{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:03:36Z","timestamp":1791349416040,"version":"4.3.1"},"reference-count":65,"publisher":"Rockefeller University Press","issue":"3","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,3,16]]},"abstract":"<jats:p>Production of high-affinity pathogenic autoantibodies appears to be central to the pathogenesis of lupus. Because normal high-affinity antibodies arise from germinal centers (GCs), aberrant selection of GC B cells, caused by either failure of negative selection or enhanced positive selection by follicular helper T (TFH) cells, is a plausible explanation for these autoantibodies. Mice homozygous for the san allele of Roquin, which encodes a RING-type ubiquitin ligase, develop GCs in the absence of foreign antigen, excessive TFH cell numbers, and features of lupus. We postulated a positive selection defect in GCs to account for autoantibodies. We first demonstrate that autoimmunity in Roquinsan\/san (sanroque) mice is GC dependent: deletion of one allele of Bcl6 specifically reduces the number of GC cells, ameliorating pathology. We show that Roquinsan acts autonomously to cause accumulation of TFH cells. Introduction of a null allele of the signaling lymphocyte activation molecule family adaptor Sap into the sanroque background resulted in a substantial and selective reduction in sanroque TFH cells, and abrogated formation of GCs, autoantibody formation, and renal pathology. In contrast, adoptive transfer of sanroque TFH cells led to spontaneous GC formation. These findings identify TFH dysfunction within GCs and aberrant positive selection as a pathway to systemic autoimmunity.<\/jats:p>","DOI":"10.1084\/jem.20081886","type":"journal-article","created":{"date-parts":[[2009,2,16]],"date-time":"2009-02-16T21:37:43Z","timestamp":1234820263000},"page":"561-576","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":555,"title":["Follicular helper T cells are required for systemic autoimmunity"],"prefix":"10.1084","volume":"206","author":[{"given":"Michelle A.","family":"Linterman","sequence":"first","affiliation":[{"name":"Division of Immunology and Genetics, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Rigby","sequence":"additional","affiliation":[{"name":"Division of Immunology and Genetics, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael. K.","family":"Wong","sequence":"additional","affiliation":[{"name":"Division of Immunology and Genetics, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Yu","sequence":"additional","affiliation":[{"name":"Division of Immunology and Genetics, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Brink","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research, Sydney, NSW 2010, Australia 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"Cannons","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela L.","family":"Schwartzberg","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew C.","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Immunology 4 and 5"},{"name":"Department of Renal Medicine, The Canberra Hospital, Canberra, ACT 2605, Australia 4 and 5"},{"name":"Australian National University Medical School, Canberra, ACT 2605, Australia 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giles D.","family":"Walters","sequence":"additional","affiliation":[{"name":"Department of Immunology 4 and 5"},{"name":"Department of Renal Medicine, The Canberra Hospital, Canberra, ACT 2605, Australia 4 and 5"},{"name":"Australian National University Medical School, Canberra, ACT 2605, Australia 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carola G.","family":"Vinuesa","sequence":"additional","affiliation":[{"name":"Division of Immunology and Genetics, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2009,2,16]]},"reference":[{"key":"2023072916370197600_bib1","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1002\/art.1780400928","article-title":"Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus","volume":"40","author":"Hochberg","year":"1997","journal-title":"Arthritis Rheum."},{"key":"2023072916370197600_bib2","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1056\/NEJMoa021933","article-title":"Development of autoantibodies before the clinical onset of systemic lupus erythematosus","volume":"349","author":"Arbuckle","year":"2003","journal-title":"N. 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