Autoantibodies Against C3b—Functional Consequences and Disease Relevance

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.

Immunological features of patients affected by Barraquer-Simons syndrome

“…Therefore, further studies are needed in order to clarify if anti-FB and anti-C3b autoantibodies have a primary mechanistic role in the pathology of the lipodystrophy or if they rather secondarily arise as a consequence of the increase in circulating complement proteins produced due to unabated complement activation in the presence of C3NeF. A plausible possibility in line with the presence of C3NeF and low C3 levels in our BSS cohort is that these autoantibodies synergistically promote further C3 convertase stabilization and C3 consumption in serum, similarly to what has already been described by Vasilev and colleagues for anti-C3 and anti-C3b autoantibodies in patients with lupus nephritis [33,34].…”

Clinical and functional consequences of anti-properdin autoantibodies in patients with lupus nephritis

“…We found that in some patients anti-properdin-positive IgG weakly increased the binding of properdin to C3b and to pro-convertase (C3bB), and did not affect the alternative complement pathway C3 convertase, unlike C3NeF, which reacted with C3 convertase and stabilized it [19]. In a case report of anti-properdin-positive IgG activated complement in serum [18], we did not detect fluid-phase complement activation by anti-properdin IgG, contrary to autoantibodies against other alternative pathway components, such as antifactor B, anti-C3b or anti-FH [29][30][31][32]. A possible explanation for the weak or absent effect of anti-properdin IgG could be the usage of low pH elution buffer for IgG purification, which may have a dramatic effect on the biological activity of IgGs and their antigen-binding behavior [33].…”

Age-related changes in brain phospholipids and bioactive lipids in the APP knock-in mouse model of Alzheimer’s disease

“…Our studies showed decreased levels of C3 in the hippocampus of 18-months-old App KI mice. Complement activation leads to the production of functional fragments, with sequential cleavages from the conversion of C3, involved in phagocytosis via C3b opsonization and chemotaxis via C3a and C5a [ 98 ]. Thus, the decrease in C3 levels may be due to cleavage into fragments since the antibody used was against intact component C3 (185 kDa) but not the fragments, suggesting complement activation at 18 months in the App KI mice [ 94 ].…”