MHC class II deficiency

Mendelian MONDO:0008855 Pathograph 18 familial severe combined immunodeficiency combined immunodeficiency primary immunodeficiency

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.

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1
Mappings
1
Definitions
1
Inheritance
6
Pathophys.
24
Phenotypes
18
Pathograph
4
Genes
3
Treatments
4
Subtypes
8
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0008855 MHC class II deficiency
skos:exactMatch Orphanet ORPHA:572
Orphanet ORPHA:572 lists MONDO:0008855 as an exact cross-reference for immunodeficiency by defective expression of MHC class II.
📘

Definitions

1
Orphanet MHC class II deficiency definition
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.
OTHER
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"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."
Orphanet defines the molecular and immunologic core of MHC class II deficiency.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
MHC class II deficiency is inherited as an autosomal recessive disorder due to biallelic loss of MHC-II regulatory factors.
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:572 SUPPORT Other
"Autosomal recessive"
Orphanet records autosomal recessive inheritance.
PMID:11258423 SUPPORT Other
"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."
This molecular genetics review directly describes MHC class II deficiency as autosomal recessive.
◆

Subtypes

4
MHC class II deficiency 1 (CIITA-related) MONDO:0971005
CIITA link
CIITA-related MHC class II deficiency caused by loss of the class II transactivator needed for MHC-II gene expression.
Show evidence (1 reference)
PMID:8402893 SUPPORT In Vitro
"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."
Complementation cloning identifies CIITA as the transactivator defective in one genetic form of MHC class II deficiency.
MHC class II deficiency 2 (RFXANK-related) MONDO:0971013
RFXANK link
RFXANK-related MHC class II deficiency caused by disruption of one subunit of the RFX DNA-binding complex.
Show evidence (1 reference)
PMID:11258423 SUPPORT Other
"Mutations in four different MHC-II regulatory genes are known to lead to BLS. These genes encode CIITA, RFXANK, RFX5 and RFXAP."
This review identifies RFXANK as one of the four disease-causing MHC-II regulatory genes.
MHC class II deficiency 3 (RFX5-related) MONDO:0971014
RFX5 link
RFX5-related MHC class II deficiency caused by disruption of one subunit of the RFX DNA-binding complex.
Show evidence (1 reference)
PMID:11258423 SUPPORT Other
"Mutations in four different MHC-II regulatory genes are known to lead to BLS. These genes encode CIITA, RFXANK, RFX5 and RFXAP."
This review identifies RFX5 as one of the four disease-causing MHC-II regulatory genes.
MHC class II deficiency 4 (RFXAP-related) MONDO:0971015
RFXAP link
RFXAP-related MHC class II deficiency, corresponding to complementation group D.
Show evidence (1 reference)
PMID:9287230 SUPPORT In Vitro
"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)."
This patient-cell complementation study identifies RFXAP as the group D MHC class II deficiency gene.
⚙

Pathophysiology

6
MHC-II regulatory gene disruption
Biallelic defects in CIITA or the RFX complex genes RFXANK, RFX5, and RFXAP disrupt the transcription-factor machinery responsible for MHC-II gene expression.
CIITA link RFXANK link RFX5 link RFXAP link
Downstream
MHC-II transcriptional failure Disrupted CIITA/RFX machinery prevents normal MHC-II gene transcription.
Show evidence (1 reference)
PMID:11258423 SUPPORT Other
"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."
This supports regulatory-gene disruption rather than primary HLA locus mutation as the initiating molecular lesion.
MHC-II transcriptional failure
Loss of CIITA or RFX-complex function impairs transcriptional activation of HLA class II genes in professional antigen-presenting cells and thymic epithelium.
professional antigen-presenting cell link thymic epithelial cell link
regulation of DNA-templated transcription link ↓ DECREASED
Downstream
MHC-II expression and antigen presentation failure Failed HLA class II transcription leads to absent or reduced surface MHC-II expression.
Show evidence (1 reference)
PMID:11258423 SUPPORT Other
"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."
The review identifies CIITA as the master transcriptional coactivator for MHC-II expression.
MHC-II expression and antigen presentation failure
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.
B cell link monocyte link thymic epithelial cell link
antigen processing and presentation of peptide antigen via MHC class II link ↓ DECREASED
Downstream
CD4 T-cell selection and helper-function impairment Loss of MHC-II antigen presentation disrupts CD4 T-cell development and helper activity.
Tolerance perturbation and autoimmunity Absence of MHC-II expression in thymic epithelium perturbs central tolerance.
Show evidence (1 reference)
PMID:29527204 SUPPORT Human Clinical
"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"
This clinical series links regulatory-factor defects to absent or reduced MHC-II expression on immune cells.
CD4 T-cell selection and helper-function impairment
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.
CD4-positive T helper cell link
CD4-positive, alpha-beta T cell differentiation link ↓ DECREASED T cell activation link ↓ DECREASED
Downstream
Combined cellular and humoral immune deficiency CD4 helper-cell impairment disrupts both cellular and humoral immune responses.
Show evidence (1 reference)
PMID:29527204 SUPPORT Human Clinical
"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."
Human clinical review material directly links MHC-II antigen presentation to CD4 helper T-cell development.
Combined cellular and humoral immune deficiency
Defective CD4 T-cell help causes combined immunodeficiency, with poor cellular responses and reduced T-cell-dependent antibody production.
CD4-positive T helper cell link B cell link
adaptive immune response link ↓ DECREASED immunoglobulin mediated immune response link ↓ DECREASED
Downstream
Lack of T cell function Defective cellular immunity manifests as impaired T-cell function.
Decreased circulating antibody level Defective T-cell help reduces antibody production.
Recurrent respiratory infections Combined immune deficiency predisposes to severe recurrent respiratory infections.
Recurrent gastrointestinal infections Combined immune deficiency predisposes to recurrent gastrointestinal infection and diarrhea.
Show evidence (1 reference)
PMID:20493394 SUPPORT Other
"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."
This management review summarizes the combined cellular and humoral immunologic defect.
Tolerance perturbation and autoimmunity
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.
thymic epithelial cell link regulatory T cell link
positive T cell selection link ↓ DECREASED
Downstream
Autoimmunity Central and peripheral tolerance perturbation contributes to autoimmune manifestations.
Show evidence (1 reference)
PMID:34211466 SUPPORT Model Organism
"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."
Mouse and patient-based immunology data support thymic epithelial and tolerance defects downstream of MHC-II absence.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for MHC class II deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

24
Blood 1
Decreased circulating antibody level FREQUENT Decreased circulating immunoglobulin concentration (HP:0004313)
Show evidence (2 references)
ORPHA:572 SUPPORT Other
"HP:0004313 | Decreased circulating antibody level | Frequent (79-30%)"
Orphanet records decreased circulating antibody level as frequent.
PMID:29527204 SUPPORT Human Clinical
"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."
Human immunologic data directly support decreased immunoglobulin levels.
Digestive 2
Diarrhea FREQUENT Diarrhea (HP:0002014)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0002014 | Diarrhea | Frequent (79-30%)"
Orphanet records diarrhea as frequent.
Sclerosing cholangitis FREQUENT Sclerosing cholangitis (HP:0030991)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0030991 | Sclerosing cholangitis | Frequent (79-30%)"
Orphanet records sclerosing cholangitis as frequent.
Head and Neck 1
Sinusitis FREQUENT Sinusitis (HP:0000246)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0000246 | Sinusitis | Frequent (79-30%)"
Orphanet records sinusitis as frequent.
Immune 3
Recurrent respiratory infections VERY_FREQUENT Recurrent respiratory infections (HP:0002205)
Show evidence (2 references)
ORPHA:572 SUPPORT Other
"HP:0002205 | Recurrent respiratory infections | Very frequent (99-80%)"
Orphanet records recurrent respiratory infections as very frequent.
PMID:29527204 SUPPORT Human Clinical
"Recurrent lower respiratory tract infection was the predominant clinical manifestation among the patients."
Human case series supports recurrent lower respiratory tract infection as a dominant presentation.
Recurrent candida infections FREQUENT Recurrent candida infections (HP:0005401)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0005401 | Recurrent candida infections | Frequent (79-30%)"
Orphanet records recurrent candida infections as frequent.
Autoimmunity OCCASIONAL Autoimmunity (HP:0002960)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0002960 | Autoimmunity | Occasional (29-5%)"
Orphanet records autoimmunity as occasional.
Growth 1
Failure to thrive FREQUENT Failure to thrive (HP:0001508)
Show evidence (2 references)
ORPHA:572 SUPPORT Other
"HP:0001508 | Failure to thrive | Frequent (79-30%)"
Orphanet records failure to thrive as frequent.
PMID:29527204 SUPPORT Human Clinical
"All patients except P2 had failure to thrive."
Human case series supports failure to thrive in most reported patients.
Other 16
Reduced MHC II surface expression OBLIGATE Reduced MHC II cell surface expression (HP:0031390)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0031390 | Reduced MHC II surface expression | Obligate (100%)"
Orphanet records reduced MHC-II surface expression as obligate.
Recurrent gastrointestinal infections VERY_FREQUENT Recurrent infection of the gastrointestinal tract (HP:0004798)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0004798 | Recurrent infection of the gastrointestinal tract | Very frequent (99-80%)"
Orphanet records recurrent gastrointestinal infection as very frequent.
Recurrent bacterial infections FREQUENT Recurrent bacterial infections (HP:0002718)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0002718 | Recurrent bacterial infections | Frequent (79-30%)"
Orphanet records recurrent bacterial infections as frequent.
Recurrent Staphylococcus aureus infections FREQUENT Recurrent Staphylococcus aureus infections (HP:0002726)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0002726 | Recurrent Staphylococcus aureus infections | Frequent (79-30%)"
Orphanet records recurrent Staphylococcus aureus infections as frequent.
Chronic mucocutaneous candidiasis FREQUENT Chronic mucocutaneous candidiasis (HP:0002728)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0002728 | Chronic mucocutaneous candidiasis | Frequent (79-30%)"
Orphanet records chronic mucocutaneous candidiasis as frequent.
Recurrent fungal infections FREQUENT Recurrent fungal infections (HP:0002841)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0002841 | Recurrent fungal infections | Frequent (79-30%)"
Orphanet records recurrent fungal infections as frequent.
Lack of T cell function VERY_FREQUENT Absent cellular immunity (HP:0005354)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0005354 | Lack of T cell function | Very frequent (99-80%)"
Orphanet records lack of T-cell function as very frequent.
Protracted diarrhea FREQUENT Protracted diarrhea (HP:0004385)
Show evidence (2 references)
ORPHA:572 SUPPORT Other
"HP:0004385 | Protracted diarrhea | Frequent (79-30%)"
Orphanet records protracted diarrhea as frequent.
PMID:8229525 SUPPORT Human Clinical
"Clinical onset occurred in the first year of life, usually involving recurrent bronchopulmonary infections and chronic diarrhea."
The 30-patient clinical series supports chronic diarrhea as a typical early manifestation.
Recurrent viral infections FREQUENT Recurrent viral infections (HP:0004429)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0004429 | Recurrent viral infections | Frequent (79-30%)"
Orphanet records recurrent viral infections as frequent.
Recurrent herpes FREQUENT Recurrent herpes (HP:0005353)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0005353 | Recurrent herpes | Frequent (79-30%)"
Orphanet records recurrent herpes as frequent.
Abnormality of humoral immunity FREQUENT Abnormality of humoral immunity (HP:0005368)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0005368 | Abnormality of humoral immunity | Frequent (79-30%)"
Orphanet records abnormality of humoral immunity as frequent.
Recurrent protozoan infections FREQUENT Recurrent protozoan infections (HP:0005386)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0005386 | Recurrent protozoan infections | Frequent (79-30%)"
Orphanet records recurrent protozoan infections as frequent.
Rhinitis FREQUENT Rhinitis (HP:0012384)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0012384 | Rhinitis | Frequent (79-30%)"
Orphanet records rhinitis as frequent.
Decreased circulating beta-2-microglobulin level FREQUENT Decreased circulating beta-2-microglobulin level (HP:0025347)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0025347 | Decreased circulating beta-2-microglobulin level | Frequent (79-30%)"
Orphanet records decreased circulating beta-2-microglobulin as frequent.
Decreased proportion of CD4-positive T cells FREQUENT Decreased CD4+ T cell proportion (HP:0032218)
Show evidence (2 references)
ORPHA:572 SUPPORT Other
"HP:0032218 | Decreased proportion of CD4-positive T cells | Frequent (79-30%)"
Orphanet records decreased CD4-positive T-cell proportion as frequent.
PMID:29527204 SUPPORT Human Clinical
"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."
Human immunophenotyping supports reduced CD4 helper T-cell counts.
Chronic hepatitis due to cryptosporidium infection FREQUENT Chronic hepatitis due to cryptosporidium infection (HP:0200124)
Show evidence (1 reference)
ORPHA:572 SUPPORT Other
"HP:0200124 | Chronic hepatitis due to cryptosporidium infection | Frequent (79-30%)"
Orphanet records chronic hepatitis due to cryptosporidium infection as frequent.
🧬

Genetic Associations

4
CIITA (Causative)
Show evidence (3 references)
ORPHA:572 SUPPORT Other
"CIITA | class II major histocompatibility complex transactivator | hgnc:7067 | Disease-causing germline mutation(s) in"
Orphanet lists CIITA as a disease-causing gene.
PMID:8402893 SUPPORT In Vitro
"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."
Complementation cloning directly establishes CIITA as a causal gene.
CGGV:assertion_0dab225e-0bdd-4f96-a351-4e490601ba15-2022-11-03T170000.000Z SUPPORT Other
"CIITA | HGNC:7067 | MHC class II deficiency | MONDO:0008855 | AR | Definitive"
ClinGen classifies the CIITA-MHC class II deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
RFXANK (Causative)
Show evidence (3 references)
ORPHA:572 SUPPORT Other
"RFXANK | regulatory factor X associated ankyrin containing protein | hgnc:9987 | Disease-causing germline mutation(s) in"
Orphanet lists RFXANK as a disease-causing gene.
PMID:11258423 SUPPORT Other
"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."
This review places RFXANK in the promoter-binding RFX complex needed for MHC-II gene expression.
CGGV:assertion_fbfd1148-ab31-4ab2-97bb-9b95387e9313-2022-11-17T180000.000Z SUPPORT Other
"RFXANK | HGNC:9987 | MHC class II deficiency | MONDO:0008855 | AR | Definitive"
ClinGen classifies the RFXANK-MHC class II deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
RFX5 (Causative)
Show evidence (3 references)
ORPHA:572 SUPPORT Other
"RFX5 | regulatory factor X5 | hgnc:9986 | Disease-causing germline mutation(s) in"
Orphanet lists RFX5 as a disease-causing gene.
PMID:11258423 SUPPORT Other
"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."
This review places RFX5 in the promoter-binding RFX complex needed for MHC-II gene expression.
CGGV:assertion_430c4041-5e07-45d8-bea5-eaa925a18a72-2023-06-15T170000.000Z SUPPORT Other
"RFX5 | HGNC:9986 | MHC class II deficiency | MONDO:0008855 | AR | Definitive"
ClinGen classifies the RFX5-MHC class II deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
RFXAP (Causative)
Show evidence (3 references)
ORPHA:572 SUPPORT Other
"RFXAP | regulatory factor X associated protein | hgnc:9988 | Disease-causing germline mutation(s) in"
Orphanet lists RFXAP as a disease-causing gene.
PMID:9287230 SUPPORT In Vitro
"Transfection with the wild-type RFXAP gene restored the expression of MHC class II molecules in the patients' cells."
Patient-cell complementation directly supports pathogenic RFXAP loss as causal.
CGGV:assertion_53b17c5d-ccea-4674-8746-a2bc39ad95f0-2023-06-15T170000.000Z SUPPORT Other
"RFXAP | HGNC:9988 | MHC class II deficiency | MONDO:0008855 | AR | Definitive"
ClinGen classifies the RFXAP-MHC class II deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
💊

Treatments

3
Hematopoietic cell transplantation
Action: hematopoietic stem cell transplantation MAXO:0000747
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.
Mechanism Target:
MHC-II expression and antigen presentation failure — Donor hematopoietic cells can restore MHC-II expression in hematopoietic antigen-presenting cells.
Show evidence (2 references)
PMID:31932845 SUPPORT Human Clinical
"Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in the previously published result was poor."
Contemporary transplant cohort identifies HCT as the curative treatment.
PMID:31932845 SUPPORT Human Clinical
"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"
The cohort provides human outcome evidence for improved modern HCT survival.
Immunoglobulin replacement therapy
Action: immunoglobulin infusion therapy MAXO:0001480
Immunoglobulin replacement is used as supportive management for reduced antibody production while awaiting transplant or when definitive therapy is not immediately available.
Mechanism Target:
Decreased circulating antibody level — Exogenous immunoglobulin partially replaces deficient humoral immunity.
Show evidence (1 reference)
PMID:20493394 SUPPORT Other
"The optimal symptomatic care that is available involves the prophylactic use of antibiotics and the administration of immunoglobulin with adequate nutritional support."
Management review supports immunoglobulin administration as part of symptomatic care.
Antibiotic prophylaxis and nutritional supportive care
Action: supportive care MAXO:0000950
Infection prophylaxis and nutritional support are used to reduce infectious morbidity and maintain growth while definitive therapy is pursued.
Mechanism Target:
Combined cellular and humoral immune deficiency — Supportive care reduces complications caused by the combined immunodeficiency.
Show evidence (1 reference)
PMID:20493394 SUPPORT Other
"The optimal symptomatic care that is available involves the prophylactic use of antibiotics and the administration of immunoglobulin with adequate nutritional support."
Management review supports antibiotic prophylaxis and nutritional support as symptomatic care.
{ }

Source YAML

click to show 
name: MHC class II deficiency
creation_date: "2026-05-06T00:47:16Z"
updated_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
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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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
  percentage: <1 per 1,000,000
  notes: Orphanet records worldwide point prevalence below 1 per 1,000,000.
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II (Orphanet structured-database record)"
    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.
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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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.
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 (Orphanet structured-database record)"
    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.
  evidence:
  - reference: ORPHA:572
    reference_title: "Immunodeficiency by defective expression of MHC class II (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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
  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.
  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.
- 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
- 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.
- 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.
  downstream:
  - target: Autoimmunity
    description: Central and peripheral tolerance perturbation contributes to autoimmune manifestations.
    causal_link_type: DIRECT
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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002960 | Autoimmunity | Occasional (29-5%)"
    explanation: Orphanet records autoimmunity 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: MAXO:0035055
      label: flow cytometry procedure
  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.
- 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: MAXO:0000533
      label: molecular genetic testing
  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.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: MAXO:0000747
      label: hematopoietic stem 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.
- 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: MAXO:0001480
      label: immunoglobulin infusion 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: MAXO:0000950
      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.
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.
📚

References & Deep Research

References

8
PMID:11258423
Molecular genetics of the Bare lymphocyte syndrome.
1 finding
CIITA, RFXANK, RFX5, and RFXAP regulatory-gene defects cause bare lymphocyte syndrome/MHC class II deficiency.
"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."
PMID:8402893
Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome).
1 finding
CIITA is essential for MHC class II gene expression and can restore expression in mutant cells.
"Complementation cloning identified CIITA as a transactivator of MHC class II expression and showed that it corrects the regulatory defect in patient cells."
PMID:9287230
Mutation of RFXAP, a regulator of MHC class II genes, in primary MHC class II deficiency.
1 finding
RFXAP mutations define a genetic complementation group of MHC class II deficiency.
"Patient-cell complementation identified RFXAP mutations and showed restoration of MHC class II expression after wild-type RFXAP transfection."
PMID:29527204
Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India.
1 finding
Human patients show absent HLA-DR expression, low CD4 helper T-cell counts, reduced immunoglobulins, respiratory infections, and failure to thrive.
"The case series reports the diagnostic immunophenotype and clinical presentation used for the YAML's phenotype, diagnostic, and mechanism entries."
PMID:8229525
Major histocompatibility complex class II deficiency: clinical manifestations, immunologic features, and outcome.
1 finding
A 30-patient series supports infantile onset, recurrent bronchopulmonary infections, chronic diarrhea, poor prognosis, and transplant as potentially curative.
"The clinical series provides natural-history and outcome support for the progression and phenotype entries."
PMID:34211466
Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency.
1 finding
MHC-II absence perturbs thymic epithelial cells, thymopoiesis, central tolerance, and peripheral tolerance.
"Mouse and patient-based work supports the separate thymic epithelial and tolerance pathophysiology node."
PMID:20493394
Hematopoietic stem cell transplantation and other management strategies for MHC class II deficiency.
1 finding
HSCT is the only known curative treatment; antibiotics, immunoglobulin, and nutritional support are symptomatic care.
"The management review supports both the curative treatment entry and supportive care entries."
PMID:31932845
Improved transplant survival and long-term disease outcome in children with MHC class II deficiency.
1 finding
Modern hematopoietic cell transplantation has improved survival and long-term outcomes in children with MHC class II deficiency.
"The Blood cohort supports the treatment entry's emphasis on improved post-2008 HCT outcomes."

Deep Research

1
MHC Class II Deficiency Deep Research Fallback ▸

MHC Class II Deficiency Deep Research Fallback

Provider Attempts

  • falcon: just research-disorder falcon MHC_Class_II_Deficiency started and remained silent for more than three minutes; terminated with signal 15.
  • openai: just research-disorder openai MHC_Class_II_Deficiency started and remained silent for more than three minutes; terminated with signal 15.
  • openscientist: just research-disorder openscientist MHC_Class_II_Deficiency started and remained silent for more than two minutes; terminated with signal 15.

Because the providers did not return a usable report, curation proceeded from generated Orphanet ORPHA:572 and fetched PubMed references. The YAML integrates the literature-backed synthesis below.

Integrated Literature Synthesis

MHC class II deficiency is a regulatory-gene disorder rather than a primary defect in the HLA class II structural loci. Reviews and original complementation studies identify CIITA, RFXANK, RFX5, and RFXAP as the central genes controlling MHC-II expression. CIITA acts as the class II transactivator, while RFXANK, RFX5, and RFXAP form the RFX complex that binds the conserved X-box in MHC-II promoters. Patient-cell studies show that wild-type CIITA or RFXAP can restore MHC class II expression in mutant cells.

The core pathophysiology is failure of MHC-II transcription and surface expression. Loss of MHC-II antigen presentation impairs CD4-positive T-helper cell development and T-helper-cell-dependent antibody production, producing combined cellular and humoral immunodeficiency. Human series support early infantile onset with recurrent bronchopulmonary infections, chronic diarrhea, failure to thrive, absent HLA-DR expression on B cells and monocytes, reduced CD4 T-cell counts, and reduced immunoglobulin levels. Orphanet frequency rows were used for the phenotype frequencies.

Thymic epithelial effects are supported by mouse and patient-based work showing perturbed thymic structure/function, impaired lymphostromal cross-talk, altered mTEC maturation, central tolerance defects, and peripheral tolerance perturbation. This supports a tolerance/autoimmunity node separate from the infection-oriented combined immunodeficiency node.

Treatment evidence supports hematopoietic cell transplantation as the only curative therapy, with improved post-2008 survival in a modern pediatric cohort. Symptomatic management includes antibiotic prophylaxis, immunoglobulin administration, and nutritional support.

Key References

  • PMID:11258423 - Molecular genetics of the Bare lymphocyte syndrome.
  • PMID:8402893 - Complementation cloning of CIITA in hereditary MHC class II deficiency.
  • PMID:9287230 - RFXAP mutations and complementation group D.
  • PMID:29527204 - Clinical, immunological, and molecular findings in five patients.
  • PMID:8229525 - Thirty-patient clinical series and natural history.
  • PMID:34211466 - Thymic epithelial and tolerance perturbation mechanisms.
  • PMID:20493394 - HSCT and symptomatic management strategies.
  • PMID:31932845 - Improved modern HCT survival and outcome.