{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T17:58:19Z","timestamp":1793383099384,"version":"4.5.0"},"reference-count":25,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2019,6]]},"abstract":"<jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>In approximately 70%\u201380% of cases of primary membranous nephropathy (MN), phospholipase A2 receptor (PLA2R)\/Thrombospondin Type-1 Domain\u2013Containing 7A (THSD7A) and anti-PLA2R\/THSD7A antibodies form immune complexes along the glomerular basement membrane (GBM) that characterize the condition. In other cases of primary MN and all secondary MN, the target antigen is unknown. Using proteomics and immunohistochemistry, the authors detected two proteins, exostosin 1 (EXT1) and exostosin 2 (EXT2), in the GBM of PLA2R-negative MN. EXT1 and EXT2 were absent in all cases of PLA2R-associated MN and controls. Clinical and biopsy findings showed features of autoimmune disease, including membranous lupus nephritis, in 81% of the 26 EXT1\/EXT2-associated MN cases the authors identified. These findings suggest that EXT1\/EXT2-associated MN represents a distinct subtype of MN, most commonly associated with autoimmune diseases (secondary MN).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>In membranous nephropathy (MN), which is characterized by deposition of immune complexes along the glomerular basement membrane (GBM), phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain\u2013containing 7A are target antigens in approximately 70% and 1%\u20135% of cases of primary MN, respectively. In other cases of primary MN and in secondary MN, the target antigens are unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We studied 224 cases of biopsy-proven PLA2R-negative MN and 102 controls (including 47 cases of PLA2R-associated MN) in pilot and discovery cohorts. We also evaluated 48 cases of PLA2R-negative presumed primary MN and lupus MN in a validation cohort. We used laser microdissection and mass spectrometry to identify new antigens, which were localized by immunohistochemistry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Mass spectrometry detected exostosin 1 (EXT1) and exostosin 2 (EXT2) in 21 cases of PLA2R-negative MN, but not in PLA2R-associated MN and control cases. Immunohistochemistry staining revealed bright granular GBM staining for EXT1 and EXT2. Clinical and biopsy findings showed features of autoimmune disease, including lupus, in 80.7% of the 26 EXT1\/EXT2-associated MN cases we identified. In the validation cohort, we confirmed that EXT1\/EXT2 staining was detected in pure class 5 lupus nephritis (eight of 18 patients) and in presumed primary MN associated with signs of autoimmunity (three of 16 patients); only one of the 14 cases of mixed class 5 and 3\/4 lupus nephritis was positive for EXT1\/EXT2. Tests in seven patients with EXT1\/EXT2-associated MN found no circulating anti-exostosin antibodies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>A subset of MN is associated with accumulation of EXT1 and EXT2 in the GBM. Autoimmune disease is common in this group of patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2018080852","type":"journal-article","created":{"date-parts":[[2019,5,7]],"date-time":"2019-05-07T13:25:45Z","timestamp":1557235545000},"page":"1123-1136","source":"Crossref","is-referenced-by-count":294,"title":["Exostosin 1\/Exostosin 2\u2013Associated Membranous Nephropathy"],"prefix":"10.1681","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4536-7709","authenticated-orcid":false,"given":"Sanjeev","family":"Sethi","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J.","family":"Madden","sequence":"additional","affiliation":[{"name":"Medical Genome Facility, Proteomics Core, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Debiec","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Universit\u00e9 Pierre et Marie Curie Paris 06, and Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Unit\u00e9 Mixte de Recherche S1155, Paris, France; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Cristine","family":"Charlesworth","sequence":"additional","affiliation":[{"name":"Medical Genome Facility, Proteomics Core, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"LouAnn","family":"Gross","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aishwarya","family":"Ravindran","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber M.","family":"Hummel","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Specks","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9952-209X","authenticated-orcid":false,"given":"Fernando C.","family":"Fervenza","sequence":"additional","affiliation":[{"name":"Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Ronco","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Universit\u00e9 Pierre et Marie Curie Paris 06, and Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Unit\u00e9 Mixte de Recherche S1155, Paris, France; and"},{"name":"Department of Nephrology and Dialysis, Assistance Publique-H\u00f4pitaux de Paris, Tenon Hospital, Paris, 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