name: MHC class II deficiency
creation_date: "2026-05-06T00:47:16Z"
category: Mendelian
synonyms:
- Bare lymphocyte syndrome type 2
- HLA class II-negative SCID
- HLA class 2-negative severe combined immunodeficiency
- MHC class II expression deficiency
description: >-
  MHC class II deficiency, also called bare lymphocyte syndrome type 2, is an
  autosomal recessive combined immunodeficiency caused by biallelic defects in
  genes that regulate HLA class II transcription. Pathogenic variants in CIITA,
  RFXANK, RFX5, or RFXAP prevent normal MHC class II expression on
  antigen-presenting cells and thymic epithelium, impairing MHC-II antigen
  presentation, CD4-positive T-cell development and helper function, and
  T-cell-dependent antibody production. Affected infants present with severe
  recurrent respiratory and gastrointestinal infections, protracted diarrhea,
  failure to thrive, low or dysfunctional CD4-positive T cells,
  hypogammaglobulinemia, and sometimes autoimmunity or hepatobiliary disease.
disease_term:
  preferred_term: MHC class II deficiency
  term:
    id: MONDO:0008855
    label: MHC class II deficiency
parents:
- familial severe combined immunodeficiency
- combined immunodeficiency
- primary immunodeficiency
classifications:
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      IUIS 2022 classification (Tangye et al., PMID:35748970), Table 1
      (immunodeficiencies affecting cellular and humoral immunity): listed as
      "MHC class II deficiency group A, B, C, D" with the four causal genes
      CIITA, RFXANK, RFX5, and RFXAP. The quoted row comes from the
      classification tables in the cached full text rather than from the
      abstract.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "MHC class II deficiency group A, B, C, D"
      explanation: >-
        Table 1 disease-row text naming MHC class II deficiency (complementation
        groups A-D) among the immunodeficiencies affecting cellular and humoral
        immunity.
    - reference: ORPHA:572
      reference_title: "Immunodeficiency by defective expression of MHC class II"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "severely impaired cellular and humoral immune response to foreign antigens, severe CD4+ T-cell lymphopenia, and hypogammaglobulinemia"
      explanation: >-
        Orphanet's definition characterizes the disorder as impairing both
        cellular and humoral immunity, matching the scope of IUIS Table 1.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008855
      label: MHC class II deficiency
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:572
    mapping_justification: >-
      Orphanet ORPHA:572 lists MONDO:0008855 as an exact cross-reference for
      immunodeficiency by defective expression of MHC class II.
external_assertions:
- name: Orphanet MHC class II deficiency record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:572
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=572
  description: >-
    Orphanet's ORPHA:572 structured record provides the exact MONDO and OMIM
    mappings, inheritance, epidemiology, disease-gene assertions, and HPO
    phenotype frequency rows used in this curation.
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0008855 | Exact"
    explanation: Orphanet maps ORPHA:572 exactly to the MONDO identifier used here.
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:209920 | Exact"
    explanation: Orphanet maps ORPHA:572 exactly to the OMIM record for this disorder.
definitions:
- name: Orphanet MHC class II deficiency definition
  definition_type: OTHER
  description: >-
    A rare autosomal recessive primary immunodeficiency with absent HLA class II
    expression on immune cells, impaired cellular and humoral immunity, CD4
    T-cell lymphopenia, hypogammaglobulinemia, severe recurrent infections,
    diarrhea with failure to thrive, autoimmunity, and frequent childhood
    lethality.
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare autosomal recessive primary immunodeficiency characterized by absence of HLA class II molecules on the surface of immune cells, leading to severely impaired cellular and humoral immune response to foreign antigens, severe CD4+ T-cell lymphopenia, and hypogammaglobulinemia."
    explanation: Orphanet defines the molecular and immunologic core of MHC class II deficiency.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    MHC class II deficiency is inherited as an autosomal recessive disorder due
    to biallelic loss of MHC-II regulatory factors.
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance.
  - reference: PMID:11258423
    reference_title: Molecular genetics of the Bare lymphocyte syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hereditary defects leading to the absence of MHC-II expression result in a severe autosomal recessive immunodeficiency disease called the Bare Lymphocyte Syndrome (BLS), also referred to as MHC-II deficiency."
    explanation: This molecular genetics review directly describes MHC class II deficiency as autosomal recessive.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_high: 0.1
  notes: >-
    Orphanet records worldwide point prevalence below 1 per 1,000,000, i.e.
    below 0.1 per 100,000. The deprecated free-text `percentage` field carrying
    the same "<1 per 1,000,000" string was removed; the structured
    prevalence_class and rate_high now carry it.
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
    explanation: Orphanet records worldwide point prevalence for this ultra-rare disorder.
- population: Worldwide reported cases in the literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Over 150 patients reported worldwide as of 2018, about two-thirds of North
    African descent (Algeria, Morocco, Tunisia). The disorder is concentrated in
    the Mediterranean region and in populations with high consanguinity, so the
    case series are geographically clustered and the worldwide point-prevalence
    band above should not be read as a uniform rate.
  evidence:
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Major histocompatibility complex (MHC) class II deficiency is a rare form of primary
      immunodeficiency disorder (PID) that follows an autosomal recessive pattern of inheritance.
      Worldwide, over 150 patients have been reported with this deficiency (1). About two-third of
      these patients have a North African descent (Algeria, Morocco, and Tunisia) (1) and belong to
      complementation group B. ... Major histocompatibility complex class II deficiency is reported
      majorly in the Mediterranean region and is prevalent in areas with high consanguinity.
    explanation: >-
      The review describes over 150 reported MHC class II deficiency patients worldwide, many of
      North African descent, and concentration in regions with high consanguinity. These are
      literature observations, not a population rate.
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Major histocompatibility complex class II deficiency is reported majorly in the Mediterranean region and is prevalent in areas with high consanguinity."
    explanation: Supports the geographic and consanguinity clustering noted here.
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| - | Worldwide | Cases/families | PMID:27510876 |"
    explanation: Orphanet records this disorder's worldwide epidemiology on a cases/families basis rather than as a measured rate.
progression:
- phase: Neonatal or infantile onset
  age_range: Neonatal to infancy
  notes: >-
    Clinical onset is usually in infancy, with severe infections and chronic
    diarrhea emerging in the first year of life.
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Infancy"
    explanation: Orphanet records infantile onset.
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Neonatal"
    explanation: Orphanet also records neonatal onset.
  - reference: PMID:8229525
    reference_title: "Major histocompatibility complex class II deficiency: clinical manifestations, immunologic features, and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical onset occurred in the first year of life, usually involving recurrent bronchopulmonary infections and chronic diarrhea."
    explanation: The 30-patient clinical series supports infantile onset with respiratory and gastrointestinal presentations.
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median age of diagnosis was 5.5 months (range, 3–7 months)."
    explanation: Gives a median age at diagnosis within the first year in a contemporary series.
- phase: Later diagnosis in milder presentations
  age_range: Up to 15 years
  notes: >-
    The disorder is not uniformly infantile. A minority present mildly enough to
    be diagnosed well into childhood or adolescence, which is one reason the
    diagnosis is missed when HLA-DR expression is not specifically checked.
  evidence:
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there are some reports with a milder clinical presentation and diagnosis later up to 15 years of age"
    explanation: Documents the milder, later-diagnosed end of the presentation spectrum.
- phase: Progressive infectious and hepatobiliary complications
  age_range: Childhood
  notes: >-
    The clinical course accumulates viral meningoencephalitis, hepatitis,
    cholangitis, and autoimmune phenomena on top of the recurrent respiratory
    and gastrointestinal infection burden.
  evidence:
  - reference: PMID:8229525
    reference_title: "Major histocompatibility complex class II deficiency: clinical manifestations, immunologic features, and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical course was complicated by viral meningoencephalitis, hepatitis, cholangitis, and various autoimmune phenomena."
    explanation: Enumerates the complications that define the intermediate course in the 30-patient series.
- phase: Death in childhood without transplantation
  age_range: Mean age at death 4 years
  notes: >-
    In the pre-modern-transplant natural history the mean age at death was 4
    years, with overwhelming viral infection the leading cause. Contemporary
    transplant results are far better (94% overall survival after 2008), so this
    phase describes the untransplanted course rather than the current
    expectation for a transplanted child.
  evidence:
  - reference: PMID:8229525
    reference_title: "Major histocompatibility complex class II deficiency: clinical manifestations, immunologic features, and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prognosis was very poor: the mean age at the time of death was 4 years. The main cause of death was overwhelming viral infection."
    explanation: Gives the untreated natural-history mortality and its leading cause.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Untransplanted MHC class II deficiency killed patients at a mean age of four
    years, usually from overwhelming viral infection, on a background of
    recurrent respiratory and gastrointestinal infection, protracted diarrhoea,
    failure to thrive, and hepatobiliary disease. Transplantation is the only
    cure and was itself historically poor (33% survival before 2008), though
    contemporary strategies reach 94%. Burden is therefore high but sharply
    era- and access-dependent, and survivors still carry a residual CD4 deficit
    from the non-haematopoietic thymic epithelial component of the disease.
  evidence:
  - reference: PMID:8229525
    reference_title: "Major histocompatibility complex class II deficiency: clinical manifestations, immunologic features, and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prognosis was very poor: the mean age at the time of death was 4 years. The main cause of death was overwhelming viral infection."
    explanation: Quantifies the untransplanted mortality underpinning the high burden assessment.
  - reference: PMID:31932845
    reference_title: Improved transplant survival and long-term disease outcome in children with MHC class II deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With a 2.9-year median follow-up, OS improved from 33% (46-68%) for HCT before 2008 (n = 6) to 94% (66-99%) for HCT after 2008"
    explanation: Supports the era dependence of the burden — the same disease, transplanted, now has very different survival.
has_subtypes:
- name: MHC class II deficiency 1
  display_name: MHC class II deficiency 1 (CIITA-related)
  subtype_term:
    preferred_term: MHC class II deficiency 1
    term:
      id: MONDO:0971005
      label: MHC class II deficiency 1
  genes:
  - preferred_term: CIITA
    term:
      id: hgnc:7067
      label: CIITA
  description: >-
    CIITA-related MHC class II deficiency caused by loss of the class II
    transactivator needed for MHC-II gene expression.
  evidence:
  - reference: PMID:8402893
    reference_title: Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This gene (CIITA) functions as a transactivator of MHC class II gene expression and restores expression of all MHC class II isotypes in mutant cells."
    explanation: Complementation cloning identifies CIITA as the transactivator defective in one genetic form of MHC class II deficiency.
- name: MHC class II deficiency 2
  display_name: MHC class II deficiency 2 (RFXANK-related)
  subtype_term:
    preferred_term: MHC class II deficiency 2
    term:
      id: MONDO:0971013
      label: MHC class II deficiency 2
  genes:
  - preferred_term: RFXANK
    term:
      id: hgnc:9987
      label: RFXANK
  description: >-
    RFXANK-related MHC class II deficiency caused by disruption of one subunit of
    the RFX DNA-binding complex.
  evidence:
  - reference: PMID:11258423
    reference_title: Molecular genetics of the Bare lymphocyte syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mutations in four different MHC-II regulatory genes are known to lead to BLS. These genes encode CIITA, RFXANK, RFX5 and RFXAP."
    explanation: This review identifies RFXANK as one of the four disease-causing MHC-II regulatory genes.
- name: MHC class II deficiency 3
  display_name: MHC class II deficiency 3 (RFX5-related)
  subtype_term:
    preferred_term: MHC class II deficiency 3
    term:
      id: MONDO:0971014
      label: MHC class II deficiency 3
  genes:
  - preferred_term: RFX5
    term:
      id: hgnc:9986
      label: RFX5
  description: >-
    RFX5-related MHC class II deficiency caused by disruption of one subunit of
    the RFX DNA-binding complex.
  evidence:
  - reference: PMID:11258423
    reference_title: Molecular genetics of the Bare lymphocyte syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mutations in four different MHC-II regulatory genes are known to lead to BLS. These genes encode CIITA, RFXANK, RFX5 and RFXAP."
    explanation: This review identifies RFX5 as one of the four disease-causing MHC-II regulatory genes.
- name: MHC class II deficiency 4
  display_name: MHC class II deficiency 4 (RFXAP-related)
  subtype_term:
    preferred_term: MHC class II deficiency 4
    term:
      id: MONDO:0971015
      label: MHC class II deficiency 4
  genes:
  - preferred_term: RFXAP
    term:
      id: hgnc:9988
      label: RFXAP
  description: >-
    RFXAP-related MHC class II deficiency, corresponding to complementation
    group D.
  evidence:
  - reference: PMID:9287230
    reference_title: "Mutation of RFXAP, a regulator of MHC class II genes, in primary MHC class II deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mutations in the RFXAP gene were found in three patients from unrelated families, and the resulting defect was classified as belonging to a novel complementation group (D)."
    explanation: This patient-cell complementation study identifies RFXAP as the group D MHC class II deficiency gene.
genetic:
- name: CIITA
  association: Causative
  gene_term:
    preferred_term: CIITA
    term:
      id: hgnc:7067
      label: CIITA
  features: >-
    CIITA encodes the class II transactivator, the master coactivator required
    for inducible and cell-type-specific MHC-II expression.
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CIITA | class II major histocompatibility complex transactivator | hgnc:7067 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists CIITA as a disease-causing gene.
  - reference: PMID:8402893
    reference_title: Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Hence, the CIITA gene is essential for MHC class II gene expression and has been shown to be responsible for hereditary MHC class II deficiency."
    explanation: Complementation cloning directly establishes CIITA as a causal gene.
  - reference: CGGV:assertion_0dab225e-0bdd-4f96-a351-4e490601ba15-2022-11-03T170000.000Z
    reference_title: "CIITA / MHC class II deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CIITA | HGNC:7067 | MHC class II deficiency | MONDO:0008855 | AR | Definitive"
    explanation: ClinGen classifies the CIITA-MHC class II deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
- name: RFXANK
  association: Causative
  gene_term:
    preferred_term: RFXANK
    term:
      id: hgnc:9987
      label: RFXANK
  features: >-
    RFXANK encodes an ankyrin-containing subunit of the RFX complex that binds
    conserved MHC-II promoter elements. RFXANK (complementation group B) is by a
    wide margin the most frequently mutated of the four genes, accounting for
    more than two-thirds of reported cases — a figure driven by a North African
    founder effect rather than by any special vulnerability of the gene.
  case_fractions:
  - population: Worldwide reported cases
    case_fraction_percent: 67.0
    case_fraction_low: 67.0
    notes: >-
      Reported as "more than two-thirds of all reported cases", so 67% is a
      lower bound rather than a point estimate. Concentrated in patients of
      North African descent; notably, RFXANK was absent from the five-patient
      Indian series that reports this figure, which found RFXAP, RFX5, and CIITA
      instead.
    evidence:
    - reference: PMID:29527204
      reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "RFXANK gene mutation that accounts for more than two-thirds of all reported cases (1) was not identified in our series."
      explanation: Gives the RFXANK share of reported cases and notes its absence from this non-Mediterranean cohort.
    - reference: PMID:29527204
      reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Worldwide, over 150 patients have been reported with this deficiency (1). About two-third of these patients have a North African descent (Algeria, Morocco, and Tunisia)"
      explanation: >-
        Supplies the ancestry concentration behind the RFXANK share and the
        total reported-case denominator.
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RFXANK | regulatory factor X associated ankyrin containing protein | hgnc:9987 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists RFXANK as a disease-causing gene.
  - reference: PMID:11258423
    reference_title: Molecular genetics of the Bare lymphocyte syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RFXANK, RFX5 and RFXAP are the three subunits of RFX (regulatory factor X), a DNA-binding complex that binds to a conserved cis-acting sequence, the X box, present in the promoters of all MHC-II genes."
    explanation: This review places RFXANK in the promoter-binding RFX complex needed for MHC-II gene expression.
  - reference: CGGV:assertion_fbfd1148-ab31-4ab2-97bb-9b95387e9313-2022-11-17T180000.000Z
    reference_title: "RFXANK / MHC class II deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RFXANK | HGNC:9987 | MHC class II deficiency | MONDO:0008855 | AR | Definitive"
    explanation: ClinGen classifies the RFXANK-MHC class II deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
- name: RFX5
  association: Causative
  gene_term:
    preferred_term: RFX5
    term:
      id: hgnc:9986
      label: RFX5
  features: >-
    RFX5 encodes a DNA-binding subunit of the RFX complex required at MHC-II
    promoters.
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RFX5 | regulatory factor X5 | hgnc:9986 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists RFX5 as a disease-causing gene.
  - reference: PMID:11258423
    reference_title: Molecular genetics of the Bare lymphocyte syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RFXANK, RFX5 and RFXAP are the three subunits of RFX (regulatory factor X), a DNA-binding complex that binds to a conserved cis-acting sequence, the X box, present in the promoters of all MHC-II genes."
    explanation: This review places RFX5 in the promoter-binding RFX complex needed for MHC-II gene expression.
  - reference: CGGV:assertion_430c4041-5e07-45d8-bea5-eaa925a18a72-2023-06-15T170000.000Z
    reference_title: "RFX5 / MHC class II deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RFX5 | HGNC:9986 | MHC class II deficiency | MONDO:0008855 | AR | Definitive"
    explanation: ClinGen classifies the RFX5-MHC class II deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
- name: RFXAP
  association: Causative
  gene_term:
    preferred_term: RFXAP
    term:
      id: hgnc:9988
      label: RFXAP
  features: >-
    RFXAP encodes an RFX-associated subunit required for MHC-II promoter
    regulation; pathogenic variants define complementation group D.
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RFXAP | regulatory factor X associated protein | hgnc:9988 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists RFXAP as a disease-causing gene.
  - reference: PMID:9287230
    reference_title: "Mutation of RFXAP, a regulator of MHC class II genes, in primary MHC class II deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transfection with the wild-type RFXAP gene restored the expression of MHC class II molecules in the patients' cells."
    explanation: Patient-cell complementation directly supports pathogenic RFXAP loss as causal.
  - reference: CGGV:assertion_53b17c5d-ccea-4674-8746-a2bc39ad95f0-2023-06-15T170000.000Z
    reference_title: "RFXAP / MHC class II deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RFXAP | HGNC:9988 | MHC class II deficiency | MONDO:0008855 | AR | Definitive"
    explanation: ClinGen classifies the RFXAP-MHC class II deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
pathophysiology:
- name: MHC-II regulatory gene disruption
  description: >-
    Biallelic defects in CIITA or the RFX complex genes RFXANK, RFX5, and RFXAP
    disrupt the transcription-factor machinery responsible for MHC-II gene
    expression.
  genes:
  - preferred_term: CIITA
    term:
      id: hgnc:7067
      label: CIITA
  - preferred_term: RFXANK
    term:
      id: hgnc:9987
      label: RFXANK
  - preferred_term: RFX5
    term:
      id: hgnc:9986
      label: RFX5
  - preferred_term: RFXAP
    term:
      id: hgnc:9988
      label: RFXAP
  evidence:
  - reference: PMID:11258423
    reference_title: Molecular genetics of the Bare lymphocyte syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The genetic lesions responsible for BLS do not lie within the MHC-II locus itself, but reside instead in genes encoding transcription factors controlling MHC-II expression."
    explanation: This supports regulatory-gene disruption rather than primary HLA locus mutation as the initiating molecular lesion.
  downstream:
  - target: MHC-II transcriptional failure
    description: Disrupted CIITA/RFX machinery prevents normal MHC-II gene transcription.
    causal_link_type: DIRECT
- name: MHC-II transcriptional failure
  description: >-
    Loss of CIITA or RFX-complex function impairs transcriptional activation of
    HLA class II genes in professional antigen-presenting cells and thymic
    epithelium.
  biological_processes:
  - preferred_term: regulation of DNA-templated transcription
    modifier: DECREASED
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
  cell_types:
  - preferred_term: professional antigen-presenting cell
    term:
      id: CL:0000145
      label: professional antigen presenting cell
  - preferred_term: thymic epithelial cell
    term:
      id: CL:0002293
      label: epithelial cell of thymus
  evidence:
  - reference: PMID:11258423
    reference_title: Molecular genetics of the Bare lymphocyte syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CIITA (Class II Transactivator) is a transcriptional coactivator that functions as a master control factor dictating the cell type specificity, induction and level of MHC-II expression."
    explanation: The review identifies CIITA as the master transcriptional coactivator for MHC-II expression.
  downstream:
  - target: MHC-II expression and antigen presentation failure
    description: Failed HLA class II transcription leads to absent or reduced surface MHC-II expression.
    causal_link_type: DIRECT
- name: MHC-II expression and antigen presentation failure
  description: >-
    HLA-DR, -DP, and -DQ expression is absent or severely reduced on B cells,
    monocytes, dendritic cells, and thymic epithelial cells, impairing MHC-II
    antigen presentation.
  biological_processes:
  - preferred_term: antigen processing and presentation of peptide antigen via MHC class II
    modifier: DECREASED
    term:
      id: GO:0002495
      label: antigen processing and presentation of peptide antigen via MHC class II
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: thymic epithelial cell
    term:
      id: CL:0002293
      label: epithelial cell of thymus
  notes: >-
    The name understates the lesion slightly. The original 30-patient series
    described not only profound loss of HLA class II expression but also
    inconsistent and incomplete class I expression, so the surface phenotype is
    not purely class II-restricted. The class II defect is the one that is
    obligate (Orphanet: 100%) and diagnostic, and it is the one that explains
    the CD4 selection failure, which is why the mechanism chain here is built on
    it.
  evidence:
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A defect in the factors that regulate the expression of MHC class II genes resulting in the absence or reduced expression of MHC class II molecules on the immune cells is thought to be the underlying cause of MHC class II deficiency"
    explanation: This clinical series links regulatory-factor defects to absent or reduced MHC-II expression on immune cells.
  - reference: PMID:8229525
    reference_title: "Major histocompatibility complex class II deficiency: clinical manifestations, immunologic features, and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "profound defects in human leukocyte antigen class II expression, inconsistent and incomplete expression of human leukocyte antigen class I molecules, and a complete lack of cellular and humoral immune responses to foreign antigens"
    explanation: >-
      Qualifies the node: class I expression is also inconsistent and
      incomplete, so the surface defect is not strictly limited to class II.
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Humans have three isotypes of HLA-class II molecules: HLA-DR, -DP, and -DQ, which are present on resting B cells, monocytes, dendritic cells, activated T lymphocytes, Langerhans cells, and epithelial cells in the thymus and intestine"
    explanation: >-
      Enumerates the isotypes and the cell types bound on this node, supporting
      the claim that both antigen-presenting cells and thymic epithelium are
      affected.
  downstream:
  - target: CD4 T-cell selection and helper-function impairment
    description: Loss of MHC-II antigen presentation disrupts CD4 T-cell development and helper activity.
    causal_link_type: DIRECT
  - target: Tolerance perturbation and autoimmunity
    description: Absence of MHC-II expression in thymic epithelium perturbs central tolerance.
  - target: Reduced MHC II surface expression
    causal_link_type: DIRECT
  - target: Decreased circulating beta-2-microglobulin level
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: CD4 T-cell selection and helper-function impairment
  description: >-
    MHC-II deficiency impairs thymic CD4-positive T-cell development and
    peripheral helper T-cell activation, reducing cellular immunity and
    T-cell-dependent antibody production.
  biological_processes:
  - preferred_term: CD4-positive, alpha-beta T cell differentiation
    modifier: DECREASED
    term:
      id: GO:0043367
      label: CD4-positive, alpha-beta T cell differentiation
  - preferred_term: T cell activation
    modifier: DECREASED
    term:
      id: GO:0042110
      label: T cell activation
  cell_types:
  - preferred_term: CD4-positive T helper cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  evidence:
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The development and thymic shaping of CD4+ T helper (Th) cells require MHC class II-mediated antigen presentation to the T cell receptor (TCR) of CD4 cells."
    explanation: Human clinical review material directly links MHC-II antigen presentation to CD4 helper T-cell development.
  downstream:
  - target: Combined cellular and humoral immune deficiency
    description: CD4 helper-cell impairment disrupts both cellular and humoral immune responses.
    causal_link_type: DIRECT
  - target: Decreased proportion of CD4-positive T cells
    causal_link_type: DIRECT
- name: Combined cellular and humoral immune deficiency
  description: >-
    Defective CD4 T-cell help causes combined immunodeficiency, with poor
    cellular responses and reduced T-cell-dependent antibody production.
  biological_processes:
  - preferred_term: adaptive immune response
    modifier: DECREASED
    term:
      id: GO:0002250
      label: adaptive immune response
  - preferred_term: immunoglobulin mediated immune response
    modifier: DECREASED
    term:
      id: GO:0016064
      label: immunoglobulin mediated immune response
  cell_types:
  - preferred_term: CD4-positive T helper cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:20493394
    reference_title: Hematopoietic stem cell transplantation and other management strategies for MHC class II deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The defect of MHC class II leads to combined immunodeficiency with defective CD4(+) T-cell development and a lack of T helper cell-dependent antibody production by B cells."
    explanation: This management review summarizes the combined cellular and humoral immunologic defect.
  downstream:
  - target: Lack of T cell function
    description: Defective cellular immunity manifests as impaired T-cell function.
    causal_link_type: DIRECT
  - target: Decreased circulating antibody level
    description: Defective T-cell help reduces antibody production.
    causal_link_type: DIRECT
  - target: Recurrent respiratory infections
    description: Combined immune deficiency predisposes to severe recurrent respiratory infections.
  - target: Recurrent gastrointestinal infections
    description: Combined immune deficiency predisposes to recurrent gastrointestinal infection and diarrhea.
  - target: Sinusitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Recurrent bacterial infections
    causal_link_type: DIRECT
  - target: Recurrent Staphylococcus aureus infections
    causal_link_type: DIRECT
  - target: Chronic mucocutaneous candidiasis
    causal_link_type: DIRECT
  - target: Recurrent fungal infections
    causal_link_type: DIRECT
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Diarrhea
    causal_link_type: DIRECT
  - target: Protracted diarrhea
    causal_link_type: DIRECT
  - target: Recurrent viral infections
    causal_link_type: DIRECT
  - target: Recurrent herpes
    causal_link_type: DIRECT
  - target: Abnormality of humoral immunity
    causal_link_type: DIRECT
  - target: Recurrent protozoan infections
    causal_link_type: DIRECT
  - target: Recurrent candida infections
    causal_link_type: DIRECT
  - target: Rhinitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Sclerosing cholangitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Chronic hepatitis due to cryptosporidium infection
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Tolerance perturbation and autoimmunity
  description: >-
    Absence of MHC-II expression perturbs thymic epithelial cell maturation,
    central tolerance, regulatory T-cell generation or function, and peripheral
    B-cell tolerance, contributing to autoimmunity in a subset of patients.
  biological_processes:
  - preferred_term: positive T cell selection
    modifier: DECREASED
    term:
      id: GO:0043368
      label: positive T cell selection
  cell_types:
  - preferred_term: thymic epithelial cell
    term:
      id: CL:0002293
      label: epithelial cell of thymus
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  evidence:
  - reference: PMID:34211466
    reference_title: Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we demonstrated that impairment of lymphostromal cross-talk in the thymus of MHCII-/- mice affects mTEC maturation and promiscuous gene expression and causes defects of central tolerance."
    explanation: Mouse and patient-based immunology data support thymic epithelial and tolerance defects downstream of MHC-II absence.
  - reference: PMID:34211466
    reference_title: Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, we observed peripheral tolerance impairment, likely due to defective Treg cell generation and/or function and B cell tolerance breakdown."
    explanation: >-
      Supports the peripheral arm of this node — the regulatory T-cell and
      B-cell tolerance components that the node description asserts alongside
      the central-tolerance defect.
  downstream:
  - target: Autoimmunity
    description: Central and peripheral tolerance perturbation contributes to autoimmune manifestations.
    causal_link_type: DIRECT
  - target: Autoimmune hemolytic anemia
    description: Loss of tolerance permits autoantibody-mediated destruction of erythrocytes.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Autoimmune thrombocytopenia
    description: Loss of tolerance permits autoantibody-mediated destruction of platelets.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Decreased total neutrophil count
    description: >-
      Neutropenia in this disorder occurs in the presence of anti-neutrophil
      antibodies, placing it downstream of the tolerance defect rather than of a
      myeloid production block.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Reduced MHC II surface expression
  category: Immunologic
  frequency: OBLIGATE
  description: >-
    Absent or markedly reduced MHC class II surface expression on immune cells
    is the diagnostic immunophenotypic hallmark.
  phenotype_term:
    preferred_term: Reduced MHC II surface expression
    term:
      id: HP:0031390
      label: Reduced MHC II cell surface expression
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031390 | Reduced MHC II surface expression | Obligate (100%)"
    explanation: Orphanet records reduced MHC-II surface expression as obligate.
- name: Recurrent respiratory infections
  category: Respiratory
  frequency: VERY_FREQUENT
  description: >-
    Severe recurrent respiratory infections are very frequent and often begin in
    infancy.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002205 | Recurrent respiratory infections | Very frequent (99-80%)"
    explanation: Orphanet records recurrent respiratory infections as very frequent.
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent lower respiratory tract infection was the predominant clinical manifestation among the patients."
    explanation: Human case series supports recurrent lower respiratory tract infection as a dominant presentation.
- name: Sinusitis
  category: Respiratory
  frequency: FREQUENT
  description: >-
    Recurrent upper respiratory tract infection can include sinusitis.
  phenotype_term:
    preferred_term: Sinusitis
    term:
      id: HP:0000246
      label: Sinusitis
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000246 | Sinusitis | Frequent (79-30%)"
    explanation: Orphanet records sinusitis as frequent.
- name: Recurrent gastrointestinal infections
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: >-
    Recurrent gastrointestinal infection and infectious diarrhea are common
    manifestations of combined immune deficiency.
  phenotype_term:
    preferred_term: Recurrent infection of the gastrointestinal tract
    term:
      id: HP:0004798
      label: Recurrent infection of the gastrointestinal tract
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004798 | Recurrent infection of the gastrointestinal tract | Very frequent (99-80%)"
    explanation: Orphanet records recurrent gastrointestinal infection as very frequent.
- name: Recurrent bacterial infections
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Combined immunodeficiency predisposes to recurrent bacterial infections.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002718 | Recurrent bacterial infections | Frequent (79-30%)"
    explanation: Orphanet records recurrent bacterial infections as frequent.
- name: Recurrent Staphylococcus aureus infections
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Staphylococcus aureus infections are among the recurrent bacterial
    infections reported for this disorder.
  phenotype_term:
    preferred_term: Recurrent Staphylococcus aureus infections
    term:
      id: HP:0002726
      label: Recurrent Staphylococcus aureus infections
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002726 | Recurrent Staphylococcus aureus infections | Frequent (79-30%)"
    explanation: Orphanet records recurrent Staphylococcus aureus infections as frequent.
- name: Chronic mucocutaneous candidiasis
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Impaired cellular immunity predisposes to chronic mucocutaneous candidiasis.
  phenotype_term:
    preferred_term: Chronic mucocutaneous candidiasis
    term:
      id: HP:0002728
      label: Chronic mucocutaneous candidiasis
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002728 | Chronic mucocutaneous candidiasis | Frequent (79-30%)"
    explanation: Orphanet records chronic mucocutaneous candidiasis as frequent.
- name: Recurrent fungal infections
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Defective cellular immunity predisposes to recurrent fungal infections.
  phenotype_term:
    preferred_term: Recurrent fungal infections
    term:
      id: HP:0002841
      label: Recurrent fungal infections
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002841 | Recurrent fungal infections | Frequent (79-30%)"
    explanation: Orphanet records recurrent fungal infections as frequent.
- name: Lack of T cell function
  category: Immunologic
  frequency: VERY_FREQUENT
  description: >-
    Impaired T-cell function reflects defective CD4 T-cell development and
    antigen-driven activation.
  phenotype_term:
    preferred_term: Lack of T cell function
    term:
      id: HP:0005354
      label: Absent cellular immunity
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005354 | Lack of T cell function | Very frequent (99-80%)"
    explanation: Orphanet records lack of T-cell function as very frequent.
- name: Failure to thrive
  category: Growth
  frequency: FREQUENT
  description: >-
    Failure to thrive accompanies recurrent infections and chronic diarrhea in
    many affected infants.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001508 | Failure to thrive | Frequent (79-30%)"
    explanation: Orphanet records failure to thrive as frequent.
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients except P2 had failure to thrive."
    explanation: Human case series supports failure to thrive in most reported patients.
- name: Diarrhea
  category: Gastrointestinal
  frequency: FREQUENT
  description: >-
    Diarrhea is a frequent gastrointestinal manifestation of recurrent infection
    and malabsorption.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002014 | Diarrhea | Frequent (79-30%)"
    explanation: Orphanet records diarrhea as frequent.
- name: Protracted diarrhea
  category: Gastrointestinal
  frequency: FREQUENT
  description: >-
    Protracted diarrhea is a frequent early manifestation and contributes to
    malnutrition and poor growth.
  phenotype_term:
    preferred_term: Protracted diarrhea
    term:
      id: HP:0004385
      label: Protracted diarrhea
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004385 | Protracted diarrhea | Frequent (79-30%)"
    explanation: Orphanet records protracted diarrhea as frequent.
  - reference: PMID:8229525
    reference_title: "Major histocompatibility complex class II deficiency: clinical manifestations, immunologic features, and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical onset occurred in the first year of life, usually involving recurrent bronchopulmonary infections and chronic diarrhea."
    explanation: The 30-patient clinical series supports chronic diarrhea as a typical early manifestation.
- name: Recurrent viral infections
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Combined cellular and humoral immune deficiency predisposes to recurrent
    viral infections.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004429 | Recurrent viral infections | Frequent (79-30%)"
    explanation: Orphanet records recurrent viral infections as frequent.
- name: Recurrent herpes
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Recurrent herpesvirus infections are part of the recurrent viral infection
    burden.
  phenotype_term:
    preferred_term: Recurrent herpes
    term:
      id: HP:0005353
      label: Recurrent herpes
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005353 | Recurrent herpes | Frequent (79-30%)"
    explanation: Orphanet records recurrent herpes as frequent.
- name: Decreased circulating antibody level
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Impaired T-cell help reduces T-cell-dependent antibody production, producing
    decreased circulating immunoglobulin levels in many patients.
  phenotype_term:
    preferred_term: Decreased circulating antibody level
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004313 | Decreased circulating antibody level | Frequent (79-30%)"
    explanation: Orphanet records decreased circulating antibody level as frequent.
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum immunoglobulin levels measured in three patients (P3, P4, and P5) revealed reduced concentrations of IgG, IgA, and IgM consistent with lack of helper T cell-dependent antibody production."
    explanation: Human immunologic data directly support decreased immunoglobulin levels.
- name: Abnormality of humoral immunity
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Humoral immune abnormalities reflect poor T-helper-cell-dependent antibody
    responses.
  phenotype_term:
    preferred_term: Abnormality of humoral immunity
    term:
      id: HP:0005368
      label: Abnormality of humoral immunity
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005368 | Abnormality of humoral immunity | Frequent (79-30%)"
    explanation: Orphanet records abnormality of humoral immunity as frequent.
- name: Recurrent protozoan infections
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Recurrent protozoan infections are reported in this combined
    immunodeficiency.
  phenotype_term:
    preferred_term: Recurrent protozoan infections
    term:
      id: HP:0005386
      label: Recurrent protozoan infections
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005386 | Recurrent protozoan infections | Frequent (79-30%)"
    explanation: Orphanet records recurrent protozoan infections as frequent.
- name: Recurrent candida infections
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Recurrent Candida infections are part of the fungal infection susceptibility
    spectrum.
  phenotype_term:
    preferred_term: Recurrent candida infections
    term:
      id: HP:0005401
      label: Recurrent candida infections
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005401 | Recurrent candida infections | Frequent (79-30%)"
    explanation: Orphanet records recurrent candida infections as frequent.
- name: Rhinitis
  category: Respiratory
  frequency: FREQUENT
  description: >-
    Rhinitis is a frequent upper-airway manifestation in the Orphanet phenotype
    profile.
  phenotype_term:
    preferred_term: Rhinitis
    term:
      id: HP:0012384
      label: Rhinitis
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012384 | Rhinitis | Frequent (79-30%)"
    explanation: Orphanet records rhinitis as frequent.
- name: Decreased circulating beta-2-microglobulin level
  category: Laboratory
  frequency: FREQUENT
  description: >-
    Decreased beta-2-microglobulin is part of the reported laboratory phenotype.
  phenotype_term:
    preferred_term: Decreased circulating beta-2-microglobulin level
    term:
      id: HP:0025347
      label: Decreased circulating beta-2-microglobulin level
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025347 | Decreased circulating beta-2-microglobulin level | Frequent (79-30%)"
    explanation: Orphanet records decreased circulating beta-2-microglobulin as frequent.
- name: Decreased proportion of CD4-positive T cells
  category: Immunologic
  frequency: FREQUENT
  description: >-
    CD4-positive T-cell numbers or proportions are frequently reduced because
    MHC-II-mediated thymic selection is impaired.
  phenotype_term:
    preferred_term: Decreased proportion of CD4-positive T cells
    term:
      id: HP:0032218
      label: Decreased CD4+ T cell proportion
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0032218 | Decreased proportion of CD4-positive T cells | Frequent (79-30%)"
    explanation: Orphanet records decreased CD4-positive T-cell proportion as frequent.
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had an absolute lymphocyte count of >2,500 count/mm3, but the absolute CD4+ Th cell counts were low (range, 214–685 count/mm3) with an inverse CD4:CD8 ratio."
    explanation: Human immunophenotyping supports reduced CD4 helper T-cell counts.
- name: Sclerosing cholangitis
  category: Hepatobiliary
  frequency: FREQUENT
  description: >-
    Chronic hepatobiliary infection and immune dysfunction can be associated
    with sclerosing cholangitis.
  phenotype_term:
    preferred_term: Sclerosing cholangitis
    term:
      id: HP:0030991
      label: Sclerosing cholangitis
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030991 | Sclerosing cholangitis | Frequent (79-30%)"
    explanation: Orphanet records sclerosing cholangitis as frequent.
- name: Chronic hepatitis due to cryptosporidium infection
  category: Hepatobiliary
  frequency: FREQUENT
  description: >-
    Chronic cryptosporidium-associated hepatitis is a frequent hepatobiliary
    infectious complication reported by Orphanet.
  phenotype_term:
    preferred_term: Chronic hepatitis due to cryptosporidium infection
    term:
      id: HP:0200124
      label: Chronic hepatitis due to cryptosporidium infection
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0200124 | Chronic hepatitis due to cryptosporidium infection | Frequent (79-30%)"
    explanation: Orphanet records chronic hepatitis due to cryptosporidium infection as frequent.
- name: Autoimmunity
  category: Immunologic
  frequency: OCCASIONAL
  description: >-
    Autoimmune manifestations occur in a subset of patients and may reflect
    central and peripheral tolerance perturbation.
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002960 | Autoimmunity | Occasional (29-5%)"
    explanation: Orphanet records autoimmunity as occasional.
  - reference: PMID:8229525
    reference_title: "Major histocompatibility complex class II deficiency: clinical manifestations, immunologic features, and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical course was complicated by viral meningoencephalitis, hepatitis, cholangitis, and various autoimmune phenomena."
    explanation: The 30-patient natural-history series records autoimmune phenomena complicating the clinical course.
- name: Autoimmune hemolytic anemia
  category: Hematologic
  frequency: OCCASIONAL
  description: >-
    Autoimmune haemolytic anaemia is one of the specific autoimmune cytopenias
    seen in this disorder, and is the kind of manifestation the tolerance defect
    downstream of absent thymic MHC-II expression would predict.
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001890 | Autoimmune hemolytic anemia | Occasional (29-5%)"
    explanation: Orphanet records autoimmune haemolytic anaemia as occasional.
- name: Autoimmune thrombocytopenia
  category: Hematologic
  frequency: OCCASIONAL
  description: >-
    Autoimmune thrombocytopenia is a second autoimmune cytopenia reported in
    this disorder.
  phenotype_term:
    preferred_term: Autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001973 | Autoimmune thrombocytopenia | Occasional (29-5%)"
    explanation: Orphanet records autoimmune thrombocytopenia as occasional.
- name: Decreased total neutrophil count
  category: Hematologic
  frequency: OCCASIONAL
  description: >-
    Neutropenia occurs occasionally, including in the presence of
    anti-neutrophil antibodies, placing it with the autoimmune cytopenias rather
    than with a primary myeloid production defect.
  phenotype_term:
    preferred_term: Decreased total neutrophil count
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001875 | Decreased total neutrophil count | Occasional (29-5%)"
    explanation: Orphanet records decreased neutrophil count as occasional.
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001904 | Neutropenia in presence of anti-neutropil antibodies | Occasional (29-5%)"
    explanation: >-
      Orphanet separately records antibody-associated neutropenia, supporting
      the autoimmune rather than production-failure reading of the cytopenia.
- name: Pancytopenia
  category: Hematologic
  frequency: OCCASIONAL
  description: >-
    Pancytopenia is reported occasionally, consistent with the multiple
    autoimmune cytopenias recorded for this disorder.
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001876 | Pancytopenia | Occasional (29-5%)"
    explanation: Orphanet records pancytopenia as occasional.
- name: Decreased total T cell count
  category: Immunologic
  frequency: OCCASIONAL
  description: >-
    Total T-cell counts are only occasionally reduced — the defect is selective
    for the CD4 compartment, and total lymphocyte counts are often normal. This
    is precisely why the disorder can be mistaken for a T-B+ SCID on a
    lymphocyte count alone and why HLA-DR staining is required.
  phenotype_term:
    preferred_term: Decreased total T cell count
    term:
      id: HP:0005403
      label: Decreased total T cell count
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005403 | Decreased total T cell count | Occasional (29-5%)"
    explanation: >-
      Orphanet records decreased total T-cell count as only occasional, in
      contrast to the frequent CD4-specific reduction.
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had an absolute lymphocyte count of >2,500 count/mm3, but the absolute CD4+ Th cell counts were low (range, 214–685 count/mm3) with an inverse CD4:CD8 ratio."
    explanation: Shows preserved total lymphocyte counts alongside selectively low CD4 counts in all five patients.
- name: Abnormal CD4:CD8 ratio
  category: Immunologic
  frequency: OCCASIONAL
  description: >-
    An inverted CD4:CD8 ratio follows directly from selective loss of the
    MHC-II-selected CD4 compartment with a preserved CD8 compartment, and is one
    of the immunophenotypic clues that prompts HLA-DR testing.
  phenotype_term:
    preferred_term: Inverse CD4:CD8 ratio
    term:
      id: HP:0031394
      label: Abnormal CD4:CD8 ratio
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031394 | Abnormal CD4:CD8 ratio | Occasional (29-5%)"
    explanation: Orphanet records an abnormal CD4:CD8 ratio.
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had an absolute lymphocyte count of >2,500 count/mm3, but the absolute CD4+ Th cell counts were low (range, 214–685 count/mm3) with an inverse CD4:CD8 ratio."
    explanation: Documents the inverted CD4:CD8 ratio in all five patients of the Indian series.
- name: Decreased mitogen-induced T-cell proliferation
  category: Immunologic
  frequency: OCCASIONAL
  description: >-
    Reduced lymphocyte proliferation in response to mitogen is a functional
    correlate of the impaired T-cell compartment.
  phenotype_term:
    preferred_term: Decreased lymphocyte proliferation in response to mitogen
    term:
      id: HP:0031381
      label: Decreased mitogen-induced T-cell proliferation
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031381 | Decreased lymphocyte proliferation in response to mitogen | Occasional (29-5%)"
    explanation: Orphanet records decreased mitogen-induced lymphocyte proliferation as occasional.
- name: Panhypogammaglobulinemia
  category: Immunologic
  frequency: OCCASIONAL
  description: >-
    Panhypogammaglobulinaemia — reduction across IgG, IgA, and IgM — is the
    severe end of the antibody deficiency caused by absent T-cell help.
  phenotype_term:
    preferred_term: Panhypogammaglobulinemia
    term:
      id: HP:0003139
      label: Panhypogammaglobulinemia
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003139 | Panhypogammaglobulinemia | Occasional (29-5%)"
    explanation: Orphanet records panhypogammaglobulinaemia as occasional.
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum immunoglobulin levels measured in three patients (P3, P4, and P5) revealed reduced concentrations of IgG, IgA, and IgM consistent with lack of helper T cell-dependent antibody production."
    explanation: Documents reduction across all three major isotypes, the pattern this term names.
- name: Acute otitis media
  category: Respiratory
  frequency: OCCASIONAL
  description: >-
    Acute otitis media is part of the recurrent upper respiratory tract
    infection burden.
  phenotype_term:
    preferred_term: Acute otitis media
    term:
      id: HP:0000371
      label: Acute otitis media
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000371 | Acute otitis media | Occasional (29-5%)"
    explanation: Orphanet records acute otitis media as occasional.
- name: Skin rash
  category: Dermatologic
  frequency: OCCASIONAL
  description: >-
    Skin rash is reported occasionally in the Orphanet phenotype profile.
  phenotype_term:
    preferred_term: Skin rash
    term:
      id: HP:0000988
      label: Skin rash
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000988 | Skin rash | Occasional (29-5%)"
    explanation: Orphanet records skin rash as occasional.
diagnosis:
- name: HLA-DR flow-cytometric immunophenotyping
  description: >-
    Flow cytometry demonstrating absent or reduced HLA-DR expression on B cells
    and monocytes supports the diagnosis and distinguishes MHC class II
    deficiency from other T-B+ severe combined immunodeficiencies.
  diagnosis_term:
    preferred_term: flow cytometry procedure
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  evidence:
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, patients displayed a reduced absolute CD4+ Th cell count and absent HLA-DR expression on B lymphocytes and monocytes."
    explanation: This directly supports flow-cytometric HLA-DR immunophenotyping for diagnosis.
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, diagnosis of MHC class II deficiency may be confounded unless HLA-DR expression is evaluated on the immune cells."
    explanation: >-
      States why this specific test is required rather than optional: without
      it the disorder is confounded with other T-B+ immunodeficiencies.
  notes: >-
    The test has to be asked for. Total lymphocyte and B-cell counts are normal
    or even elevated, so nothing on a routine subset panel forces the question;
    only HLA-DR staining on B cells and monocytes distinguishes this disorder
    from a T-B+ SCID.
- name: TREC newborn screening (does not detect this disorder)
  description: >-
    TREC-based newborn screening for SCID does not reliably detect MHC class II
    deficiency. The block lies downstream of T-cell receptor recombination, so
    excision circles are still produced: measured TREC levels in these patients
    sit above the screening cut-off, and affected infants screen normal. This is
    recorded here as a negative diagnostic finding rather than as a usable test.
  presence: ABSENT
  diagnosis_term:
    preferred_term: newborn screening
    term:
      id: NCIT:C81178
      label: Newborn Screening
  evidence:
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Detectable level of T cell receptor excision circles (TRECs) were measured in our patients, highlighting that this form of PID may be missed by TREC-based newborn screening program for severe combined immunodeficiency."
    explanation: Directly documents detectable TRECs in affected patients and the resulting screening blind spot.
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TREC levels in MHC class II patients have been reported to be higher than the NBS TREC cut-off for SCID and other T cell lymphopenia conditions"
    explanation: Explains the mechanism of the false-negative — TREC levels exceed the screening threshold.
- name: Molecular genetic testing for MHC-II regulatory genes
  description: >-
    Molecular genetic testing of CIITA, RFXANK, RFX5, and RFXAP confirms the
    causative regulatory-gene defect and defines the genetic subtype.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, with the application of next-generation sequencing (NGS) technology, screening of all the four causative factors can be performed at the same time, thereby reducing the cost and time for getting a diagnosis."
    explanation: Human clinical diagnostic discussion supports sequencing all four causative regulatory genes.
treatments:
- name: Hematopoietic cell transplantation
  description: >-
    Allogeneic hematopoietic cell transplantation is the only established
    curative therapy and can restore hematopoietic immune function, although
    outcomes depend on transplant strategy, donor type, infection burden, and
    residual nonhematopoietic thymic epithelial defects.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: MHC-II expression and antigen presentation failure
    description: Donor hematopoietic cells can restore MHC-II expression in hematopoietic antigen-presenting cells.
  evidence:
  - reference: PMID:31932845
    reference_title: Improved transplant survival and long-term disease outcome in children with MHC class II deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in the previously published result was poor."
    explanation: Contemporary transplant cohort identifies HCT as the curative treatment.
  - reference: PMID:31932845
    reference_title: Improved transplant survival and long-term disease outcome in children with MHC class II deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With a 2.9-year median follow-up, OS improved from 33% (46-68%) for HCT before 2008 (n = 6) to 94% (66-99%) for HCT after 2008"
    explanation: The cohort provides human outcome evidence for improved modern HCT survival.
  - reference: PMID:31932845
    reference_title: Improved transplant survival and long-term disease outcome in children with MHC class II deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All survivors were off immunoglobulin replacement and had protective vaccine responses to tetanus and Haemophilus influenzae. None had any significant infection or autoimmunity."
    explanation: >-
      Gives the functional outcome, not just survival: restored T-cell-dependent
      antibody responses sufficient to stop immunoglobulin replacement, and
      resolution of the autoimmune manifestations.
  - reference: PMID:31932845
    reference_title: Improved transplant survival and long-term disease outcome in children with MHC class II deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Latest CD4+ T-lymphocyte number was significantly lower in transplant survivors (n = 14) compared with posttransplant disease controls (P = .01)."
    explanation: >-
      Substantiates the residual non-haematopoietic defect asserted in this
      treatment's description: donor cells cannot restore MHC-II expression on
      recipient thymic epithelium, so CD4 reconstitution stays subnormal
      relative to other transplanted immunodeficiencies.
  - reference: PMID:34211466
    reference_title: Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Overall, our findings reveal disease-specific TEC defects resulting in perturbation of central tolerance and limiting the potential benefits of hematopoietic stem cell transplantation in MHCII deficiency."
    explanation: >-
      States the mechanistic reason the benefit of transplantation is capped —
      the thymic epithelial compartment is not of donor origin and is not
      corrected.
  - reference: PMID:8229525
    reference_title: "Major histocompatibility complex class II deficiency: clinical manifestations, immunologic features, and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Long-term survival after human leukocyte antigen-identical and haploidentical bone marrow transplantation seemed to depend primarily on the presence of preexisting viral infections."
    explanation: >-
      Identifies pre-existing viral infection, rather than donor type, as the
      dominant determinant of transplant survival — the argument for
      transplanting before infection accrues.
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Even with immunosuppression, residual host immunity in these patients is reported to be adequate to cause graft rejection."
    explanation: >-
      Records graft rejection driven by residual host immunity as a
      disorder-specific transplant obstacle.
  notes: >-
    Two obstacles are specific to this disorder rather than generic to
    transplantation. First, graft rejection: residual host immunity is adequate
    to reject even under immunosuppression, and donor antigen-presenting cells
    presenting donor antigen to recipient T cells has been proposed as the
    mechanism, so second transplants have been needed. Second, an irreducible
    ceiling: the thymic epithelium is not haematopoietic, so donor cells cannot
    restore MHC-II expression there. Survivors' CD4 counts stay significantly
    below those of other transplanted patients, and mouse work frames this as
    the reason the benefit of transplantation is limited rather than complete.
    Neither obstacle prevents cure — post-2008 survival is 94%, with survivors
    off immunoglobulin and making protective vaccine responses.
- name: Immunoglobulin replacement therapy
  description: >-
    Immunoglobulin replacement is used as supportive management for reduced
    antibody production while awaiting transplant or when definitive therapy is
    not immediately available.
  treatment_term:
    preferred_term: immunoglobulin infusion therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: Decreased circulating antibody level
    description: Exogenous immunoglobulin partially replaces deficient humoral immunity.
  evidence:
  - reference: PMID:20493394
    reference_title: Hematopoietic stem cell transplantation and other management strategies for MHC class II deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The optimal symptomatic care that is available involves the prophylactic use of antibiotics and the administration of immunoglobulin with adequate nutritional support."
    explanation: Management review supports immunoglobulin administration as part of symptomatic care.
- name: Antibiotic prophylaxis and nutritional supportive care
  description: >-
    Infection prophylaxis and nutritional support are used to reduce infectious
    morbidity and maintain growth while definitive therapy is pursued.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Combined cellular and humoral immune deficiency
    description: Supportive care reduces complications caused by the combined immunodeficiency.
  evidence:
  - reference: PMID:20493394
    reference_title: Hematopoietic stem cell transplantation and other management strategies for MHC class II deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The optimal symptomatic care that is available involves the prophylactic use of antibiotics and the administration of immunoglobulin with adequate nutritional support."
    explanation: Management review supports antibiotic prophylaxis and nutritional support as symptomatic care.
differential_diagnoses:
- name: T-B+ severe combined immunodeficiency
  description: >-
    The most consequential confusion, and it goes in one direction: MHC class II
    deficiency is misread as a T-B+ SCID. Both present in infancy with severe
    respiratory and gastrointestinal infection, failure to thrive,
    hypogammaglobulinaemia, and a low CD4 count with preserved B cells. In MHC
    class II deficiency the absolute lymphocyte and B-cell counts are normal or
    even elevated, and TRECs are detectable, so neither a routine subset panel
    nor newborn screening separates the two. Only HLA-DR staining on B cells and
    monocytes does.
  distinguishing_features:
  - Absent HLA-DR expression on B lymphocytes and monocytes is obligate in MHC class II deficiency and is the single discriminating test; it is normal in T-B+ SCID.
  - TRECs are detectable and above the newborn-screening cut-off in MHC class II deficiency because the block is downstream of T-cell receptor recombination; typical SCID has very low or undetectable TRECs.
  - Absolute B-lymphocyte counts are normal or elevated in MHC class II deficiency, and the total lymphocyte count is often preserved with a selectively low CD4 count and inverted CD4:CD8 ratio.
  - The causal genes are the MHC-II regulatory factors CIITA, RFXANK, RFX5, and RFXAP, none of which are SCID genes.
  evidence:
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these patients presented with normal or elevated absolute B lymphocyte count that could potentially lead to misdiagnosis of MHC class II deficiency as T−B+ form of severe combined immunodeficiency (SCID)"
    explanation: States the misdiagnosis risk and the specific finding that causes it.
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, diagnosis of MHC class II deficiency may be confounded unless HLA-DR expression is evaluated on the immune cells."
    explanation: Identifies HLA-DR immunophenotyping as the discriminating test.
  - reference: PMID:29527204
    reference_title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Detectable level of T cell receptor excision circles (TRECs) were measured in our patients, highlighting that this form of PID may be missed by TREC-based newborn screening program for severe combined immunodeficiency."
    explanation: Supports the TREC-based distinguishing feature and the screening blind spot.
biochemical: []
environmental: []
references:
- reference: PMID:11258423
  title: Molecular genetics of the Bare lymphocyte syndrome.
  found_in:
  - MHC_Class_II_Deficiency-deep-research-fallback.md
  findings:
  - statement: CIITA, RFXANK, RFX5, and RFXAP regulatory-gene defects cause bare lymphocyte syndrome/MHC class II deficiency.
    supporting_text: >-
      The review describes MHC class II deficiency as a regulatory-gene disorder
      caused by mutations in CIITA, RFXANK, RFX5, and RFXAP, rather than by
      mutations in the HLA class II structural locus.
- reference: PMID:8402893
  title: Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome).
  found_in:
  - MHC_Class_II_Deficiency-deep-research-fallback.md
  findings:
  - statement: CIITA is essential for MHC class II gene expression and can restore expression in mutant cells.
    supporting_text: >-
      Complementation cloning identified CIITA as a transactivator of MHC class
      II expression and showed that it corrects the regulatory defect in patient
      cells.
- reference: PMID:9287230
  title: "Mutation of RFXAP, a regulator of MHC class II genes, in primary MHC class II deficiency."
  found_in:
  - MHC_Class_II_Deficiency-deep-research-fallback.md
  findings:
  - statement: RFXAP mutations define a genetic complementation group of MHC class II deficiency.
    supporting_text: >-
      Patient-cell complementation identified RFXAP mutations and showed
      restoration of MHC class II expression after wild-type RFXAP transfection.
- reference: PMID:29527204
  title: "Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India."
  found_in:
  - MHC_Class_II_Deficiency-deep-research-fallback.md
  findings:
  - statement: Human patients show absent HLA-DR expression, low CD4 helper T-cell counts, reduced immunoglobulins, respiratory infections, and failure to thrive.
    supporting_text: >-
      The case series reports the diagnostic immunophenotype and clinical
      presentation used for the YAML's phenotype, diagnostic, and mechanism
      entries.
- reference: PMID:8229525
  title: "Major histocompatibility complex class II deficiency: clinical manifestations, immunologic features, and outcome."
  found_in:
  - MHC_Class_II_Deficiency-deep-research-fallback.md
  findings:
  - statement: A 30-patient series supports infantile onset, recurrent bronchopulmonary infections, chronic diarrhea, poor prognosis, and transplant as potentially curative.
    supporting_text: >-
      The clinical series provides natural-history and outcome support for the
      progression and phenotype entries.
- reference: PMID:34211466
  title: Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency.
  found_in:
  - MHC_Class_II_Deficiency-deep-research-fallback.md
  findings:
  - statement: MHC-II absence perturbs thymic epithelial cells, thymopoiesis, central tolerance, and peripheral tolerance.
    supporting_text: >-
      Mouse and patient-based work supports the separate thymic epithelial and
      tolerance pathophysiology node.
- reference: PMID:20493394
  title: Hematopoietic stem cell transplantation and other management strategies for MHC class II deficiency.
  found_in:
  - MHC_Class_II_Deficiency-deep-research-fallback.md
  findings:
  - statement: HSCT is the only known curative treatment; antibiotics, immunoglobulin, and nutritional support are symptomatic care.
    supporting_text: >-
      The management review supports both the curative treatment entry and
      supportive care entries.
- reference: PMID:31932845
  title: Improved transplant survival and long-term disease outcome in children with MHC class II deficiency.
  found_in:
  - MHC_Class_II_Deficiency-deep-research-fallback.md
  findings:
  - statement: Modern hematopoietic cell transplantation has improved survival and long-term outcomes in children with MHC class II deficiency.
    supporting_text: >-
      The Blood cohort supports the treatment entry's emphasis on improved
      post-2008 HCT outcomes.