Immunoregulatory programs in anti‐N‐methyl‐D‐aspartate receptor encephalitis identified by single‐cell multi‐omics analysis
Abstract Background Anti‐N‐methyl‐D‐aspartate receptor encephalitis (anti‐NMDARE) is a prevalent type of autoimmune encephalitis caused by antibodies targeting the NMDAR's GluN1 subunit. While significant progress has been made in elucidating the pathophysiology of autoimmune diseases, the immu...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-01-01
|
| Series: | Clinical and Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ctm2.70173 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832586786293940224 |
|---|---|
| author | Xinhui Li Yicong Xu Weixing Zhang Zihao Chen Dongjie Peng Wenxu Ren Zhongjie Tang Huilu Li Jin Xu Yaqing Shu |
| author_facet | Xinhui Li Yicong Xu Weixing Zhang Zihao Chen Dongjie Peng Wenxu Ren Zhongjie Tang Huilu Li Jin Xu Yaqing Shu |
| author_sort | Xinhui Li |
| collection | DOAJ |
| description | Abstract Background Anti‐N‐methyl‐D‐aspartate receptor encephalitis (anti‐NMDARE) is a prevalent type of autoimmune encephalitis caused by antibodies targeting the NMDAR's GluN1 subunit. While significant progress has been made in elucidating the pathophysiology of autoimmune diseases, the immunological mechanisms underlying anti‐NMDARE remain elusive. This study aimed to characterize immune cell interactions and dysregulation in anti‐NMDARE by leveraging single‐cell multi‐omics sequencing technologies. Methods Peripheral blood mononuclear cells (PBMCs) from patients in the acute phase of anti‐NMDARE and healthy controls were sequenced using single‐cell joint profiling of transcriptome and chromatin accessibility. Differential gene expression analysis, transcription factor activity profiling, and cell‐cell communication modeling were performed to elucidate the immune mechanisms underlying the disease. In parallel, single‐cell B cell receptor sequencing (scBCR‐seq) and repertoire analysis were conducted to assess antigen‐driven clonal expansion within the B cell population. ResultsThe study revealed a significant clonal expansion of B cells, particularly plasma cells, in anti‐NMDARE patients. The novel finding of type I interferon (IFN‐I) pathway activation suggests a regulatory mechanism that may drive this expansion and enhance antibody secretion. Additionally, activation of Toll‐like receptor 2 (TLR2) in myeloid cells was noted, which may connect to tumor necrosis factor‐alpha (TNF‐α) secretion. This cytokine may contribute to the activation of B and T cells, thereby perpetuating immune dysregulation. Conclusions This study presents a comprehensive single‐cell multi‐omics characterization of immune dysregulation in anti‐NMDARE, highlighting the expansion of B cell and the activation of the IFN‐I and TLR2 pathways. These findings provide deeper insights into the molecular mechanism driving the pathogenesis of anti‐NMDARE and offer promising targets for future therapeutic intervention. Key points Significant B cell clonal expansion, particularly in plasma cells, driven by antigen recognition. IFN‐I pathway activation in plasma cells boosts their antibody production and potentially exacerbates immune dysregulation. TLR2 pathway activation in myeloid cells contributes to TNF‐α secretion and could influence adaptive immune responses. |
| format | Article |
| id | doaj-art-4feb50dfc06549acb764a48c6b318c4a |
| institution | Kabale University |
| issn | 2001-1326 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj-art-4feb50dfc06549acb764a48c6b318c4a2025-01-25T04:00:38ZengWileyClinical and Translational Medicine2001-13262025-01-01151n/an/a10.1002/ctm2.70173Immunoregulatory programs in anti‐N‐methyl‐D‐aspartate receptor encephalitis identified by single‐cell multi‐omics analysisXinhui Li0Yicong Xu1Weixing Zhang2Zihao Chen3Dongjie Peng4Wenxu Ren5Zhongjie Tang6Huilu Li7Jin Xu8Yaqing Shu9State Key Laboratory of Biocontrol｜Innovation Center for Evolutionary Synthetic Biology School of Life Sciences Sun Yat‐sen University Guangzhou ChinaState Key Laboratory of Biocontrol｜Innovation Center for Evolutionary Synthetic Biology School of Life Sciences Sun Yat‐sen University Guangzhou ChinaState Key Laboratory of Biocontrol｜Innovation Center for Evolutionary Synthetic Biology School of Life Sciences Sun Yat‐sen University Guangzhou ChinaInstitute of Experimental Cardiology Heidelberg University Heidelberg GermanyState Key Laboratory of Biocontrol｜Innovation Center for Evolutionary Synthetic Biology School of Life Sciences Sun Yat‐sen University Guangzhou ChinaState Key Laboratory of Biocontrol｜Innovation Center for Evolutionary Synthetic Biology School of Life Sciences Sun Yat‐sen University Guangzhou ChinaState Key Laboratory of Biocontrol｜Innovation Center for Evolutionary Synthetic Biology School of Life Sciences Sun Yat‐sen University Guangzhou ChinaDepartment of Neurology The Third Affiliated Hospital of Sun Yat‐sen University Guangzhou ChinaState Key Laboratory of Biocontrol｜Innovation Center for Evolutionary Synthetic Biology School of Life Sciences Sun Yat‐sen University Guangzhou ChinaDepartment of Neurology The Third Affiliated Hospital of Sun Yat‐sen University Guangzhou ChinaAbstract Background Anti‐N‐methyl‐D‐aspartate receptor encephalitis (anti‐NMDARE) is a prevalent type of autoimmune encephalitis caused by antibodies targeting the NMDAR's GluN1 subunit. While significant progress has been made in elucidating the pathophysiology of autoimmune diseases, the immunological mechanisms underlying anti‐NMDARE remain elusive. This study aimed to characterize immune cell interactions and dysregulation in anti‐NMDARE by leveraging single‐cell multi‐omics sequencing technologies. Methods Peripheral blood mononuclear cells (PBMCs) from patients in the acute phase of anti‐NMDARE and healthy controls were sequenced using single‐cell joint profiling of transcriptome and chromatin accessibility. Differential gene expression analysis, transcription factor activity profiling, and cell‐cell communication modeling were performed to elucidate the immune mechanisms underlying the disease. In parallel, single‐cell B cell receptor sequencing (scBCR‐seq) and repertoire analysis were conducted to assess antigen‐driven clonal expansion within the B cell population. ResultsThe study revealed a significant clonal expansion of B cells, particularly plasma cells, in anti‐NMDARE patients. The novel finding of type I interferon (IFN‐I) pathway activation suggests a regulatory mechanism that may drive this expansion and enhance antibody secretion. Additionally, activation of Toll‐like receptor 2 (TLR2) in myeloid cells was noted, which may connect to tumor necrosis factor‐alpha (TNF‐α) secretion. This cytokine may contribute to the activation of B and T cells, thereby perpetuating immune dysregulation. Conclusions This study presents a comprehensive single‐cell multi‐omics characterization of immune dysregulation in anti‐NMDARE, highlighting the expansion of B cell and the activation of the IFN‐I and TLR2 pathways. These findings provide deeper insights into the molecular mechanism driving the pathogenesis of anti‐NMDARE and offer promising targets for future therapeutic intervention. Key points Significant B cell clonal expansion, particularly in plasma cells, driven by antigen recognition. IFN‐I pathway activation in plasma cells boosts their antibody production and potentially exacerbates immune dysregulation. TLR2 pathway activation in myeloid cells contributes to TNF‐α secretion and could influence adaptive immune responses.https://doi.org/10.1002/ctm2.70173anti‐N‐methyl‐D‐aspartate receptor encephalitisautoimmune diseaseregulatory programsingle‐cell multi‐omics sequencing |
| spellingShingle | Xinhui Li Yicong Xu Weixing Zhang Zihao Chen Dongjie Peng Wenxu Ren Zhongjie Tang Huilu Li Jin Xu Yaqing Shu Immunoregulatory programs in anti‐N‐methyl‐D‐aspartate receptor encephalitis identified by single‐cell multi‐omics analysis Clinical and Translational Medicine anti‐N‐methyl‐D‐aspartate receptor encephalitis autoimmune disease regulatory program single‐cell multi‐omics sequencing |
| title | Immunoregulatory programs in anti‐N‐methyl‐D‐aspartate receptor encephalitis identified by single‐cell multi‐omics analysis |
| title_full | Immunoregulatory programs in anti‐N‐methyl‐D‐aspartate receptor encephalitis identified by single‐cell multi‐omics analysis |
| title_fullStr | Immunoregulatory programs in anti‐N‐methyl‐D‐aspartate receptor encephalitis identified by single‐cell multi‐omics analysis |
| title_full_unstemmed | Immunoregulatory programs in anti‐N‐methyl‐D‐aspartate receptor encephalitis identified by single‐cell multi‐omics analysis |
| title_short | Immunoregulatory programs in anti‐N‐methyl‐D‐aspartate receptor encephalitis identified by single‐cell multi‐omics analysis |
| title_sort | immunoregulatory programs in anti n methyl d aspartate receptor encephalitis identified by single cell multi omics analysis |
| topic | anti‐N‐methyl‐D‐aspartate receptor encephalitis autoimmune disease regulatory program single‐cell multi‐omics sequencing |
| url | https://doi.org/10.1002/ctm2.70173 |
| work_keys_str_mv | AT xinhuili immunoregulatoryprogramsinantinmethyldaspartatereceptorencephalitisidentifiedbysinglecellmultiomicsanalysis AT yicongxu immunoregulatoryprogramsinantinmethyldaspartatereceptorencephalitisidentifiedbysinglecellmultiomicsanalysis AT weixingzhang immunoregulatoryprogramsinantinmethyldaspartatereceptorencephalitisidentifiedbysinglecellmultiomicsanalysis AT zihaochen immunoregulatoryprogramsinantinmethyldaspartatereceptorencephalitisidentifiedbysinglecellmultiomicsanalysis AT dongjiepeng immunoregulatoryprogramsinantinmethyldaspartatereceptorencephalitisidentifiedbysinglecellmultiomicsanalysis AT wenxuren immunoregulatoryprogramsinantinmethyldaspartatereceptorencephalitisidentifiedbysinglecellmultiomicsanalysis AT zhongjietang immunoregulatoryprogramsinantinmethyldaspartatereceptorencephalitisidentifiedbysinglecellmultiomicsanalysis AT huiluli immunoregulatoryprogramsinantinmethyldaspartatereceptorencephalitisidentifiedbysinglecellmultiomicsanalysis AT jinxu immunoregulatoryprogramsinantinmethyldaspartatereceptorencephalitisidentifiedbysinglecellmultiomicsanalysis AT yaqingshu immunoregulatoryprogramsinantinmethyldaspartatereceptorencephalitisidentifiedbysinglecellmultiomicsanalysis |