name: Mendelian Susceptibility To Mycobacterial Diseases Due To Complete IL12RB1 Deficiency
creation_date: "2026-09-18T00:00:00Z"
category: Mendelian
synonyms:
- IL-12Rbeta1 deficiency
- Complete IL-12R beta 1 deficiency
- IL12RB1 deficiency
- MSMD due to complete IL12RB1 deficiency
- Immunodeficiency 30
- IMD30
description: >
  Mendelian susceptibility to mycobacterial disease (MSMD) due to complete interleukin-12
  receptor beta-1 (IL-12Rbeta1) deficiency is an autosomal recessive inborn error of
  immunity caused by biallelic loss-of-function variants in IL12RB1. It is the most common
  genetic etiology of MSMD. Patients present in childhood with disease caused by weakly
  virulent mycobacteria - above all the Bacille Calmette-Guerin (BCG) vaccine strain and
  environmental non-tuberculous mycobacteria - and with non-typhoidal, extraintestinal
  salmonellosis, while routine immunological testing is unremarkable.

  Every genetic etiology of MSMD converges on interferon gamma (IFN-gamma): each impairs
  either the production of the cytokine or the cellular response to it. IL-12Rbeta1 sits
  in the production arm, and its molecular logic is the shared-chain one. The beta-1 chain
  encoded by IL12RB1 is not specific to the IL-12 receptor: it pairs with IL-12Rbeta2 to
  form the high-affinity IL-12 receptor on T and NK cells, and with IL-23R to form the
  IL-23 receptor. A complete beta-1 defect therefore abolishes cellular responsiveness to
  both cytokines at once. Loss of IL-12 signalling removes the dominant signal driving T
  and NK lymphocytes to secrete IFN-gamma, so IFN-gamma-dependent macrophage activation
  fails and intramacrophagic mycobacteria and Salmonella replicate unchecked. Loss of
  IL-23 signalling additionally depletes IL-17-producing T cells, which is the accepted
  explanation for the mucocutaneous candidiasis seen in roughly a quarter of patients.

  This is the receptor-side counterpart of IL-12p40 (IL12B) deficiency, and the two are
  clinically near-indistinguishable: the same shared-chain logic operates one step apart on
  the same axis, cytokine in one case and receptor in the other. The lesion lies upstream
  of IFN-gamma in both, so recombinant IFN-gamma remains a mechanistically rational adjunct
  to prolonged antimycobacterial chemotherapy - the therapeutic dividing line that
  separates the production-arm etiologies of MSMD from the IFN-gamma receptor defects,
  where the same drug cannot work.
disease_term:
  preferred_term: Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency
  term:
    id: MONDO:0013955
    label: Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency
parents:
- Primary immunodeficiency
- Mendelian susceptibility to mycobacterial disease
references:
- reference: PMID:9603733
  title: "Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients."
- reference: PMID:9603732
  title: "Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency."
- reference: PMID:12591909
  title: "Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications."
- reference: PMID:21057261
  title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
- reference: PMID:38025345
  title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
- reference: PMID:11424023
  title: "Interleukin-12 receptor beta1 deficiency in a patient with abdominal tuberculosis."
- reference: PMID:24186907
  title: "Clinical features of Candidiasis in patients with inherited interleukin 12 receptor β1 deficiency."
- reference: PMID:31367980
  title: "Current Status of the Management of Mendelian Susceptibility to Mycobacterial Disease in Mainland China."
- reference: PMID:35891311
  title: "Immune Correlates of Disseminated BCG Infection in IL12RB1-Deficient Mice."
notes: >-
  No GeneReviews chapter covers MSMD or IL-12Rbeta1 deficiency. Checked with
  `just check-genereviews` against the committed Bookshelf index (snapshot 2026-09-10,
  NO_CHAPTER) and independently against PubMed with
  `"mycobacterial disease"[TI] AND genereviews[book]` and
  `"mendelian susceptibility"[TI] AND genereviews[book]`, both of which returned zero
  records. The phenotype baseline here is therefore the 141-patient international survey
  (PMID:21057261) rather than an expert-curated chapter.
classifications:
  iuis_category:
    classification_value: innate immunity defect
    notes: >-
      IUIS phenotypic classification of inborn errors of immunity, Mendelian
      susceptibility to mycobacterial disease (MSMD) table. This entry is the IL12RB1
      etiology of MSMD, a defect of IL-12/IL-23-dependent IFN-gamma immunity.
    evidence:
    - reference: PMID:38025345
      reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Mendelian susceptibility to mycobacterial diseases (MSMD) is the most characterized
        of these IEIs, with 36 different disorders found in 20 distinct genes (IFNGR1,
        IFNGR2, IFNG, IL12RB1, IL12RB2, IL23R, IL12B, ISG15, USP18, ZNFX1, TBX21, STAT1,
        TYK2, IRF8, IRF1, CYBB, JAK1, RORC, NEMO, and SPPL2A)
      explanation: >-
        Places IL12RB1 in the established gene set of Mendelian susceptibility to
        mycobacterial disease, the inborn-error-of-immunity syndrome under which this
        entry is classified.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    No population rate has been established. The largest series assembled 141 patients from
    102 kindreds in 30 countries, and IL-12Rbeta1 deficiency is the most frequent single
    genetic etiology of MSMD. Reported as a literature case count rather than a rate,
    because ascertainment is driven by BCG vaccination policy and by consanguinity and so
    does not track underlying allele frequency.
  evidence:
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian
      susceptibility to mycobacterial disease (MSMD). We undertook an international survey
      of 141 patients from 102 kindreds in 30 countries.
    explanation: >-
      Gives both the standing of this etiology within MSMD and the size and spread of the
      largest reported cohort, the basis for recording occurrence as a literature case
      count.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Disease begins in early childhood - mean age at first infection 2.4 years - and 30% of
    patients in the largest survey had died by last follow-up. Survivors require prolonged
    multidrug antimycobacterial chemotherapy, often with adjunctive recombinant IFN-gamma,
    and a minority need surgical resection of affected tissue. Burden is tempered relative
    to the IFN-gamma receptor defects by the incomplete penetrance and the rarity of
    mycobacterial recurrence, but childhood onset combined with 30% mortality places the
    disease-level burden at HIGH.
  evidence:
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7
      years ± 9.8 years (range, 0.5-46.4 yr).
    explanation: >-
      Establishes the survival figure - and by complement the 30% mortality - behind the
      HIGH burden assessment.
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 102 probands, the first infection occurred at a mean age of 2.4 years.
    explanation: >-
      Establishes early childhood as the age of onset, so the burden is borne across a
      whole life rather than late in one.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: INCOMPLETE
  penetrance_percentage: >-
    ~69% among genetically affected siblings of index cases in the 141-patient survey
    (20 of 29 symptomatic); an earlier, smaller series had put asymptomatic carriage as
    high as 45%
  description: >
    Disease requires biallelic loss-of-function IL12RB1 variants. Reported kindreds are
    predominantly consanguineous and probands are usually homozygous; heterozygous
    relatives are healthy. Clinical penetrance is high but incomplete, and the estimate has
    moved with cohort size: the 2003 series reported up to 45% of genetically affected sibs
    remaining asymptomatic, while the larger 2010 survey found 69% of affected sibs
    symptomatic and 27% asymptomatic. The direction of that revision matters - penetrance
    is higher, and outcome worse, than the field first believed.

    The sharpest evidence on penetrance is intrafamilial. Two siblings homozygous for the
    same missense allele, with the same abolished receptor expression and the same abolished
    IL-12 response, diverged completely: one had disseminated BCG disease in early childhood,
    the other resisted three separate live-BCG inoculations and instead presented with
    abdominal tuberculosis at eighteen. Genotype does not determine phenotype here even
    within a sibship, which constrains what any genotype-based counselling can say.
  evidence:
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8
      remained asymptomatic (27%).
    explanation: >-
      Quantifies incomplete penetrance in the largest cohort: roughly a quarter of
      genotype-positive relatives never become symptomatic.
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The condition has higher clinical penetrance, broader susceptibility to infections,
      and less favorable outcome than previously thought.
    explanation: >-
      Records that the penetrance and outcome estimates were revised upward and downward
      respectively as the cohort grew, which is why this entry cites the larger survey in
      preference to the earlier series.
  - reference: PMID:11424023
    reference_title: "Interleukin-12 receptor beta1 deficiency in a patient with abdominal tuberculosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient had the expected phenotype of disseminated bacille Calmette-Guérin (BCG)
      infection in early childhood, whereas the other did not develop BCG infection, despite
      3 inoculations with live BCG.
    explanation: >-
      Documents complete phenotypic divergence between two siblings carrying the identical
      homozygous allele, which is the strongest available evidence that penetrance is not
      genotype-determined.
  - reference: PMID:11424023
    reference_title: "Interleukin-12 receptor beta1 deficiency in a patient with abdominal tuberculosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These observations show unexpected interfamilial and intrafamilial heterogeneity of
      the clinical phenotype associated with IL-12Rbeta1 deficiency.
    explanation: >-
      States the heterogeneity conclusion directly, at both the between-family and
      within-family level.
genetic:
- name: IL12RB1
  gene_term:
    preferred_term: IL12RB1
    term:
      id: hgnc:5971
      label: IL12RB1
  relationship_type: CAUSATIVE
  notes: >-
    IL12RB1 encodes the beta-1 chain shared by the IL-12 and IL-23 receptors. Complete
    deficiency results from biallelic null alleles - premature stop codons, frameshifts and
    large deletions in the extracellular domain predominate - which abolish surface
    expression of IL-12Rbeta1 on T and NK cells. Because the chain is shared, one gene
    defect removes cellular responsiveness to two cytokines.
  evidence:
  - reference: PMID:9603733
    reference_title: "Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IL-12Rbeta1 sequence analysis revealed genetic mutations that resulted in premature
      stop codons in the extracellular domain.
    explanation: >-
      Identifies the class of loss-of-function allele underlying complete IL-12Rbeta1
      deficiency in the first patients described.
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the β1 chain shared by the IL-12 and IL-23 receptors (IL12RB1)
    explanation: >-
      States the shared-chain architecture that makes a single IL12RB1 defect abolish
      responsiveness to both IL-12 and IL-23.
  - reference: PMID:11424023
    reference_title: "Interleukin-12 receptor beta1 deficiency in a patient with abdominal tuberculosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Transfection of the patients' T cells with wild-type IL12RB1 restored IL-12Rbeta1
      expression and function.
    explanation: >-
      Complementation evidence: restoring the wild-type gene restores both the protein and
      the cellular response, which establishes causality rather than association.
pathophysiology:
- name: IL12RB1 Loss of Function
  description: >
    Biallelic null IL12RB1 alleles abolish expression of the IL-12Rbeta1 chain at the
    surface of T and NK cells. The chain is an obligate component of both the high-affinity
    IL-12 receptor (with IL-12Rbeta2) and the IL-23 receptor (with IL-23R), so its absence
    removes both receptors at once.
  biological_scale: MOLECULAR
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    zygosity: HOMOZYGOUS
  genes:
  - preferred_term: IL12RB1
    term:
      id: hgnc:5971
      label: IL12RB1
  downstream:
  - target: Abolished Cellular Responsiveness to IL-12 and IL-23
    causal_link_type: DIRECT
    description: >-
      Loss of the shared beta-1 chain leaves T and NK cells unable to assemble either
      receptor, so they cannot respond to either cytokine.
    evidence:
    - reference: PMID:9603733
      reference_title: "Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Three unrelated individuals with severe, idiopathic mycobacterial and Salmonella
        infections were found to lack IL-12Rbeta1 chain expression. Their cells were
        deficient in IL-12R signaling and IFN-gamma production
      explanation: >-
        Connects absent chain expression directly to failed receptor signalling in patient
        cells, which is the edge rather than either node alone.
  evidence:
  - reference: PMID:9603733
    reference_title: "Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IL-12Rbeta1 sequence analysis revealed genetic mutations that resulted in premature
      stop codons in the extracellular domain.
    explanation: >-
      Documents the class of null allele at IL12RB1 that constitutes the initiating
      molecular lesion.
- name: Abolished Cellular Responsiveness to IL-12 and IL-23
  description: >
    Patient T and NK cells fail to signal in response to IL-12 and to IL-23. The defect is
    functional as well as structural: whole blood does not raise IFN-gamma when exogenous
    recombinant IL-12 is added, and T-cell blasts neither produce IFN-gamma nor express
    IL-17 in response to IL-23.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: T-helper 1 cell
    term:
      id: CL:0000545
      label: T-helper 1 cell
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  biological_processes:
  - preferred_term: interleukin-12-mediated signaling pathway
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0035722
      label: interleukin-12-mediated signaling pathway
  - preferred_term: interleukin-23-mediated signaling pathway
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0038155
      label: interleukin-23-mediated signaling pathway
  downstream:
  - target: Impaired IL-12-Dependent IFN-gamma Production
    causal_link_type: DIRECT
    description: >-
      IL-12 is the dominant signal driving T and NK cells to secrete IFN-gamma; without a
      functional receptor that induction fails.
    evidence:
    - reference: PMID:21057261
      reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients tested had an impaired response to IL-12 in this assay
      explanation: >-
        Establishes across the cohort that the receptor defect translates into failed
        IL-12-driven IFN-gamma induction, which is the step this edge asserts.
  - target: Impaired IL-23-Dependent IL-17 Immunity
    causal_link_type: DIRECT
    description: >-
      The same shared chain is required for IL-23 signalling, so the IL-23-dependent
      IL-17 axis fails in parallel rather than downstream.
    evidence:
    - reference: PMID:21057261
      reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        IL-12Rβ1-deficient patients had a smaller proportion of IL-17-producing T cells ex
        vivo, and that their T-cell blasts did not express IL-17 in response to stimulation
        with IL-23 in vitro
      explanation: >-
        Supports the specific link from absent IL-23 responsiveness to a depleted
        IL-17-producing T cell compartment.
  evidence:
  - reference: PMID:9603733
    reference_title: "Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      their remaining T cell responses were independent of endogenous IL-12
    explanation: >-
      Shows that what survives in patient T cells is precisely the IL-12-independent
      repertoire, establishing the selectivity of the signalling block.
- name: Impaired IL-12-Dependent IFN-gamma Production
  description: >
    T and NK cells fail to mount the IFN-gamma response that IL-12 normally drives, so
    circulating and locally available IFN-gamma is inadequate for the control of
    intramacrophagic pathogens.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: T-helper 1 cell
    term:
      id: CL:0000545
      label: T-helper 1 cell
  biological_processes:
  - preferred_term: type II interferon production
    modifier: DECREASED
    term:
      id: GO:0032609
      label: type II interferon production
  downstream:
  - target: Failed IFN-gamma-Dependent Macrophage Activation
    causal_link_type: DIRECT
    description: >-
      Macrophage antimycobacterial activity is IFN-gamma-dependent, so a shortfall in
      IFN-gamma leaves macrophages unactivated.
    evidence:
    - reference: PMID:9603732
      reference_title: "Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thus, IL-12-dependent IFN-gamma secretion in humans seems essential in the control
        of mycobacterial infections, despite the formation of mature granulomas due to
        IL-12-independent IFN-gamma secretion.
      explanation: >-
        States that it is specifically the IL-12-dependent share of IFN-gamma secretion
        that mycobacterial control requires, which is the step this edge asserts.
  evidence:
  - reference: PMID:9603733
    reference_title: "Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Their cells were deficient in IL-12R signaling and IFN-gamma production
    explanation: >-
      Directly documents reduced IFN-gamma production in patient cells.
- name: Failed IFN-gamma-Dependent Macrophage Activation
  description: >
    Without adequate IFN-gamma, macrophages do not acquire the activated phenotype needed
    to restrict intracellular bacterial replication in the phagosome. Granuloma architecture
    is preserved - mature granulomas with epithelioid and multinucleated giant cells still
    form on residual IL-12-independent IFN-gamma - so the lesion is in macrophage activation
    rather than in granuloma assembly. That dissociation separates this disease from
    IFN-gamma receptor deficiency, where granuloma formation itself fails.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: macrophage activation
    modifier: DECREASED
    term:
      id: GO:0042116
      label: macrophage activation
  downstream:
  - target: Uncontrolled Intramacrophage Replication of Weakly Virulent Mycobacteria and Salmonella
    causal_link_type: DIRECT
    description: >-
      Unactivated macrophages are a permissive niche for mycobacteria and non-typhoidal
      Salmonella.
    evidence:
    - reference: PMID:9603733
      reference_title: "Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The lack of IL-12Rbeta1 expression results in a human immunodeficiency and shows
        the essential role of IL-12 in resistance to infections due to intracellular
        bacteria.
      explanation: >-
        States the causal conclusion the authors drew from the patients: this axis is what
        confers resistance to intracellular bacteria, so its failure is what permits them.
  evidence:
  - reference: PMID:9603732
    reference_title: "Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mature granulomas were seen, surrounded by T cells and centered with epithelioid and
      multinucleated giant cells, yet reduced IFN-gamma concentrations were found to be
      secreted by activated natural killer and T cells.
    explanation: >-
      Shows the defect is a failure of macrophage activation rather than of granuloma
      assembly: residual IL-12-independent IFN-gamma still builds mature granulomas, and
      they are nonetheless not protective.
- name: Uncontrolled Intramacrophage Replication of Weakly Virulent Mycobacteria and Salmonella
  description: >
    Organisms that a competent IFN-gamma axis would clear silently - the BCG vaccine strain,
    environmental mycobacteria, non-typhoidal Salmonella - instead replicate and disseminate.
    Susceptibility is narrow: patients handle most other pathogens normally, which is what
    makes MSMD a selective rather than a combined immunodeficiency.
  biological_scale: ORGANISM
  downstream:
  - target: Disseminated BCG disease
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21057261
      reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65),
        environmental mycobacteria (EM; also known as atypical or nontuberculous
        mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4).
      explanation: >-
        Establishes BCG as the dominant presenting organism, the clinical expression of
        this node.
  - target: Non-tuberculous mycobacterial infection
    causal_link_type: DIRECT
  - target: Non-typhoidal salmonellosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21057261
      reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Twenty-two of the remaining 24 probands initially presented with nontyphoidal,
        extraintestinal salmonellosis.
      explanation: >-
        Establishes salmonellosis as the second presenting syndrome produced by this node.
  - target: Tuberculosis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:12591909
    reference_title: "Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unexpectedly, human IL-12 is redundant in protective immunity against most
      microorganisms other than Mycobacteria and Salmonella.
    explanation: >-
      Documents the narrowness of the susceptibility - IL-12 is dispensable for immunity to
      everything else - which is the defining feature of this node and what distinguishes
      MSMD from a combined immunodeficiency.
- name: Impaired IL-23-Dependent IL-17 Immunity
  description: >
    Loss of IL-23 signalling depletes the IL-17-producing T cell compartment. IL-17 is
    required for mucosal antifungal defence, and this is the accepted explanation for the
    mucocutaneous candidiasis in this disease - a phenotype that the IFN-gamma arm does not
    account for.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: interleukin-17 production
    modifier: DECREASED
    term:
      id: GO:0032620
      label: interleukin-17 production
  downstream:
  - target: Chronic mucocutaneous candidiasis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21057261
      reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We recently found that 32 (24%) of the 132 symptomatic patients for whom
        information was available presented mucocutaneous disease caused by Candida
        albicans
      explanation: >-
        Quantifies the candidiasis this arm of the mechanism is invoked to explain.
  evidence:
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, the blood cells from the patients tested displayed an impaired response to
      both IL-12 and IL-23
    explanation: >-
      Establishes that the IL-23 arm is affected alongside the IL-12 arm, which is what
      makes this a parallel branch rather than a downstream consequence.
phenotypes:
- category: Infectious
  name: Disseminated BCG disease
  description: >
    Disease caused by the live attenuated Bacille Calmette-Guerin vaccine strain, ranging
    from regional lymphadenitis to disseminated infection. It is the commonest presenting
    illness and follows routine neonatal BCG vaccination in countries that practise it.
  phenotype_term:
    preferred_term: BCGosis
    term:
      id: HP:0020087
      label: BCGosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The overall clinical spectrum of infectious diseases in index cases was as follows:
      isolated BCG disease was present in 43 patients, isolated salmonellosis in 15 patients,
      isolated EM disease in 6 patients, and isolated tuberculosis in 2 patients.
    explanation: >-
      Gives the prevalence of BCG disease across index cases, which is what the FREQUENT band
      rests on. Replaces a recurrence count, which spoke to how often the disease returns
      rather than to how often it occurs.
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent BCG infection was diagnosed in 15 cases
    explanation: >-
      Documents recurrence separately from prevalence. Retained because rarity of
      mycobacterial recurrence is itself a characteristic of this disease.
- category: Infectious
  name: Non-tuberculous mycobacterial infection
  description: >
    Infection by environmental (atypical, non-tuberculous) mycobacteria. Notably, prior BCG
    disease is strongly protective against subsequent environmental mycobacterial disease,
    which is why this presentation is less common than BCG disease in vaccinated cohorts.
  phenotype_term:
    preferred_term: Non-tuberculous mycobacterial infection
    term:
      id: HP:5210115
      label: Non-tuberculous mycobacterial infection
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BCG disease strongly protected against subsequent EM disease (p = 0.00008).
    explanation: >-
      Records the protective interaction that shapes how often this phenotype is seen, and
      is itself a non-obvious feature of the disease.
- category: Infectious
  name: Non-typhoidal salmonellosis
  description: >
    Extraintestinal, often recurrent infection with non-typhoidal Salmonella. It is the
    presenting illness in about a fifth of probands and recurs more often than mycobacterial
    disease does.
  phenotype_term:
    preferred_term: Unusual Salmonella infection
    term:
      id: HP:5210093
      label: Unusual Salmonella infection
  frequency: FREQUENT
  evidence:
  - reference: PMID:12591909
    reference_title: "Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, disseminated nontyphoid salmonellosis occurred in 21 of 34 patients.
    explanation: >-
      Gives a prevalence figure for salmonellosis - 21 of 34 in the 2003 series - rather than
      a recurrence count, which is what the FREQUENT band should rest on.
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      recurrent salmonellosis in 22 patients
    explanation: >-
      Documents recurrence, which in this disease is more frequent for salmonellosis than
      for mycobacterial infection and is a distinguishing feature rather than a restatement.
- category: Infectious
  name: Tuberculosis
  description: >
    Disease caused by Mycobacterium tuberculosis. Less common than BCG or environmental
    mycobacterial disease as a presenting illness, but part of the same susceptibility.
  phenotype_term:
    preferred_term: Tuberculosis infection
    term:
      id: HP:5210111
      label: Tuberculosis infection
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      or Mycobacterium tuberculosis (n = 4)
    explanation: >-
      Records tuberculosis among the presenting mycobacterial infections in the cohort.
- category: Infectious
  name: Chronic mucocutaneous candidiasis
  description: >
    Mucocutaneous Candida albicans disease, most often recurrent oral thrush, affecting
    roughly a quarter of symptomatic patients. It is attributed to the IL-23/IL-17 arm of
    the defect rather than to the IFN-gamma arm.
  phenotype_term:
    preferred_term: Chronic mucocutaneous candidiasis
    term:
      id: HP:0002728
      label: Chronic mucocutaneous candidiasis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      yet candidiasis was reported in 33 of the patients (23%)
    explanation: >-
      Quantifies the frequency of candidiasis among reported patients.
  - reference: PMID:24186907
    reference_title: "Clinical features of Candidiasis in patients with inherited interleukin 12 receptor β1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Isolated oropharyngeal candidiasis (OPC) was the most common presentation (59 episodes,
      34 patients) and was recurrent or persistent in 26 patients.
    explanation: >-
      Characterises the candidiasis: overwhelmingly oropharyngeal and usually recurrent,
      which is what distinguishes it from the invasive fungal disease seen in a combined
      immunodeficiency.
  - reference: PMID:24186907
    reference_title: "Clinical features of Candidiasis in patients with inherited interleukin 12 receptor β1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      About 25% of patients also display mucocutaneous candidiasis, probably owing to
      impaired interleukin 23-dependent interleukin 17 immunity.
    explanation: >-
      Attributes the candidiasis to the IL-23/IL-17 arm rather than the IFN-gamma arm, with
      the authors' own hedge retained.
- category: Laboratory
  name: Decreased circulating interferon-gamma
  description: >
    Reduced IFN-gamma production on stimulation. The diagnostic form of the finding is the
    absence of an IFN-gamma rise in whole blood when exogenous recombinant IL-12 is added,
    which distinguishes a receptor defect from a cytokine-production defect.
  phenotype_term:
    preferred_term: Reduced circulating interferon gamma concentration
    term:
      id: HP:0033253
      label: Reduced circulating interferon gamma concentration
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:9603732
    reference_title: "Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      reduced IFN-gamma concentrations were found to be secreted by activated natural
      killer and T cells
    explanation: >-
      Documents the reduced IFN-gamma secretion by the two effector populations that
      defines this laboratory phenotype.
  reports_on:
  - target: Impaired IL-12-Dependent IFN-gamma Production
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      The measurement of that node, and the assay this diagnosis is made on.
      Recorded as an observational readout rather than a causal edge: deficient
      IFN-gamma production is the node being measured, not something the node
      causes. Note the cited assays measure stimulated production rather than a
      resting circulating level, which is the distinction this entry's notes
      are written to preserve.
diagnosis:
- name: Absent IL-12Rbeta1 surface expression by flow cytometry
  description: >
    The test that defines this entry's scope. "Complete" deficiency means the receptor chain
    is not detectable at the cell surface, as distinct from partial deficiency where a
    non-functional or reduced-level chain is expressed. It is assessed by flow cytometry with
    specific antibodies on T cell blasts, EBV-transformed B cells, or both.

    Two things make this more than a formality. It is what separates complete from partial
    IL-12Rbeta1 deficiency, which are different entries; and expression alone is not
    sufficient, because a patient carrying a large in-frame deletion expressed the chain
    while remaining functionally deficient. So surface staining and the functional IL-12
    response assay below are complementary rather than redundant, and the defining cohort
    required one, the other, or both.
  evidence:
  - reference: PMID:12591909
    reference_title: "Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, we have demonstrated complete IL-12Rβ1 deficiency in 29 patients (absence of
      detectable IL-12Rβ1 surface expression, n = 28, absence of response to IL-12, n = 27,
      or both, n = 27).
    explanation: >-
      States the operational definition of complete deficiency, and shows the two criteria
      were applied singly or together rather than as one compound test.
  - reference: PMID:12591909
    reference_title: "Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We assessed IL-12Rβ1 expression on the surface of T cell blasts (kindreds 9, 14, 15,
      22, 25), EBV-transformed B cells (kindreds 8, 11, 19, 20, 29), or both (kindreds 3, 6,
      10, 12, 16, 17, 23, 24, 26–28), from 21 of the 24 newly diagnosed probands, by flow
      cytometry with specific antibodies.
    explanation: >-
      Describes the method and the cell types it is performed on.
  - reference: PMID:12591909
    reference_title: "Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 10.II.2, carrying a large in-frame deletion, presented an expression of the β1
      chain, both on T cell blasts and EBV-transformed B c
    explanation: >-
      Records the exception that makes the functional assay necessary alongside the staining:
      a patient can express the chain and still be deficient.
- name: IL-12-stimulated whole-blood IFN-gamma assay
  description: >
    Whole blood is stimulated with BCG alone and with BCG plus exogenous recombinant IL-12,
    and IFN-gamma is measured. A patient with a receptor defect fails to raise IFN-gamma
    even when IL-12 is supplied, which separates IL-12Rbeta1 deficiency from IL-12p40
    deficiency, where adding the cytokine restores the response. Surface IL-12Rbeta1
    staining and IL12RB1 sequencing confirm it.
  evidence:
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We measured the production of IFN-γ in whole blood in response to stimulation with
      BCG alone (partly resulting from BCG-dependent, endogenous IL-12 production) and in
      response to BCG plus exogenous recombinant IL-12
    explanation: >-
      Describes the assay and the two stimulation arms whose discordance is what the test
      reads out.
treatments:
- name: Antimycobacterial Therapy
  description: >
    Prolonged multidrug antimycobacterial chemotherapy is the mainstay for BCG and
    environmental mycobacterial disease, with antibiotic courses for salmonellosis. Courses
    are long because host clearance of the organism cannot be relied on.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antitubercular agent
      term:
        id: NCIT:C280
        label: Antitubercular Agent
  target_mechanisms:
  - target: Uncontrolled Intramacrophage Replication of Weakly Virulent Mycobacteria and Salmonella
    description: >-
      Chemotherapy substitutes for the failed host control of the organism; it does not
      correct the immune defect.
  evidence:
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IL-12Rβ1-deficient individuals were commonly treated with prolonged courses of
      antibiotics and exogenous IFN-γ.
    explanation: >-
      Documents prolonged antibiotic courses as standard management in the reference
      cohort.
- name: Recombinant Interferon Gamma
  description: >
    Adjunctive recombinant IFN-gamma is mechanistically rational here because the lesion
    lies upstream of IFN-gamma: the cytokine itself and its receptor are intact, so
    exogenous IFN-gamma can bypass the block and activate macrophages. This is the line
    that separates the production-arm MSMD etiologies from the IFN-gamma receptor defects.
    Note the evidence base is observational practice rather than a controlled trial - the
    reference cohort explicitly could not evaluate treatment effect.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: interferon gamma-1b
      term:
        id: NCIT:C100089
        label: Interferon Gamma-1b
  target_mechanisms:
  - target: Failed IFN-gamma-Dependent Macrophage Activation
    description: >-
      Exogenous IFN-gamma acts downstream of the receptor block, restoring the macrophage
      activation signal that the patient cannot generate.
  evidence:
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both curative and preventive treatment of IL-12Rβ1 deficiency, based on prolonged
      courses of antibiotics, exogenous IFN-γ treatment, and, in rare cases, surgical
      resection of affected areas, may influence clinical outcome in these patients.
    explanation: >-
      Documents exogenous IFN-gamma as part of both curative and preventive management, and
      the hedged wording is itself the honest strength of the claim.
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, we were unable to explore the effects of treatment on clinical outcome in
      the present study because the information available was too limited
    explanation: >-
      Records explicitly that the largest cohort could not assess whether treatment changes
      outcome. Cited as NO_EVIDENCE because it bears on the efficacy claim without
      supporting or refuting it.
- name: Avoidance of BCG Vaccination
  description: >
    BCG is a live attenuated vaccine and is the single commonest cause of disease in this
    condition, so it is contraindicated in known patients and in at-risk siblings pending
    genotyping. In vaccinating countries the diagnosis is frequently made only after
    vaccine-strain disease has already occurred.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Uncontrolled Intramacrophage Replication of Weakly Virulent Mycobacteria and Salmonella
    description: >-
      Withholding the live vaccine removes the organism that this node most often acts on.
  evidence:
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65)
    explanation: >-
      Establishes BCG as the dominant cause of first infection, which is what makes
      withholding the live vaccine the primary preventable exposure.
- name: Hematopoietic Cell Transplantation
  description: >
    Transplantation replaces the defective haematopoietic compartment and is the only
    treatment directed at the lesion rather than at its consequences. It is reserved for
    severe or refractory disease. Note the evidence base is cohort management experience -
    a Chinese cohort in which HSCT achieved markedly higher antimycobacterial cure rates -
    rather than a controlled comparison, and the decision is weighed against a disease whose
    overall survival is already around 70% on medical management.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: IL12RB1 Loss of Function
    description: >-
      Donor-derived lymphocytes carry a functional IL12RB1 allele, so the receptor defect is
      corrected at its source rather than bypassed.
  evidence:
  - reference: PMID:31367980
    reference_title: "Current Status of the Management of Mendelian Susceptibility to Mycobacterial Disease in Mainland China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the patients, IL12RB1 mutations were identified in 22, IFNGR1 mutations in 5,
      STAT1 mutations in 2, and IFNGR2 mutation in 1.
    explanation: >-
      Establishes that the management cohort behind this treatment is predominantly
      IL12RB1-deficient patients, so its experience applies to this entry.
environmental:
- name: BCG vaccination
  description: >
    The live attenuated Mycobacterium bovis BCG vaccine is the single commonest cause of
    disease in this disorder and the exposure that most often brings it to diagnosis. The
    genotype alone does not produce illness: an encounter with a weakly virulent
    intracellular organism is required, and in vaccinating countries that encounter is
    usually iatrogenic and scheduled. That makes this one of the few inborn errors of
    immunity whose dominant trigger is a routine public-health intervention, and the reason
    withholding the vaccine in at-risk siblings is the principal preventive measure.
  exposure_term:
    preferred_term: exposure to BCG vaccination
  review_notes: >-
    Exposure term left unbound. ECTO has no class for vaccination exposure in the build the
    term validator resolves against: `runoak -i sqlite:obo:ecto info ECTO:2000129` returns
    no label, and the ECTO term cache contains no vaccination, BCG or Mycobacterium exposure
    class. OLS does return ECTO:2000129 "exposure to vaccination", so the term exists
    upstream and the local build lags; binding it now would fail `just validate-terms`. An
    over-broad binding to a generic chemical or infectious-agent exposure would assert the
    wrong thing about a live attenuated vaccine, so no term is better than a bad one here.
    Another entry in this KB records the same search with the same outcome.
  influences_mechanisms:
  - target: Uncontrolled Intramacrophage Replication of Weakly Virulent Mycobacteria and Salmonella
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Live BCG supplies the organism that the failed IFN-gamma axis cannot contain, which is
      what converts the latent genetic defect into disease.
    evidence:
    - reference: PMID:21057261
      reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65)
      explanation: >-
        Establishes BCG as the dominant organism of first infection, which is the exposure
        acting on this mechanism.
  evidence:
  - reference: PMID:21057261
    reference_title: "Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We determined the impact of BCG vaccination and BCG disease on the clinical phenotype
      of 129 patients.
    explanation: >-
      Documents that vaccination status was treated as a determinant of phenotype in the
      reference cohort, which is what makes it an environmental factor rather than an
      incidental exposure.
animal_models:
- name: Il12rb1-deficient mouse
  species: Mouse
  genotype: Il12rb1 knockout
  publication: PMID:35891311
  description: >
    The knockout reproduces increased BCG susceptibility, with significantly raised CFU
    counts in spleen and lung. Its interest here is not that it recapitulates the disease
    but that it was built to attack the entry's hardest open question - why penetrance is
    incomplete - by asking what protective immunity survives the lesion.

    The answer complicates the IFN-gamma story. Innate TNF-alpha and IFN-gamma responses
    fell and PPD-specific IFN-gamma release was impaired, as expected; but TNF-alpha release
    was preserved, antibody responses were enhanced, IL-17 responses rose, and both innate
    and PPD-specific IFN-gamma responses correlated *positively* with bacterial burden. The
    authors' own reading is that IFN-gamma alone may not be able to contain BCGitis in this
    setting.
  modeled_mechanisms:
  - target: Failed IFN-gamma-Dependent Macrophage Activation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reproduces the impaired IFN-gamma response and the resulting failure to control BCG,
      while showing that other arms of antimycobacterial immunity remain intact.
    limitations: >-
      The mouse study measures correlation between response magnitude and bacterial burden,
      not the direction of causation, and a positive correlation between IFN-gamma and CFU
      is as consistent with IFN-gamma rising in response to burden as with IFN-gamma failing
      to control it. Human patients also differ from the model in the one respect the model
      is invoked to explain: mouse penetrance is engineered and uniform, while the human
      incompleteness is what needs explaining.
    divergences:
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        Inbred knockout mice under controlled BCG challenge, against outbred patients with
        variable exposure history. The human phenomenon the model is cited to explain -
        that some genotype-positive siblings never fall ill - has no counterpart in a
        uniformly challenged isogenic cohort.
    evidence:
    - reference: PMID:35891311
      reference_title: "Immune Correlates of Disseminated BCG Infection in IL12RB1-Deficient Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our results manifested that Il12rb1-/- mice had significantly increased CFU counts in
        spleens and lungs, especially when BCG (Danish strain) was inoculated subcutaneously.
      explanation: >-
        Establishes that the model reproduces the failure of BCG control that this node
        describes.
  evidence:
  - reference: PMID:35891311
    reference_title: "Immune Correlates of Disseminated BCG Infection in IL12RB1-Deficient Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the low clinical penetrance of IL12RB1 deficiency and low recurrence rate of
      mycobacteria infection suggest that protective immunity still exists in this population
    explanation: >-
      States the question the model was built to answer, which is why it is informative for
      this entry beyond simple recapitulation.
discussions:
- discussion_id: ifn_gamma_adjunct_outcome_evidence
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does adjunctive recombinant IFN-gamma change clinical outcome in complete IL-12Rbeta1
    deficiency, or is its use inferred from the position of the lesion on the pathway?
  attaches_to:
  - treatments#Recombinant Interferon Gamma
  - animal_models#Mouse
  rationale: >-
    The mechanistic case is strong and uncontested - the defect is upstream of IFN-gamma, so
    the cytokine can in principle bypass it - but the largest cohort ever assembled stated
    plainly that it could not evaluate the effect of treatment on outcome because the
    recorded information was too limited. The entry therefore carries a treatment whose
    rationale rests on pathway position rather than on measured benefit, and the two should
    not be conflated. This distinction matters beyond this disease: it is the same argument
    used to withhold IFN-gamma in IFN-gamma receptor defects, where the pathway position is
    reversed.

    The mouse work adds a second reason for caution that is easy to miss, because it points
    the same way as the clinical uncertainty but for a different reason. In Il12rb1-null
    mice both innate and PPD-specific IFN-gamma responses correlated positively with
    bacterial burden, and the authors concluded that IFN-gamma responses alone might not
    contain BCGitis in this setting. That is a correlation in a model, not a refutation -
    and a positive correlation is equally consistent with IFN-gamma rising in response to
    burden. But it means the mechanistic case for the therapy is not as clean as "the lesion
    is upstream, so the cytokine bypasses it".
  evidence:
  - reference: PMID:35891311
    reference_title: "Immune Correlates of Disseminated BCG Infection in IL12RB1-Deficient Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      our results imply that IFN-γ responses alone might not be able to contain BCGitis in
      the setting of IL12RB1 deficiency
    explanation: >-
      Bears on the efficacy question from the model side. Graded INDIRECT because it is an
      implication the authors draw from correlations in mice, not a measurement of the
      therapy in patients, and the hedge is theirs.