@article{9b6dc0b1b76846d880b47ae5bc6c5a97,
title = "DOCK8-expressing T follicular helper cells newly generated beyond self-organized criticality cause systemic lupus erythematosus",
abstract = "Pathogens including autoantigens all failed to induce systemic lupus erythematosus (SLE). We, instead, studied the integrity of host's immune response that recognized pathogen. By stimulating TCR with an antigen repeatedly to levels that surpass host's steady-state response, self-organized criticality, SLE was induced in mice normally not prone to autoimmunity, wherein T follicular helper (Tfh) cells expressing the guanine nucleotide exchange factor DOCK8 on the cell surface were newly generated. DOCK8+Tfh cells passed through TCR re-revision and induced varieties of autoantibody and lupus lesions. They existed in splenic red pulp and peripheral blood of active lupus patients, which subsequently declined after therapy. Autoantibodies and disease were healed by anti-DOCK8 antibody in the mice including SLE-model (NZBxNZW) F1 mice. Thus, DOCK8+Tfh cells generated after repeated TCR stimulation by immunogenic form of pathogen, either exogenous or endogenous, in combination with HLA to levels that surpass system's self-organized criticality, cause SLE.",
keywords = "Cell biology, Immune response, Immunology",
author = "Shunichi Shiozawa and Ken Tsumiyama and Yumi Miyazaki and Kenichi Uto and Keiichi Sakurai and Toshie Nakashima and Hiroko Matsuyama and Ai Doi and Miho Tarui and Manabu Izumikawa and Mai Kimura and Yuko Fujita and Chisako Satonaka and Takahiko Horiuchi and Tsukasa Matsubara and Motohiro Oribe and Takashi Yamane and Hidetoshi Kagawa and Li, {Quan Zhen} and Keiko Mizuno and Yohei Mukai and Kazuhiro Murakami and Takuji Enya and Shota Tsukimoto and Yoshiyuki Hakata and Masaaki Miyazawa and Kazuko Shiozawa",
note = "Funding Information: This study was supported by the grant of the Institute for Rheumatic Diseases , and the grant-in-aid 25515003 , 17659301 , 13204059 , 11557026 , 12204074 , 13204059 , and the Global Center of Excellence (COE) Program grant to S.S. and 18K06933 to K.T. of the Ministry of Education, Culture, Sports, Science and Technology of Japan ; the New Industry Research Organization grant 0003 to S.S.; the grant of the Contract Development Program of Japan Science and Technology Organization to S.S. Funding Information: We thank Prof. Yoshinori Fukui, Medical Institute of Bioregulation, Kyushu University for kindly providing DOCK8 −/− mice, Prof. Nancy J. Olsen, Penn State M.S. Hershey Medical Center, for kindly arranging autoantibody microarray, Prof. Takashi Sawai, Sendai Open Hospital, and Dr. Hiroshi Ishii, Oita Red Cross Hospital, for patients' samples under written consent, Dr. Marc Lamphier for English edition, and Mitsufumi Uemura, Institute for Rheumatic Disease and Aperat, for graphic art-works. This study was supported by the grant of the Institute for Rheumatic Diseases, and the grant-in-aid 25515003, 17659301, 13204059, 11557026, 12204074, 13204059, and the Global Center of Excellence (COE) Program grant to S.S. and 18K06933 to K.T. of the Ministry of Education, Culture, Sports, Science and Technology of Japan; the New Industry Research Organization grant 0003 to S.S.; the grant of the Contract Development Program of Japan Science and Technology Organization to S.S. Conceptualization, S.S.; Methodology, S.S.; Investigation, S.S. K.T. Y.M. K.U. K.S. T.N. H.M. A.D. M.T. M.I. M.K. Y.F. C.S. Q-Z.L. K.M. Y.M. T.E. S.T. Y.H. and M.M.; Resources, S.S. T.H. T.M. M.O. T.Y. H.K. K.M. and K.S.; Writing, S.S.; Project Administration, S.S.; Funding Acquisition, S.S. and K.T. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2022",
month = jan,
day = "21",
doi = "10.1016/j.isci.2021.103537",
language = "English (US)",
volume = "25",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "1",
}