Memory B cells and their transcriptomic profiles associated with belimumab resistance in systemic lupus erythematosus in the maintenance phase
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 and three and six months after treatment. RNA-Seq of...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1506298/full |
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| author | Takeshi Iwasaki Takeshi Iwasaki Hajime Yoshifuji Koji Kitagori Shuji Sumitomo Shuji Akizuki Ran Nakashima Hideaki Tsuji Ryosuke Hiwa Mirei Shirakashi Kosaku Murakami Akira Onishi Hideo Onizawa Masao Tanaka Fumihiko Matsuda Akio Morinobu Koichiro Ohmura Koichiro Ohmura |
| author_facet | Takeshi Iwasaki Takeshi Iwasaki Hajime Yoshifuji Koji Kitagori Shuji Sumitomo Shuji Akizuki Ran Nakashima Hideaki Tsuji Ryosuke Hiwa Mirei Shirakashi Kosaku Murakami Akira Onishi Hideo Onizawa Masao Tanaka Fumihiko Matsuda Akio Morinobu Koichiro Ohmura Koichiro Ohmura |
| author_sort | Takeshi Iwasaki |
| collection | DOAJ |
| description | 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 and three and six months after treatment. RNA-Seq of whole blood was performed, and gene expression was quantified. 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. A higher proportion of memory B cells before treatment predicted poor response (p=5.1×10-4). 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. |
| format | Article |
| id | doaj-art-d88ad3ddec98466fb2607ac5cd6358c7 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-d88ad3ddec98466fb2607ac5cd6358c72025-02-05T07:32:11ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.15062981506298Memory B cells and their transcriptomic profiles associated with belimumab resistance in systemic lupus erythematosus in the maintenance phaseTakeshi Iwasaki0Takeshi Iwasaki1Hajime Yoshifuji2Koji Kitagori3Shuji Sumitomo4Shuji Akizuki5Ran Nakashima6Hideaki Tsuji7Ryosuke Hiwa8Mirei Shirakashi9Kosaku Murakami10Akira Onishi11Hideo Onizawa12Masao Tanaka13Fumihiko Matsuda14Akio Morinobu15Koichiro Ohmura16Koichiro Ohmura17Graduate School of Medicine, Kyoto University, Department of Rheumatology and Clinical Immunology, Kyoto, JapanGraduate School of Medicine, Kyoto University, Center for Genomic Medicine, Kyoto, JapanGraduate School of Medicine, Kyoto University, Department of Rheumatology and Clinical Immunology, Kyoto, JapanGraduate School of Medicine, Kyoto University, Department of Rheumatology and Clinical Immunology, Kyoto, JapanKobe City Medical Center General Hospital, Department of Rheumatology, Kobe, JapanGraduate School of Medicine, Kyoto University, Department of Rheumatology and Clinical Immunology, Kyoto, JapanGraduate School of Medicine, Kyoto University, Department of Rheumatology and Clinical Immunology, Kyoto, JapanGraduate School of Medicine, Kyoto University, Department of Rheumatology and Clinical Immunology, Kyoto, JapanGraduate School of Medicine, Kyoto University, Department of Rheumatology and Clinical Immunology, Kyoto, JapanGraduate School of Medicine, Kyoto University, Department of Rheumatology and Clinical Immunology, Kyoto, JapanDivision of Clinical Immunology and Cancer Immunotherapy, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine, Kyoto, JapanGraduate School of Medicine, Kyoto University, Center for Genomic Medicine, Kyoto, JapanGraduate School of Medicine, Kyoto University, Department of Rheumatology and Clinical Immunology, Kyoto, JapanGraduate School of Medicine, Kyoto University, Department of Rheumatology and Clinical Immunology, Kyoto, JapanKobe City Medical Center General Hospital, Department of Rheumatology, Kobe, JapanThe 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 and three and six months after treatment. RNA-Seq of whole blood was performed, and gene expression was quantified. 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. A higher proportion of memory B cells before treatment predicted poor response (p=5.1×10-4). 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.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1506298/fullsystemic lupus erythematosusbelimumabmemory B cellRNA-Seqomicsmaintenance phase |
| spellingShingle | Takeshi Iwasaki Takeshi Iwasaki Hajime Yoshifuji Koji Kitagori Shuji Sumitomo Shuji Akizuki Ran Nakashima Hideaki Tsuji Ryosuke Hiwa Mirei Shirakashi Kosaku Murakami Akira Onishi Hideo Onizawa Masao Tanaka Fumihiko Matsuda Akio Morinobu Koichiro Ohmura Koichiro Ohmura Memory B cells and their transcriptomic profiles associated with belimumab resistance in systemic lupus erythematosus in the maintenance phase Frontiers in Immunology systemic lupus erythematosus belimumab memory B cell RNA-Seq omics maintenance phase |
| title | Memory B cells and their transcriptomic profiles associated with belimumab resistance in systemic lupus erythematosus in the maintenance phase |
| title_full | Memory B cells and their transcriptomic profiles associated with belimumab resistance in systemic lupus erythematosus in the maintenance phase |
| title_fullStr | Memory B cells and their transcriptomic profiles associated with belimumab resistance in systemic lupus erythematosus in the maintenance phase |
| title_full_unstemmed | Memory B cells and their transcriptomic profiles associated with belimumab resistance in systemic lupus erythematosus in the maintenance phase |
| title_short | Memory B cells and their transcriptomic profiles associated with belimumab resistance in systemic lupus erythematosus in the maintenance phase |
| title_sort | memory b cells and their transcriptomic profiles associated with belimumab resistance in systemic lupus erythematosus in the maintenance phase |
| topic | systemic lupus erythematosus belimumab memory B cell RNA-Seq omics maintenance phase |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1506298/full |
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