Transcriptome Profiling of Immune Cell Types in Peripheral Blood Reveals Common and Specific Pathways Involved in the Pathogenesis of Myositis-Specific Antibody-Positive Inflammatory Myopathies

Yusuke Sugimori; Yukiko Iwasaki; Yusuke Takeshima; Mai Okubo; Satomi Kobayashi; Hiroaki Hatano; Saeko Yamada; Masahiro Nakano; Ryochi Yoshida; Mineto Ota; Yumi Tsuchida; Yasuo Nagafuchi; Kenichi Shimane; Ken Yoshida; Daitaro Kurosaka; Shuji Sumitomo; Hirofumi Shoda; Kazuhiko Yamamoto; Tomohisa Okamura; Keishi Fujio

doi:10.1002/acr2.11521

Transcriptome Profiling of Immune Cell Types in Peripheral Blood Reveals Common and Specific Pathways Involved in the Pathogenesis of Myositis-Specific Antibody-Positive Inflammatory Myopathies

ACR Open Rheumatol. 2023 Feb;5(2):93-102. doi: 10.1002/acr2.11521. Epub 2023 Jan 18.

Authors

Yusuke Sugimori¹, Yukiko Iwasaki², Yusuke Takeshima³, Mai Okubo³, Satomi Kobayashi³, Hiroaki Hatano³, Saeko Yamada³, Masahiro Nakano³, Ryochi Yoshida³, Mineto Ota³, Yumi Tsuchida³, Yasuo Nagafuchi³, Kenichi Shimane⁴, Ken Yoshida⁵, Daitaro Kurosaka⁵, Shuji Sumitomo³, Hirofumi Shoda³, Kazuhiko Yamamoto⁶, Tomohisa Okamura³, Keishi Fujio³

Affiliations

¹ The University of Tokyo and Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.
² The University of Tokyo, Tokyo, Japan, and Saitama Medical University, Saitama, Japan.
³ The University of Tokyo, Tokyo, Japan.
⁴ Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.
⁵ The Jikei University School of Medicine, Tokyo, Japan.
⁶ University of Tokyo, Japan, and RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Abstract

Objective: Idiopathic inflammatory myopathies (IIM) demonstrate characteristic clinical phenotypes depending on the myositis-specific antibody (MSAs) present. We aimed to identify common or MSA-specific immunological pathways in different immune cell types from peripheral blood by transcriptome analysis.

Methods: We recruited 33 patients with IIM who were separated into the following groups: 15 patients with active disease at onset and 18 with inactive disease under treatment. All patients were positive for MSAs: anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab) in 10 patients, anti-Mi-2 Ab in 7, and anti-aminoacyl-transfer RNA synthetase (ARS) Ab in 16. The patients were compared with 33 healthy controls. Twenty-four immune cell types sorted from peripheral blood were analyzed by flow cytometry, RNA sequencing, and differentially expressed gene analysis combined with pathway analysis.

Results: The frequencies of memory B cell types were significantly decreased in active patients, and the frequency of plasmablasts was prominently increased in active patients with anti-MDA5 Ab in comparison with healthy controls. The expression of type I interferon (IFN)-stimulated genes of all immune cell types was increased in the active, but not inactive, patients. Endoplasmic reticulum stress-related genes in all IIM memory B cells and oxidative phosphorylation-related genes in inactive IIM double negative B cells were also increased, suggesting prominent B cell activation in IIM. Furthermore, active patients with anti-MDA5 Ab, anti-Mi-2 Ab, or anti-ARS Ab were distinguished by IFN-stimulated and oxidative phosphorylation-related gene expression in plasmablasts.

Conclusion: Unique gene expression patterns in patients with IIM with different disease activity levels and MSA types suggest different pathophysiologies. Especially, B cells may contribute to common and MSA-specific immunological pathways in IIM.

Abstract

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