CIITA was first reported in relation to autosomal recessive major histocompatibility complex (MHC) class II deficiency by (Steimle et al., PMID:8402893). MHC class II molecules are essential for the presentation of exogenous peptides to CD4+ helper T cells and thus in the adaptive immune response. Mutations in four trans-acting genes CIITA, RFXANK, RFX5, and RFXAP are responsible for the primary immunodeficiency. 21 total variants, including (nonsense, missense, and splice site) have been reported in 11 probands in 11 publications. Affected individuals typically present in infancy with severe, recurrent infections, failure to thrive, low levels of CD4+ T cells, and undetectable HLA-DR expression on monocytes and B cells. The mechanism of pathogenicity appears to be loss of function.
This gene-disease association is supported by experimental evidence including animal models (PMID: 8624807). Mice that are homozygous with loss of function CIITA alleles (-/-) display a lack of MHC class II molecules on B cells and macrophages and low levels of peripheral CD4+ cells. They are also unable to form a proliferative T-cell response following immunization. Further experimental evidence that supports a causative role of CIITA for this disorder includes co-immunoprecipitation (PMID: 10913187), rescue of function in patient and non-patient cells (PMIDs: 8402893, 25940550), expression (PMID:16818750) and biochemical function (PMID: 11332992).
In summary, CIITA is definitively associated with autosomal recessive MHC class II deficiency. This has been repeatedly demonstrated in both research and the clinical diagnostic setting and has been upheld over time. Heterozygous carriers of CIITA variants are not clinically reported to have the disease. Classification approved by SCID-CID GCEP on 10/20/2022 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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