Brain Advance Access originally published online on April 27, 2005
Brain 2005 128(8):1887-1896; doi:10.1093/brain/awh518
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Published by Oxford University Press on behalf of the Guarantors of Brain
Gene expression profile in the muscles of patients with inflammatory myopathies: effect of therapy with IVIg and biological validation of clinically relevant genes
Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, 20892, USA
Correspondence to: Marinos C. Dalakas, Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10 Room 4N252, 10 Center Drive, Bethesda, MD 20892, USA E-mail: dalakasm{at}ninds.nih.gov
To explore the biological significance of gene expression in the pathogenesis of inflammatory myopathies, we performed microarray experiments followed by real-time PCR and immunohistochemistry on muscle biopsies obtained before and after therapy from patients with dermatomyositis (DM) who improved and patients with inclusion body myositis (sIBM) who did not improve after controlled trials with three monthly intravenous immunoglobulin (IVIg) infusions. The pretreatment biopsies showed high expression of immunoglobulin, adhesion molecules, chemokines and cytokine genes in both sIBM and DM (sIBM > DM). In the repeated biopsies of DM patients who clinically improved, 2206 genes were downregulated more than 1.5-fold; in contrast, 1700 of the same genes remained unchanged in sIBM patients who did not improve. Genes markedly downregulated in DM, but not sIBM, were interleukin 22, Kallmann syndrome 1 (KAL-1), an adhesion molecule shown for the first time in muscle, ICAM-1, complement C1q, and several structural protein genes. Because mRNA for KAL-1 was selectively upregulated in vitro by transforming growth factor (TGF) ß1, a fibrogenic cytokine immunolocalized in the endomysial connective tissue of pretreatment DM muscles, the downregulation of both TGF-ß and KAL-1 after IVIg only in DM suggests that these molecules have a functional role in connective tissue proliferation and fibrosis. The improved muscles of DM, but not sIBM, showed upregulation of chemokines CXCL9 (Mig) and CXCL11, and several immunoglobulin-related genes, suggesting an effect on muscle remodelling and regeneration. The results suggest that IVIg modulates several immunoregulatory or structural muscle genes, but only a subset of them associated with inflammatory mediators, fibrosis and muscle remodelling are connected with the clinical response. Gene arrays, when combined with clinical assessments, may provide important information in the pathogenesis of inflammatory myopathies.
Key Words: neuroimmunology; autoimmunity; inflammation; adhesion molecules
Abbreviations:
BMP-4 = bone morphogenetic protein 4; DAVID = Database for Annotation, Visualization and Integrated Discovery; DM = dermatomyositis; IBM = inclusion body myositis; Ig = immunoglobulin; IL = interleukin; IVIg = intravenous immunoglobulin; KAL-1 = Kallman Syndrome-1; Mig = monokine induced by 
-interferon; TGF = transforming growth factor; TNF-
= tumour necrosis factor
Received October 21, 2004. Revised March 21, 2005. Accepted March 23, 2005.
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