ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 0928

Skewing of B Cell Receptor Repertoire in Unswitched Memory B Cells Is Associated with Disease Activity of Systemic Lupus Erythematosus and Targeted by Belimumab

Keishi Fujio1, Mineto Ota1, Masahiro Nakano2, Yasuo Nagafuchi3, Satomi Kobayashi1, Hiroaki Hatano2, Ryochi Yoshida1, Yuko Akutsu1, Takahiro Itamiya1, Nobuhiro Ban4, Yumi Tsuchida1, Hirofumi Shoda1, Kazuhiko Yamamoto5, Kazuyoshi Ishigaki6 and Tomohisa Okamura7, 1Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 2Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan, 3Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 4Research Division, Chugai Pharmaceutical Co., Ltd., Yokohama, Japan, 5Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo and Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan, 6RIKEN, Tokyo, Japan, 7Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo and Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Meeting: ACR Convergence 2023

Keywords: , ,

Session Information

Date: Monday, November 13, 2023

Title: (0899–0933) SLE – Etiology & Pathogenesis Poster

Session Type: Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Despite the involvement of B cells in the pathogenesis of immune-mediated diseases, the biological mechanisms underlying their function are poorly understood. To address this gap, we constructed and investigated a large-scale repertoire catalog of five B cell subsets from patients with immune-mediated diseases, including systemic lupus erythematosus (SLE).

Methods: We mapped B cell receptor regions from RNA sequencing data of sorted B cell subsets. Our dataset consisted of 595 donors with immune-mediated diseases and healthy individuals. We characterized the repertoire features from various aspects, including their association with immune cell transcriptomes and clinical features, as well as their response to belimumab treatment.

Results: In healthy individual, gene usage preference among 5 B cell subsets was observed. Principal component analysis (PCA) of VDJ gene usage revealed clear separation according to cell types, suggesting B cell development based on VDJ gene segments. In 136 SLE patient, VDJ gene usage was skewed, particularly in plasmablasts and unswitched-memory B cells. We developed a scoring system, repertoire naiveness (RN) score, to assess this skewing. RN scores in plasmablasts and USM B showed significant positive correlations with SLEDAI-2K. Moreover, RN score positively correlated with peripheral helper T (TPH) cell transcriptomic signatures and negatively correlated with the amount of somatic hypermutations in plasmablasts, suggesting an association with the extra-follicular pathway. Furthermore, this skewing led to increased usage of IGHV4-34 in unswitched-memory B cells, with its usage showing a significant positive correlation with disease activity in SLE. Mediation analysis indicated that over one-half of the association between RN scores in USM B and SLEDAI-2K was mediated by IGHV4-34 usage. Notably, belimumab treatment ameliorated gene usage skewing in unswitched-memory B cells, but not in the other subsets. These results were consistent with our previous functional genome analysis of ImmuNexUT dataset that indicated the association between generic risk of SLE and unswitched memory B cells (Ota M et al. Cell 2021;184:3006-3021).

Conclusion: Our multimodal repertoire analysis revealed the importance of unswitched-memory B cells in the pathogenesis of SLE.

Disclosures: K. Fujio: AbbVie/Abbott, 6, Asahi Kasei, 5, 6, Astellas, 6, AstraZeneca, 6, Ayumi, 6, Bristol-Myers Squibb(BMS), 5, 6, Chugai Pharmaceutical., 5, 6, Daiichi-Sankyo, 6, Eisai, 5, 6, Eli Lilly, 5, 6, Janssen, 6, Novartis, 6, Ono, 6, Pfizer, 6, Sanofi, 6, Tanabe Mitsubishi, 5, 6, Tsumura, 5; M. Ota: Chugai, 12, MO belonged to the Social Cooperation Program, Department of functional genomics and immunological diseases, supported by Chugai Pharmaceu; M. Nakano: None; Y. Nagafuchi: AbbVie/Abbott, 6, Bristol-Myers Squibb(BMS), 5, 6, Chugai Pharmaceutical., 12, belong to the Social Cooperation Program, Department of Functional Genomics and Immunological Diseases, supported by Chugai Pharmaceutical., GlaxoSmithKlein(GSK), 5, Novartis, 6; S. Kobayashi: None; H. Hatano: None; R. Yoshida: None; Y. Akutsu: None; T. Itamiya: Chugai Pharmaceutical Co., Ltd., 5; N. Ban: Chugai, 3; Y. Tsuchida: None; H. Shoda: AbbVie/Abbott, 6, Asahi Kasei, 6, Astellas, 6, AstraZeneca, 6, Boehringer-Ingelheim, 6, Bristol-Myers Squibb(BMS), 6, Chugai Pharmaceutical., 6, Daiichi-Sankyo, 6, Eisai, 6, Eli Lilly, 6, Gilead, 6, GlaxoSmithKline, 6, Jansen, 6, Novartis, 6, Pfizer, 6, Sanofi, 6, Taisho Pharmaceutical, 6, Takeda, 6; K. Yamamoto: AbbVie, 6, Pfizer Japan Inc, 12, Outsourcing contract, RegCell, 1, Sun Pharmaceutical Industries Ltd, 6; K. Ishigaki: None; T. Okamura: Chugai Pharmaceutical., 12, belong to the Social Cooperation Program, Department of Functional Genomics and Immunological Diseases, supported by Chugai Pharmaceutical..

To cite this abstract in AMA style:

Fujio K, Ota M, Nakano M, Nagafuchi Y, Kobayashi S, Hatano H, Yoshida R, Akutsu Y, Itamiya T, Ban N, Tsuchida Y, Shoda H, Yamamoto K, Ishigaki K, Okamura T. Skewing of B Cell Receptor Repertoire in Unswitched Memory B Cells Is Associated with Disease Activity of Systemic Lupus Erythematosus and Targeted by Belimumab [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/skewing-of-b-cell-receptor-repertoire-in-unswitched-memory-b-cells-is-associated-with-disease-activity-of-systemic-lupus-erythematosus-and-targeted-by-belimumab/. Accessed .

« Back to ACR Convergence 2023

ACR Meeting Abstracts - https://acrabstracts.org/abstract/skewing-of-b-cell-receptor-repertoire-in-unswitched-memory-b-cells-is-associated-with-disease-activity-of-systemic-lupus-erythematosus-and-targeted-by-belimumab/