English: Figure 1. Proposed pathogenesis of IgAN and novel treatment strategies. (1) Mucosal infection primes naïve B cells to class switch to become IgA+ antibody secreting cells (ASCs) through T cell-dependent (cytokine mediated) and T cell-independent (Toll-like receptor (TLR) ligation) pathways. (2) Some IgA+ ASC mis-home to the systemic compartment during lymphocyte trafficking. (3) Displaced IgA+ ASCs take up residence in systemic sites and secrete normal ‘mucosal-type’ poorly galactosylated (galactose deficient) and polymeric IgA1 into the systemic circulation. (4) IgA1 secretion by displaced mucosal ASC is augmented by TLR ligation from mucosal-derived pathogen-associated molecular patterns, which have entered the systemic compartment. (5) IgA1 immune complexes form in the systemic circulation. Poorly galactosylated polymeric IgA1 molecules are the substrate for immune complex formation and combine with IgG and IgA autoantibodies reactive to exposed neoepitopes in the poorly galactosylated IgA1 hinge region. (6) IgA1 immune complexes deposit in the mesangium through a combination of mesangial trapping and increased affinity of poorly galactosylated IgA1 for extracellular matrix components. Immune complex deposition triggers a series of downstream pathways leading to glomerular injury and tubulointerstitial scarring. APRIL, a proliferation-inducing ligand; BAFF, B cell activating factor; MASP-2, mannan-binding lectin-associated serine protease-2. Reprinted from ref. [10], with permission from Elsevier.