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

doi:10.1016/j.isci.2021.103537

DOCK8-expressing T follicular helper cells newly generated beyond self-organized criticality cause systemic lupus erythematosus

iScience. 2021 Dec 2;25(1):103537. doi: 10.1016/j.isci.2021.103537. eCollection 2022 Jan 21.

Authors

Shunichi Shiozawa^{1

2

3

4}, Ken Tsumiyama^{1

2

3

4}, Yumi Miyazaki^{2

3}, Kenichi Uto³, Keiichi Sakurai^{1

2}, Toshie Nakashima³, Hiroko Matsuyama³, Ai Doi³, Miho Tarui³, Manabu Izumikawa³, Mai Kimura³, Yuko Fujita³, Chisako Satonaka³, Takahiko Horiuchi², Tsukasa Matsubara⁴, Motohiro Oribe⁵, Takashi Yamane⁶, Hidetoshi Kagawa⁷, Quan-Zhen Li⁸, Keiko Mizuno⁹, Yohei Mukai⁹, Kazuhiro Murakami¹⁰, Takuji Enya^{11

12}, Shota Tsukimoto^{11

13}, Yoshiyuki Hakata¹¹, Masaaki Miyazawa^{11

14}, Kazuko Shiozawa^{4

15}

Affiliations

¹ Institute for Rheumatic Diseases, 944-25 Fujita, Katoshi 673-1462, Japan.
² Department of Medicine, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu 874-0838, Japan.
³ Division of Bioregulation, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Sumaku, Kobe 654-0142, Japan.
⁴ Department of Medicine, Rheumatology and Orthopedic Surgery, Matsubara Mayflower Hospital, 944-25 Fujita, Katoshi 673-1462, Japan.
⁵ Oribe Clinic, 1-8-15 Higashi-Odori, Oita 870-0823, Japan.
⁶ Department of Rheumatology, Kakogawa City Hospital, 439 Honmachi, Kakogawa 675-8611, Japan.
⁷ Department of Medicine, Red Cross Society Himeji Hospital, 1-12-1 Shimoteno, Himeji 670-8540, Japan.
⁸ Department of Immunology, University of Texas Southwestern Medical Center, 6001 Forest Park Road/ND 6.504, Dallas, TX 75390-8814, USA.
⁹ Drug Discovery Platform, KAN Research Institute, Inc., 6-8-2 Minatojimaminamicho, Kobe 650-0047, Japan.
¹⁰ Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsujima, Aobaku 981-8558, Japan.
¹¹ Department of Immunology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
¹² Department of Pediatrics, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
¹³ Department of Anesthesiology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
¹⁴ Kindai University Anti-Aging Center, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan.
¹⁵ Rheumatology and Collagen Disease Center, Hyogo Prefectural Kakogawa Medical Center, 203 Kanno, Kakogawa 675-8555, Japan.

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.