1: Multi-dimensional analysis identified rheumatoid arthritis-driving pathway in human T cell.

Ann Rheum Dis.

2019 Jun 5. pii: annrheumdis-2018-214885. doi: 10.1136/annrheumdis-2018-214885.

Takeshita M, Suzuki K, Kondo Y, Morita R, Okuzono Y, Koga K, Kassai Y, Gamo K, Takiguchi M, Kurisu R, Mototani H, Ebisuno Y, Yoshimura A, Takeuchi T.

Rheumatoid arthritis is a disease in which the immune system, which is supposed to protect the body from foreign invaders, becomes activated within the joints, leading to the destruction of bone and cartilage. In this study, we focused on T cells, which are considered to play a central role in the pathogenesis of rheumatoid arthritis. We obtained clinical samples of blood and synovial fluid from a large number of patients and performed a detailed analysis of the quantitative and qualitative changes in their T cells. We identified subsets that were increased in the peripheral blood of patients with rheumatoid arthritis (Effector memory Tfh cells, CD8-Temra cells) and subsets that fluctuated with disease activity (Effector memory Th17 cells, Effector memory Tfh cells). Furthermore, by analyzing the genes expressed by each cell type, we revealed that T cells at the site of the lesion are the most activated and differentiated, expressing various immune-related molecules such as cytokines. We also found that these molecular groups are highly expressed in the peripheral blood of rheumatoid arthritis patients before treatment, and that many of them improve after treatment. The T cell subsets and gene groups we discovered are thought to play an important role in the pathogenesis of rheumatoid arthritis, and the development of new therapeutic drugs targeting them is expected in the future.

(Tsutomu Takeuchi, Katsuya Suzuki, and Masaru Takeshita, Division of Rheumatology)

JOURNAL OF CLINICAL INVESTIGATION,

129 (8):3201-3213;10.1172/JCI125863 AUG 1 2019

Koda, Y; Nakamoto, N; Chu, PS; Ugamura, A; Mikami, Y; Teratani, T; Tsujikawa, H; Shiba, S; Taniki, N; Sujino, T; Miyamoto, K; Suzuki, T; Yamaguchi, A; Morikawa, R; Sato, K; Sakamoto, M; Yoshimoto, T; Kanai, T

Acute liver failure (fulminant hepatitis) is a liver disease with a high mortality rate in which hepatocytes are rapidly destroyed through the host's immune response, and there are few effective treatments other than liver transplantation. To identify the immune cells that contribute to the pathogenesis of this disease, our group analyzed the types of immune cells in the liver and blood of patients with acute liver failure. We discovered a significant decrease in plasmacytoid dendritic cells, a type of dendritic cell (Fig. 1, top panel). Furthermore, we demonstrated that plasmacytoid dendritic cells function protectively against acute hepatitis, as the condition worsened when acute hepatitis was induced in mice lacking plasmacytoid dendritic cells through genetic modification, and improved when mice with acute hepatitis were transplanted with plasmacytoid dendritic cells mass-cultured from bone marrow cells. As for the immunological mechanism for improving the condition, we clarified that plasmacytoid dendritic cells increase the inhibitory cytokine IL-35 produced by regulatory T cells, thereby suppressing TH1 cells and the hepatitis-exacerbating factor they produce, IFN-γ (Fig. 1, bottom panel). This achievement is expected to lead to the development of new therapies and diagnostic agents for acute liver failure, for which there are few effective medical treatments.

(Nobuhiro Nakamoto, Division of Gastroenterology and Hepatology)

CELL METABOLISM,

30 (2):329-+; 10.1016/j.cmet.2019.05.015 AUG 6 2019

Yoshida, M ; Satoh, A; Lin, JB; Mills, KF; Sasaki, Y; Rensing, N; Wong, M; Apte, RS; Imai, SI

NATURE CELL BIOLOGY,

21 (8):1003-+; 10.1038/s41556-019-0363-9 AUG 2019

Kofuji, S; Hirayama, A; Eberhardt, AO; Kawaguchi, R; Sugiura, Y; Sampetrean, O; Ikeda, Y; Warren, M; Sakamoto, N; Kitahara, S; Yoshino, H; Yamashita, D; Sumita, K; Wolfe, K; Lange, L; Ikeda, S; Shimada, H; Minami, N; Malhotra, A; Morioka, S; Ban, YL; Asano, M; Flanary, VL; Ramkissoon, A; Chow, LML; Kiyokawa, J; Mashimo, T; Lucey, G; Mareninov, S; Ozawa, T; Onishi, N; Okumura, K; Terakawa, J; Daikoku, T; Wise-Draper, T; Majd, N; Kofuji, K; Sasaki, M; Mori, M; Kanemura, Y; Smith, EP; Anastasiou, D; Wakimoto, H; Holland, EC; Yong, WH; Horbinski, C; Nakano, I; DeBerardinis, RJ; Bachoo, RM; Mischel, PS; Yasui, W; Suematsu, M; Saya, H; Soga, T; Grummt, I; Bierhoff, H; Sasaki, AT

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION,

322 (4):315-325; 10.1001/jama.2019.9055 JUL 23 2019

Genovese, MC; Kalunian, K; Gottenberg, JE; Mozaffarian, N; Bartok, B; Matzkies, F; Gao, J; Guo, Y; Tasset, C; Sundy, JS; de Vlam, K; Walker, D; Takeuchi, T

BRIEFINGS IN BIOINFORMATICS,

20 (3):866-876; 10.1093/bib/bbx147 MAY 2019

Jayakumar, V; Sakakibara, Y