{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T14:22:13Z","timestamp":1793110933425,"version":"4.5.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and is characterized by mesangial deposition of nephritogenic IgA-containing immune complexes. Increasing evidence suggests that dysregulated mucosal innate immune responses contribute to disease pathogenesis, particularly through activation of endosomal Toll-like receptors (TLRs). Among these, TLR7 and TLR9, which recognize single-stranded RNA and unmethylated CpG DNA, respectively, have been implicated in the abnormal mucosal immune activation observed in IgAN. Experimental and clinical studies have demonstrated increased expression of TLR7 and TLR9 in mucosal tissues, including the tonsils of patients with IgAN. Activation of these pathways may promote galactose-deficient IgA1 (Gd-IgA1) production through interleukin-6 (IL-6)- and APRIL-mediated mechanisms, thereby contributing to the formation of nephritogenic immune complexes. IgAN-prone mouse studies further support the role of TLR-mediated immune activation in mesangial IgA deposition and glomerular injury, although limitations remain in fully recapitulating human disease. Recent humanized mouse models further suggest that Gd-IgA1 alone may be insufficient to induce disease, highlighting the importance of mucosal immune context in shaping nephritogenic IgA responses. In addition, emerging genetic and translational studies suggest potential links between TLR signaling pathways and susceptibility to IgAN. Recent therapeutic advances targeting mucosal immunity and related downstream pathways, including hydroxychloroquine and APRIL\/BAFF-directed therapies, have further highlighted the clinical relevance of innate immune dysregulation in IgAN. In this review, we summarize current evidence regarding the roles of TLR7 and TLR9 in IgAN, with particular emphasis on their contribution to mucosal immune abnormalities and their potential therapeutic implications.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1843019","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:58:55Z","timestamp":1783490335000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["TLR7\/9-mediated mucosal innate immune dysregulation in IgA nephropathy"],"prefix":"10.3389","volume":"17","author":[{"given":"Mingfeng","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Nephrology, Juntendo University Faculty of Medicine","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Juntendo University Faculty of 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