CD40 was first reported in relation to autosomal recessive hyper-IgM syndrome type 3 in 2006 (Ferrari S, et al., 2001, PMID: 11675497). CD40 is a cell surface receptor that is expressed on the surface of all mature B cells, the encoded protein is a receptor on antigen-presenting cells of the immune system and is essential for mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. Adaptor protein TNFR2 interacts with this receptor and serves as a mediator of the signal transduction. Deleterious biallelic variation in this gene thus disrupt immature B cells from receiving signal 2 from helper T cells, which is necessary to mature into mature B cells. These patients are characterized by hypogammaglobulinemia with normal or elevated levels of IgM. This gene-disease relationship is supported by both genetic and experimental evidence. At least sixteen variants (missense, splice site, and in frame indels) have been reported in eight probands from seven publications (PMIDs: 24122029, 12584544, 26545377, 25511220, 11675497, 17502893, 22443339) and seven additional affected family members. A role in disease is supported by the function of CD40 in generating or maintaining human CD21low B cells in vivo (PMID: 34623902), which can be observed as patient B cells defective in isotype switching and IgG/IgA/IgM production (PMID: 11675497). Additionally, a knock out mouse model which mounted IgM responses but no IgG, IgA, and IgE responses to thymus dependent (TD) antigens and CD40 was shown to be essential for T cell-dependent immunoglobulin class switching and germinal center formation, but not for in vivo T cell-dependent IgM responses and T cell-independent antibody responses (PMID: 7534202). In summary CD40 is definitively associated with autosomal recessive autosomal recessive hyper-IgM syndrome type 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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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