Session Title: Innate Immunity and Rheumatic Disease: Signaling Mechanisms
Session Type: Abstract Submissions (ACR)
Autoimmune muscle diseases such as polymyositis (PM) and dermatomyositis (DM) are characterized by infiltration of inflammatory cells, production of cytokines and chemokines, as well as the expression of major histocompatibility complex (MHC) class I on skeletal muscle fibers. Patients are conventionally treated with high doses of glucocorticoids in combination with additional immunosuppressive drugs. Nevertheless, many patients have persisting muscle weakness even after prolonged treatment.
Objectives: To investigate the effect of conventional immunosuppressive treatment on gene expression profiling in skeletal muscle biopsies from patients with PM and DM, taken before and after treatment in order to develop further understanding of molecular mechanisms that might contribute to the persisting compromised function.
Biopsies (vastus lateralis muscle) from six newly diagnosed, untreated patients with PM (n=2) or DM (n=4) before and after a median of 8.5 months of immunosuppressive treatment were examined by gene expression microarray analysis. Functional associations were analyzed by using Ingenuity Pathway Analysis. Tissue sections from corresponding biopsies were evaluated for MHC class I molecule expression, inflammatory infiltrates, and signs of fiber regeneration/degeneration. Selected genes that displayed changes in expression were validated by western blot (WB).
Evaluation of the biopsies taken after a median of 8.5 months of treatment showed MHC class I staining in muscle fibers, presence of CD3 positive cells (low in general with few positive cells scattered throughout the tissue) and CD68 positive cells (frequent but also ranging from scattered mononuclear cells to infiltrates). By microarray analyses alterations were observed in the overall gene expression in muscle tissue. As expected most of the genes related to immune response such as interferon (IFN) pathway and inflammasome (e.g. AIM-2 and Caspase-1) were down-regulated. In addition alterations were seen in the expression of genes involved in muscle tissue remodeling suggesting protein breakdown as well as muscle regeneration (e.g. by up-regulation of the FKBP5 gene which encodes the protein important in basic cellular processes involving protein folding/trafficking). Validation of changes in gene expression by WB confirmed changes in protein expression; AIM-2 (p=0.044) and Caspase-1 (p=0.035) were significantly down-regulated, while FKBP5 (p=0.020) was up-regulated after chronic glucocorticoid treatment.
Together, these data indicate that during conventional immunosuppressive treatment of myositis patients transcriptional modifications in genes involved in muscle tissue inflammation and remodelling are taking place and their changes could be validated by changes in protein expression. The alteration indicate that besides the beneficial down-regulation of inflammatory pathways there are signs of protein breakdown which may have a negative consequence in muscle repair and may contribute to a defect recovery of muscle strength that may be seen in patients with PM/DM despite immunosuppressive treatment.
I. M. Loell,
Y. W. Chen,
I. E. Lundberg,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gene-expression-profile-in-muscle-tissue-before-and-after-immunosuppressive-treatment-in-patients-with-myositis/