Induction of arthritis by single monoclonal IgG anti‐collagen type II antibodies and enhancement of arthritis in mice lacking inhibitory FcγRIIB

Abstract

IgG anti-collagen type II (CII) antibodies (Ab) can induce arthritis in healthy mice. Here we have investigated if single monoclonal IgG anti-CII Ab can induce arthritis in CIA-susceptible DBA/1 mice and if there is an IgG subclass dependency. The involvement of Fc receptors for IgG (Fc + R) in anti-CII Ab-mediated arthritis was also investigated by comparing the clinical outcome in DBA/1 mice to those in Fc + R-deficient mice. We demonstrate for the first time that single mAb to naive DBA/1 mice can induce persistent arthritis. Histology of the inflamed joints revealed massive cellular infiltrate and cartilage and bone destruction. All IgG subclasses tested (IgG1, IgG2a and IgG2b) were arthritogenic, with the IgG1 and IgG2b isotypes as the dominating arthritogenic Ab. Pathogenicity was dependent on engagement of activating Fc + R, as FcR + -deficient mice were completely resistant to Ab-mediated arthritis. The arthritis induced with the IgG1 and IgG2b Ab was also inhibited by Fc + RIII disruption, whereas arthritis mediated by the IgG2a Ab was not substantially affected. The arthritic response of the IgG1 and IgG2b isotypes, but not of the IgG2a Ab, was further enhanced in mice lacking the inhibitory Fc + RIIB. These results demonstrate that single IgG anti-CII mAb can induce erosive arthritis and that IgG anti-CII Ab mediate arthritis by engagement of Fc + R.

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

“…In collagen-induced arthritis (CIA), high titres of IgG against collagen type II (CII) are essential for disease onset and transfer of the IgG to naive mice induces 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.…”

Endoglycosidase treatment abrogates IgG arthritogenicity: Importance of IgG glycosylation in arthritis

“…CII-specific mAb induce an acute form of arthritis in mice, the collagen Ab-induced arthritis (CAIA) [30][31][32][33] that resembles the effector phase of collagen-induced arthritis (CIA) without involving a priming phase. This Ab-mediated arthritis is dependent on complement components [34], FccR [35,36], effector cytokines TNF-a and IL-1b [37], and on the cellular players, neutrophils and macrophages [32]. We used CAIA in the present study to understand the importance of glycosylation of the IgG molecule by EndoS treatment.…”