Current directions in autoimmunity最新文献

The association between C1q and autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus (SLE) is well established. Deficiency in C1q is considered to be a strong susceptibility factor and is corroborated by the fact that > or = 92% of the known cases of hereditary deficiency in C1q develop rheumatic disease. Furthermore, the observation of the presence of high-affinity autoantibodies against C1q antibodies in patients with SLE provides a strong correlation between these antibodies and the inflammatory processes that occur in this disease. Recent evidence using C1q-deficient mice has shown the presence of glomerulonephritis with immune deposits and a large number of apoptotic bodies in the diseased glomeruli suggesting a defect in the clearance of apoptotic cell by macrophages and dendritic cells (DCs). Although these data are consistent with the hypothesis that C1q deficiency may induce a generalized failure to clear immune complexes and apoptotic cells, this concept alone cannot wholly explain why individuals with C1q deficiency are prone to develop SLE. Therefore, C1q alone or in conjunction with other surface molecules must play a much more fundamental role in immunoregulation, especially those processes that regulate T cell function and tolerance. In support of this hypothesis is the finding that C1q causes inhibition of mitrogen-induced T cell-proliferative response by interaction with C1q receptors. Furthermore, macrophages and possibly DCs not only synthesize but also display C1q as a type II cell surface molecule, especially at sites of inflammation. Although it is not yet known what role the surface-expressed C1q plays, it is tempting to assume that it plays a role in the priming of naïve T cells by DCs. This work will review the current concepts of the role of C1q and C1q receptors in autoimmunity.

The complement system plays a complex role in the pathogenesis of autoimmune diseases. It inhibits autoimmunity development by helping to maintain self-tolerance and/or by facilitating the disposal of immune complexes and apoptotic cell antigens. On the other hand, complement activation is thought to contribute significantly to end organ damage in antibody-mediated autoimmune and inflammatory conditions, although the relevant importance of complement and Fe receptor pathways in these processes has recently been debated. To avoid autologous complement-mediated tissue injury, host cells normally express a number of soluble and membrane-bound complement regulatory proteins. Recent studies with gene knockout mice have suggested that membrane-bound complement regulatory proteins may critically determine the sensitivity of host tissues to complement injury in autoimmune and inflammatory disorders. Evidence is also accumulating to support the hypothesis that membrane complement regulatory proteins may not only inhibit complement-mediated injury during the effector phase of autoimmunity but also influence the adaptive immune response through complement-dependent or -independent mechanisms. The latter mechanism is likely related to their potential as cell surface signaling molecules.

B cell complement receptors have been shown to be important in the generation of normal humoral immune responses, and they likely also participate in the development of autoimmunity. Complement component and receptor deficiencies have been associated with SLE in both animal models and patients with disease. Recent data suggest that Cr2 is a lupus susceptibility gene in the NZM2410 mouse model for lupus, as it generates complement receptors that are structurally and functionally altered. Complement deficiency may result in autoimmune disease because of the inability to appropriately clear immune complexes or apoptotic cells or by the impaired generation of C3-coated autoantigens for CR1/CR2. In turn, CR1/CR2 may participate in the maintenance of B cell tolerance by lowering the threshold for negative selection of autoreactive B cells, by targeting autoantigen to FDCs in secondary lymphoid organs, or by regulating autoreactive T cell function. The effect of CR2 has not been dissected from that of CR1 in the animal studies performed to date. Furthermore, the effects of CR1/CR2 dysfunction or partial deficiency, which are found in the NZM2410 mouse model and in patients with SLE respectively, have not been delineated from those of complete deficiency, which has been studied in several animal models of autoimmunity and tolerance. Although CR1/CR2 dysfunction or deficiency may confer only a modest phenotype in isolation, it is likely that when combined with other disease susceptibility genes it will result in a fully penetrant end-stage disease phenotype. Understanding the mechanisms by which these receptors participate in the maintenance of B cell tolerance will be critical in developing appropriate therapeutic interventions for patients with autoimmune diseases such as SLE.