The complement system in stherosclerosis and arthritis
Abstract: The complement system plays an essential role in the humoral immune response. Activated complement has diverse functions, including the initiation of inflammation, recruitment of leukocytes, clearance of immune complexes, neutralization of pathogens, regulation of antibody responses and disruption of cell membranes. The complement system can be activated by three pathways: the classical, the lectin and the alternative pathway.The aim of the present study is to evaluate the role of the complement system in two chronic inflammatory diseases; atherosclerosis and rheumatoid arthritis, using third complement component (C3) deficient or factor B deficient mice. C3 deficient mice cannot activate the complement cascade beyond the formation of the C3-convertase of the classical/lectin pathway, and factor B deficient mice are unable to activate the alternative pathway. The use of these two complement deficient strains enabled us to assess the relative roles of these activation pathways.The C3 deficient mice on atherosclerosis-prone genetic background had more severe hyperlipidemia and larger atherosclerotic plaques than control mice. The C3 deficient mice also had a more pro-atherogenic lipoprotein profile with more VLDL triglycerides and more LDL cholesterol. Factor B deficiency did not affect serum lipid levels or atherogenesis. Complement activation by the classical or lectin pathway appears to exert atheroprotective effects through the regulation of lipid metabolism.Intravenously applied normal polyclonal immunoglobulins (ivIg) have broad therapeutic applications in the treatment of autoimmune and systemic inflammatory diseases. Recently, ivIg have been shown to inhibit atherogenesis in experimental animal models. In our study, the ivIg treatment led to reduction of lesion fraction area in the aortic root of the complement sufficient mice whereas the lesion fraction area of the C3 deficient mice was not affected. We also observed an increase in macrophage accumulation in ivIg treated mice, although this effect was not complement dependent. Complement fragments generated through Fc-dependent complement activation may mediate the anti-atherosclerotic effects of ivIg.In rheumatoid arthritis, the complement system seems to play a major role in the perpetuation of inflammation and tissue damage, as demonstrated by the amelioration of arthritis in C3 deficient and to a lesser extent in factor B deficient mice.In conclusion, the complement system is involved in the pathogenesis of rheumatoid arthritis and atherosclerosis in mice.
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