Fcrn Is A Cd32a Coreceptor That Determines Susceptibility To Igg Immune Complex-Driven Autoimmunity

IgG immune complexes (ICs) promote autoimmunity through binding fragment crystallizable (Fc) gamma-receptors (FcyRs). Of these, the highly prevalent FcyRIIa (CD32a(H)) histidine (H)-131 variant (CD32(H)) is strongly linked to human autoimmune diseases through unclear mechanisms. We show that, relative to the CD32a arginine (R)-131 (CD32a(R)) variant, CD32a(H) more avidly bound human (h) IgG' IC and formed a ternary complex with the neonatal Fc receptor (FcRn) under acidic conditions. In primary human and mouse cells, both CD32a variants required FcRn to induce innate and adaptive immune responses to hIgG1 ICs, which were augmented in the setting of CD32a(H). Conversely, FcRn induced responses to IgG IC independently of classical FcyR, but optimal responses required FcRn and FcyR. Finally, FcRn blockade decreased inflammation in a rheumatoid arthritis model without reducing circulating autoantibody levels, providing support for FcRn's direct role in IgG IC-associated inflammation. Thus, CD32a and FcRn coregulate IgG IC-mediated immunity in a manner favoring the CD32a(H) variant, providing a novel mechanism for its disease association.