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Abstract
Objectives: Juvenile dermatomyositis (JDM), adult dermatomyositis, and polymyositis (PM) are idiopathic inflammatory myopathies (IIMs) characterized by muscle infiltration and specific muscle fiber alterations. They are thought to have an autoimmune etiology, but triggering factors, and how immunologic attack induces muscle weakness, remain unknown. Recent evidence suggests a key role for type I interferon (IFN)-mediated innate immunity in dermatomyositis, which we explored in JDM, dermatomyositis, and PM by gene expression profiling, and other methods.
Methods: Ten IIM and 5 control muscle biopsies were assessed for expression of approximately 16,000 genes by microarray; 37 additional IIM, 10 dystrophinopathic, and 14 nonmyopathic control muscles were studied for type I IFN-dependent genes, and Toll-like receptor (TLR) expression by immunochemistry and PCR.
Results: Type I IFN-dependent transcripts were significantly upregulated in IIM muscles compared to controls; in JDM the most expressed were ISG15 (408-fold), IFIT3 (261-fold), MX1 (99-fold), and IRF7 (37-fold). IFN-β (but not IFN-α) transcripts were upregulated in PM as well as dermatomyositis/JDM. TLR3 was upregulated particularly in JDM, being localized on vascular endothelial cells, muscle infiltrating cells (mainly myeloid dendritic cells), and regenerating myofibers; TLR7 and TLR9 proteins were present in IIM (prominently in PM), mainly on cell infiltrates, particularly plasma cells, and on some injured myofibers.
Conclusions: IFN-β and type I IFN-induced molecules are involved in PM as well as JDM/dermatomyositis. Endosomal TLRs (effectors of innate immunity) are also involved (but differently) in the 3 conditions, further suggesting viral involvement, although TLR activation could be secondary to tissue damage.
Footnotes
Study funding: Supported by the Italian Ministry of Health 2007–2009 (annual research funding to P.B. and R.M.); the Associazione Volontari Aiuti per la Sclerosi Multipla (RP16 to R.M.); the Fondazione Italiana Sclerosi Multipla (FISM 2009/R/7 to E.M.C.); and the European Union (TOLERAGE HEALTH-F4-2008-202156 to F.Z. and D.B.).
Supplemental data at www.neurology.org
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- cDNA
- complementary DNA
- DC
- dendritic cells
- DDX58
- DEAD box polypeptide 58
- DEG
- differentially expressed genes
- IFIT1
- interferon-induced protein with tetratricopeptide repeats 1
- IFIT3
- interferon-induced protein with tetratricopeptide repeats 3
- IFN
- interferon
- IgG
- immunoglobulin G
- IIM
- idiopathic inflammatory myopathy
- IRF7
- interferon regulatory factor 7
- ISG15
- 15-kDa interferon-stimulated protein
- ISGF3G
- interferon-stimulated transcription factor 3 gamma
- JDM
- juvenile dermatomyositis
- mDC
- myeloid dendritic cell
- MHCdev
- developmental myosin heavy chain
- MX1
- myxovirus resistance protein 1
- MyD88
- myeloid differentiation primary response gene (88)
- pDC
- plasmacytoid dendritic cell
- PM
- polymyositis
- STAT1
- signal transducer and activator of transcription protein 1
- TLR
- Toll-like receptor
- Received July 6, 2010.
- Accepted February 25, 2011.
- Copyright © 2011 by AAN Enterprises, Inc.
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