The instructive role of the complement system in the generation and maintenance of rheumatoid arthritis

Evidence was provided that complement activation is important in the initiation and for the maintenance of inflammation in RA. In particular, complement activation is common in RA synovial fluids when compared to disease controls, as RF and other autoantibodies can activate complement and precede RA by months to years . Evidence of the involvement of complement in the disease process, however, was limited to measurement of complement and complement split products in the synovial fluid or in the blood of RA patients and to complement receptor expression in the synovial lining. A major goal of this study is to show that activated macrophages in the inflamed synovium produce complement locally. Local synthesis of complement in the pannus creates a specific microenvironment that influences the pathogenesis of RA by regulating production of cytokines, chemokines, growth factors and angiogenic factors. Furthermore, complement is a candidate system that can provide instructions enabling the cellular immunity to select appropriate strategies for elimination of potentially noxious substances. This capability permits complement to mediate selective monocyte-endothelial cell interaction, to influence selection of autoantigens by B cells, to bias the development of Th1 cells and to induce the production of Th1 cytokines such as IL-2, IFN-gammand TGF- beta. In addition, IFN-gamma produced by Th1 cells, can upregulate directly local synthesis of C3 by activated macrophage to provide an increased concentration of C3 for covalent attachment to antigen within inflamed tissues or lymphoid compartments. Finally, we want to show that the local environment created by activated complement split products in the pannus, can attract blood derived cells and create an optimal condition for autoreactive B cells to form germinal centers (GCs). In order to survive in the GC and to express immunoreactive RAG-1 and RAG-2 proteins necessary for recombination of immunoglobulin genes, autoreactive B cells need signals via CD21. We hope that exciting insights will arise from this and similar studies, while some current dogmas may be questioned.