Activation of the alternative pathway of complement by human serum IgA

Abstract

In order to study the activation of complement by soluble aggregates of human polyclonal serum IgA, lysis of sheep erythrocytes (E) coated with several IgA preparations was used as a model. A complement nonactivating monoclonal mouse IgG1 against IgA was used to coat the cells. IgA, isolated from normal human serum, was aggregated by either N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP), glutaraldehyde, carbodiimide or heating. Depending on the size of the aggregates, and on the method of aggregation, E coated with aggregated IgA (E gamma 1.AIgA) could be lysed. The alternative pathway of complement appeared to mediate the lysis because the latter was observed in the presence of EGTA containing 5 mM Mg2+ (MgEGTA) and properdin (P) was deposited on the cells. Furthermore, no lysis was observed in C3-deficient serum. In the absence of AIgA the cells were not lysed, and no P deposition was observed. In another set of experiments E gamma 1.AIgA were first reacted with purified C3, B, D and P for 30 min at 30 degrees C, and subsequently in rat serum EDTA at 37 degrees C. Lysis occurred when E gamma 1.AIgA were prepared using SPDP-, glutaraldehyde- or carbodiimide-AIgA. Incubation of 100 micrograms/ml SPDP-AIgA with normal human serum for 30 min at 37 degrees C in the presence or absence of MgEGTA also induced consumption of total complement. The other soluble AIgA preparations were less effective in activating complement. These results suggest that polymeric serum IgA is capable of activating the alternative pathway of complement.

IgG and IgA antibodies to the collagen‐like region of C1q in rheumatoid vasculitis

“…The classical pathway is activated by IC containing IgM or IgG that bind with low affinity to Clq through its globular heads (24). More recently, the alternative pathway of the complement system has been demonstrated to be activated by IgA-containing IC (25,26). The demonstration of IgG antibodies to Clq in the serum of SLE patients demonstrated that not only IC, but also low molecular weight immunoglobulins, are able to bind to Clq.…”

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

“…IgA was purified from pooled normal human serum (NHS) or recalcified donor plasma, as described by Hiemstra et al (16), with minor modifications. In brief, the majority of serum proteins were removed by dialysis against H 2 O, and precipitation by ZnSO 4 .…”

“…Complement activation by IgA has been previously shown to involve the alternative, but not the classical complement pathway (16,17). No data are available concerning the possible involvement of the lectin pathway.…”

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

“…C3 can be activated by the alternative pathway [8], which is initiated as a result of a spontaneous and continuous hydrolysis of C3 (tickover process). This results in the generation of C3b which can react with complement-binding surface molecules (e.g.…”

“…Several studies suggest that C3 bound to IgA confers a particular nephrotoxicity to the IgA1-containing immune material, leading to the hypothesis that this step is the crucial hit in the pathogenetic event cascade of IgAN [8,9,11]. A different efficacy of complement activation may modulate the glomerular inflammatory reaction and the final tissue damage, driving different renal outcomes.…”