It has been shown that GITR interacts with the pro-apoptotic protein Siva, leading to cell death.[46] Mouse gene knockout studies have shown that the TNF receptor superfamily plays a role in CD4+ T cell response and T cell-dependent B cell proliferation and differentiation.[47] Byun identified the c.193C/T mutation in the TNFRSF4 gene, leading to arg65-to-cys substitution, which is associated with immunodeficiency.[48] Clinvar suggested that the TNFRSF4 gene c.193C/T locus was the pathogenic locus of abortion. This evidence concerns the gene CD4 and immune system disorder.