Session Type: Abstract Submissions (ACR)
Background/Purpose: Fibrosis in Systemic Sclerosis is characterized by excessive collagen production and accumulation in the skin and lungs. It has been increasingly appreciated that a substantial number of SSc patients display a type I interferon (IFN) signature. Microarray studies support a pivotal role of type I IFN in the pathophysiology of connective tissue diseases. Type I IFN and associated gene signatures might serve as a marker for more severe disease. Interferon regulatory factors (IRFs) are characterized as transcriptional regulators of type I IFNs and IFN-inducible genes. Interferon regulatory factor 7 (IRF7) polymorphisms are associated with many autoimmune diseases including SSc. However, no specific mechanism for its involvement in SSc has been identified.
Methods: Healthy adult dermal fibroblasts and SSc fibroblasts were studied in parallel. Scleroderma and normal skin biopsies (61 SSc patients and 36 healthy controls) were used for microarray studies to quantitate IRF7 levels and for immunohistochemistry (IHC) analyses (6 SSc patients and 5 healthy controls) to determine expression pattern of IRF7. In addition to patient samples, IRF7 was examined in bleomycin induced scleroderma mouse model. Lesional murine skin tissues were examined by microarray and immunohistochemistry analysis.
Results: IRF7 protein levels were significantly elevated in explanted SSc skin fibroblasts and skin tissues from patients with SSc compared to healthy controls. Microarray studies showed that IRF7 mRNA levels were up-regulated in skin and monocytes from SSc patients. TGF-ß, PolyI(c) and IFN-α caused a time- and dose-dependent increase in IRF7 protein and mRNA expression in normal and SSc skin fibroblasts. IRF7 protein and mRNA levels were found to be up-regulated in skin from the bleomycin induced mouse model of scleroderma.
Conclusion: Up-regulation of IRF7 in SSc might contribute to amplification or persistence of the IFN driven inflammatory response and TGF-ß-driven fibrotic response. Blocking IRF-7 may therefore represent a novel therapeutic strategy in SSc.
M. R. Blackburn,
J. D. Reveille,
F. K. Tan,
S. K. Agarwal,
M. D. Mayes,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/type-i-interferon-associated-gene-irf7-in-the-pathogenesis-of-fibrosis-in-systemic-sclerosis-ssc/