Figure 1.

“Four Hits” Hypothesis of IgA Nephropathy. In individuals with a genetic predisposition to IgA nephropathy, infection, or other events destroy the mucosal barrier defense function. Chronic stimulation such as pathogenic microbial or alimentary antigens are taken up by antigen-presenting cells, thereby activating B cells, and differentiating into plasma cell secreted IgA in T-cell-dependent or non-dependent manners. Due to the abnormal regulation of mucosal-bone marrow axis, the mis-expression of homing receptors on the surface of B/plasm cells leads to increased synthesis of poorly glycosylated IgA1 (Gd-IgA1) and self-aggregation to form aggregated Gd-IgA1 (Hit 1). The aberrant exposure of GalNAc of Gd-IgA1 as antigen stimulates B cells to differentiate into plasma cells and synthesizes anti-Gd-IgA1 autoantibodies (Hit 2). The Gd-IgA1 immune complex (Gd-IgA1-IC) is formed by anti-Gd-IgA1 autoantibodies binding to Gd-IgA1 along with soluble sCD89 (Hit 3). Macromolecular Gd-IgA1-IC binds to the IgA receptor (CD71) expressed on mesangial cells and deposits on the glomerular mesangium. Subsequently, the mesangial cells release various inflammatory factors (cytokines, chemokines, growth factors, etc.) under the stimulation of ICs, attracting and recruiting multiple subsets of T cells, macrophages, neutrophils infiltration, and activating the lectin pathway and alternative pathway of the complement system. Synergistic effects lead to glomerular injuries such as mesangial hyperplasia, matrix expansion, and interstitial fibrosis (Hit 4). DC, Dendritic cell; TLRs, Toll like receptors; APRIL, a proliferation-inducing ligand; DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; Gd-IgA1, poorly glycosylated IgA1/Galactose-deficient IgA1; AP, The alternative pathway; LP, The lectin pathway.