Mucosal immune anatomy of IgA responses and the ‘multi-hit’ model of IgAN. IgA is the most abundant antibody isotype in the body, with the majority of IgA found in mucosal secretions. Mucosal IgA production is induced by T-cell-dependent and T-cell-independent mechanisms. In individuals with a genetic predisposition to IgA nephropathy, chronic bacterial infection and gut dysbiosis initiate T-cell-independent pathways that trigger the expression of TLRs on antigen-presenting cells that recognize pathogens and release a variety of lymphocyte inflammatory cytokines, such as IL-6, IL-10, IL-21, BAFF, TGF-β and APRIL, stimulate B-cell differentiation and proliferation, have class switching from IgM to IgA1. IgA-secreting plasma cells migrate to lamina propria, where they release dimeric IgA1 (dIgA1). The dimers are formed through an interaction of two IgA1 molecules with a joining chain (J-chain), which is synthesized by plasma cells. IgA1 dimers can bind to the polymeric Ig receptor (pIgR) on the basolateral surface of the mucosal epithelium and undergo transcytosis to the apical surface, where they dissociate from pIgR and are secreted into the lumen carrying the secretory component of the receptor. In the T-cell-dependent pathway, B-cell type switching occurs after antigen-specific T-cell activation. The level of IgA1 bearing galactose-deficient O-glycans (Gd-IgA1) is increased in the circulation of patients with IgA nephropathy (hit 1). These IgA1 glycoforms are recognized as autoantigens by antiglycan autoantibodies (anti-Gd-IgA1 autoantibodies; hit 2), resulting in the formation of nephritogenic immune complexes (hit 3), some of which deposit in the kidney and activate mesangial cells (hit 4). Mesangial cells start to proliferate and overproduce components of extracellular matrix, cytokines and chemokines. Some of these cytokines can then cause podocyte injury and induce proteinuria. The figure refers to the pathogenesis of IgAN by Gesualdo et al.⁵¹