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). 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, 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%). (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 (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; 29459143).

3. Phenotypes

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

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 (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)

1. 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.)
2. 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.)
3. 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.)
4. 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.)
5. 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 (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 (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; 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 (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 (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 (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 (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 (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 (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 (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.