Eleni Tiniakou, Alex Girgis, Tiara Siafei, Jemima Albayda, Brittany Adler, Julie J Paik, Christopher A Mecoli, Alison Rebman, Mark J Soloski, Lisa Christopher-Stine, Kellie N Smith, Antony Rosen, Andrew Lee Mammen, Erika Darrah
{"title":"在抗 HMGCR 免疫介导的坏死性肌病患者的靶组织中精确识别和追踪 HMGCR 反应性 CD4+ T 细胞。","authors":"Eleni Tiniakou, Alex Girgis, Tiara Siafei, Jemima Albayda, Brittany Adler, Julie J Paik, Christopher A Mecoli, Alison Rebman, Mark J Soloski, Lisa Christopher-Stine, Kellie N Smith, Antony Rosen, Andrew Lee Mammen, Erika Darrah","doi":"10.1136/ard-2024-225732","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR)-positive immune-mediated necrotising myopathy (IMNM) is characterised by the presence of IgG autoantibodies against HMGCR and a strong association with specific HLA-DR alleles. Although these findings implicate HMGCR-specific CD4<sup>+</sup>T-cells in the disease's pathogenesis, no such cells have been described. In this study, we aimed to identify and characterise HMGCR-reactive CD4<sup>+</sup>T-cells and assess their presence in affected muscle tissue from patients with anti-HMGCR+IMNM.</p><p><strong>Methods: </strong>Peripheral blood mononuclear cells from patients with anti-HMGCR+IMNM (n=10) and dermatomyositis (DM; n=10) were stimulated with HMGCR protein and peptides identified using a natural antigen processing assay (NAPA; n=6). CD4<sup>+</sup>T-cell activation was assessed by CD154 upregulation via flow cytometry. T-cell receptor β(TCR) sequencing was performed on paired HMGCR-reactive T-cells and muscle biopsy tissue (n=5).</p><p><strong>Results: </strong>CD4<sup>+</sup>T-cell responses to HMGCR protein were higher in patients with anti-HMGCR+IMNM compared with DM (median 0.06 vs 0.00, p=0.0059). These responses were enriched in Th1-Th17 cells, and when present, they positively correlated with anti-HMGCR antibody levels (r<sup>2</sup>=0.89, p=0.0012). NAPA revealed convergent presentation of seven HMGCR core peptides, with substantial overlap in the peptide repertoires between patients. These HMGCR peptides elicited robust CD4<sup>+</sup>T-cell responses, with 9/10 anti-HMGCR+IMNM patients responding to at least one peptide, compared with 1/10 DM (p=0.0003). Analysis of HMGCR-reactive TCRs β yielded antigen-reactive motifs that were enriched in muscle biopsies (projection score 0.03 vs 0.63, p=0.007).</p><p><strong>Conclusion: </strong>HMGCR-antigen-reactive CD4<sup>+</sup>T-cells are present in the circulation and target tissue of patients with anti-HMGCR+IMNM, suggesting an active role for these cells in the pathogenesis of anti-HMGCR+IMNM.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3000,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Precise identification and tracking of HMGCR-reactive CD4+ T cells in the target tissue of patients with anti-HMGCR immune-mediated necrotising myopathy.\",\"authors\":\"Eleni Tiniakou, Alex Girgis, Tiara Siafei, Jemima Albayda, Brittany Adler, Julie J Paik, Christopher A Mecoli, Alison Rebman, Mark J Soloski, Lisa Christopher-Stine, Kellie N Smith, Antony Rosen, Andrew Lee Mammen, Erika Darrah\",\"doi\":\"10.1136/ard-2024-225732\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR)-positive immune-mediated necrotising myopathy (IMNM) is characterised by the presence of IgG autoantibodies against HMGCR and a strong association with specific HLA-DR alleles. Although these findings implicate HMGCR-specific CD4<sup>+</sup>T-cells in the disease's pathogenesis, no such cells have been described. In this study, we aimed to identify and characterise HMGCR-reactive CD4<sup>+</sup>T-cells and assess their presence in affected muscle tissue from patients with anti-HMGCR+IMNM.</p><p><strong>Methods: </strong>Peripheral blood mononuclear cells from patients with anti-HMGCR+IMNM (n=10) and dermatomyositis (DM; n=10) were stimulated with HMGCR protein and peptides identified using a natural antigen processing assay (NAPA; n=6). CD4<sup>+</sup>T-cell activation was assessed by CD154 upregulation via flow cytometry. T-cell receptor β(TCR) sequencing was performed on paired HMGCR-reactive T-cells and muscle biopsy tissue (n=5).</p><p><strong>Results: </strong>CD4<sup>+</sup>T-cell responses to HMGCR protein were higher in patients with anti-HMGCR+IMNM compared with DM (median 0.06 vs 0.00, p=0.0059). These responses were enriched in Th1-Th17 cells, and when present, they positively correlated with anti-HMGCR antibody levels (r<sup>2</sup>=0.89, p=0.0012). NAPA revealed convergent presentation of seven HMGCR core peptides, with substantial overlap in the peptide repertoires between patients. These HMGCR peptides elicited robust CD4<sup>+</sup>T-cell responses, with 9/10 anti-HMGCR+IMNM patients responding to at least one peptide, compared with 1/10 DM (p=0.0003). Analysis of HMGCR-reactive TCRs β yielded antigen-reactive motifs that were enriched in muscle biopsies (projection score 0.03 vs 0.63, p=0.007).</p><p><strong>Conclusion: </strong>HMGCR-antigen-reactive CD4<sup>+</sup>T-cells are present in the circulation and target tissue of patients with anti-HMGCR+IMNM, suggesting an active role for these cells in the pathogenesis of anti-HMGCR+IMNM.</p>\",\"PeriodicalId\":8087,\"journal\":{\"name\":\"Annals of the Rheumatic Diseases\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":20.3000,\"publicationDate\":\"2024-10-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of the Rheumatic Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1136/ard-2024-225732\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RHEUMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of the Rheumatic Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/ard-2024-225732","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
Precise identification and tracking of HMGCR-reactive CD4+ T cells in the target tissue of patients with anti-HMGCR immune-mediated necrotising myopathy.
Background: Anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR)-positive immune-mediated necrotising myopathy (IMNM) is characterised by the presence of IgG autoantibodies against HMGCR and a strong association with specific HLA-DR alleles. Although these findings implicate HMGCR-specific CD4+T-cells in the disease's pathogenesis, no such cells have been described. In this study, we aimed to identify and characterise HMGCR-reactive CD4+T-cells and assess their presence in affected muscle tissue from patients with anti-HMGCR+IMNM.
Methods: Peripheral blood mononuclear cells from patients with anti-HMGCR+IMNM (n=10) and dermatomyositis (DM; n=10) were stimulated with HMGCR protein and peptides identified using a natural antigen processing assay (NAPA; n=6). CD4+T-cell activation was assessed by CD154 upregulation via flow cytometry. T-cell receptor β(TCR) sequencing was performed on paired HMGCR-reactive T-cells and muscle biopsy tissue (n=5).
Results: CD4+T-cell responses to HMGCR protein were higher in patients with anti-HMGCR+IMNM compared with DM (median 0.06 vs 0.00, p=0.0059). These responses were enriched in Th1-Th17 cells, and when present, they positively correlated with anti-HMGCR antibody levels (r2=0.89, p=0.0012). NAPA revealed convergent presentation of seven HMGCR core peptides, with substantial overlap in the peptide repertoires between patients. These HMGCR peptides elicited robust CD4+T-cell responses, with 9/10 anti-HMGCR+IMNM patients responding to at least one peptide, compared with 1/10 DM (p=0.0003). Analysis of HMGCR-reactive TCRs β yielded antigen-reactive motifs that were enriched in muscle biopsies (projection score 0.03 vs 0.63, p=0.007).
Conclusion: HMGCR-antigen-reactive CD4+T-cells are present in the circulation and target tissue of patients with anti-HMGCR+IMNM, suggesting an active role for these cells in the pathogenesis of anti-HMGCR+IMNM.
期刊介绍：
Annals of the Rheumatic Diseases (ARD) is an international peer-reviewed journal covering all aspects of rheumatology, which includes the full spectrum of musculoskeletal conditions, arthritic disease, and connective tissue disorders. ARD publishes basic, clinical, and translational scientific research, including the most important recommendations for the management of various conditions.
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