Search

Recent work has emphasised the marked genetic variability that exists in the Fc receptor locus. This variation can contribute to the risk of autoimmune disease in both mice and humans, but can also have a profound impact on defence against infection. Using FcγRIIB and FcγRIIIB as examples, we demonstrate that variations associated with increased susceptibility to autoimmunity may be maintained in populations for their beneficial effect against infection. We examine the KIR locus from the same perspective and highlight similarities between the two loci. Intense selection pressure by pathogens presumably accounts for the marked variability within both regions and leads to susceptibility to autoimmunity for some alleles., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

FcgammaRIIb is an inhibitory Fc receptor expressed on B cells and myeloid cells. It is important in controlling responses to infection, and reduced expression or function predisposes to autoimmunity. To determine if increased expression of FcgammaRIIb can modulate these processes, we created transgenic mice overexpressing FcgammaRIIb on B cells or macrophages. Overexpression of FcgammaRIIb on B cells reduced the immunoglobulin G component of T-dependent immune responses, led to early resolution of collagen-induced arthritis (CIA), and reduced spontaneous systemic lupus erythematosus (SLE). In contrast, overexpression on macrophages had no effect on immune responses, CIA, or SLE but increased mortality after Streptococcus pneumoniae infection. These results help define the role of FcgammaRIIb in immune responses, demonstrate the contrasting roles played by FcgammaRIIb on B cells and macrophages in the control of infection and autoimmunity, and emphasize the therapeutic potential for modulation of FcgammaRIIb expression on B cells in inflammatory and autoimmune disease.