{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T02:14:22Z","timestamp":1769652862309,"version":"3.49.0"},"reference-count":56,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2009,12,27]],"date-time":"2009-12-27T00:00:00Z","timestamp":1261872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lyn-deficient (Lyn\u2212\/\u2212) mice develop an age-dependent autoimmune disease similar to systemic lupus erythematosus, characterized by the production of IgG anti-nuclear Ab. To determine the extent to which this autoimmune phenotype is driven by T cell costimulation, we generated Lyn\u2212\/\u2212 mice expressing a soluble form of the T cell inhibitory molecule, CTLA4 (CTLA4Ig). Surprisingly, although CTLA4Ig prevented myeloid hyperplasia, splenomegaly and IgG anti-nuclear Ab production in Lyn\u2212\/\u2212 mice, it did not inhibit immune complex deposition and tissue destruction in the kidney. In fact, regardless of CTLA4Ig expression, Lyn\u2212\/\u2212 serum contained elevated titers of IgA anti-nuclear Ab, although generally IgA deposition in the kidney was only revealed in the absence of self-reactive IgG. This demonstrated that activation of autoreactive B cell clones in Lyn\u2212\/\u2212 mice can still occur despite impaired costimulation. Indeed, CTLA4Ig did not alter perturbed Lyn\u2212\/\u2212 B cell development and behavior, and plasma cell frequencies were predominantly unaffected. These results suggest that when self-reactive B cell clones are unimpeded in acquiring T cell help, they secrete pathogenic IgG autoantibodies that trigger the fulminant autoimmunity normally observed in Lyn\u2212\/\u2212 mice. The absence of these IgG immune complexes reveals an IgA-mediated axis of autoimmunity that is not sufficient to cause splenomegaly or extramedullary myelopoiesis, but which mediates destructive glomerulonephritis. These findings have implications for the understanding of the basis of Ab-mediated autoimmune diseases and for their treatment with CTLA4Ig.<\/jats:p>","DOI":"10.4049\/jimmunol.0804349","type":"journal-article","created":{"date-parts":[[2009,12,4]],"date-time":"2009-12-04T21:30:00Z","timestamp":1259962200000},"page":"757-763","source":"Crossref","is-referenced-by-count":26,"title":["CTLA4Ig Alters the Course of Autoimmune Disease Development in Lyn\u2212\/\u2212 Mice"],"prefix":"10.1093","volume":"184","author":[{"given":"Sarah A","family":"Oracki","sequence":"first","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research , Parkville"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evelyn","family":"Tsantikos","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, Royal Melbourne Hospital , Melbourne, Victoria,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cathy","family":"Quilici","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, Royal Melbourne Hospital , Melbourne, Victoria,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Light","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research , Parkville"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research , Parkville"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew M","family":"Lew","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research , Parkville"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanne E","family":"Martin","sequence":"additional","affiliation":[{"name":"Pathology Group, Institute of Cell and Molecular Sciences, St Bartholomew\u2019s and the London Hospital School of Medicine and Dentistry , London"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken G","family":"Smith","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke\u2019s Hospital , Cambridge,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret L","family":"Hibbs","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, Royal Melbourne Hospital , Melbourne, Victoria,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M","family":"Tarlinton","sequence":"additional","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research , Parkville"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,12,27]]},"reference":[{"key":"2026012808093721700_r1","first-page":"9","article-title":"Lyn tyrosine kinase: accentuating the positive and the negative.","volume":"22","author":"Xu","year":"2005","journal-title":"Immunity"},{"key":"2026012808093721700_r2","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.4049\/jimmunol.175.3.1867","article-title":"Lyn-deficient mice develop severe, persistent asthma: Lyn is a critical negative regulator of Th2 immunity.","volume":"175","author":"Beavitt","year":"2005","journal-title":"J. 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