rifampin (C769), Isoniazid (C566), Pyrazinamide (C1029), Ethambutol (C61785).

13. Prevention

Primary prevention: avoid/limit Mtb exposure; BCG is tolerated and may be given (no BCG-osis), though its protective efficacy in this specific defect is unknown. Household TB source control.
Secondary prevention: latent-TB screening (IGRA/TST) and preventive therapy in genotype-positive relatives; early symptom-triggered evaluation.
Tertiary prevention: adherence support, monitoring for recurrence and pulmonary sequelae.
Genetic counseling: autosomal recessive — 25% recurrence risk per pregnancy for carrier couples; cascade testing; the consanguineous context warrants counseling. Prenatal/preimplantation testing feasible for the known familial variant.
Public-health note: IMD127 exemplifies why TB screening is mandated before anti-TNF biologic therapy in the general population (PMID 29459143).

14. Other Species / Natural Disease

Taxonomy of affected host: Homo sapiens (NCBI Taxon 9606).
Orthologous gene: mouse Tnf (NCBI Gene 21926; MGI:104798); rat Tnf (NCBI Gene 24835). Highly conserved TNF-superfamily cytokine.
Natural animal disease: No described naturally occurring inherited-TNF-deficiency disease in companion animals/wildlife (OMIA has no corresponding entry). TNF's anti-mycobacterial role is conserved across mammals (mouse KO data).
Comparative pathology: Mouse Tnf/Tnfr1 loss produces more severe, lethal mycobacterial disease (failed granulomas, death from attenuated BCG/M. avium) than the narrow human TB-only phenotype — an important species difference (PMID 10878503, 11433391, 10861087).
Zoonotic/cross-species transmission: not applicable (host genetic trait, not a transmissible disease).

15. Model Organisms

Cellular / iPSC (in vitro) — most disease-relevant: patient-derived and gene-edited TNF-KO and TNFR1-KO iPSC-derived, GM-CSF-matured macrophages and alveolar-macrophage-like (AML) cells; TNF-blocker-treated healthy MDMs/AML and ex vivo lung macrophages. Recapitulate the respiratory-burst defect and demonstrate TNF rescue (PMID 39198650). Cellosaurus/ATCC-type resources apply for iPSC lines.
Mouse (mammalian, Mus musculus, Taxon 10090):
Available models: Tnf−/−, Tnf/Lta double-KO (± LTα transgene), Tnfrsf1a (TNFR1/TNFRp55)−/−, Tnfrsf1b (TNFR2)−/−; conditional/humanized TNF strains via MGI/IMSR/MMRRC.
Phenotype recapitulation: reproduce mycobacterial susceptibility and establish TNFR1 (not TNFR2) as the essential receptor (PMID 10878503); model granuloma biology.
Limitations: phenotype is broader and lethal (susceptibility to BCG/M. avium, granuloma necrosis/disintegration, death) — does not capture the human specificity for virulent Mtb with sparing of BCG and other microbes; also TNF's roles in murine lymphoid architecture differ.
Applications: dissecting TNF–TNFR1 → respiratory-burst axis; testing TNF/IFN-γ rescue; granuloma dynamics; anti-TNF safety modeling.
Resources: MGI (Tnf MGI:104798), IMSR, MMRRC; Cellosaurus for iPSC/macrophage lines.

Ontology term appendix (for KB population)

Disease: OMIM:620977; MONDO → OMIM:620977 (verify term).
Gene/protein: HGNC:11892 (TNF); NCBI Gene 7124; UniProt P01375; Ensembl ENSG00000232810.
HPO: HP:0032262 (Pulmonary tuberculosis), HP:0032251 (Tuberculosis), HP:0002205 (Recurrent respiratory infections), HP:0002718 (Recurrent bacterial infections).
GO (BP): GO:0045730 (respiratory burst), GO:0006801 (superoxide metabolic process), GO:0071356 (cellular response to TNF), GO:0045087 (innate immune response), GO:0032496 (response to LPS).
GO (CC): GO:0045335 (phagosome), GO:0005615 (extracellular space), GO:0005886 (plasma membrane).
CL: CL:0000583 (alveolar macrophage), CL:0000235 (macrophage), CL:0001054 (CD14+ monocyte).
UBERON: UBERON:0002048 (lung), UBERON:0002299 (alveolus), UBERON:0001004 (respiratory system), UBERON:0002405 (immune system).
CHEBI: CHEBI:26523 (reactive oxygen species), CHEBI:18421 (superoxide).
NCIT (treatment): C769 (rifampin), C566 (isoniazid), C1029 (pyrazinamide), C61785 (ethambutol).
NCBI Taxon: 9606 (human), 10090 (mouse), 1773 (M. tuberculosis), 1639 (L. monocytogenes).

Supported vs. refuted hypotheses

Supported: (1) Biallelic TNF LOF causes isolated susceptibility to pulmonary TB (autosomal recessive). (2) TNF is required for the macrophage respiratory burst that kills Mtb; rescued by TNF. (3) TNFR1 is the essential receptor (mouse + iPSC). (4) Anti-TNF drugs phenocopy the disease (2–5× TB risk). (5) TNF deficiency is mechanistically distinct from IFN-γ-circuit MSMD.
Refuted / not supported: TNF is not broadly required for human host defense or systemic inflammation (patients otherwise healthy); the disorder does not cause BCG-osis or broad infection susceptibility (contrast with mouse KO and CGD).

Limitations

Single family (n=2); no prevalence, penetrance, long-term survival, or QoL data; treatment is extrapolated from general TB guidelines; no human omics datasets; mouse models over-represent severity. Findings should be revisited as additional families are identified.

Key references (PMID)

39198650 — Arias et al., Nature 2024 (primary description of IMD127 / inherited TNF deficiency).
32055999 — Boisson-Dupuis, monogenic basis of human TB.
35985287 — Casanova & Abel, rare-to-common infection genetics.
38025345 — Errami & Bousfiha, MSMD state of the art.
32602053 — Mahdaviani et al., MSMD cohort.
10878503 — Jacobs et al., TNFR1 vs TNFR2 in mycobacterial immunity (mouse).
11433391 — Bopst et al., TNF/LTα and BCG (mouse).
10861087 — Ehlers et al., TNFRp55 and M. avium granuloma disintegration (mouse).
29459143 — Baddley et al., ESGICH anti-TNF safety/TB.
42226371 — Alves et al., umbrella review of TB risk with biologics/JAKi.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	5
Resolved	5
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	5
On topic	3
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	37
Resolved	32
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	4
Terms whose name was checked	21
Terms named correctly	12
Terms named as a different term	3
Terms whose name is worth a second look	6

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:

HP:0032251 (2 mentions) - the report calls it "Tuberculosis"; HP calls it Abnormal immune system morphology
CL:0000583 (3 mentions) - the report calls it "Tissue/cell level: mononuclear phagocytes — alveolar macrophages", "alveolar macrophage"; CL calls it alveolar macrophage
UBERON:0002048 (2 mentions) - the report calls it "lung", "Primary organ: lung"; UBERON calls it lung

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0005615 (obsolete extracellular space) (2 mentions) - replaced by GO:0005576

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:

GO:0032496 (2 mentions) - the report calls it "response to LPS"; GO calls it response to lipopolysaccharide, and lists "response to LPS" among its other names
CL:0001054 (2 mentions) - the report calls it "CD14+ monocyte"; CL calls it CD14-positive monocyte, and lists "monocyte" among its other names
UBERON:0002299 (2 mentions) - the report calls it "alveolus"; UBERON calls it alveolus of lung, and lists "alveolus" among its other names
UBERON:0001004 (2 mentions) - the report calls it "respiratory system", "Body system: respiratory system"; UBERON calls it respiratory system
GO:0045335 (2 mentions) - the report calls it "phagosome"; GO calls it phagocytic vesicle, and lists "phagosome" among its other names
GO:0005615 (2 mentions) - the report calls it "extracellular space"; GO calls it obsolete extracellular space, and lists "intercellular space" among its other names

Terms named inconsistently

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

CL:0000583 - called "Tissue/cell level: mononuclear phagocytes — alveolar macrophages", "alveolar macrophage"
UBERON:0002048 - called "lung", "Primary organ: lung"
UBERON:0001004 - called "respiratory system", "Body system: respiratory system"

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: OMIM, ORPHA, MGI.

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Environmental Factors

Diagnosis

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Differential Diagnoses

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References & Deep Research

References

Deep Research

Immunodeficiency 127 (IMD127) — Comprehensive Disease Characteristics Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation)

Mechanistic detail by category

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Ontology term appendix (for KB population)

Supported vs. refuted hypotheses

Limitations

Key references (PMID)

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver