Tnfrsf13c, also known as the gene encoding BAFF-receptor (BAFFR), is a crucial gene for B-cell survival [1]. BAFFR is one of the main pro-survival receptors in B cells, and its function is related to B-cell development and humoral immune responses. BAFF, a member of the TNF family, binds to BAFFR, which is essential in mediating the survival function of BAFF [1,3].

In humans, a homozygous deletion within exon 2 of Tnfrsf13c leads to an almost complete block of B-cell development at the immature/transitional B-cell stage, resulting in immunodeficiency characterized by B-lymphopenia, agammaglobulinemia, and impaired humoral immune responses. However, BAFFR-deficient B cells can still develop into IgA-secreting plasma cells, leading to very few circulating B cells, low IgM and IgG serum concentrations but normal or high IgA levels [1]. Two common polymorphisms of Tnfrsf13c, P21R (rs77874543) and H159Y (rs61756766), affect BAFFR assembly and signaling. The H159Y polymorphism is more prevalent in multiple sclerosis patients, suggesting enhanced BAFFR-signaling might contribute to the disease pathogenesis [2]. The minor allele of the p.His159Tyr (H159Y) variant in Tnfrsf13c, which increases NF-κB activation and B-cell production, is more frequent in severe COVID-19 patients, indicating it as a potential genetic risk factor for severe COVID-19 [4].

In conclusion, Tnfrsf13c, through encoding BAFFR, plays a vital role in B-cell survival, development, and humoral immune responses. Genetic variations in Tnfrsf13c are associated with multiple diseases such as immunodeficiency, multiple sclerosis, and severe COVID-19, highlighting its significance in understanding disease mechanisms and potentially developing targeted therapies [1,2,4].