The role of the complement system in arthritis and stroke

Abstract: Complement is part of the innate immune system and functions primarily as a first line of defense against invading microorganisms. It is a complex cascade, which can be activated via three pathways: the classical, alternative and mannan-binding lectin pathway. To study the role of the complement system in disease pathogenesis, we have generated mice deficient in C3, which is the central protein in all three pathways, and mice deficient in factor B, which is critical for the activation of the alternative pathway. Using these complement deficient mice, we have found that complement activation by both the classical and the alternative pathways plays a critical role in two models of rheumatoid arthritis, namely collagen-induced arthritis and arthritis induced by arthritogenic monoclonal antibodies. Our findings indicate that antibody binding to collagen triggers the activation of the classical pathway, which is then amplified by the alternative pathway.When subjected to permanent focal brain ischemia by middle cerebral artery occlusion, the infarction volume in the C3 deficient mice was significantly larger than that in control mice. These results, together with the finding of reduced number of presumed neural progenitor cells in the penumbra and infarction area of C3 deficient mice, implicate the complement system as a positive regulator of neurogenesis in brain ischemia. Thus, besides its well-established role in host defense against pathogens, the complement system may have additional roles in disease pathogenesis: its activation appears to augment tissue damage in autoantibody-associated diseases such as arthritis, but may contribute to tissue repair after cerebral ischemia.Designing drugs targeting complement activation may be a rational therapeutic strategy. However, great care will have to be executed in defining and reaching the proper balance between the two contradictory effects of the complement system.