{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T03:24:45Z","timestamp":1789529085538,"version":"build-2803163510"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2013,10,1]],"date-time":"2013-10-01T00:00:00Z","timestamp":1380585600000},"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":[[2013,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Lymphopenic hosts offer propitious microenvironments for expansion of autoreactive B and T cells. Despite this, many lymphopenic hosts do not develop autoimmune disease, suggesting that additional factors are required for breaching self-tolerance in the setting of lymphopenia. Mice deficient in guanine nucleotide exchange factor Rasgrp1 develop a lymphoproliferative disorder with features of human systemic lupus erythematosus. Early in life, Rasgrp1-deficient mice have normal B cell numbers but are T lymphopenic, leading to defective homeostatic expansion of CD4 T cells. To investigate whether B cell\u2013intrinsic mechanisms also contribute to autoimmunity, Rasgrp1-deficient mice were bred to mice containing a knockin autoreactive BCR transgene (564Igi), thereby allowing the fate of autoreactive B cells to be assessed. During B cell development, the frequency of receptor-edited 564Igi B cells was reduced in Rasrp1-deficient mice compared with Rasgrp1-sufficient littermate control mice, suggesting that tolerance was impaired. In addition, the number of 564Igi transitional B cells was increased in Rasgrp1-deficient mice compared with control mice. Immature 564Igi B cells in bone marrow and spleen lacking RasGRP1 expressed lower levels of Bim mRNA and protein, suggesting that autoreactive B cells elude clonal deletion during development. Concomitant with increased serum autoantibodies, Rasgrp1-deficient mice developed spontaneous germinal centers at 8\u201310 wk of age. The frequency and number of 564Igi B cells within these germinal centers were significantly increased in Rasgrp1-deficient mice relative to control mice. Taken together, these studies suggest that autoreactive B cells lacking Rasgrp1 break central and peripheral tolerance through both T cell\u2013independent and \u2013dependent mechanisms.<\/jats:p>","DOI":"10.4049\/jimmunol.1202892","type":"journal-article","created":{"date-parts":[[2013,8,31]],"date-time":"2013-08-31T04:32:38Z","timestamp":1377923558000},"page":"3605-3613","source":"Crossref","is-referenced-by-count":19,"title":["Multiple Checkpoint Breach of B Cell Tolerance in <i>Rasgrp1<\/i>-Deficient Mice"],"prefix":"10.1093","volume":"191","author":[{"given":"Amber","family":"Bartlett","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of South Alabama , Mobile, AL 36688"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet E","family":"Buhlmann","sequence":"additional","affiliation":[{"name":"Centers for Therapeutic Innovation , Pfizer, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Stone","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Alberta , Edmonton, Alberta T6G 2H7,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School , Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A","family":"Barrington","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of South Alabama , Mobile, AL 36688"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,10,1]]},"reference":[{"key":"2025032405403720200_r1","first-page":"320","article-title":"Regulation and Function of the RasGRP Family of Ras Activators in Blood Cells","volume-title":"Genes Cancer","author":"Stone"},{"key":"2025032405403720200_r2","doi-asserted-by":"crossref","first-page":"7179","DOI":"10.4049\/jimmunol.175.11.7179","article-title":"RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor-Ras signaling","volume":"175","author":"Coughlin","year":"2005","journal-title":"J. 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