Targeting NF-kappaB-inducing kinase shapes B-cell homeostasis in myasthenia gravis
Abstract Background B cell immune dysregulation plays a critical role in myasthenia gravis (MG). However, targeted B-cell therapy such as rituximab may result in long-term peripheral B cell clearance and allow for the survival of plasma cells, contributing to frequent infections and relapses. Theref...
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| Format: | Article |
| Language: | English |
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BMC
2025-01-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-025-03342-5 |
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| author | Xiaoyu Huang Zhouao Zhang Zhouyi Wang Tiancheng Luo Mingjin Yang Xinyan Guo Xue Du Tianyu Ma Yong Zhang |
| author_facet | Xiaoyu Huang Zhouao Zhang Zhouyi Wang Tiancheng Luo Mingjin Yang Xinyan Guo Xue Du Tianyu Ma Yong Zhang |
| author_sort | Xiaoyu Huang |
| collection | DOAJ |
| description | Abstract Background B cell immune dysregulation plays a critical role in myasthenia gravis (MG). However, targeted B-cell therapy such as rituximab may result in long-term peripheral B cell clearance and allow for the survival of plasma cells, contributing to frequent infections and relapses. Therefore, we aimed to identify potential novel therapeutic targets that preserve part of B cell function while inhibiting antibody-secreting cells (ASCs). Methods The transcriptome of sorted CD19+B cells obtained from MG patients in active and remission state was performed by RNA sequencing. The hallmark gene NF-kappaB-inducing kinase (NIK/MAP3K14) associated with NF-κB and TNF signaling was identified, and the expression levels of NIK in CD19+B cells, CD4+T cells and serum from new-onset MG patients and controls were validated by flow cytometry, qPCR and ELISA. In vitro and in vivo, the effects of NIK inhibitor (B022) on the function of CD19+B cells and CD4+T cells were detected under the MG PBMCs, sorted B cells and experimental autoimmune MG (EAMG) rat model, respectively. Results The expression levels of NIK were upregulated in CD19+B cells, CD4+T cells and serum from new-onset MG patients. Notably, increased serum NIK levels were positively correlated with disease severity and decreased with disease remission. NIK inhibitor B022 significantly reduced B-cell activation, proliferation, ASCs differentiation and pathogenic function, as well as CD4+T cell activation and Th17 cells differentiation in vitro. Intraperitoneal injection of B022 ameliorated the severity of EAMG rats, and reduced proportion of pathogenic B and T cell subsets, antibody levels and postsynaptic membrane damage. Conclusions Targeting NIK with small molecule kinase inhibitors can effectively shape B cell homeostasis, and exhibit protective effects in the EAMG rat model, which may be an effective novel treatment strategy for MG. |
| format | Article |
| id | doaj-art-dbbfffc962c343859828eb4c6a126a37 |
| institution | Kabale University |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-dbbfffc962c343859828eb4c6a126a372025-01-26T12:45:17ZengBMCJournal of Neuroinflammation1742-20942025-01-0122111610.1186/s12974-025-03342-5Targeting NF-kappaB-inducing kinase shapes B-cell homeostasis in myasthenia gravisXiaoyu Huang0Zhouao Zhang1Zhouyi Wang2Tiancheng Luo3Mingjin Yang4Xinyan Guo5Xue Du6Tianyu Ma7Yong Zhang8Department of Neurology, Affiliated Hospital of Xuzhou Medical UniversityDepartment of Neurology, Affiliated Hospital of Xuzhou Medical UniversityDepartment of Neurology, Affiliated Hospital of Xuzhou Medical UniversityDepartment of Neurology, Affiliated Hospital of Xuzhou Medical UniversityDepartment of Neurology, Affiliated Hospital of Xuzhou Medical UniversityDepartment of Neurology, Affiliated Hospital of Xuzhou Medical UniversityDepartment of Neurology, Affiliated Hospital of Xuzhou Medical UniversityDepartment of Neurology, Affiliated Hospital of Xuzhou Medical UniversityDepartment of Neurology, Affiliated Hospital of Xuzhou Medical UniversityAbstract Background B cell immune dysregulation plays a critical role in myasthenia gravis (MG). However, targeted B-cell therapy such as rituximab may result in long-term peripheral B cell clearance and allow for the survival of plasma cells, contributing to frequent infections and relapses. Therefore, we aimed to identify potential novel therapeutic targets that preserve part of B cell function while inhibiting antibody-secreting cells (ASCs). Methods The transcriptome of sorted CD19+B cells obtained from MG patients in active and remission state was performed by RNA sequencing. The hallmark gene NF-kappaB-inducing kinase (NIK/MAP3K14) associated with NF-κB and TNF signaling was identified, and the expression levels of NIK in CD19+B cells, CD4+T cells and serum from new-onset MG patients and controls were validated by flow cytometry, qPCR and ELISA. In vitro and in vivo, the effects of NIK inhibitor (B022) on the function of CD19+B cells and CD4+T cells were detected under the MG PBMCs, sorted B cells and experimental autoimmune MG (EAMG) rat model, respectively. Results The expression levels of NIK were upregulated in CD19+B cells, CD4+T cells and serum from new-onset MG patients. Notably, increased serum NIK levels were positively correlated with disease severity and decreased with disease remission. NIK inhibitor B022 significantly reduced B-cell activation, proliferation, ASCs differentiation and pathogenic function, as well as CD4+T cell activation and Th17 cells differentiation in vitro. Intraperitoneal injection of B022 ameliorated the severity of EAMG rats, and reduced proportion of pathogenic B and T cell subsets, antibody levels and postsynaptic membrane damage. Conclusions Targeting NIK with small molecule kinase inhibitors can effectively shape B cell homeostasis, and exhibit protective effects in the EAMG rat model, which may be an effective novel treatment strategy for MG.https://doi.org/10.1186/s12974-025-03342-5Myasthenia gravisNIKB cellsTherapeutic targets |
| spellingShingle | Xiaoyu Huang Zhouao Zhang Zhouyi Wang Tiancheng Luo Mingjin Yang Xinyan Guo Xue Du Tianyu Ma Yong Zhang Targeting NF-kappaB-inducing kinase shapes B-cell homeostasis in myasthenia gravis Journal of Neuroinflammation Myasthenia gravis NIK B cells Therapeutic targets |
| title | Targeting NF-kappaB-inducing kinase shapes B-cell homeostasis in myasthenia gravis |
| title_full | Targeting NF-kappaB-inducing kinase shapes B-cell homeostasis in myasthenia gravis |
| title_fullStr | Targeting NF-kappaB-inducing kinase shapes B-cell homeostasis in myasthenia gravis |
| title_full_unstemmed | Targeting NF-kappaB-inducing kinase shapes B-cell homeostasis in myasthenia gravis |
| title_short | Targeting NF-kappaB-inducing kinase shapes B-cell homeostasis in myasthenia gravis |
| title_sort | targeting nf kappab inducing kinase shapes b cell homeostasis in myasthenia gravis |
| topic | Myasthenia gravis NIK B cells Therapeutic targets |
| url | https://doi.org/10.1186/s12974-025-03342-5 |
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