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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1506298

Memory B Cells and Their Transcriptomic Profiles Associated with Belimumab Resistance in Systemic Lupus Erythematosus in the Maintenance Phase

Provisionally accepted
Takeshi Iwasaki Takeshi Iwasaki 1Hajime Yoshifuji Hajime Yoshifuji 1*Koji Kitagori Koji Kitagori 1Shuji Sumitomo Shuji Sumitomo 2Shuji Akizuki Shuji Akizuki 1Ran Nakashima Ran Nakashima 1HIDEAKI TSUJI HIDEAKI TSUJI 1Ryosuke Hiwa Ryosuke Hiwa 1Mirei Shirakashi Mirei Shirakashi 1Kosaku Murakami Kosaku Murakami 1Akira Onishi Akira Onishi 1Hideo Onizawa Hideo Onizawa 1MASAO TANAKA MASAO TANAKA 1Fumihiko Matsuda Fumihiko Matsuda 1Akio Morinobu Akio Morinobu 1Koichiro Ohmura Koichiro Ohmura 2
  • 1 Kyoto University, Kyoto, Japan
  • 2 Kobe City Medical Center General Hospital, Kobe, Hyōgo, Japan

The final, formatted version of the article will be published soon.

    The factors contributing to the treatment efficacy of belimumab in patients with systemic lupus erythematosus (SLE) in the maintenance phase are unknown. Here, we collected blood samples from patients with SLE (n=44) treated with belimumab before treatment and three, and six months after treatment. RNA-Seq of whole blood was performed, and gene expression was quantified.Deconvolution immune cell type enrichment analysis estimated immune cell subtype proportions and gene expression in each subtype. The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) < 4 at six months was set as the primary efficacy criterion. Non-responders exhibited upregulated B cell proliferation signals before treatment, associated with an increased number of memory B cells. Higher proportions of memory B cells before treatment predicted poor response (p=5.1×10 -45 ). This was also associated with changes in disease activity and glucocorticoid dose at six months compared with baseline. Belimumab did not affect memory B cell proportion during the treatment time course, in contrast to naïve B cells. Higher memory B cell proportion was associated with higher type-I interferon (IFN) scores and lower white blood cell and complement C4 levels.Transcriptomic analysis of memory B cells in non-responders revealed significant upregulation of immunoglobulin genes (Ig). Memory B cells and high Ig expression in them were identified as a treatment-resistant factor of belimumab in SLE patients. Lower C4 and white blood cell counts may serve as clinical markers of higher memory B cells.

    Keywords: systemic lupus erythematosus, belimumab, memory B cell, RNA-Seq, omics, Maintenance phase

    Received: 04 Oct 2024; Accepted: 16 Jan 2025.

    Copyright: © 2025 Iwasaki, Yoshifuji, Kitagori, Sumitomo, Akizuki, Nakashima, TSUJI, Hiwa, Shirakashi, Murakami, Onishi, Onizawa, TANAKA, Matsuda, Morinobu and Ohmura. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Hajime Yoshifuji, Kyoto University, Kyoto, Japan

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