4.8 Article

High-Dimensional Analysis Reveals Distinct Endotypes in Patients With Idiopathic Inflammatory Myopathies

Journal

FRONTIERS IN IMMUNOLOGY
Volume 13, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.756018

Keywords

idiopathic inflammatory myopathies (IIM); dermatomyositis (DM); polymyositis (PM); mass cytometry (CyTOF); immunophenotype

Categories

Funding

  1. CTSA award [UL1TR000445]
  2. National Center for Advancing Translational Sciences, National Institutes of Health [T32HL087738, KL2TR002245, K12HD043483, T32AR0590139, K00-CA212447, R01CA226833, U54CA217450, P30CA68485]
  3. Myositis UK
  4. Vanderbilt Faculty Research Scholars Award
  5. Vanderbilt Human Immunology Discovery Initiative
  6. Porter Family Fund for Autoimmunity Research
  7. Myositis Association

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This study identifies two distinct immune endotypes in patients with idiopathic inflammatory myopathies and reveals shared immunologic features among all patients, despite different clinical features.
The idiopathic inflammatory myopathies (IIM) are a rare clinically heterogeneous group of conditions affecting the skin, muscle, joint, and lung in various combinations. While myositis specific autoantibodies are well described, we postulate that broader immune endotypes exist in IIM spanning B cell, T cell, and monocyte compartments. This study aims to identify immune endotypes through detailed immunophenotyping of peripheral blood mononuclear cells (PBMCs) in IIM patients compared to healthy controls. We collected PBMCs from 17 patients with a clinical diagnosis of inflammatory myositis and characterized the B, T, and myeloid cell subsets using mass cytometry by time of flight (CyTOF). Data were analyzed using a combination of the dimensionality reduction algorithm t-distributed stochastic neighbor embedding (t-SNE), cluster identification, characterization, and regression (CITRUS), and marker enrichment modeling (MEM); supervised biaxial gating validated populations identified by these methods to be differentially abundant between groups. Using these approaches, we identified shared immunologic features across all IIM patients, despite different clinical features, as well as two distinct immune endotypes. All IIM patients had decreased surface expression of RP105/CD180 on B cells and a reduction in circulating CD3+CXCR3+ subsets relative to healthy controls. One IIM endotype featured CXCR4 upregulation across all cellular compartments. The second endotype was hallmarked by an increased frequency of CD19+CD21loCD11c+ and CD3+CD4+PD1+ subsets. The experimental and analytical methods we describe here are broadly applicable to studying other immune-mediated diseases (e.g., autoimmunity, immunodeficiency) or protective immune responses (e.g., infection, vaccination).

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