Defects of CTLA-4 Are Associated with Regulatory T Cells in Myasthenia Gravis Implicated by Intravenous Immunoglobulin Therapy
Myasthenia gravis (MG) is a CD4+ T cell-dependent autoimmune disease resulting from aberrant immune response mediated by circulating autoantibodies at the neuromuscular junction. Intravenous immunoglobulin (IVIg) is an expensive and commonly used immunotherapeutic approach to treat patients with MG....
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-01-01
|
| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2020/3645157 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832547077060558848 |
|---|---|
| author | Wenhua Xu Mingshan Ren Swagata Ghosh Kai Qian Zhaofeng Luo Aimei Zhang Cuiping Zhang Jiajun Cui |
| author_facet | Wenhua Xu Mingshan Ren Swagata Ghosh Kai Qian Zhaofeng Luo Aimei Zhang Cuiping Zhang Jiajun Cui |
| author_sort | Wenhua Xu |
| collection | DOAJ |
| description | Myasthenia gravis (MG) is a CD4+ T cell-dependent autoimmune disease resulting from aberrant immune response mediated by circulating autoantibodies at the neuromuscular junction. Intravenous immunoglobulin (IVIg) is an expensive and commonly used immunotherapeutic approach to treat patients with MG. The mechanisms of actions involved in IVIg treatment, however, remain to be investigated. In an effort to examine the roles of various subsets of CD4+ T cells in the periphery blood of MG and uncover the mechanisms that contribute to the therapeutical effects of IVIg, we first demonstrated that a subset of CD4+ T cells, CTLA-4-expressing regulatory T (Treg) cells, were underrepresented and functionally defective in MG patients. The dynamic profiling during the IVIg therapy course further revealed an inverse relationship between the frequency of CTLA-4+ Treg and the quantitative MG (QMG) score that represents disease severity. Our mechanistic studies indicated that IVIg expands CTLA-4-Treg cells via modulating antigen-presenting dendritic cells (DCs). To determine the molecular defects of CTLA-4 in abnormities of Treg in MG patients, we demonstrated hypermethylation at -658 and -793 CpGs of CTLA-4 promoter in MG Tregs. Interestingly, IVIg therapy significantly reduced the methylation level at these two sites in MG patients. Overall, our study may suggest a role of CTLA-4 in functionally defected Treg cells in MG and its actions involved in IVIg therapy. |
| format | Article |
| id | doaj-art-4daacda51d42427eba15e9fa85be4225 |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-4daacda51d42427eba15e9fa85be42252025-02-03T06:46:08ZengWileyMediators of Inflammation0962-93511466-18612020-01-01202010.1155/2020/36451573645157Defects of CTLA-4 Are Associated with Regulatory T Cells in Myasthenia Gravis Implicated by Intravenous Immunoglobulin TherapyWenhua Xu0Mingshan Ren1Swagata Ghosh2Kai Qian3Zhaofeng Luo4Aimei Zhang5Cuiping Zhang6Jiajun Cui7Department of Neurology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaDepartment of Neurology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaDepartment of Internal Medicine, Division of Infectious Diseases and International Health, University of Virginia, Virginia 22908, USAThe Center for Translational Medicine, Yichun University, Yichun, ChinaHefei National Laboratory for Physical Science, Core Facility Center for Life Sciences, University of Science and Technology of China, Hefei, ChinaCentral Laboratory, The First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaCentral Laboratory, The First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaThe Center for Translational Medicine, Yichun University, Yichun, ChinaMyasthenia gravis (MG) is a CD4+ T cell-dependent autoimmune disease resulting from aberrant immune response mediated by circulating autoantibodies at the neuromuscular junction. Intravenous immunoglobulin (IVIg) is an expensive and commonly used immunotherapeutic approach to treat patients with MG. The mechanisms of actions involved in IVIg treatment, however, remain to be investigated. In an effort to examine the roles of various subsets of CD4+ T cells in the periphery blood of MG and uncover the mechanisms that contribute to the therapeutical effects of IVIg, we first demonstrated that a subset of CD4+ T cells, CTLA-4-expressing regulatory T (Treg) cells, were underrepresented and functionally defective in MG patients. The dynamic profiling during the IVIg therapy course further revealed an inverse relationship between the frequency of CTLA-4+ Treg and the quantitative MG (QMG) score that represents disease severity. Our mechanistic studies indicated that IVIg expands CTLA-4-Treg cells via modulating antigen-presenting dendritic cells (DCs). To determine the molecular defects of CTLA-4 in abnormities of Treg in MG patients, we demonstrated hypermethylation at -658 and -793 CpGs of CTLA-4 promoter in MG Tregs. Interestingly, IVIg therapy significantly reduced the methylation level at these two sites in MG patients. Overall, our study may suggest a role of CTLA-4 in functionally defected Treg cells in MG and its actions involved in IVIg therapy.http://dx.doi.org/10.1155/2020/3645157 |
| spellingShingle | Wenhua Xu Mingshan Ren Swagata Ghosh Kai Qian Zhaofeng Luo Aimei Zhang Cuiping Zhang Jiajun Cui Defects of CTLA-4 Are Associated with Regulatory T Cells in Myasthenia Gravis Implicated by Intravenous Immunoglobulin Therapy Mediators of Inflammation |
| title | Defects of CTLA-4 Are Associated with Regulatory T Cells in Myasthenia Gravis Implicated by Intravenous Immunoglobulin Therapy |
| title_full | Defects of CTLA-4 Are Associated with Regulatory T Cells in Myasthenia Gravis Implicated by Intravenous Immunoglobulin Therapy |
| title_fullStr | Defects of CTLA-4 Are Associated with Regulatory T Cells in Myasthenia Gravis Implicated by Intravenous Immunoglobulin Therapy |
| title_full_unstemmed | Defects of CTLA-4 Are Associated with Regulatory T Cells in Myasthenia Gravis Implicated by Intravenous Immunoglobulin Therapy |
| title_short | Defects of CTLA-4 Are Associated with Regulatory T Cells in Myasthenia Gravis Implicated by Intravenous Immunoglobulin Therapy |
| title_sort | defects of ctla 4 are associated with regulatory t cells in myasthenia gravis implicated by intravenous immunoglobulin therapy |
| url | http://dx.doi.org/10.1155/2020/3645157 |
| work_keys_str_mv | AT wenhuaxu defectsofctla4areassociatedwithregulatorytcellsinmyastheniagravisimplicatedbyintravenousimmunoglobulintherapy AT mingshanren defectsofctla4areassociatedwithregulatorytcellsinmyastheniagravisimplicatedbyintravenousimmunoglobulintherapy AT swagataghosh defectsofctla4areassociatedwithregulatorytcellsinmyastheniagravisimplicatedbyintravenousimmunoglobulintherapy AT kaiqian defectsofctla4areassociatedwithregulatorytcellsinmyastheniagravisimplicatedbyintravenousimmunoglobulintherapy AT zhaofengluo defectsofctla4areassociatedwithregulatorytcellsinmyastheniagravisimplicatedbyintravenousimmunoglobulintherapy AT aimeizhang defectsofctla4areassociatedwithregulatorytcellsinmyastheniagravisimplicatedbyintravenousimmunoglobulintherapy AT cuipingzhang defectsofctla4areassociatedwithregulatorytcellsinmyastheniagravisimplicatedbyintravenousimmunoglobulintherapy AT jiajuncui defectsofctla4areassociatedwithregulatorytcellsinmyastheniagravisimplicatedbyintravenousimmunoglobulintherapy |