The Role of Fc gamma Receptors and Mast Cell Chymase in Autoimmune Arthritis

Sammanfattning: In autoimmune diseases such as rheumatoid arthritis (RA), self-reactive antibodies are present at high levels, which contributes to disease pathogenesis. The antibodies mediate their effect predominantly by binding to Fc gamma receptors (Fc?R) on various leukocytes, such as monocytes, macrophages and mast cells, where Fc?R ligation leads to cell activation. In this thesis the role of Fc?R in RA was investigated. We could, for the first time, demonstrate an increased expression of the inhibitory Fc?RIIb in RA synovial tissue, while this receptor as well as Fc?RI were almost absent in healthy synovial tissue. The enhanced Fc?RI expression in RA synovia was reduced by one intraarticular injection of glucocorticoids, indicating that Fc?RI participates in the joint inflammation. Interestingly, RA patients with an ongoing joint inflammation exhibited blood monocytes with immune compromised features, such as decreased Fc?R binding of IgG1-IC and reduced TNF production. These effects were associated with high levels of auto-antibodies in the patients, implying that the monocyte Fc?R are saturated with IgG. In order to investigate whether soluble Fc?R could be used as a therapy in arthritis, we injected human soluble Fc?R into mice with collagen-induced arthritis (CIA). The soluble Fc?R reduced the levels of pathogenic IgG anti-collagen type II (CII) antibodies, arthritis severity and pro-inflammatory cytokines. Thus, suggesting that soluble Fc?R may represent a novel therapeutic agent in RA.We also studied the disease-aggravating role of mast cells in arthritis by investigating mouse mast cell protease-4 (mMCP-4) in CIA. We found that mMCP-4 deficient mice displayed a reduced IgG anti-CII response and reduced arthritis severity. This indicates a role for mMCP-4 in adaptive immunity.In conclusion, these data demonstrate that IgG occupancy of Fc?R and mast cell secretion of mMCP-4 play vital roles in the development of autoimmune arthritis.