Complement and autoimmunity: new insights into old questions

The innate immune system is now known to play an important role in modification of adaptive immunity. In addition, innate immunity is centrally important to the development of collagen-induced arthritis (CIA), a widely studied model for the human disease rheumatoid arthritis. Complement is a key component of the innate immune system, and complement activation in inflamed joints has been previously shown to both characterize active disease in patients with rheumatoid arthritis as well as to be essential to the development of CIA in mice and other similar animal models. There is little understanding, however, of the specific mechanisms by which complement influences cellular and humoral autoimmunity in CIA, or how complement activation fragments intersect with other innate or adaptive immune mechanisms in the disease process. We have recently found that the alternative complement pathway component factor B is centrally involved in disease pathogenesis in the CIA model. Following transfer of anti-type II collagen monoclonal antibodies into factor B-deficient mice, only modest inflammation results as compared with wild-type mice. In addition, expression of complement receptor 2 (CR2/CD21) and complement receptor 1 (CR1/CD35), molecules that are expressed on B lymphocytes and T lymphocytes as well as follicular dendritic cells and are known links for innate and adaptive immunity, is required to develop CIA. Specifically, elimination of CR2/CR1 expression by gene targeting results in a marked decrease in the generation of arthritis following immunization with type II collagen in DBA1/j mice. Of interest, despite substantial protection from disease in receptor-deficient mice, only modest changes occur in IgG anti-type II collagen antibody subclass and isotype responses. Understanding the mechanisms by which the alternative pathway as well as complement receptors modulate inflammatory arthritis should provide important insights into the relationships between innate and adaptive immunity.