Destructive Arthritis in the Absence of Both FcγRI and FcγRIII

Abstract

Fc receptors for IgG (FcγR) have been implicated in the development of arthritis. However, the precise contribution of the individual FcγR to joint pathology is unclear. In this study, the role of the different FcγR was assessed both in an active and in a passive mouse model of arthritis by analyzing disease development in double and triple knockout (KO) offspring from crosses of FcγRI KO, FcγRIII KO, FcγRI/III double KO, or FcR γ-chain KO with the FcγRII KO on C57BL6 background, which is susceptible for collagen-induced arthritis (CIA). In the active CIA model, onset was significantly delayed in the absence of FcγRIII, whereas incidence and maximum severity were significantly decreased in FcγRI/II/III triple KO but not in FcγRII/III double KO and FcγRI/II double KO mice as compared with FcγRII KO animals. Remarkably, fully destructive CIA developed in FcγRI/II/III triple KO mice. In contrast, FcR γ/FcγRII double KO mice were resistant to CIA. These findings were confirmed with the passive KRN serum-induced arthritis model. These results indicate that all activating FcγR play a role in the development of arthritis, mainly in the downstream effector phase. FcγRIII is critically required for early arthritis onset, and FcγRI can substantially contribute to arthritis pathology. Importantly, FcγRI and FcγRIII were together dispensable for the development of destructive arthritis but the FcR γ-chain was not, suggesting a role for another FcR γ-chain associated receptor, most likely FcγRIV. In addition, FcγRII plays a negative regulatory role in both the central and effector phase of arthritis.

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

“…K/BxN-PA is abrogated in mice lacking the FcRg subunit (5,6) that is required for the expression and function of these FcgRs (7). Interestingly, K/BxN-PA is reduced, but not abolished, in FcgRIIIA 2/2 mice (5,8), suggesting that FcgRI and/or FcgRIV contribute to disease. K/BxN-PA is, however, unaffected in mice lacking FcgRI (5,6).…”

Properties of mouse and human IgG receptors and their contribution to disease models

“…on May 9, 2018. by guest www.bloodjournal.org From collagen type II in Freund adjuvant. 65 Because these mice express only Fc␥RIV as an activating IgG receptor, it was deduced that Fc␥RIV contributes to collagen-induced arthritis. These mice, nevertheless, express the high-affinity IgE receptor Fc⑀RI that may also contribute to collagen-induced arthritis, as immunizations in Freund adjuvant leads to antigen-specific IgG but also IgE production.…”

The Inhibiting Fc Receptor for IgG, FcγRIIB, Is a Modifier of Autoimmune Susceptibility

“…Induction and clinical evaluation of collagen-induced arthritis (CIA) and K/ B3N serum-induced arthritis was performed as described (19). In the CIA model, on days 35 and 60 after the primary immunization, serum was collected for the measurement of anti-collagen type II (CII) Ab titers by ELISA.…”