{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T06:02:46Z","timestamp":1762408966573},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2013,12,16]],"date-time":"2013-12-16T00:00:00Z","timestamp":1387152000000},"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":[[2014,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Fas mutant mice are well recognized as autoimmune mouse models, which develop symptoms similar to human systemic lupus erythematosus. Although disease severity in Fas mutant mice is greatly affected by the genetic background, the mechanisms affecting pathological heterogeneity among different strains of Fas mutant mice are poorly understood. In this study, we examined the phenotypic differences between Fas-deficient (Fas\u2212\/\u2212) mice on the BALB\/c and C57BL\/6 backgrounds to gain insight into the etiological and pathological heterogeneity of monogenic autoimmune diseases. Fas\u2212\/\u2212 mice on the BALB\/c background (BALB\/c-Fas\u2212\/\u2212) developed more severe autoimmune disease with high serum auto-antibodies and renal disease compared with those on the C57BL\/6 background (C57BL\/6-Fas\u2212\/\u2212). Splenic B cells were highly activated, and germinal center formation was enhanced in BALB\/c-Fas\u2212\/\u2212 but not in C57BL\/6-Fas\u2212\/\u2212 mice. Follicular helper T (Tfh) cells were equally abundant in the spleens from both strains of Fas\u2212\/\u2212 mice. However, Tfh cells from BALB\/c-Fas\u2212\/\u2212 mice produced much higher amounts of B-cell-activating cytokines, including IL-4 and IL-10, a phenotype reminiscent of Th2-type Tfh cells described in human studies. Our results revealed a qualitative difference in Tfh cells between the two strains of Fas\u2212\/\u2212 mice. We propose that the pathogenic Th2-type Tfh cells in BALB\/c-Fas\u2212\/\u2212 mice contribute to the excessive activation of B cells, resulting in high serum immunoglobulin levels and the severe lupus phenotype, which may account for the differential outcomes of human monogenic autoimmune diseases.<\/jats:p>","DOI":"10.1093\/intimm\/dxt070","type":"journal-article","created":{"date-parts":[[2013,12,17]],"date-time":"2013-12-17T04:16:15Z","timestamp":1387253775000},"page":"221-231","source":"Crossref","is-referenced-by-count":9,"title":["Pathogenic Th2-type follicular helper T cells contribute to the development of lupus in<i>Fas<\/i>-deficient mice"],"prefix":"10.1093","volume":"26","author":[{"given":"Shizue","family":"Futatsugi-Yumikura","sequence":"first","affiliation":[{"name":"Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 1 663-8501, Japan"},{"name":"Department of Immunology and Medical Zoology, Hyogo College of Medicine 2 , Nishinomiya, Hyogo 663-8501 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazufumi","family":"Matsushita","sequence":"additional","affiliation":[{"name":"Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 1 663-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayumi","family":"Fukuoka","sequence":"additional","affiliation":[{"name":"Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 1 663-8501, Japan"},{"name":"Laboratory of Molecular and Cellular Biology, Graduate School of Biostudies, Kyoto University 3 , Kyoto 606-8501 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzuka","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Biology, Graduate School of Biostudies, Kyoto University 3 , Kyoto 606-8501 , Japan"},{"name":"4 Present address: Institute for Genome Research, Tokushima University, Tokushima 770-8503, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nayu","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Biology, Graduate School of Biostudies, Kyoto University 3 , Kyoto 606-8501 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin","family":"Yonehara","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Biology, Graduate School of Biostudies, Kyoto University 3 , Kyoto 606-8501 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Nakanishi","sequence":"additional","affiliation":[{"name":"Department of Immunology and Medical Zoology, Hyogo College of Medicine 2 , Nishinomiya, Hyogo 663-8501 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomohiro","family":"Yoshimoto","sequence":"additional","affiliation":[{"name":"Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 1 663-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2013,12,16]]},"reference":[{"key":"2022072100181393500_CIT0001","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.immuni.2009.01.001","article-title":"The many roles of FAS receptor signaling in the immune system","volume":"30","author":"Strasser","year":"2009","journal-title":"Immunity"},{"key":"2022072100181393500_CIT0002","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/S1359-6101(02)00024-2","article-title":"Death receptor Fas and autoimmune disease: from the original generation to therapeutic application of agonistic anti-Fas monoclonal antibody","volume":"13","author":"Yonehara","year":"2002","journal-title":"Cytokine Growth Factor Rev"},{"key":"2022072100181393500_CIT0003","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/0090-1229(84)90190-9","article-title":"The influence of the lpr gene on B cell activation: differential antibody expression in lpr congenic mouse strains","volume":"31","author":"Warren","year":"1984","journal-title":"Clin. 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