Distinct cell-specific control of autoimmunity and infection by FcγRIIb

Abstract

FcγRIIb 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 FcγRIIb can modulate these processes, we created transgenic mice overexpressing FcγRIIb on B cells or macrophages. Overexpression of FcγRIIb 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 FcγRIIb in immune responses, demonstrate the contrasting roles played by FcγRIIb on B cells and macrophages in the control of infection and autoimmunity, and emphasize the therapeutic potential for modulation of FcγRIIb expression on B cells in inflammatory and autoimmune disease.

FcγRIIb on Myeloid Cells and Intrinsic Renal Cells Rather than B Cells Protects from Nephrotoxic Nephritis

“…In contrast, transgenic overexpression of FcgRIIb on B cells was found to reduce the severity of collagen-induced arthritis in mice as well as lower the level of anti-collagen Abs (18). Our results suggest that in glomerulonephritis, B cell expression of FcgRIIb is not the sole determinant of protection from injury.…”

Marginal zone B cells are naturally reactive to collagen type II and are involved in the initiation of the immune response in collagen-induced arthritis

“…In fact, overexpression of FccRIIb on B cells in mice profoundly decreases IgG responses. 39 CIA is regarded as an IgG-mediated disease, but previous studies have also shown that IgM play an important role. 40 Thus, mice deficient in IgM (lacking both membrane and secreted IgM) develop significantly reduced CIA and decreased IgG2a anti-CII Abs.…”

Apoptotic and antitumor activity of death receptor antibodies require inhibitory Fcγ receptor engagement

“…In contrast, FcγRIIB is a negative regulator of immune cell activation and antibody-antigen immune complex-triggered inflammation, thereby contributing to the regulation of effector cell activation (25,26). In addition, FcγRIIB's expression on follicular B cells and plasma cells is critical to the maintenance of peripheral tolerance (27)(28)(29)(30). Each FcγR interacts differently with Fcs of the different IgG subclasses within a species and displays unpredictable crossspecies interactions, precluding extrapolation from one species to another.…”