Copy number of <i>FCGR3B,</i> which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake

TLDR

Copy number variation in immune‑related genes is common, and low FCGR3B copy number has been linked to systemic lupus erythematosus; FcγRIIIb is a low‑affinity IgG receptor on neutrophils. The study aims to define how FCGR3B copy‑number variation influences immune‑complex clearance and its link to systemic lupus erythematosus. We found that FCGR3B copy number correlates with receptor expression, immune‑complex uptake, and serum levels; low copy number impairs clearance and associates with SLE, whereas high copy number associates with AASV, establishing a novel link between CNV, protein function, and autoimmune disease susceptibility.

Abstract

Copy number (CN) variation (CNV) has been shown to be common in regions of the genome coding for immune-related genes, and thus impacts upon polygenic autoimmunity. Low CN of FCGR3B has recently been associated with systemic lupus erythematosus (SLE). FcγRIIIb is a glycosylphosphatidylinositol-linked, low affinity receptor for IgG found predominantly on human neutrophils. We present novel data demonstrating that both in a family with FcγRIIIb-deficiency and in the normal population, FCGR3B CNV correlates with protein expression, with neutrophil uptake of and adherence to immune complexes, and with soluble serum FcγRIIIb. Reduced FcγRIIIb expression is thus likely to contribute to the impaired clearance of immune complexes, which is a feature of SLE, explaining the association between low FCGR3B CNV and SLE that we have confirmed in a Caucasian population. In contrast, antineutrophil cytoplasmic antibody–associated systemic vasculitis (AASV), a disease not associated with immune complex deposition, is associated with high FCGR3B CN. Thus, we define a role for FCGR3B CNV in immune complex clearance, a function that may explain why low FCGR3B CNV is associated with SLE, but not AASV. This is the first report of an association between disease-related gene CNV and variation in protein expression and function that may contribute to autoimmune disease susceptibility.