Abstract
BackgroundAccumulating evidences proved the important roles of circulating IgA1-containing immune complexes (cIgA1) in IgA nephropathy (IgAN). Galactose-deficient IgA1 (Gd-IgA1) and glycan-specific IgG antibody have been identified as major components in cIgA1. Before, Gd-IgA1 was reported as a vital factor in IgAN, partly via of its pathogenic role to induce mesangial cells activation. However, we still lack direct evidences to clarify the biological effect of glycan-specific IgG antibody in IgAN.MethodsIn the present study, we enrolled 35 IgAN patients and 17 age- and sex-matched healthy controls. Using uniform aberrant glycosylated IgA1 molecules, and IgG from different individuals, we in vitro prepared IgG-ddIgA1 complexes, and compared the biological differences among these immune complexes regarding their proliferative and inflammatory effects on mesangial cells.ResultsIgG-ddIgA1 complexes from both patients with IgA nephropathy (IgAN-IgG-dd-IgA1) and healthy controls (HC-IgG-dd-IgA1) could induce the proliferation of mesangial cells and up-regulate expression of MCP-1, IL-6 and CXCL1. The levels of mesangial cells proliferation induced by IgAN-IgG-dd-IgA1 were significantly higher than those induced by HC-IgG-dd-IgA1 (1.10 ± 0.05 vs. 1.03 ± 0.03; p < 0.001). However, the levels of secreted MCP-1, IL-6 and CXCL1 from mesangial cells challenged by IgAN-IgG-dd-IgA1 and HC-IgG-dd-IgA1 were comparable.ConclusionsWe found that glycan-specific IgG antibodies derived from patients with IgAN had the biological effect to induce mesangial cells proliferation. Moreover, in the present study we also established a method for in vitro preparation of pathogenic IgG-ddIgA1 complexes, which could be applied in future studies exploring IgAN pathogenesis.
Highlights
Accumulating evidences proved the important roles of circulating IgA1-containing immune complexes in IgA nephropathy (IgAN)
Compared with IgA1 molecules, desialic acid/de-galactose IgA1 molecules (ddIgA1) showed less binding to SNA and more binding to VVL (Fig. 1A), which indicated that ddIgA1 presented with decreased sialic acid and increased exposure of GalNAc, resulted by galactose deficient
IgG-ddIgA1 complexes derived from IgAN patients induced activation of human mesangial cells IgG-ddIgA1 complexes from both patients with IgA nephropathy (IgAN-IgG-ddIgA1) and healthy controls (HCIgG-ddIgA1) could induce the proliferation of mesangial cells and up-regulate the expression of multiple inflammatory cytokines, including IL-6, MCP-1 and CXCL1
Summary
Accumulating evidences proved the important roles of circulating IgA1-containing immune complexes (cIgA1) in IgA nephropathy (IgAN). Galactose-deficient IgA1 (Gd-IgA1) and glycan-specific IgG antibody have been identified as major components in cIgA1. Gd-IgA1 was reported as a vital factor in IgAN, partly via of its pathogenic role to induce mesangial cells activation. We still lack direct evidences to clarify the biological effect of glycan-specific IgG antibody in IgAN. In recent years, accumulating evidences proved that circulating IgA1-containing immune complexes played important roles in the initiation and development of IgAN, because they could induce mesangial cells proliferation and matrix expansion, and activate. The exact composition of circulating IgA1containing immune complexes in patients with IgAN are still unclear today, galactose-deficient IgA1 (Gd-IgA1) and glycan-specific IgG antibody have been identified as major two components. Reports from multiple countries showed that, compared with healthy controls, patients with IgAN had higher
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