{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:54:32Z","timestamp":1790704472382,"version":"4.1.0"},"reference-count":33,"publisher":"National Academy of Sciences","issue":"10","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2006,3,7]]},"abstract":"<jats:p>Multiple mechanisms of tolerance induction limit autoimmunity, but their relative contribution for lymphocytes recognizing self-antigens of differing availability is incompletely understood. The mechanisms applied to arthritogenic B cells expressing antigen-specific B cell receptors (BCRs) with different affinities for glucose-6-phosphate isomerase (GPI) were examined in the corresponding Ig gene knock-in mice. This ubiquitously expressed and blood-borne enzyme is the target autoantigen in the K\/BxN model of inflammatory arthritis and perhaps in some humans with arthritis. Negative selection of B cells expressing high-affinity anti-GPI specificities, whose surface receptors were occupied by GPI, operated mainly at the transitional B cell stages in the spleen, preventing their final differentiation and entry into follicular areas. Receptor editing contributed to the purging of cells displaying anti-GPI BCRs, and significant numbers of autoreactive cells escaped through expression of an additional Ig light (L) chain, accumulating gradually in lymphoid organs. In contrast, low-affinity anti-GPI B cells, whose surface receptors did not carry GPI, matured normally. The \u201cescaped\u201d dual-L-chain cells and the \u201cignored\u201d low-affinity cells are the likely precursors of cells that produce pathogenic autoantibodies once T cell help is provided. These studies portray, in a single system, the range of tolerance mechanisms applied to potentially pathogenic B cells, and serve as a base for dissecting where T cell help intervenes and where therapeutic agents impinge.<\/jats:p>","DOI":"10.1073\/pnas.0600214103","type":"journal-article","created":{"date-parts":[[2006,2,27]],"date-time":"2006-02-27T20:34:16Z","timestamp":1141072456000},"page":"3734-3739","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":36,"title":["Induction of tolerance in arthritogenic B cells with receptors of differing affinity for self-antigen"],"prefix":"10.1073","volume":"103","author":[{"given":"Haochu","family":"Huang","sequence":"first","affiliation":[{"name":"*Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02215;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Kearney","sequence":"additional","affiliation":[{"name":"Division of Developmental and Clinical Immunology and Department of Microbiology, University of Alabama, Birmingham, AL 35294; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Grusby","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Diseases, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Benoist","sequence":"additional","affiliation":[{"name":"*Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02215;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Mathis","sequence":"additional","affiliation":[{"name":"*Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02215;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2006,2,27]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81989-3"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.286.5445.1732"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80045-X"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20011941"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni772"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/334676a0"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/337562a0"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.177.4.999"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.177.4.1165"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.177.4.1009"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20022144"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.26.14602"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2004.01.006"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1056600"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.18.6211"},{"key":"e_1_3_3_16_2","doi-asserted-by":"crossref","first-page":"4431","DOI":"10.4049\/jimmunol.151.9.4431","volume":"151","author":"Allman D. 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