FcγRIIb on Myeloid Cells Rather than on B Cells Protects from Collagen-Induced Arthritis

Abstract

Extensive analysis of a variety of arthritis models in germline KO mice has revealed that all four receptors for the Fc part of IgG (FcγR) play a role in the disease process. However, their precise cell type–specific contribution is still unclear. In this study, we analyzed the specific role of the inhibiting FcγRIIb on B lymphocytes (using CD19Cre mice) and in the myeloid cell compartment (using C/EBPαCre mice) in the development of arthritis induced by immunization with either bovine or chicken collagen type II. Despite their comparable anti-mouse collagen autoantibody titers, full FcγRIIb knockout (KO), but not B cell–specific FcγRIIb KO, mice showed a significantly increased incidence and severity of disease compared with wild-type control mice when immunized with bovine collagen. When immunized with chicken collagen, disease incidence was significantly increased in pan-myeloid and full FcγRIIb KO mice, but not in B cell–specific KO mice, whereas disease severity was only significantly increased in full FcγRIIb KO mice compared with incidence and severity in wild-type control mice. We conclude that, although anti-mouse collagen autoantibodies are a prerequisite for the development of collagen-induced arthritis, their presence is insufficient for disease development. FcγRIIb on myeloid effector cells, as a modulator of the threshold for downstream Ab effector pathways, plays a dominant role in the susceptibility to collagen-induced arthritis, whereas FcγRIIb on B cells, as a regulator of Ab production, has a minor effect on disease susceptibility.

FcγRIIB and autoimmunity

“…Of note, Yilmaz‐Elis et al . were not able to detect an increase in cCIA in CD19‐cre × FcγRIIb fl/fl mice. However, they observed a modest increase in the severity of bovine CIA using this model.…”

“…Conversely, the restoration of FcγRIIb levels on bone marrow cells of (NZB × NZW) F1 mice (a mouse model of SLE) using an FcγRIIb‐expressing retrovirus can prevent autoimmunity , and transgenic overexpression of FcγRIIb on B cells reduces the development of SLE in MRL‐ lpr mice . In contrast, B‐cell FcγRIIB deficiency does not play a significant role in controlling disease severity in nephrotoxic nephritis and CIA, where myeloid cell FcγRIIB expression is more important , although transgenic overexpression of FcγRIIb on B cells can control some aspects of CIA .…”

New revelations from an old receptor: Immunoregulatory functions of the inhibitory Fc gamma receptor, FcγRIIB (CD32B)

“…In otherwise resistant strains of mice, FcγRIIB deficiency results in several Ab‐ or IC‐dependent autoimmune symptoms such as alveolitis and lupus nephritis, which can be mitigated by transgenic overexpression of hFcγRIIB on B cells . FcγRIIB deficiency is also associated with elevated collagen‐specific IgG titers and disease severity in collagen‐induced arthritis (CIA) models . In humans, similar associations are seen.…”

“…However, deficiency of FcγRIIB on B cells is only a susceptibility factor under the influence of epistatic modifiers for the development of autoimmunity . Thus, the presence of FcγRIIB on B cells would simply be a prerequisite for autoantibody production and may have only a minor effect on disease susceptibility, whereas its presence on myeloid effector cells, as a modulator of the threshold for the downstream Ab effector pathway may play a dominant role in the susceptibility for autoimmune pathology . For example, overexpression of FcγRIIB on B cells seems to have no effect on the frequency or disease course of CIA, but results in early resolution, reduction in joint destruction, and reduced levels of autoantibodies, whereas overexpression on macrophages results in reduced bacterial phagocytosis rather than an effect on the autoimmune disease process .…”

FcγRIIb inhibits immune complex-induced VEGF-A production and intranodal lymphangiogenesis

“…Collagen-induced arthritis (CIA) is a model of inflammatory arthritis with some similarities to human rheumatoid arthritis. Autoantibodies against type II collagen play an important role in CIA pathogenesis via FcγR ligation, and deficiency of FcγRIIb on myeloid cells results in increased disease severity (21). Of note, VEGF-A inhibition ameliorates disease (22).…”