Biologically Active Circulatory Immune Complexes in IgA Nephropathy Contain Polymeric IgA1, With Galactose-Deficient and Minimally Sialylated O-Glycans, IgG, and Complement C3b and iC3b

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Background: IgA nephropathy (IgAN) is an autoimmune disease wherein pathogenic immune complexes (IC) are thought to form in the circulation from IgA1 with some hinge-region O-glycans deficient in galactose (galactose-deficient IgA1; Gd-IgA1) bound by IgG autoantibodies. Some of these IC deposit in the glomeruli to induce kidney injury. The glomerular immunodeposits are enriched for Gd-IgA1 and the corresponding IgG autoantibodies. However, the composition of the circulating IC in IgAN is not fully understood. Methods: We isolated different molecular forms of IgA1 from sera of 20 patients with IgAN by lectin-affinity and size-exclusion chromatography (SEC). Isolated monomeric IgA1 (mIgA1), polymeric IgA1 (pIgA1), and IgA1 bound in IC (IgA1-IC) were analyzed for their degree of galactose deficiency by a lectin ELISA performed without and with neuraminidase treatment to remove sialic acid. For assessment of biological activity, IgA1-IC were isolated by SEC directly from serum and tested for proliferation-stimulating and signaling-inducing activities in cultured primary human mesangial cells. SDS-PAGE immunoblotting was used for detection of IgA, IgG, complement C3, and phosphorylated (P-) and total ERK1/2, and P- and total Akt. Results: Molecular forms of serum IgA1 included mIgA1 (˜90%), pIgA1 (˜9%) and IgA1-IC (<0.4%). Relative degree of galactose deficiency of the IgA1 was highest in IgA1-IC, less in pIgA1, and least in mIgA1. IgA1 in IC had minimally sialylated O-glycans. IgA1-IC isolated by SEC from sera of IgAN patients had molecular mass >700 kDa. These circulatory IC induced signaling (e.g., P-ERK1/2, P-Akt) and cellular proliferation of the mesangial cells. These biologically active IgA1-IC contained pIgA1, IgG, and complement C3b and iC3b. Conclusions: Biologically active circulatory immune complexes in patients with IgAN had molecular mass >700 kDa and contained polymeric Gd-IgA1 with a high degree of galactose deficiency and minimal sialylation, IgG, C3b, and iC3b. Collectively, these findings support the pathogenic role of IgA1-containing immune complexes in IgAN. Funding: NIDDK Support

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