Induction and Suppression of Collagen-Induced Arthritis Is Dependent on Distinct Fcγ Receptors

Abstract

Receptors for immunoglobulin (Ig)G (FcγRs) are important for the antibody-mediated effector functions of the immune system. FcγRI and FcγRIII trigger cell activation through a common γ chain, whereas FcγRII acts as a negative regulator of antibody production and immune complex–triggered activation. Here we describe the in vivo consequences of FcγR deficiency in a mouse model of human rheumatoid arthritis. FcRγ chain–deficient mice on arthritis-susceptible DBA/1 background were immunized with collagen for induction of collagen-induced arthritis. The DBA/1 mice lacking FcRγ chain were protected from collagen-induced arthritis in contrast to wild-type mice, although both groups produced similar levels of IgG anticollagen antibodies. In comparison, DBA/1 mice lacking FcγRII developed an augmented IgG anticollagen response and arthritis. These observations suggest a crucial role of FcγRI and FcγRIII in triggering autoimmune arthritis.

Cutting Edge: The Murine High-Affinity IgG Receptor FcγRIV Is Sufficient for Autoantibody-Induced Arthritis

“…1A). FcgRIIB deficiency has indeed been reported to increase the susceptibility to K/BxN-PA (17), as well as to other arthritis models (18,19). FcgRIIIA-independent K/BxN-PA is therefore negatively regulated by FcgRIIB.…”

Complement activation by both classical and alternative pathways is critical for the effector phase of arthritis

“…Thus, binding of the C3b and/or C4b fragments to these receptors is unlikely to have any role in arthritis. Fc gamma receptors, however, are of clear importance for arthritis [30,40,41], and engagement of these receptors may lead to development of arthritis in the absence of complement activation.…”

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

“…1,2 In addition, mice lacking activating Fc receptors for IgG (Fc gamma receptors (FccRs)) are protected from CIA, while absence of the inhibitory FccRIIb results in augmented CIA. 3,4 Thus, FccRIIb is a negative regulator of B cells dampening the signaling strength of the B-cell receptor (BCR) and reducing Ab secretion, particularly in autoreactive B cells. 5 A direct role of B cells in arthritis is further proven in B cell-deficient mice that do not develop CIA.…”