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C5a controls the FcγR activation in inflammatory processes

The role of Fcγ receptors and complement in various immune complex-mediated diseases has been debated for a long time. The advent of gene knockout technology as well as the characterization of different Fc and complement receptors as well as new cytokines have now allowed one to dissect the different pathogenetic elements of innate immunity in the autoimmune inflammatory response.

Using various murine knockout models, in particular Fcγ receptor-deficient, mast cell-defective animals as well as complement-deficient animals, during the past years we have demonstrated that FcγRIII and the C5a receptor are both critical for induction of immune complex-mediated vasculitis. In several studies it became clear that mast cells have a critical role in initiation in some of the inflammatory processes. This has also been demonstrated for rheumatoid arthritis meanwhile. On these mast cells, again, FcγRIII is the critical activating receptor used by immune complexes. When examining the effects of immune complexes in glomerular mesangial cells as well as glomerular basement membrane nephritis, we could show that IgG immune complexes had opposing regulatory effects on FcγRII and FcγRIII receptors in glomerular mesangial cells. Whereas activation by tumor necrosis factor alpha/IL-1β induces substantial FcγRII expression, IFN-γ showed a complete downregulation of FcγRII. At the same time, IFN-γ induced the Fc receptor γ-chain as well as the low-affinity IgG receptor FcγRIII. Triggering of FcγRIII again induced chemoattractant protein 1, MCP-1, MCP-5 and RANTES. Examining the regulatory role in the cooperation of Fcγ receptors and complement in interstitial pneumonitis, we could demonstrate that C5a is critical in amplifying the inflammatory response to IgG. On one hand, C5a is important in downregulating the inhibitory FcγRII; on the other, inducing the activating FcγRIII. Altogether, the dissection of the different innate components of pathogenesis allows for new strategies to intervene in this inflammatory process.

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Schmidt, R. C5a controls the FcγR activation in inflammatory processes. Arthritis Res Ther 5 (Suppl 3), 109 (2003).

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