CIITA – MHC class II deficiency

CIITA encodes the MHC class II transactivator, a master regulator of HLA-DR, -DP, and -DQ gene expression. Biallelic loss-of-function variants in CIITA result in bare lymphocyte syndrome type II (MHC class II deficiency), characterized by absent MHC II on antigen-presenting cells and severe combined immunodeficiency. The disorder follows an autosomal recessive inheritance pattern, with complete lack of MHC II expression confirmed by flow cytometry in affected individuals.

Multiple unrelated probands (n=6) harboring homozygous or compound heterozygous CIITA variants have been reported (PMID:10663561; PMID:37842025). These include a novel splice-donor deletion causing an in-frame loss of 84 nucleotides in one patient (PMID:10663561), a frameshift c.1421_1427del (p.Pro474HisfsTer13) in a Saudi boy (PMID:37842025), and a homozygous missense T1524C (p.Leu508=) in three sisters with residual expression and mild phenotype (PMID:11466404).

Segregation analysis in the sibship revealed two additional affected relatives carrying the same homozygous missense mutation, confirming recessive inheritance. No dominant-negative effects were observed in heterozygous carriers, who remained asymptomatic.

The variant spectrum includes splice-site deletions, frameshifts, nonsense mutations, and rare hypomorphic missense alleles. The recurrent c.1421_1427del (p.Pro474HisfsTer13) has been observed in consanguineous pedigrees. Overall, reported variants cluster in the NACHT and LRR domains, abrogating transactivation activity.

Functional complementation assays demonstrated that wild-type CIITA restores MHC II expression in CIITA-deficient cell lines, confirming loss-of-function as the pathogenic mechanism (PMID:8402893). C-terminal deletion and dominant-negative CIITA mutants further delineated critical domains for nuclear import and promoter activation, proving concordance with human immunophenotypes.

In summary, autosomal recessive CIITA variants consistently cause MHC class II deficiency through loss of transactivator function. Early molecular diagnosis facilitates prompt immunological management and hematopoietic stem cell transplantation. Key Take-home: CIITA sequencing is essential for definitive diagnosis of bare lymphocyte syndrome type II and guides curative therapy.

References

• Immunogenetics • 2000 • Defective MHC class II expression in an MHC class II deficiency patient is caused by a novel deletion of a splice donor site in the MHC class II transactivator gene. PMID:10663561
• Frontiers in Pediatrics • 2023 • Case report: A late and isolated presentation of meningoencephalomyelitis uncovers a novel pathogenic variant in the CIITA gene. PMID:37842025
• Journal of Immunology • 2001 • Mutation in the class II trans-activator leading to a mild immunodeficiency. PMID:11466404
• Cell • 1993 • Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). PMID:8402893

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