Intrinsic and Innate Immunity Defect IEIs (IUIS Table 6)

name: Intrinsic and Innate Immunity Defect IEIs
display_name: Intrinsic and Innate Immunity Defect IEIs (IUIS Table 6)
creation_date: "2026-08-20T00:00:00Z"
description: >-
  IUIS Table 6 — defects in intrinsic and innate immunity. These inborn errors
  of immunity leave the adaptive compartment broadly intact and instead break a
  pattern-recognition, cytokine-signalling, or cell-intrinsic antimicrobial
  circuit. The grouping covers Table 6 as a whole, and the table is not uniform
  in what its members share. Sections 1-7 are defined by narrow susceptibility:
  a single pathogen class — Candida, mycobacteria, herpesviruses,
  papillomavirus, invasive pyogenic bacteria — rather than the broad infection
  burden of combined or antibody deficiency. Section 8, "Other Inborn Errors of
  Immunity Related to Non-Hematopoietic Tissues", instead collects cell-intrinsic
  defects confined to a single non-hematopoietic tissue, with no pathogen
  restriction and sometimes no infection phenotype at all. Autosomal recessive
  osteopetrosis 1, where the lesion is in the osteoclast, and heme oxygenase 1
  deficiency, where a macrophage-intrinsic failure of heme catabolism presents
  as haemolysis and systemic inflammation rather than as infection, are the
  KB's section 8 members.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped on IUIS Table 6 membership: a lesion in intrinsic or innate immunity,
  which in sections 1-7 produces pathogen-restricted rather than general
  infection susceptibility. Members are kept as separate Disease entries because
  the broken circuit and the pathogen it admits differ — the IL-17 axis and
  Candida in chronic mucocutaneous candidiasis, type I interferon signalling and
  severe viral disease in STAT2 deficiency. The grouping is the natural home for
  the KB's Mendelian susceptibility entries, and it is what makes "narrow
  susceptibility" queryable as a class rather than restated per entry. The
  membership criterion is Table 6 assignment itself rather than narrow
  susceptibility, which is what admits the section 8 members: IUIS places those
  in this table on the strength of a cell-intrinsic defect in a
  non-hematopoietic tissue, not on a pathogen-restricted infection pattern. A
  member is therefore not required to show narrow susceptibility, and its own
  differentiating_mechanisms should say which of the two readings it satisfies.
  No MONDO mapping: MONDO has no
  grouping class corresponding to IUIS Table 6, and the nearest candidates
  (e.g. immunodeficiency by pathogen) subsume only individual subtables.
membership_criteria:
- description: >-
    A disorder belongs to IUIS Table 6 if it is an inborn error of immunity
    whose primary lesion is in intrinsic or innate immunity — pattern
    recognition, innate cytokine signalling, a cell-intrinsic antimicrobial
    program, or (section 8) another cell-intrinsic defect confined to a
    non-hematopoietic tissue. In sections 1-7 this typically produces
    susceptibility restricted to one pathogen class; section 8 members need not
    show any pathogen restriction.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_CLASSIFICATION
    classification: "iuis_category:innate immunity defect"
    description: >-
      Assigned to IUIS Table 6 (defects in intrinsic and innate immunity) via
      classifications.iuis_category on the member Disease entry. Stated in the
      keyed `<slot>:<value>` form so the audit reads the structured
      classifications block.
members:
- member: Chronic Mucocutaneous Candidiasis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Not one gene's disease but a convergent phenotype: every established
      etiology lies somewhere on the IL-17 circuit — the cytokine (IL17F), its
      receptor chains (IL17RA, IL17RC), the receptor-proximal adaptor
      (ACT1/TRAF3IP2), the Th17 master transcription factor (RORC), or STAT1
      gain of function repressing Th17 development. The clearest demonstration
      of the Table 6 logic that one circuit guards one pathogen class, here
      Candida at skin and mucosa.
    gene:
      preferred_term: STAT1
      term:
        id: hgnc:11362
        label: STAT1
- member: STAT2 Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic loss of STAT2, a required subunit of the ISGF3 transcription
      factor (STAT1-STAT2-IRF9) downstream of the type I (and type III)
      interferon receptors. ISGF3-dependent induction of antiviral
      interferon-stimulated genes collapses, producing severe viral illness
      including disseminated disease after live attenuated viral vaccines
      (vaccine-strain measles) - IUIS Table 6 section 3 (predisposition to
      severe viral infection).
    gene:
      preferred_term: STAT2
      term:
        id: hgnc:11363
        label: STAT2
- member: Immunodeficiency 65 (IRF9 Deficiency)
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic loss of IRF9, the DNA-binding subunit of the same ISGF3
      complex. The sibling lesion to STAT2 deficiency, distinguished by its
      subunit and its founding phenotype (life-threatening influenza A
      pneumonitis), with a hyperinflammatory second arm from prolonged,
      USP18-unrestrained signalling through the type I interferon receptor -
      IUIS Table 6 section 3.
    gene:
      preferred_term: IRF9
      term:
        id: hgnc:6131
        label: IRF9
- member: CD16 Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Reported as a homozygous FCGR3A L66H substitution producing a dissociated
      NK cell functional defect: spontaneous (antibody-independent) cytotoxicity
      fails while antibody-dependent cellular cytotoxicity is retained, with
      severe herpesvirus (VZV, EBV) and papillomavirus disease. Unlike the ISGF3
      members it breaks an innate effector cell's killing program, not an
      interferon signalling circuit - IUIS Table 6 section 3. The member entry
      records the gene-disease relationship as DISPUTED and L66H as of uncertain
      significance, because the allele sits at roughly 5% frequency with about a
      hundred homozygotes in gnomAD; listing the entry records the nosology's
      assignment, not a resolution of that question.
    gene:
      preferred_term: FCGR3A
      term:
        id: hgnc:3619
        label: FCGR3A
- member: Immunodeficiency 101 (Varicella Zoster Virus-Specific)
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous partial-loss-of-function POLR3F missense variants impair
      RNA polymerase III sensing of AT-rich viral DNA, and because the VZV
      genome is distinctively AT-rich the susceptibility is restricted to a
      single virus - the narrowest
      pathogen restriction in the grouping, and the POLR3F arm of the IUIS
      three-gene RNA polymerase III deficiency row (Table 6 section 3).
    gene:
      preferred_term: POLR3F
      term:
        id: hgnc:15763
        label: POLR3F
- member: Heme Oxygenase 1 Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic loss of heme oxygenase 1 disables the macrophage-intrinsic
      heme catabolism and iron recycling program, so heme-dependent damage
      drives haemolysis, nephritis and systemic inflammation. The grouping's
      exemplar of IUIS Table 6 section 8 (other inborn errors of immunity
      related to non-hematopoietic tissues): an innate housekeeping lesion
      presenting as inflammation rather than as narrow infection
      susceptibility.
    gene:
      preferred_term: HMOX1
      term:
        id: hgnc:5013
        label: HMOX1
- member: Immunodeficiency 88
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic loss of function of TBX21 removes T-bet, the transcription
      factor that specifies type 1 immunity. Where the other members lose a
      cytokine circuit or an effector lineage through a general cellular
      defect, this one loses the transcriptional instruction that builds the
      IFN-gamma-producing compartment: NK, iNKT, MAIT and Vdelta2+ gamma-delta
      T lymphocytes fail to develop. The purely adaptive CD8+ and CD4+ TH1-star
      cells that remain make IFN-gamma normally and do not compensate, which is
      the entry's demonstration that these innate and innate-like compartments
      are non-redundant for anti-mycobacterial immunity in humans.
    gene:
      preferred_term: TBX21
      term:
        id: hgnc:11599
        label: TBX21
- member: Autosomal Recessive Osteopetrosis 1
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic loss of function of TCIRG1, encoding the osteoclast-specific
      a3 subunit of the vacuolar H+-ATPase, leaves osteoclasts unable to
      acidify the resorption lacuna. Where the other members lose a cytokine
      circuit or a lymphocyte lineage, this one loses an osteoclast-intrinsic
      effector function with no lymphocyte or cytokine-signalling defect at
      all — the narrowest possible reading of "intrinsic" in this table's
      name, restricted to a single non-hematopoietic tissue (bone) rather than
      a pathogen class.
    gene:
      preferred_term: TCIRG1
      term:
        id: hgnc:11647
        label: TCIRG1
notes: >-
  Created 2026-08-20 to give the IUIS Table 6 disorders a place in the Inborn
  Errors of Immunity tree; the founding members already carried
  `classifications.iuis_category: innate immunity defect` but were unreachable
  from the umbrella grouping. Immunodeficiency 88 (TBX21 / T-bet deficiency)
  was added 2026-09-01 alongside its own curation; it carries the same
  `iuis_category` and is the MSMD etiology this grouping's own notes describe
  it as the natural home for. Immunodeficiency 80 (MCM10) was removed
  2026-08-29 when its classification was corrected to `combined
  immunodeficiency with syndromic features`: MCM10's only row in the IUIS 2022
  tables is Table 2 section 2 (DNA repair defects), so the entry belongs to the
  syndromic-CID grouping, whose member list carries it. That correction has
  landed, so IMD80 no longer satisfies this grouping's NECESSARY classification
  criterion and is not a qualifying-but-unlisted entry.

  Autosomal Recessive Osteopetrosis 1 (TCIRG1) was added 2026-09-17: all seven
  IUIS Table 6 osteopetrosis rows (CLCN7, SNX10, OSTM1, PLEKHM1, TCIRG1,
  TNFRSF11A, TNFSF11) are autosomal recessive, and the umbrella `Osteopetrosis`
  entry was deliberately left unclassified because it lumps autosomal dominant
  ADO2/Albers-Schönberg, which IUIS does not list — see the
  `iuis_category_backfill_candidates` discussion on the umbrella grouping for
  that non-assignment.

  The 2026-09 IUIS campaign sync added five further backfilled Table 6 entries
  as members: STAT2 Deficiency, Immunodeficiency 65, CD16 Deficiency,
  Immunodeficiency 101 and Heme Oxygenase 1 Deficiency. STAT2 Deficiency was
  recorded here until that sync as a strong candidate that could not be listed
  for want of an `iuis_category` assignment; supplying that assignment is what
  made it listable, and the same is true of the other four.

  Seven entries satisfy the membership criterion and are still not listed:
  Immunodeficiency 69 (IFNG), Immunodeficiency 28, Immunodeficiency 127, IRF1
  Deficiency, MSMD due to complete IL12B deficiency, MSMD due to complete
  IL12RB1 deficiency, and combined immunodeficiency due to GINS1 deficiency.
  The list was re-derived against the tree this change sits on rather than
  carried forward: it stood at five when this branch was first written, and two
  further entries have been classified since. They are named here rather
  than left as a count because `check-groupings` validates listed members only
  and structurally cannot surface a qualifying-but-unlisted entry, so the only
  record of them is prose somebody wrote down. See the
  `iuis_category_backfill_candidates` discussion on the umbrella Inborn Errors
  of Immunity grouping, which tracks this across all tables.