IL-17 Immunity Defects

name: IL17 Immunity Defects
display_name: IL-17 Immunity Defects
creation_date: "2026-08-04T00:00:00Z"
description: >-
  Disorders in which loss of IL-17A/F-mediated mucosal barrier immunity is the
  route to chronic mucocutaneous candidiasis (CMC): a germline defect
  anywhere in the cytokine-receptor-adaptor-transcription-factor circuit that
  produces IL-17A/F responses, or an acquired phenocopy of that circuit via
  neutralizing anti-IL-17 autoantibodies.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PATHWAY
grouping_rationale: >-
  Grouped on convergent failure of IL-17A/F-dependent mucosal antifungal
  immunity, the mechanism `kb/disorders/Chronic_Mucocutaneous_Candidiasis.yaml`
  curates across its has_subtypes entries. Members are kept as separate
  Disease entries — as `CLAUDE.md`'s Disease Groupings section prescribes for
  a curated union over already-distinct entries — because each has its own
  MONDO identity, causal gene(s), and (for APS-1 and AD-HIES) a much broader
  non-CMC phenotype that is fully curated on its own entry and deliberately
  not duplicated here. Direction matters: this grouping is specifically about
  LOSS of IL-17A/F signal (or its acquired autoantibody-mediated phenocopy),
  the converse of the much larger set of disorders (psoriasis, spondyloarthritis,
  Crohn disease, etc.) driven by IL-17 EXCESS, which are out of scope.
  Membership is deliberately narrow today: only entities with their own
  `Disease` entry can be listed (see `notes`); several genuine IL-17-circuit
  lesions curated as `has_subtypes` on the CMC entry (IL17RA, IL17RC, IL17F,
  ACT1/TRAF3IP2, STAT1 GOF, RORC, CARD9 deficiency) have no standalone entry
  yet and are represented only through the parent CMC entry via this
  grouping's CMC member.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0015279
      label: chronic mucocutaneous candidiasis
    mapping_predicate: skos:relatedMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO has no single class for "IL-17 immunity defect" as a mechanism
      family; MONDO:0015279 (CMC) is the closest existing class and is one
      member's disease_term, not the grouping concept itself. relatedMatch
      rather than exactMatch/broadMatch because the grouping also includes
      AD-HIES and APS-1, which are not CMC in MONDO (CMC is one component of
      each, not their primary classification).
    consistency:
    - reference: MONDO
      consistent: UNKNOWN
      notes: >-
        Only the CMC member is a MONDO CMC entity; APS-1 (MONDO:0009411) and
        AD-HIES (MONDO:0007818) are separate MONDO branches (autoimmune
        polyendocrinopathy and hyper-IgE syndrome respectively) that
        secondarily produce the same IL-17-loss phenotype. This is expected
        for a mechanism-defined grouping and is recorded rather than treated
        as an error.
membership_criteria:
- description: >-
    A disorder belongs to this grouping if its Disease entry curates a
    germline or acquired lesion that abolishes or substantially impairs
    IL-17A/F-mediated mucosal antifungal signaling (cytokine, receptor,
    adaptor, transcription factor, or a neutralizing autoantibody phenocopy
    of that circuit), with chronic mucocutaneous candidiasis as a resulting
    phenotype. Excludes the much larger set of disorders driven by IL-17
    EXCESS (e.g. psoriasis, spondyloarthritis) and excludes broader combined
    immunodeficiencies (e.g. DOCK8 deficiency) in which reduced Th17 numbers
    are a secondary feature of a much wider T-cell defect rather than the
    organizing lesion.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: OTHER
    description: >-
      Germline or acquired loss of IL-17A/F circuit signaling (cytokine,
      receptor, adaptor, transcription factor, or neutralizing autoantibody),
      curated as a mechanism on the member's own Disease entry (or, for CMC,
      on one of its has_subtypes), with CMC as a resulting phenotype.
members:
- member: Chronic Mucocutaneous Candidiasis
  member_type: DISEASE
  disease_term:
    preferred_term: chronic mucocutaneous candidiasis
    term:
      id: MONDO:0015279
      label: chronic mucocutaneous candidiasis
  differentiating_mechanisms:
  - description: >-
      The core entity: curates the full spread of germline IL-17-circuit
      lesions (STAT1 GOF, IL17RA/IL17RC/ACT1 receptor-adaptor loss, IL17F
      dominant-negative, RORC transcription-factor loss) plus the acquired
      anti-IL-17 autoantibody route (APECED/APS-1) as `has_subtypes`, and
      CARD9 deficiency (a broader myeloid antifungal defect that also
      depresses Th17 numbers) as a dual subtype/differential.
- member: Autoimmune Polyendocrine Syndrome Type 1
  member_type: DISEASE
  disease_term:
    preferred_term: autoimmune polyendocrine syndrome type 1
    term:
      id: MONDO:0009411
      label: autoimmune polyendocrine syndrome type 1
  differentiating_mechanisms:
  - description: >-
      AIRE-deficiency-driven loss of central thymic tolerance produces
      high-titre neutralizing autoantibodies against IL-17A, IL-17F and
      IL-22 — an acquired phenocopy of the genetic IL-17-circuit lesions,
      typically preceding the syndrome's defining endocrine autoimmunity
      (hypoparathyroidism, adrenal insufficiency) by years. Only the CMC/
      anti-IL-17-autoantibody arm is in scope for this grouping; the full
      polyendocrine phenotype is curated on this member's own entry.
    gene:
      preferred_term: AIRE
      term:
        id: hgnc:360
        label: AIRE
- member: Autosomal Dominant Hyper-IgE Syndrome
  member_type: DISEASE
  disease_term:
    preferred_term: Autosomal Dominant Hyper-IgE Syndrome
    term:
      id: MONDO:0007818
      label: hyper-IgE recurrent infection syndrome 1, autosomal dominant
  differentiating_mechanisms:
  - description: >-
      Dominant-negative STAT3 variants block naive T-cell differentiation
      into Th17 cells, abolishing IL-17 production and producing CMC as one
      component of a much wider syndrome (staphylococcal abscesses,
      pneumatoceles, eczema, elevated IgE, connective-tissue and skeletal
      abnormalities) curated in full on this member's own entry.
    gene:
      preferred_term: STAT3
      term:
        id: hgnc:11364
        label: STAT3
notes: >-
  Follow-up from #7644 (itself raised from the automated reviewer's #7643
  notes on `kb/disorders/Chronic_Mucocutaneous_Candidiasis.yaml`), which found
  that entry's `has_subtypes` list asserting a MONDO subsumption the ontology
  does not support for several members. This grouping is the sanctioned
  `kb/groupings/` union over the already-distinct Disease entries per
  `CLAUDE.md`'s Disease Groupings section. Scope decisions, per the issue's
  own review comment:

  (1) Membership is currently 3 entries because `GroupingMember.member` must
  resolve to a real `Disease.name`/module/grouping — IL17RA, IL17RC, IL17F,
  ACT1/TRAF3IP2, STAT1 GOF, RORC and CARD9 deficiency have no standalone
  dismech entry (they are curated only as `has_subtypes` on the CMC entry),
  so they cannot be listed as members yet. `GroupingMember` has no
  subtype-reference slot (`member_type: SUBTYPE` still names the parent
  Disease, per `tests/test_data.py`'s FK-test comments) — adding one is a
  small schema change worth its own issue if this grouping's coverage needs
  to reach subtype granularity.

  (2) No `SUFFICIENT` block is included deliberately. ~64 dismech entries
  mention IL-17/Th17 (psoriasis, spondyloarthritis, Crohn, MS, RA,
  sarcoidosis...), overwhelmingly via IL-17 EXCESS, the mechanistic inverse
  of this grouping. A bare `HAS_BIOLOGICAL_PROCESS` leaf on a GO IL-17 term
  cannot express that direction and would surface most of that corpus as
  false candidate members; the `NECESSARY` criterion instead uses a
  description-only `OTHER` predicate the way the parent
  `Inborn_Errors_of_Immunity` grouping does, deferring structured
  loss-of-function criteria to (3).

  (3) A dedicated `il17_mucosal_barrier_immunity` mechanism module (per the
  CMC entry's own notes) would let members `conforms_to` a directional
  "Impaired IL-17-Mediated Mucosal Antifungal Defence" node and swap this
  criterion to `CONFORMS_TO_MODULE`, which is directional for free. Deferred
  as a follow-up rather than attempted in this same PR.

  (4) DOCK8 deficiency is deliberately excluded: reduced Th17 numbers there
  are one feature of a much broader combined immunodeficiency (severe viral
  infection, atopy, eosinophilia, malignancy), not the organizing lesion —
  see the CMC entry's own differential-diagnosis framing.

  (5) Nesting: not yet added as a member of `Inborn_Errors_of_Immunity`. Its
  four existing sub-groupings are IUIS Table 1-4; this grouping is closer to
  IUIS Table 6 (innate/intrinsic immunity defects), which has no dismech
  grouping yet. Left for a follow-up rather than nested ad hoc, per the
  issue's own suggested execution order.