Human IgA Activates the Complement System Via the Mannan-Binding Lectin Pathway

Abstract

The recently identified lectin pathway of the complement system, initiated by binding of mannan-binding lectin (MBL) to its ligands, is a key component of innate immunity. MBL-deficient individuals show an increased susceptibility for infections, especially of the mucosal system. We examined whether IgA, an important mediator of mucosal immunity, activates the complement system via the lectin pathway. Our results indicate a dose-dependent binding of MBL to polymeric, but not monomeric IgA coated in microtiter plates. This interaction involves the carbohydrate recognition domain of MBL, because it was calcium dependent and inhibited by mannose and by mAb against this domain of MBL. Binding of MBL to IgA induces complement activation, as demonstrated by a dose-dependent deposition of C4 and C3 upon addition of a complement source. The MBL concentrations required for IgA-induced C4 and C3 activation are well below the normal MBL plasma concentrations. In line with these experiments, serum from individuals having mutations in the MBL gene showed significantly less activation of C4 by IgA and mannan than serum from wild-type individuals. We conclude that MBL binding to IgA results in complement activation, which is proposed to lead to a synergistic action of MBL and IgA in antimicrobial defense. Furthermore, our results may explain glomerular complement deposition in IgA nephropathy.

Mannose‐binding lectin engagement with late apoptotic and necrotic cells

“…In addition, MBL containing MASP was purified from healthy donors as described earlier [18,19]. C1q was isolated essentially as described [3,20].…”

“…To determine whether MBL/MASP complexes in different concentrations added to apoptotic Jurkat T cells were able to mediate activation of complement, purified plasmaderived C4 [19] was added at a concentration of 1 ? g/ml.…”

“…Activation of complement by mannan in whole serum was analyzed essentially as described previously [19]. The obtained results were standardized using a calibration curve generated with pooled normal human serum, and expressed as arbitrary units per ml (U/ml).…”

C4d deposits in IgA nephropathy: where does complement activation come from?

“…carbohydrates expressed on microorganisms or altered tissues [9]. The lectin pathway includes two collectins [mannose-binding lectin (MBL) and collectin-LK] and the three ficolins (ficolin-1, -2 and -3) and MBL-associated proteases (MASP-1,-2 and -3), which enable activation of C4 and C2, leading to the formation of C4bC2a, the same convertase found in the classical complement pathway.…”

Pathogenic implications for autoantibodies against C-reactive protein and other acute phase proteins

“…In addition, MBL binds both dimeric and polymeric IgA and activates complement [134]; it binds agalactosyl IgG and IgM, including IgM rheumatoid factor complexes from RA patients [135]. Occurrence of autoantibodies against MBL (anti-MBL) has been reported by several groups [136][137][138][139].…”