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Dysregulation of peripheral blood B-cells and NK-cells is associated with myocarditis in idiopathic inflammatory myopathies

ABSTRACT: Idiopathic inflammatory myopathies (IIM), or myositis, are a group of systemic autoimmune diseases leading to proximal muscle weakness. Myocarditis is estimated to affect up to 50% of IIM patients and is a major cause of adverse outcomes in these patients. Yet, we know very little about the underlying immunologic processes that are driving myocarditis in the context of IIM. In this study we use single-cell RNA sequencing of peripheral blood mononuclear cells of 12 patients with myositis alone (n=4), myositis plus myocarditis(n=4) and healthy controls(n=4), in order to better understand the immunologic alterations characterizing this manifestation of the disease. We found the most notable changes in B cells and NK cells with myositis plus myocarditis patients B cells having gene expression signatures suggestive of increased DNA replication and repair, somatic hypermutation, and lymphocyte activation, but a smaller proportion of memory B cells, suggesting a greater activation of naive B cells in the periphery. NK cells on the other hand showed gene expression signatures suggestive of reduced proliferation, but increased effector functions such as leukocyte degranulation, myeloid cell activation, and tumor necrosis factor secretion, suggesting that NK cells in myocarditis plus myositis are more activated but less proliferative than in myositis alone. Together this data suggests that B cells and NK cells may be playing important roles in mediating myocarditis pathogenesis in the context of IIM, and may be important future therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310662 | GEO | 2026/09/23

REPOSITORIES: GEO

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Project description:Objective: In idiopathic inflammatory myopathies (IIM) infiltration of immune cells into muscle and upregulation of MHC-I expression implies increased antigen presentation and involvement of the proteasome system. To decipher the role of immunoproteasomes in myositis, we investigated individual cell types and muscle tissues and focused on possible immune triggers. Methods: Expression of constitutive (PSMB5, -6, -7) and corresponding immunoproteasomal subunits (PSMB8, -9, -10) was analyzed by real-time RT-PCR in muscle biopsies and sorted peripheral blood cells of patients with IIM, non-inflammatory myopathies (NIM) and healthy donors (HD). Protein analysis in muscle biopsies was performed by western blot. Affymetrix HG-U133 platform derived transcriptome data from biopsies of different muscle diseases and from immune cell types as well as monocyte stimulation experiments were used for validation, coregulation and coexpression analyses. Results: Real-time RT-PCR revealed significantly increased expression of immunoproteasomal subunits (PSMB8/-9/-10) in DC, monocytes and CD8+ T-cells in IIM. In muscle biopsies, the immunosubunits were elevated in IIM compared to NIM and exceeded levels of matched blood samples. Proteins of PSMB8 and -9 were found only in IIM but not NIM muscle biopsies. Reanalysis of 78 myositis and 20 healthy muscle transcriptomes confirmed these results and revealed involvement of the antigen processing and presentation pathway. Comparison with reference profiles of sorted immune cells and healthy muscle confirmed upregulation of PSMB8 and -9 in myositis biopsies beyond infiltration related changes. This upregulation correlated highest with STAT1, IRF1 and IFNM-NM-3 expression. Elevation of T-cell specific transcripts in active IIM muscles was accompanied by increased expression of DC and monocyte marker genes and thus reflects the cell type specific involvement observed in peripheral blood. Conclusions: Immunoproteasomes seem to indicate IIM activity and suggest that dominant involvement of antigen processing and presentation may qualify these diseases exemplarily for the evolving therapeutic concepts of immunoproteasome specific inhibition. Investigation of constitutive and immunoproteasomal subunit expression in muscle tissue of patients with inflammatory and non-inflammatory myopathies These transcriptomes were used as reference signatures of different immune cell types in order to estimate the contribution of immune cell transcripts to the muscle transcriptomes investigated in the datasets GSE2044, GSE3112, GSE5370, GSE39454, GSE3307, GSE13205, GSE10685.

Project description:Objective: In idiopathic inflammatory myopathies (IIM) infiltration of immune cells into muscle and upregulation of MHC-I expression implies increased antigen presentation and involvement of the proteasome system. To decipher the role of immunoproteasomes in myositis, we investigated individual cell types and muscle tissues and focused on possible immune triggers. Methods: Expression of constitutive (PSMB5, -6, -7) and corresponding immunoproteasomal subunits (PSMB8, -9, -10) was analyzed by real-time RT-PCR in muscle biopsies and sorted peripheral blood cells of patients with IIM, non-inflammatory myopathies (NIM) and healthy donors (HD). Protein analysis in muscle biopsies was performed by western blot. Affymetrix HG-U133 platform derived transcriptome data from biopsies of different muscle diseases and from immune cell types as well as monocyte stimulation experiments were used for validation, coregulation and coexpression analyses. Results: Real-time RT-PCR revealed significantly increased expression of immunoproteasomal subunits (PSMB8/-9/-10) in DC, monocytes and CD8+ T-cells in IIM. In muscle biopsies, the immunosubunits were elevated in IIM compared to NIM and exceeded levels of matched blood samples. Proteins of PSMB8 and -9 were found only in IIM but not NIM muscle biopsies. Reanalysis of 78 myositis and 20 healthy muscle transcriptomes confirmed these results and revealed involvement of the antigen processing and presentation pathway. Comparison with reference profiles of sorted immune cells and healthy muscle confirmed upregulation of PSMB8 and -9 in myositis biopsies beyond infiltration related changes. This upregulation correlated highest with STAT1, IRF1 and IFNγ expression. Elevation of T-cell specific transcripts in active IIM muscles was accompanied by increased expression of DC and monocyte marker genes and thus reflects the cell type specific involvement observed in peripheral blood. Conclusions: Immunoproteasomes seem to indicate IIM activity and suggest that dominant involvement of antigen processing and presentation may qualify these diseases exemplarily for the evolving therapeutic concepts of immunoproteasome specific inhibition.

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Dysregulation of peripheral blood B-cells and NK-cells is associated with myocarditis in idiopathic inflammatory myopathies

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