B-cell immune dysregulation with low soluble CD22 levels in refractory seronegative myasthenia gravis
Myasthenia gravis (MG), primarily caused by acetylcholine receptor (AChR) autoantibodies, is a chronic autoimmune disorder causing severe muscle weakness and fatigability. In particular, seronegative MG constitutes 10%–15% of MG cases and presents diagnostic challenges especially in early-onset fema...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1382320/full |
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| author | Yuumi Okuzono Shuuichi Miyakawa Tatsuo Itou Masaki Sagara Masashi Iwata Kei Ishizuchi Koji Sekiguchi Haruhiko Motegi Haruhiko Motegi Munenori Oyama Dnyaneshwar Warude Yusuke Kikukawa Shigeaki Suzuki |
| author_facet | Yuumi Okuzono Shuuichi Miyakawa Tatsuo Itou Masaki Sagara Masashi Iwata Kei Ishizuchi Koji Sekiguchi Haruhiko Motegi Haruhiko Motegi Munenori Oyama Dnyaneshwar Warude Yusuke Kikukawa Shigeaki Suzuki |
| author_sort | Yuumi Okuzono |
| collection | DOAJ |
| description | Myasthenia gravis (MG), primarily caused by acetylcholine receptor (AChR) autoantibodies, is a chronic autoimmune disorder causing severe muscle weakness and fatigability. In particular, seronegative MG constitutes 10%–15% of MG cases and presents diagnostic challenges especially in early-onset female patients who often show severe disease and resistance to immunosuppressive therapy. Furthermore, the immunopathology of seronegative MG remains unclear. Thus, in this study, we aimed to elucidate the pathogenic mechanism of seronegative MG using scRNA-seq analysis and plasma proteome analysis; in particular, we investigated the relationship between immune dysregulation status and disease severity in refractory seronegative MG. Employing single-cell RNA-sequencing and plasma proteome analyses, we analyzed peripheral blood samples from 30 women divided into three groups: 10 healthy controls, 10 early-onset AChR-positive MG, and 10 refractory early-onset seronegative MG patients, both before and after intravenous immunoglobulin treatment. The disease severity was evaluated using the MG-Activities of Daily Living (ADL), MG composite (MGC), and revised 15-item MG-Quality of Life (QOL) scales. We observed numerical abnormalities in multiple immune cells, particularly B cells, in patients with refractory seronegative MG, correlating with disease activity. Notably, severe MG cases had fewer regulatory T cells without functional abnormalities. Memory B cells were found to be enriched in peripheral blood cells compared with naïve B cells. Moreover, plasma proteome analysis indicated significantly lower plasma protein levels of soluble CD22, expressed in the lineage of B-cell maturation (including mature B cells and memory B cells), in refractory seronegative MG patients than in healthy donors or patients with AChR-positive MG. Soluble CD22 levels were correlated with disease severity, B-cell frequency, and RNA expression levels of CD22. In summary, this study elucidates the immunopathology of refractory seronegative MG, highlighting immune disorders centered on B cells and diminished soluble CD22 levels. These insights pave the way for novel MG treatment strategies focused on B-cell biology. |
| first_indexed | 2024-04-24T06:55:17Z |
| format | Article |
| id | doaj.art-349ba8e139934bc890e5dfe759296f04 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-24T06:55:17Z |
| publishDate | 2024-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-349ba8e139934bc890e5dfe759296f042024-04-22T12:53:22ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-04-011510.3389/fimmu.2024.13823201382320B-cell immune dysregulation with low soluble CD22 levels in refractory seronegative myasthenia gravisYuumi Okuzono0Shuuichi Miyakawa1Tatsuo Itou2Masaki Sagara3Masashi Iwata4Kei Ishizuchi5Koji Sekiguchi6Haruhiko Motegi7Haruhiko Motegi8Munenori Oyama9Dnyaneshwar Warude10Yusuke Kikukawa11Shigeaki Suzuki12Oncology Drug Discovery Unit Japan, Research, Takeda Pharmaceutical Company Limited, Kanagawa, JapanOncology Drug Discovery Unit Japan, Research, Takeda Pharmaceutical Company Limited, Kanagawa, JapanOncology Drug Discovery Unit Japan, Research, Takeda Pharmaceutical Company Limited, Kanagawa, JapanOncology Drug Discovery Unit Japan, Research, Takeda Pharmaceutical Company Limited, Kanagawa, JapanOncology Drug Discovery Unit Japan, Research, Takeda Pharmaceutical Company Limited, Kanagawa, JapanDepartment of Neurology, Keio University School of Medicine, Tokyo, JapanDepartment of Neurology, Keio University School of Medicine, Tokyo, JapanDepartment of Neurology, Keio University School of Medicine, Tokyo, JapanDepartment of Neurology, The Jikei University School of Medicine, Tokyo, JapanDepartment of Neurology, Keio University School of Medicine, Tokyo, JapanOncology Drug Discovery Unit Japan, Research, Takeda Pharmaceutical Company Limited, Kanagawa, JapanOncology Drug Discovery Unit Japan, Research, Takeda Pharmaceutical Company Limited, Kanagawa, JapanDepartment of Neurology, Keio University School of Medicine, Tokyo, JapanMyasthenia gravis (MG), primarily caused by acetylcholine receptor (AChR) autoantibodies, is a chronic autoimmune disorder causing severe muscle weakness and fatigability. In particular, seronegative MG constitutes 10%–15% of MG cases and presents diagnostic challenges especially in early-onset female patients who often show severe disease and resistance to immunosuppressive therapy. Furthermore, the immunopathology of seronegative MG remains unclear. Thus, in this study, we aimed to elucidate the pathogenic mechanism of seronegative MG using scRNA-seq analysis and plasma proteome analysis; in particular, we investigated the relationship between immune dysregulation status and disease severity in refractory seronegative MG. Employing single-cell RNA-sequencing and plasma proteome analyses, we analyzed peripheral blood samples from 30 women divided into three groups: 10 healthy controls, 10 early-onset AChR-positive MG, and 10 refractory early-onset seronegative MG patients, both before and after intravenous immunoglobulin treatment. The disease severity was evaluated using the MG-Activities of Daily Living (ADL), MG composite (MGC), and revised 15-item MG-Quality of Life (QOL) scales. We observed numerical abnormalities in multiple immune cells, particularly B cells, in patients with refractory seronegative MG, correlating with disease activity. Notably, severe MG cases had fewer regulatory T cells without functional abnormalities. Memory B cells were found to be enriched in peripheral blood cells compared with naïve B cells. Moreover, plasma proteome analysis indicated significantly lower plasma protein levels of soluble CD22, expressed in the lineage of B-cell maturation (including mature B cells and memory B cells), in refractory seronegative MG patients than in healthy donors or patients with AChR-positive MG. Soluble CD22 levels were correlated with disease severity, B-cell frequency, and RNA expression levels of CD22. In summary, this study elucidates the immunopathology of refractory seronegative MG, highlighting immune disorders centered on B cells and diminished soluble CD22 levels. These insights pave the way for novel MG treatment strategies focused on B-cell biology.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1382320/fullmyasthenia gravissingle-cell RNA-sequencingimmune dysregulationB cellsoluble CD22 |
| spellingShingle | Yuumi Okuzono Shuuichi Miyakawa Tatsuo Itou Masaki Sagara Masashi Iwata Kei Ishizuchi Koji Sekiguchi Haruhiko Motegi Haruhiko Motegi Munenori Oyama Dnyaneshwar Warude Yusuke Kikukawa Shigeaki Suzuki B-cell immune dysregulation with low soluble CD22 levels in refractory seronegative myasthenia gravis Frontiers in Immunology myasthenia gravis single-cell RNA-sequencing immune dysregulation B cell soluble CD22 |
| title | B-cell immune dysregulation with low soluble CD22 levels in refractory seronegative myasthenia gravis |
| title_full | B-cell immune dysregulation with low soluble CD22 levels in refractory seronegative myasthenia gravis |
| title_fullStr | B-cell immune dysregulation with low soluble CD22 levels in refractory seronegative myasthenia gravis |
| title_full_unstemmed | B-cell immune dysregulation with low soluble CD22 levels in refractory seronegative myasthenia gravis |
| title_short | B-cell immune dysregulation with low soluble CD22 levels in refractory seronegative myasthenia gravis |
| title_sort | b cell immune dysregulation with low soluble cd22 levels in refractory seronegative myasthenia gravis |
| topic | myasthenia gravis single-cell RNA-sequencing immune dysregulation B cell soluble CD22 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1382320/full |
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