Complement Therapeutics in Autoimmune Disease

Abstract

Many autoimmune diseases are characterized by generation of autoantibodies that bind to host proteins or deposit within tissues as a component of immune complexes. The autoantibodies can activate the complement system, which can mediate tissue damage and trigger systemic inflammation. Complement inhibitory drugs may, therefore, be beneficial across a large number of different autoimmune diseases. Many new anti-complement drugs that target specific activation mechanisms or downstream activation fragments are in development. Based on the shared pathophysiology of autoimmune diseases, some of these complement inhibitory drugs may provide benefit across multiple different diseases. In some antibody-mediated autoimmune diseases, however, unique features of the autoantibodies, the target antigens, or the affected tissues may make it advantageous to block individual components or pathways of the complement system. This paper reviews the evidence that complement is involved in various autoimmune diseases, as well as the studies that have examined whether or not complement inhibitors are effective for treating these diseases.

Keywords: antibody; autoimmunity; complement; immune complex; therapeutic.

Figure 1

The complement system has both pathogenic and protective roles in systemic lupus erythematosus. Complement proteins have multiple functions that affect lupus, both positively and negatively. The classical pathway may help facilitate the removal of apoptotic and damaged cells as well as immune complexes, reducing the risk of developing autoimmunity to nuclear components. C1q may also directly reduce CD8 T cell activation, thereby attenuating downstream immunity and autoantibody generation. Once activated, however, the complement system can promote tissue injury and disease severity. The complement system can directly cause cytotoxic injury in tissues, and also increases inflammation by attracting leukocytes and inducing interferon production by dendritic cells. Complement fragments may also increase T cell and B cell responsiveness, increasing the response to autoantigens.

Figure 2

Pro- and anti-inflammatory effects of complement activation in tissues. Complement proteins can directly bind to injured and apoptotic cells. The complement system can also be activated by natural antibodies bound to injured cells. Autoantibodies that are bound to self-antigens can activate complement directly on the cell surface or on immune complexes deposited near the cells. C5b-9 formed on the cell surface can lead to cell activation or lysis. C3a and C5a generated within tissues can promote tissue inflammation by activating nearby cells (which may then secrete cytokines and chemokines) or by causing infiltration of the tissue by circulating leukocytes.

Figure 3

Complement activation may directly injure the podocytes in membranous nephropathy. In membranous nephropathy, immune complexes are located between the glomerular basement membrane (GBM) and the podocyte foot processes. Activation at this location generates C5b-9, which may directly damage podocytes. Because of the location of the immune complexes, however, most of the C3a and C5a that is generated probably passes into the urine and does not enter the bloodstream. This may explain why leukocytes do not typically infiltrate the glomeruli in this disease.