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 MizunoYohei Mukai, Kazuhiro Murakami, Takuji Enya, Shota Tsukimoto, Yoshiyuki Hakata, Masaaki Miyazawa, Kazuko Shiozawa

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Article number103537
JournaliScience
Volume25
Issue number1
DOIs
Publication statusPublished - Jan 21 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

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