Abstract
The complement component C3 is at the heart of the complement cascade. It is a complex protein, which generates different functional activated fragments (C3a, C3b, iC3b, C3c, C3d). C3b is a constituent of the alternative pathway C3 convertase (C3bBb), binds multiple regulators, and receptors, affecting thus the functioning of the immune system. The activated forms of C3 are a target for autoantibodies. This review focuses on the discovery, disease relevance, and functional consequences of the anti-C3b autoantibodies. They were discovered about 70 years ago and named immunoconglutinins. They were found after infections and considered convalescent factors. At the end of the twentieth century IgG against C3b were found in systemic lupus erythematosus and recently in lupus nephritis, correlating with the disease severity and flare. Cases of C3 glomerulopathy and immune complex glomerulonephritis were also reported. These antibodies recognize epitopes, shared between C3(H2O)/C3b/iC3b/C3c and have overt functional activity. They correlate with low plasmatic C3 levels in patients. In vitro, they increase the activity of the alternative pathway C3 convertase, without being C3 nephritic factors. They perturb the binding of the negative regulators Complement Receptor 1 and Factor H. The clear functional consequences and association with disease severity warrant further studies to establish the link between the anti-C3b autoantibodies and tissue injury. Comparative studies with such antibodies, found in patients with infections, may help to uncover their origin and epitopes specificity. Patients with complement overactivation due to presence of anti-C3b antibodies may benefit from therapeutic targeting of C3.
Highlights
The complement system is apart of the innate immune defense [1, 2]
It was hypothesized that immunoconglutinins could enhance the clearance of bacteria by phagocytes. This view was challenged, when immunoconglutinins/anti-C3 activated forms Ab were established in patients with autoimmune diseases. Such Ab were detected in systemic lupus erythematosus (SLE) [29,30,31,32], lupus nephritis (LN) [33, 34], in Crohn disease [35], in some nephrotic kidney diseases [36,37,38], in dense deposit disease (DDD) [39], in C3 glomerulopathy (C3G), and Immune Complex glomerulonephritis (IC-GN) [40] as well as in autoimmune-prone mice [32]
Growing body of experimental data revealed that the anti-C3b Ab have overt functional consequences [30, 32, 33, 40] and correlate with disease severity at least in LN [33, 34]
Summary
The complement system is apart of the innate immune defense [1, 2]. Autoantibodies against complement components and regulators have proven pathogenic effect. This view was challenged, when immunoconglutinins/anti-C3 activated forms Ab were established in patients with autoimmune diseases Such Ab were detected in systemic lupus erythematosus (SLE) [29,30,31,32], lupus nephritis (LN) [33, 34], in Crohn disease [35], in some nephrotic kidney diseases [36,37,38], in dense deposit disease (DDD) [39], in C3 glomerulopathy (C3G), and Immune Complex glomerulonephritis (IC-GN) [40] as well as in autoimmune-prone mice [32]. The levels of anti-C3b Ab (measured as immunoconglutinins) were higher in active SLE compared to patients with inactive disease [29]. There is still not sufficient data that could determine the diagnostic value of anti-C3b Ab in patient with C3G and IC-GN
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