TY - JOUR
T1 - Precise identification and tracking of HMGCR-reactive CD4+ T cells in the target tissue of patients with anti-HMGCR immune-mediated necrotising myopathy
AU - Tiniakou, Eleni
AU - Girgis, Alex
AU - Siafei, Tiara
AU - Albayda, Jemima
AU - Adler, Brittany
AU - Paik, Julie
AU - Mecoli, Christopher A.
AU - Rebman, Alison
AU - Soloski, Mark J.
AU - Christopher, Lisa
AU - Smith, Kellie
AU - Rosen, Antony
AU - Mammen, Andrew Lee
AU - Darrah, Erika Darrah
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.
PY - 2024/10/11
Y1 - 2024/10/11
N2 - 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 (r 2 =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.
AB - 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 (r 2 =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.
KW - Autoimmunity
KW - Polymyositis
KW - T-Lymphocytes
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U2 - 10.1136/ard-2024-225732
DO - 10.1136/ard-2024-225732
M3 - Article
C2 - 39393845
AN - SCOPUS:85207311427
SN - 0003-4967
JO - Annals of the rheumatic diseases
JF - Annals of the rheumatic diseases
M1 - ard-2024-225732
ER -