IgA nephropathy (IgAN) is caused by the accumulation of IgA-immune complexes (IC) in glomeruli. The enzymes that assemble the glycan side chains on various glycoproteins and glycolipids are highly sensitive to external stimuli, including cytokines. Some of the Th2 cytokines that dominate the cellular immune responses in Peyer's patches and elicit increased production of IgA also promote hypogalactosylation of IgA on both O-linked and N-linked glycans, at least in vitro. In patients with IgAN, increased IgA synthesis (increased ks and/or ks') represents humoral responses to mucosal antigens. The IgA within single samples of IC from individual IgAN patients is not only polyclonal but also polyspecific, that is, the IgA includes antibodies that bind to several antigens, and the complexed antigens often originate from distinct sources. Furthermore, the antigens implicated in IgAN are often associated with mucosal portals of entry, and temporal associations between mucosal antigen entry (via dietary exposure and/or infection) and exacerbations of nephritis in IgAN are well established. Thus, the glomerular IgA deposits represent complexes of mucosal antigens combined with antibodies synthesized in large part by mucosal (or mucosally derived) plasma cells. © 2005 Elsevier Inc. All rights reserved.