Recognition molecules of the complement system: C1q and mannan-binding lectin in autoimmunity and immune defence

The C1 subcomponent C1q and the mannan-binding lectin (MBL) are recognition proteins of the complement system, and have similar structure. C1q binds to IgG and IgM and activates the classical pathway. MBL binds to carbohydrate structures and activates the lectin pathway. Autoantibodies to C1q are frequently found in severe systemic lupus erythematosus (SLE) and are present in virtually all patients with the hypocomplementemic urticarial vasculitis syndrome (HUVS). In order to investigate possible heterogeneity with regard to epitope specificity, anti-C1q antibodies in the sera of 12 patients with SLE, HUVS or SLE/HUVS overlap syndromes were subjected to Western blot analysis. The SLE sera were negative by Western blot analysis. By contrast, HUVS sera showed reactivity with the B and C polypeptide chains of C1q. Investigation of 69 consecutive sera with anti-C1q antibodies and low C1q confirmed the findings, but there were also exceptions to the rule. Anti-C1q antibodies are directed against the collagen-like region of C1q, and the question was asked if the antibodies cross-react with the structurally related collectins MBL, lung surfactant protein A, and bovine conglutinin. Anti-C1q autoantibodies did not cross-react with these proteins. Serial analysis of anti-C1q antibodies in SLE patients with mild extrarenal flares, severe extrarenal flares and flares of lupus nephritis showed a very high prevalence of anti-C1q in the nephritis group, usually in conjunction with anti-dsDNA, and correlation to hypocomplementemia (low C1q). Anti-C1q antibodies did not cross-react with collagen type II antibodies and anti-dsDNA. With regard to complement activation by MBL, strong controversy exists concerning C3-activation and the alternative pathway independent of the C3 convertase C4b2a. Using a C3 deposition ELISA and microtiter plate wells coated with a Salmonella serogroup C-specific oligosaccharide, which binds MBL, we have provided strong evidence for MBL-dependent C2 bypass activation of C3 and the alternative pathway. The mechanism does not require MBL associated serine proteases (MASPs), but may be enhanced by MASP-1. Finally, complement requirements for C3 and C4 deposition on apoptotic cells were investigated by flow cytometry. Assay conditions strongly influenced the results. The classical pathway was of predominant importance. Interestingly, C4 deposition was enhanced in C2-deficient sera