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Shunichi Shiozawa, Ken Tsumiyama, Yumi Miyazaki, Kenichi Uto, Keiichi Sakurai, Toshie Nakashima, Hiroko Matsuyama, Ai Doi, Miho Tarui, Manabu Izumikawa, Mai Kimura, Chisato Satonaka, Yoko Fujita, 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, DOCK8-expressing Tfh cells cause SLE: autoimmunity via repeated TCR stimulation by antigen to levels that surpass system’s self-organized criticality, The Journal of Immunology, Volume 206, Issue 1_Supplement, May 2021, Page 52.21, https://doi.org/10.4049/jimmunol.206.Supp.52.21
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Abstract
The cause of autoimmunity remains unclear. Candidate pathogens including autoantigens all failed to induce, exist in, or heal upon their removal the prototypical autoimmune disease, systemic lupus erythematosus (SLE). We here investigated, instead of antigen, the immune response of host that recognized antigen.
We test the integrity of host’s immune response by stimulating TCR maximally to levels that surpass the limit of host’s steady-state immune response, self-organized criticality, by an antigen.
After repeated stimulation by any immunogenic antigen, SLE was induced in mice normally not prone to autoimmune disease, wherein a novel T follicular helper (Tfh) cell type expressing the guanine nucleotide exchange factor DOCK8 on the cell surface was newly generated via resuscitation from antigen-induced anergy. DOCK8+ Tfh cells passed through TCR revision at the periphery, and induced a variety of autoantibodies and the lesion characteristic of SLE. They existed in splenic red pulp and in the circulation of active patients with SLE, which subsequently declined after conventional therapy. Lupus lesions of mice and the classical (NZBxNZW) F1 model mice were mostly cured by anti-DOCK8 antibody.
Thus, disruption of host’s steady-state immune response by repeated TCR stimulation by immunogenic pathogen, either exogenous or endogenous, results in generation of DOCK8-expressing Tfh cells that cause autoantibodies and SLE.
