iScience (Jan 2022)
DOCK8-expressing T follicular helper cells newly generated beyond self-organized criticality cause systemic lupus erythematosus
- Shunichi Shiozawa,
- Ken Tsumiyama,
- Yumi Miyazaki,
- Kenichi Uto,
- Keiichi Sakurai,
- Toshie Nakashima,
- Hiroko Matsuyama,
- Ai Doi,
- Miho Tarui,
- Manabu Izumikawa,
- Mai Kimura,
- Yuko Fujita,
- Chisako Satonaka,
- Takahiko Horiuchi,
- Tsukasa Matsubara,
- Motohiro Oribe,
- Takashi Yamane,
- Hidetoshi Kagawa,
- Quan-Zhen Li,
- Keiko Mizuno,
- Yohei Mukai,
- Kazuhiro Murakami,
- Takuji Enya,
- Shota Tsukimoto,
- Yoshiyuki Hakata,
- Masaaki Miyazawa,
- Kazuko Shiozawa
Affiliations
- Shunichi Shiozawa
- Institute for Rheumatic Diseases, 944-25 Fujita, Katoshi 673-1462, Japan; Department of Medicine, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan; Division of Bioregulation, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Sumaku, Kobe 654-0142, Japan; Department of Medicine, Rheumatology and Orthopedic Surgery, Matsubara Mayflower Hospital, 944-25 Fujita, Katoshi 673-1462, Japan; Corresponding author
- Ken Tsumiyama
- Institute for Rheumatic Diseases, 944-25 Fujita, Katoshi 673-1462, Japan; Department of Medicine, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan; Division of Bioregulation, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Sumaku, Kobe 654-0142, Japan; Department of Medicine, Rheumatology and Orthopedic Surgery, Matsubara Mayflower Hospital, 944-25 Fujita, Katoshi 673-1462, Japan
- Yumi Miyazaki
- Department of Medicine, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan; Division of Bioregulation, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Sumaku, Kobe 654-0142, Japan
- Kenichi Uto
- Division of Bioregulation, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Sumaku, Kobe 654-0142, Japan
- Keiichi Sakurai
- Institute for Rheumatic Diseases, 944-25 Fujita, Katoshi 673-1462, Japan; Department of Medicine, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan
- Toshie Nakashima
- Division of Bioregulation, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Sumaku, Kobe 654-0142, Japan
- Hiroko Matsuyama
- Division of Bioregulation, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Sumaku, Kobe 654-0142, Japan
- Ai Doi
- Division of Bioregulation, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Sumaku, Kobe 654-0142, Japan
- Miho Tarui
- Division of Bioregulation, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Sumaku, Kobe 654-0142, Japan
- Manabu Izumikawa
- Division of Bioregulation, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Sumaku, Kobe 654-0142, Japan
- Mai Kimura
- Division of Bioregulation, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Sumaku, Kobe 654-0142, Japan
- Yuko Fujita
- Division of Bioregulation, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Sumaku, Kobe 654-0142, Japan
- Chisako Satonaka
- Division of Bioregulation, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Sumaku, Kobe 654-0142, Japan
- Takahiko Horiuchi
- Department of Medicine, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan
- Tsukasa Matsubara
- Department of Medicine, Rheumatology and Orthopedic Surgery, Matsubara Mayflower Hospital, 944-25 Fujita, Katoshi 673-1462, Japan
- Motohiro Oribe
- Oribe Clinic, 1-8-15 Higashi-Odori, Oita 870-0823, Japan
- Takashi Yamane
- Department of Rheumatology, Kakogawa City Hospital, 439 Honmachi, Kakogawa 675-8611, Japan
- Hidetoshi Kagawa
- Department of Medicine, Red Cross Society Himeji Hospital, 1-12-1 Shimoteno, Himeji 670-8540, Japan
- Quan-Zhen Li
- Department of Immunology, University of Texas Southwestern Medical Center, 6001 Forest Park Road/ND 6.504, Dallas, TX 75390-8814, USA
- Keiko Mizuno
- Drug Discovery Platform, KAN Research Institute, Inc., 6-8-2 Minatojimaminamicho, Kobe 650-0047, Japan
- Yohei Mukai
- Drug Discovery Platform, KAN Research Institute, Inc., 6-8-2 Minatojimaminamicho, Kobe 650-0047, Japan
- Kazuhiro Murakami
- Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsujima, Aobaku 981-8558, Japan
- Takuji Enya
- Department of Immunology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan; Department of Pediatrics, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
- Shota Tsukimoto
- Department of Immunology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan; Department of Anesthesiology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
- Yoshiyuki Hakata
- Department of Immunology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
- Masaaki Miyazawa
- Department of Immunology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan; Kindai University Anti-Aging Center, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan
- Kazuko Shiozawa
- Department of Medicine, Rheumatology and Orthopedic Surgery, Matsubara Mayflower Hospital, 944-25 Fujita, Katoshi 673-1462, Japan; Rheumatology and Collagen Disease Center, Hyogo Prefectural Kakogawa Medical Center, 203 Kanno, Kakogawa 675-8555, Japan
- Journal volume & issue
-
Vol. 25,
no. 1
p. 103537
Abstract
Summary: 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.
