{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T17:14:39Z","timestamp":1697044479133},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2000,10,1]],"date-time":"2000-10-01T00:00:00Z","timestamp":970358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2001,12,24]]},"abstract":"<jats:title>SUMMARY<\/jats:title><jats:p>The role of CD4 molecules in the autoimmune and lymphoproliferative syndrome caused by murine Fas mutations was studied using the novel systemic lupus erythematosus (SLE) model, MRL-Faslprcg\/Faslprcg (MRL-lprcg) mice, in combination with the novel mutant CD4 gene producing soluble CD4 (sCD4) instead of membrane-bound CD4 (mCD4). For this purpose, various autoimmune manifestations were compared among MRL-lprcg mice homozygous (CD4slprcg), heterozygous (CD4s\/mlprcg), and wild-type (CD4mlprcg) for the CD4 mutation. The mortality, glomerulonephritis, proteinuria, and lymphadenopathy were significantly ameliorated in CD4slprcg compared with CD4mlprcg and CD4s\/mlprcg mice, both being comparable in these clinical characteristics. In parallel with the clinical improvement, the serum levels of immunoglobulin, anti-DNA antibodies, anti-nuclear antibodies and immune complexes, and the extent of glomerular immune deposition, were significantly lower in the former. The results indicate that mCD4 is important and can not be replaced by sCD4 in full development of SLE-like manifestations, and suggest that CD4+ T cells may aggravate the autoimmune disease by stimulating autoreactive B cells to produce autoantibodies through their helper activity in Fas mutant models. The sCD4 levels in the serum and spleen elevated with the increased accumulation of B220+CD4\u2212CD8\u2212 (double-negative (DN)) T cells in CD4slprcg mice. This, together with the significantly milder lymphadenopathy associated with lower DN T cell contents in CD4slprcg than CD4mlprcg mice, implies that some of abnormal DN T cells may be derived from cells of the CD4 lineage.<\/jats:p>","DOI":"10.1046\/j.1365-2249.2000.01347.x","type":"journal-article","created":{"date-parts":[[2003,3,11]],"date-time":"2003-03-11T10:23:59Z","timestamp":1047378239000},"page":"124-132","source":"Crossref","is-referenced-by-count":3,"title":["A pivotal role of cell-bound but not soluble CD4 molecules in full development of lupus-like manifestations in MRL<i>-Fas<\/i><i>lprcg<\/i><i>\/Fas<\/i><i>lprcg<\/i>mice"],"prefix":"10.1093","volume":"122","author":[{"given":"Y","family":"Zhang","sequence":"first","affiliation":[{"name":"Laboratory Animal Research Centre"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Laboratory Animal Research Centre"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C R","family":"Wang","sequence":"additional","affiliation":[{"name":"Departments of Allergology and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T","family":"Yoshimoto","sequence":"additional","affiliation":[{"name":"Departments of Allergology and"},{"name":"Intractable Disease Research Centre, Tokyo Medical University, Tokyo"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H","family":"Nagase","sequence":"additional","affiliation":[{"name":"Department of Parasitology, Shinshu University School of Medicine, Matsumoto"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Takamoto","sequence":"additional","affiliation":[{"name":"Department of Parasitology, Shinshu University School of Medicine, Matsumoto"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Tsubura","sequence":"additional","affiliation":[{"name":"Department of Pathology, Kansai Medical University, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Kimura","sequence":"additional","affiliation":[{"name":"Internal Medicine, Institute of Medical Science, University of Tokyo and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Matsuzawa","sequence":"additional","affiliation":[{"name":"Laboratory Animal Research Centre"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2001,12,24]]},"reference":[{"key":"2022011221084951900_b1","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S0065-2776(08)60342-9","article-title":"Murine models of systemic lupus erythematosus","volume":"37","author":"Theofilopoulos","year":"1985","journal-title":"Adv Immunol"},{"key":"2022011221084951900_b2","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S0065-2776(08)60651-3","article-title":"Molecular genetics of murine lupus model","volume":"46","author":"Theofilopoulos","year":"1989","journal-title":"Adv Immunol"},{"key":"2022011221084951900_b3","doi-asserted-by":"crossref","first-page":"871","DOI":"10.4049\/jimmunol.125.2.871","article-title":"Effects of thymectomy or androgen administration upon the autoimmune disease of MRL\/Mp-lpr\/lpr mice","volume":"125","author":"Steinbereg","year":"1980","journal-title":"J Immunol"},{"key":"2022011221084951900_b4","doi-asserted-by":"crossref","first-page":":1713","DOI":"10.4049\/jimmunol.130.4.1713","article-title":"Treatment of autoimmune MRL-lpr mice with monoclonal antibody to Thy-1.2: a single injection has sustained effects on lymphoproliferation and renal disease","volume":"130","author":"Seaman","year":"1983","journal-title":"J Immunol"},{"key":"2022011221084951900_b5","doi-asserted-by":"crossref","first-page":":852","DOI":"10.4049\/jimmunol.134.2.852","article-title":"Treatment of murine lupus with monoclonal anti-T cell antibody","volume":"134","author":"Wofsy","year":"1985","journal-title":"J Immunol"},{"key":"2022011221084951900_b6","doi-asserted-by":"crossref","first-page":"6509","DOI":"10.4049\/jimmunol.151.11.6509","article-title":"Polyclonal B cell activation arises from different mechanisms in lupus-prone (NZB x NZW) F1 and MRL\/MpJ-lpr\/lpr mice","volume":"151","author":"Merino","year":"1993","journal-title":"J Immunol"},{"key":"2022011221084951900_b7","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/0008-8749(92)90166-M","article-title":"Anti-CD4 monoclonal antibody therapy suppresses autoimmune disease in MRL\/Mp-lpr\/lpr mice","volume":"141","author":"Jabs","year":"1992","journal-title":"Cell Immunol"},{"key":"2022011221084951900_b8","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1006\/cimm.1994.1057","article-title":"Effects of early and late treatment with anti-CD4 monoclonal antibody on autoimmune disease in MRL\/Mp-lpr\/lpr mice","volume":"154","author":"Jabs","year":"1993","journal-title":"Cell Immunol"},{"key":"2022011221084951900_b9","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/S0090-1229(05)80013-3","article-title":"Long-term anti-CD4 treatment of MRL\/lpr mice ameliorates immunopathology and lymphoproliferation but fails to suppress rheumatoid factor production","volume":"61","author":"O\u2019Sullivan","year":"1991","journal-title":"Clin Immunol Immunopathol"},{"key":"2022011221084951900_b10","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1084\/jem.167.5.1713","article-title":"The contribution of L3T4+ T cells to lymphoproliferation and autoantibody production in MRL-lpr\/lpr mice","volume":"167","author":"Santro","year":"1988","journal-title":"J Exp Med"},{"key":"2022011221084951900_b11","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1002\/art.1780370422","article-title":"Reduction of mortality and lymphadenopathy in MRL-lpr\/lpr mice treated with nonmitogenic anti-CD3 monoclonal antibody","volume":"37","author":"Henrickson","year":"1994","journal-title":"Arthritis Rheum"},{"key":"2022011221084951900_b12","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1084\/jem.179.4.1137","article-title":"Prevention of nephritis in major histocompatibility complex class II-deficient MRL-lpr mice","volume":"179","author":"Jevinkar","year":"1994","journal-title":"J Exp Med"},{"key":"2022011221084951900_b13","doi-asserted-by":"crossref","first-page":"2558","DOI":"10.1002\/eji.1830250923","article-title":"Murine lupus in MRL\/lpr mice lacking CD4 or CD8 T cells","volume":"25","author":"Koh","year":"1995","journal-title":"Eur J Immunol"},{"key":"2022011221084951900_b14","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/356314a0","article-title":"Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis","volume":"356","author":"Watanabe-Fukunaga","year":"1992","journal-title":"Nature"},{"key":"2022011221084951900_b15","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/0167-5699(95)80069-7","article-title":"Fas and Fas ligand: lpr and gld mutations","volume":"16","author":"Nagata","year":"1995","journal-title":"Immunol Today"},{"key":"2022011221084951900_b16","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1084\/jem.171.2.519","article-title":"A new allele of the lpr locus, lprcg, that complements the gld gene in induction of lymphadenopathy in the mouse","volume":"171","author":"Matsuzawa","year":"1990","journal-title":"J Exp Med"},{"key":"2022011221084951900_b17","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/0092-8674(95)90013-6","article-title":"Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative disease","volume":"81","author":"Fisher","year":"1995","journal-title":"Cell"},{"key":"2022011221084951900_b18","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1126\/science.7539157","article-title":"Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity","volume":"268","author":"Rieux-Laucat","year":"1995","journal-title":"Science"},{"key":"2022011221084951900_b19","doi-asserted-by":"crossref","first-page":"193","DOI":"10.3109\/08830189409061727","article-title":"Autoimmunity in mice bearing lprcg: a novel mutant gene","volume":"11","author":"Kimura","year":"1994","journal-title":"Int Rew Immunol"},{"key":"2022011221084951900_b20","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/(SICI)1521-4141(199802)28:02<403::AID-IMMU403>3.0.CO;2-5","article-title":"Novel mutant mice secreting soluble CD4 without expression of membrane CD4","volume":"28","author":"Nagase","year":"1998","journal-title":"Eur J Immunol"},{"key":"2022011221084951900_b21","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1002\/art.1780331013","article-title":"Binding of anti-DNA antibodies and inhibition of glomerulonephritis in MRL-lpr\/lpr mice by heparin","volume":"33","author":"Naparstek","year":"1990","journal-title":"Arthritis Rheum"},{"key":"2022011221084951900_b22","first-page":"498","article-title":"Nephritogenicity of the lprcg gene on the MRL background","volume":"76","author":"Kimura","year":"1992","journal-title":"Immunology"},{"key":"2022011221084951900_b23","doi-asserted-by":"crossref","first-page":"5484","DOI":"10.4049\/jimmunol.158.11.5484","article-title":"IFN-\u03b3 is essential for the development of autoimmune glomerulonephritis in MRL\/lpr mice","volume":"158","author":"Haas","year":"1997","journal-title":"J Immunol"},{"key":"2022011221084951900_b24","first-page":"243","article-title":"lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease","volume":"9","author":"Cohen","year":"1991","journal-title":"Adv Immuol"},{"key":"2022011221084951900_b25","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1002\/eji.1830230232","article-title":"Constitutive expression of high levels of soluble mouse CD4 in transgenic mice does not interfere with their immune functions","volume":"23","author":"Weber","year":"1993","journal-title":"Eur J Immunol"},{"key":"2022011221084951900_b26","first-page":"1541","article-title":"Crescentic glomerulonephritis in CD4- and CD8-deficient mice. Requirement for CD4 but not CD8 cells","volume":"152","author":"Tipping","year":"1998","journal-title":"Am J Pathol"},{"key":"2022011221084951900_b27","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1084\/jem.176.6.1645","article-title":"Genetic analysis of MRL-lpr mice: relationship of the Fas apoptosis gene to disease manifestations and renal disease-modifying loci","volume":"176","author":"Watson","year":"1992","journal-title":"J Exp Med"},{"key":"2022011221084951900_b28","first-page":"1791","article-title":"Host modifier genes affect mouse autoimmunity induced by the lpr gene","volume":"151","author":"Wang","year":"1997","journal-title":"Am J Pathol"},{"key":"2022011221084951900_b29","doi-asserted-by":"crossref","first-page":"6999","DOI":"10.4049\/jimmunol.161.12.6999","article-title":"Genetic determinants of autoimmune disease and coronary vasculitis in the MRL-lpr\/lpr mouse model of systemic lupus erythematosus","volume":"161","author":"Gu","year":"1998","journal-title":"J Immunol"},{"key":"2022011221084951900_b30","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1258\/002367700780578019","article-title":"Immunological characterization of C3H mice congenic for Faslprcg, C3H\/HeJ-Faslprcg\/Faslprcg","volume":"34","author":"Yasuda","year":"2000","journal-title":"Lab Anim"},{"key":"2022011221084951900_b31","doi-asserted-by":"crossref","first-page":"3948","DOI":"10.4049\/jimmunol.153.9.3948","article-title":"In vivo CD4+ lymph node T cells from lpr mice generate CD4\u2212CD8\u2212B220+TCR-\u03b2 low cells","volume":"153","author":"Laouar","year":"1994","journal-title":"J Immunol"},{"key":"2022011221084951900_b32","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1002\/eji.1830250108","article-title":"Reduced development of CD4\u22128\u2212B220+ T cells but normal autoantibody production in lpr\/lpr mice lacking major histocompatibility complex class I molecules","volume":"25","author":"Ohteki","year":"1995","journal-title":"Eur J Immunol"},{"key":"2022011221084951900_b33","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1002\/eji.1830240942","article-title":"Class II major histocompatibility complex-restricted T cell function in CD4-deficient mice","volume":"24","author":"Rehemtulla","year":"1994","journal-title":"Eur J Immunol"},{"key":"2022011221084951900_b34","doi-asserted-by":"crossref","first-page":"10038","DOI":"10.1073\/pnas.87.24.10038","article-title":"Cryoglobulinemia induced by a murine IgG3 rheumatoid factor: skin vasculitis and glomerulonephritis arise from distinct pathogenic mechanisms","volume":"87","author":"Reininger","year":"1990","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Clinical and Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1046%2Fj.1365-2249.2000.01347.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1046%2Fj.1365-2249.2000.01347.x","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/122\/1\/124\/42135183\/j.1365-2249.2000.01347.x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/122\/1\/124\/42135183\/j.1365-2249.2000.01347.x.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T08:46:30Z","timestamp":1682066790000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/122\/1\/124\/6461546"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,10]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2001,12,24]]},"published-print":{"date-parts":[[2001,12,24]]}},"URL":"https:\/\/doi.org\/10.1046\/j.1365-2249.2000.01347.x","relation":{},"ISSN":["1365-2249","0009-9104"],"issn-type":[{"value":"1365-2249","type":"electronic"},{"value":"0009-9104","type":"print"}],"subject":[],"published-other":{"date-parts":[[2000,10]]},"published":{"date-parts":[[2000,10]]}}}