AFF3, a susceptibility factor for autoimmune diseases, is a molecular facilitator of immunoglobulin class switch recombination

Abstract

Immunoglobulin class switch recombination (CSR) plays critical roles in controlling infections and inflammatory tissue injuries. Here, we show that <i>AFF3</i>, a candidate gene for both rheumatoid arthritis and type 1 diabetes, is a molecular facilitator of CSR with an isotype preference. <i>Aff3</i>-deficient mice exhibit low serum levels of immunoglobulins, predominantly immunoglobulin G2c (IgG2c) followed by IgG1 and IgG3 but not IgM. Furthermore, <i>Aff3</i>-deficient mice show weak resistance to <i>Plasmodium yoelii</i> infection, confirming that <i>Aff3</i> modulates immunity to this pathogen. Mechanistically, the AFF3 protein binds to the IgM and IgG1 switch regions via a C-terminal domain, and <i>Aff3</i> deficiency reduces the binding of AID to the switch regions less efficiently. One <i>AFF3</i> risk allele for rheumatoid arthritis is associated with high mRNA expression of <i>AFF3</i>, <i>IGHG2</i>, and <i>IGHA2</i> in human B cells. These findings demonstrate that AFF3 directly regulates CSR by facilitating the recruitment of AID to the switch regions.