Immune Dysregulation IEIs (IUIS Table 4)

name: Immune Dysregulation IEIs
display_name: Immune Dysregulation IEIs (IUIS Table 4)
creation_date: "2026-06-13T00:00:00Z"
description: >-
  IUIS Table 4 — diseases of immune dysregulation. These inborn errors of
  immunity feature uncontrolled lymphocyte activation, impaired immune
  checkpoints, or hyperinflammatory cytokine storms rather than isolated
  humoral or cellular deficiency. Clinical overlap includes
  lymphoproliferation, autoimmunity, hemophagocytic syndromes, and
  endocrinopathy.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped on the shared immune-dysregulation phenotype recognized by IUIS
  Table 4. Members are kept as separate Disease entries because the causal
  gene and dominant pathway differ (cytotoxic granule exocytosis in HLH,
  FAS-mediated apoptosis in ALPS, AIRE-driven tolerance failure in APS-1,
  CTLA4/LRBA checkpoint recycling defects). No MONDO mapping: IUIS Table 4 has no
  equivalent MONDO grouping class (candidates such as lymphoproliferative
  syndrome or ALPS subsume only a subset of members). Criteria are NECESSARY
  and aspirational until IEI mechanism modules and iuis_category backfill are
  complete across the knowledge base.
membership_criteria:
- description: >-
    A disorder belongs to IUIS Table 4 (immune dysregulation) if it is an IEI
    with dominant immune dysregulation — lymphoproliferation, autoimmunity,
    or hyperinflammation — rather than isolated antibody or T-cell deficiency.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_CLASSIFICATION
    classification: "iuis_category:immune dysregulation"
    description: >-
      Assigned to IUIS Table 4 (immune dysregulation) on the member Disease
      entry via classifications.iuis_category. Stated in the keyed
      `<slot>:<value>` form so the audit reads the structured classifications
      block.
members:
- member: Hemophagocytic Lymphohistiocytosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic or X-linked defects in the cytotoxic granule exocytosis
      pathway (PRF1, UNC13D, STX11, STXBP2, RAB27A, LYST, SH2D1A, XIAP)
      impair CTL/NK killing, causing IFN-gamma-driven cytokine storm and
      hemophagocytosis.
    gene:
      preferred_term: PRF1
      term:
        id: hgnc:9360
        label: PRF1
- member: FAS-related Autoimmune Lymphoproliferative Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      FAS (TNFRSF6) pathway defects impair activation-induced lymphocyte
      apoptosis, causing chronic lymphoproliferation, autoimmunity, and
      increased lymphoma risk (canonical ALPS).
    gene:
      preferred_term: FAS
      term:
        id: hgnc:11920
        label: FAS
- member: Autoimmune Polyendocrine Syndrome Type 1
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic AIRE loss impairs thymic negative selection, causing
      multi-organ autoimmunity with chronic mucocutaneous candidiasis and
      endocrine failure (APECED/IPEX-like regulatory failure).
    gene:
      preferred_term: AIRE
      term:
        id: hgnc:360
        label: AIRE
- member: LRBA Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic LRBA loss destabilizes intracellular CTLA-4 recycling,
      combining hypogammaglobulinemia with lymphoproliferation, enteropathy,
      and autoimmunity.
    gene:
      preferred_term: LRBA
      term:
        id: hgnc:1742
        label: LRBA
- member: CTLA4 Haploinsufficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous CTLA4 loss reduces inhibitory checkpoint signaling,
      causing lymphoproliferation, hypogammaglobulinemia, and multi-organ
      autoimmunity (CHAI disease).
    gene:
      preferred_term: CTLA4
      term:
        id: hgnc:2505
        label: CTLA4
- member: CD27-related lymphoproliferative and immune disorder
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic CD27 or CD70 defects impair germinal-center B-cell
      homeostasis and EBV control, causing lymphoproliferation and
      Hodgkin-like lymphoma susceptibility.
    gene:
      preferred_term: CD27
      term:
        id: hgnc:11922
        label: CD27
- member: Autoimmune Lymphoproliferative Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The ALPS concept itself, curated as a thin root over the Fas-pathway
      subtypes (ALPS-FAS, ALPS-sFAS, ALPS-FASLG, ALPS-CASP10, ALPS-U) that the
      2009 NIH revision retained. It is listed alongside, not instead of, the
      gene-specific `FAS-related Autoimmune Lymphoproliferative Syndrome`
      entry: this entry carries the genotype classification axis and the shared
      apoptosis-defect chain, that one carries the FAS-specific
      pathophysiology, diagnostics and management. IUIS likewise enumerates
      FAS, FASLG and CASP10 as separate Table 4 gene entries under one clinical
      syndrome.
    gene:
      preferred_term: FAS
      term:
        id: hgnc:11920
        label: FAS
- member: IPEX Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Loss-of-function FOXP3 variants abolish the master transcription factor
      of CD4+CD25+ regulatory T cells, so dominant peripheral tolerance fails
      outright. Where the checkpoint members (CTLA4, LRBA) attenuate Treg
      function, IPEX removes the Treg compartment itself — the X-linked
      prototype of monogenic autoimmunity, presenting in infant boys with
      autoimmune enteropathy, endocrinopathy and dermatitis.
    gene:
      preferred_term: FOXP3
      term:
        id: hgnc:6106
        label: FOXP3
- member: Chediak-Higashi Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic LYST loss disrupts the biogenesis and fusion of lysosomes and
      lysosome-related organelles, giving pathognomonic giant leukocyte
      granules. It reaches the HLH phenotype shared with the familial
      hemophagocytic members by a different route — organelle biogenesis
      rather than granule exocytosis — and pays for it outside the immune
      system too, with partial oculocutaneous albinism from the same
      LRO defect in melanocytes.
    gene:
      preferred_term: LYST
      term:
        id: hgnc:1968
        label: LYST
notes: >-
  Intentionally unmapped to MONDO: no single MONDO class covers IUIS Table 4.
  Run `uv run python scripts/grouping_mondo_gaps.py --grouping "Inborn"` for
  umbrella IEI descendant coverage and curation gaps.

  Expanded 2026-08-20 with Autoimmune Lymphoproliferative Syndrome, IPEX
  Syndrome and Chediak-Higashi Syndrome, all three of which already carried
  `classifications.iuis_category: immune dysregulation` but were not listed
  here. STAT6 Gain-of-Function Disease was reclassified from Table 4 to Table 2
  in the same pass (the IUIS 2024 update places it there, PMID:41608114) and is
  now listed under Combined Immunodeficiency with Syndromic Features IEIs. It
  was never listed in this file's `members:`, so nothing was removed here — what
  changed is the entry's `iuis_category`, and therefore which sub-grouping's
  criterion it satisfies.
discussions:
- discussion_id: alps_umbrella_and_gene_entry_both_listed
  kind: KNOWLEDGE_GAP
  prompt: >-
    This grouping lists both the ALPS concept and the FAS-specific ALPS entry as
    separate members. Is a grouping the right place to express that
    relationship, or does it double-count one disease?
  rationale: >-
    `Autoimmune Lymphoproliferative Syndrome` is curated as a thin root carrying
    the genotype classification axis over the 2009 NIH Fas-pathway subtypes,
    while `FAS-related Autoimmune Lymphoproliferative Syndrome` carries the
    FAS-specific pathophysiology, diagnostics and management in depth. Both are
    genuine Table 4 entities under IUIS, which itself enumerates FAS, FASLG and
    CASP10 as separate gene entries beneath one clinical syndrome, so listing
    both is defensible. But dismech's Grouping class is documented as a union
    over already-distinct entries, and these two are not distinct in the usual
    sense — one subsumes the other. A consumer counting members of this grouping
    will count ALPS twice, and a consumer following `differentiating_mechanisms`
    will find the FAS gene named on both. The KB has no parent/child member
    relation to express "member A contains member B", so the containment is
    currently only stated in prose. Whether the fix is a new member relation, a
    nested GROUPING member, or dropping one of the two entries is unresolved.
  proposed_experiments:
  - experiment_id: survey_umbrella_plus_subtype_member_pairs
    name: Survey the KB for grouping members that subsume other members
    description: >-
      Across all kb/groupings/, find member pairs where one member's
      `has_subtypes` or MONDO descendants include the other member, and count
      how often the pattern occurs. If ALPS is the only instance it is a local
      curation call; if the pattern recurs, it argues for a first-class
      "subsumes" relation on `members[]` so containment is machine-readable
      rather than restated per grouping.