Background 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.
Objectives To decipher the role of proteasome in myositis, we investigated the expression of catalytic proteasomal subunits in 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 PCR in muscle biopsies and sorted peripheral blood cells of patients with IIM, non-inflammatory myopathies (NIM) and healthy donors (HD). 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 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 also elevated in IIM compared to NIM and even more than in matched blood samples. Reanalysis of 78 myositis and 20 healthy muscle transcriptomes confirmed high-ranking upregulation of these immunosubunits in IIM including strong association with molecular disease activity and identified antigen processing and presentation as involved pathways.
Comparison with reference profiles of sorted immune cell types and healthy muscle confirmed upregulation of PSMB8 and -9 in myositis biopsies beyond infiltration related changes. This upregulation correlated highest with STAT1 and IRF1 expression and was associated with interferon gamma. The strong 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 indicate that antigen processing is dominantly involved in the pathophysiology of active IIM. Association with antigen presenting cells, T-cells, CD8 and IFN gamma suggests perpetuating crosstalk sustained by antigen processing. Therefore, these diseases may exemplarily qualify for the evolving therapeutic concepts of immunoproteasome specific inhibition.
Disclosure of Interest None declared
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