{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T20:06:14Z","timestamp":1786133174971,"version":"build-2736575974"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K22352"],"award-info":[{"award-number":["19K22352"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21H04751"],"award-info":[{"award-number":["21H04751"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007434","name":"Suzuken Memorial Foundation","doi-asserted-by":"publisher","award":["18-057"],"award-info":[{"award-number":["18-057"]}],"id":[{"id":"10.13039\/100007434","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Nakajima Foundation","award":["H31"],"award-info":[{"award-number":["H31"]}]},{"DOI":"10.13039\/501100006567","name":"Suhara Memorial Foundation","doi-asserted-by":"publisher","award":["H30"],"award-info":[{"award-number":["H30"]}],"id":[{"id":"10.13039\/501100006567","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>Tertiary lymphoid structures (TLSs) form in organs exhibiting chronic inflammation. Immune responses to infections, autoimmune responses, or allergic responses may trigger TLS development. We observed urine\u2013urothelium barrier alterations in the renal pelvis of a mouse model and in human subjects with chronic nephritis, with or without infection. Furthermore, urine leaked from the renal lumen into the parenchyma in nephritic mice. This stimulated the production of cytokines\/chemokines in renal stromal cells, resulting in TLS development termed \u201curinary tract\u2013associated lymphoid structures\u201d (UTALSs). UTALS development correlated with chronic nephritis in humans and mice regardless of UTI, thus possibly revealing a novel pathologic mechanism. Elucidation is crucial for better understanding of noninfectious chronic nephritis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Kidneys with chronic inflammation develop tertiary lymphoid structures (TLSs). Infectious pyelonephritis is characterized by renal pelvis (RP) inflammation. However, the pathologic features of TLSs, including their formation and association with non-infectious nephritis, are unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>RPs from humans and mice that were healthy or had non-infectious chronic nephritis were analyzed for TLS development, and the mechanism of TLS formation investigated using urothelium or lymphoid structure cultures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Regardless of infection, TLSs in the RP, termed urinary tract\u2013associated lymphoid structures (UTALSs), formed in humans and mice with chronic nephritis. Moreover, urine played a unique role in UTALS formation. Specifically, we identified urinary IFN-\n                      <jats:italic toggle=\"yes\">\u03b3<\/jats:italic>\n                      as a candidate factor affecting urothelial barrier integrity because it alters occludin expression. In a nephritis mouse model, urine leaked from the lumen of the RP into the parenchyma. In addition, urine immunologically stimulated UTALS-forming cells\n                      <jats:italic toggle=\"yes\">via<\/jats:italic>\n                      cytokine (IFN-\n                      <jats:italic toggle=\"yes\">\u03b3<\/jats:italic>\n                      , TNF-\n                      <jats:italic toggle=\"yes\">\u03b1<\/jats:italic>\n                      ) and chemokine (CXCL9, CXCL13) production. CXCL9 and CXCL13 were expressed in UTALS stromal cells and urine stimulation specifically induced CXCL13 in cultured fibroblasts. Characteristically, type XVII collagen (BP180), a candidate autoantigen of bullous pemphigoid, was ectopically localized in the urothelium covering UTALSs and associated with UTALS development by stimulating CXCL9 or IL-22 induction\n                      <jats:italic toggle=\"yes\">via<\/jats:italic>\n                      the TNF-\n                      <jats:italic toggle=\"yes\">\u03b1<\/jats:italic>\n                      \/FOS\/JUN pathway. Notably, UTALS development indices were positively correlated with chronic nephritis development.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>TLS formation in the RP is possible and altered urine\u2013urothelium barrier\u2013based UTALS formation may represent a novel mechanism underlying the pathogenesis of chronic nephritis, regardless of urinary tract infection.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2021040575","type":"journal-article","created":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T16:12:12Z","timestamp":1634919132000},"page":"88-107","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":22,"title":["Close Association between Altered Urine\u2013Urothelium Barrier and Tertiary Lymphoid Structure Formation in the Renal Pelvis during Nephritis"],"prefix":"10.1681","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6643-1554","authenticated-orcid":false,"given":"Osamu","family":"Ichii","sequence":"first","affiliation":[{"name":"Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan"},{"name":"Laboratory of Agrobiomedical Science, Faculty of Agriculture, Hokkaido University, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0360-3360","authenticated-orcid":false,"given":"Marina","family":"Hosotani","sequence":"additional","affiliation":[{"name":"Laboratory of Anatomy, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8274-5510","authenticated-orcid":false,"given":"Md. 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