{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T05:32:57Z","timestamp":1793424777846,"version":"4.5.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"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":"\n Background<\/jats:title>\n The widely accepted \u201cmulti-hit hypothesis\u201d of IgAN pathogenesis was challenged, as efficient depletion of CD20+ B cells failed to reduce serum galactose-deficient IgA1 (Gd-IgA1) or proteinuria in IgAN patients. Our group has discovered glomerular mesangial cells (GMCs) as another source of IgA, while immunoglobulin produced by non-B cells (non-B Ig) participating in several inflammatory and neoplastic diseases arose as a new concept in immunology. It is still unclear whether IgA produced by GMCs participates in the pathogenesis of IgAN and what its preliminary mechanism is.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n The transcription of\n IGHA1<\/jats:italic>\n and its associated function in GMCs were demonstrated by single-cell RNA sequencing (scRNA-seq) analysis.\n IGHA1<\/jats:italic>\n transcription in glomerular mesangium was detected in para-cancerous renal tissues by fluorescence\n in situ<\/jats:italic>\n hybridization (FISH).\n Staphylococcus aureus<\/jats:italic>\n enterotoxin B (SEB), Toll-like receptor 4 (TLR4) antagonist, and small interfering RNA (siRNA) were used to investigate the pro-inflammatory effect of Gd-IgA1 and its overproduction pathway. The IgAN model was established in \u03bcMT mice (lacking B lymphocytes with reduced serum IgA) and mice with\n IGHA<\/jats:italic>\n conditional knockout in GMCs to observe the causality between GMC-expressed IgA and the formation of IgAN.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Expression of IgA in GMCs was reconfirmed by detecting\n IGHA1<\/jats:italic>\n transcription in single cells and in para-cancerous renal tissue\n in situ<\/jats:italic>\n . Gene set enrichment analysis (GSEA) indicated that\n IGHA1<\/jats:italic>\n transcription in GMC was significantly associated with response to bacterium, innate immune response, complement activation, and galactose metabolism. Cultured human GMC experiments revealed that SEB could stimulate Gd-IgA1 overproduction through the TLR4 signaling pathway, and Gd-IgA1 deficiency in GMCs relieved the extracellular matrix component (ECM) deposition and C3 and IL-6 production induced by SEB. Mesangial IgA deposition and ECM expansion pattern in the \u03bcMT mouse IgAN model were similar to those in Balb\/c mice, and mice with\n IGHA<\/jats:italic>\n conditional knockout in GMCs relieved glomerular inflammatory response and alleviated the hematuria and proteinuria in the mouse IgAN model.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n We reconfirmed the expression of IgA in GMCs and demonstrated that overexpression of Gd-IgA1 in GMCs induced by SEB through the TLR4 pathway in human GMC may play an important role in inducing an inflammatory response in IgAN.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1638818","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T06:26:35Z","timestamp":1764051995000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["IgA expressed by glomerular mesangial cells is involved in the pathogenesis of IgA 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