Background Rheumatoid arthritis is characterized by immune complexes dependent chronic joint inflammation and severe cartilage and bone destruction. Earlier we found that in the absence of activatory FcγRI and III, joint destruction during the early phase of murine antigen-induced arthritis (AIA) was protected (1). Recent studies show a crucial role of activatory FcγRIV in the K/BxN serum transfer arthritis model (2) but the role of this receptor in chronic phase of arthritis has not yet been elucidated.
Objectives To study the role of activatory FcγRIV in joint pathology in acute and chronic phase of AIA.
Methods AIA was induced by injection of mBSA into the knee joint of FcγRI,II,III–/–, FcγI,II,III,IV–/– and wildtype (WT) control mice previously immunized with mBSA/CFA. Histology of total knee joints was taken at day 7 and 21 after arthritis induction. Joint inflammation and bone destruction was scored using an arbitrary scale (0-3). Cartilage damage was measured as proteoglycan (PG) depletion and matrix erosion. mBSA antibody titers were determined using ELISA.
Results Both KO strains showed significantly higher antibody titers against mBSA when compared to immunized control mice. In the early phase of AIA (day 7), joint inflammation was significantly higher in FcγRI,II,III–/– (infiltrate 47% and exudate 107% higher) when compared to WT controls. In FcγRI,II,III,IV–/– however, although high antibody titers were present, inflammation was significantly lower (infiltrate 30% and exudate 46% lower) than in WT controls. Early cartilage was protected in both strains reflected by significantly lower PG depletion (34% and 20% lower respectively) when compared to their WT controls.
During the chronic phase at day 21, joint inflammation in FcγI/II/III–/– was still significantly higher (infiltrate 450% and exudate 170% higher) when compared to WT controls. Protection of cartilage damage seen in early AIA was lost and PG depletion significantly increased in FcγRI,II,III–/– by 260%. Bone erosion also increased by 150%. These results suggest that FcγR I and III regulate destruction in the early phase whereas FcγRIV may be more important in chronic stages of arthritis.
In line with this we found that at day 21 joint inflammation in FcγRI,II,III,IV–/– was much lower when compared with FcγI/II/III–/– and remained at the same level as their WT controls, implying an active role of FcγRIV in inflammation during the chronic phase. The amount of PG depletion in FcγRI,II,III,IV–/– was comparable to that observed in WT. In contrast erosion of cartilage matrix but also of bone were found to be significantly lower when compared to WT controls (76% and 34% lower respectively).
Conclusions Activatory FcγRIV is crucial in mediating severe cartilage and bone destruction during the chronic phase of antigen-induced arthritis probably by regulating joint inflammation and stimulating myeloid cells by binding immune complexes.
van Lent P et al., Arthritis Rheum. 2006.
Nimmerjahn F et al., Proc. Natl. Acad Sci. U. S. A 2010.
Disclosure of Interest None declared