Session Information
Session Type: Poster Session B
Session Time: 8:30AM-10:30AM
Background/Purpose: Anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR)-positive immune mediated necrotizing myopathy (anti-HMGCR+ IMNM) is a unique myopathy characterized by IgG autoantibodies against HMGCR and a strong association with a specific HLA class II allele (HLA-DRB1*11:01). Although this implicates HMGCR-specific CD4+ T cells in disease pathogenesis, no such cells have been identified thus far. In this study, we aimed to define HMGCR T cell epitopes using a natural antigen processing assay (NAPA).
Methods: Monocyte-derived dendritic cells (MoDCs) from 6 patients with anti-HMGCR+ IMNM were incubated with the C-terminal portion of HMGCR protein (amino acids 340-888) and presented peptides were identified using NAPA. Briefly, HLA-DR/peptide complexes were isolated by immunoprecipitation, and bound HMGCR peptides were sequenced by mass spectrometry. HMGCR peptides corresponding to the putative CD4+ T cell epitopes were synthesized and used to stimulate peripheral blood mononuclear cells (PBMCs) from 6 patients with anti-HMGCR+ IMNM and 6 patients with dermatomyositis, as negative controls. HMGCR-reactive CD4+ T cells were identified by flow cytometry based on activation status (CD154 upregulation).
Results: A total of 7 different naturally processed HMGCR peptides were identified using NAPA (Table 1). The number of distinct peptides presented per patient ranged from 1 to 5, with 5 epitopes being presented by at least two patients. All naturally presented HMGCR peptides elicited robust CD4+ T cell responses in the 6 anti-HMGCR+ IMNM patients, compared to only 2/6 patients with dermatomyositis (p=0.014). All anti-HMGCR+ IMNM patients responded to 3-7 peptides (median 5.5) (Figure 1), and the T cell responses were significantly higher than those observed in patients with dermatomyositis (p< 0.0001).
Conclusion: Our findings represent the first report of antigen-specific CD4+ T cells in anti-HMGCR+ IMNM. Leveraging NAPA, we were able to define a core set of HMGCR peptides naturally presented by MoDCs from patients with anti-HMGCR+ IMNM, defining precise immunologically relevant autoantigenic CD4+ T cell epitopes. Definition of these epitopes is key in understanding disease pathogenesis and will aid in the future development of antigen-specific research and therapeutic tools.
To cite this abstract in AMA style:
Tiniakou E, Mammen A, Darrah E. Discovery of Antigen Specific CD4+ T Cells in Anti-HMGCR-positive Immune Mediated Necrotizing Myopathy [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/discovery-of-antigen-specific-cd4-t-cells-in-anti-hmgcr-positive-immune-mediated-necrotizing-myopathy/. Accessed .« Back to ACR Convergence 2021
ACR Meeting Abstracts - https://acrabstracts.org/abstract/discovery-of-antigen-specific-cd4-t-cells-in-anti-hmgcr-positive-immune-mediated-necrotizing-myopathy/