Interferon-α/β-mediated innate immune mechanisms in dermatomyositis
ABSTRACT Dermatomyositis has been modeled as an autoimmune disease largely mediated by the adaptive immune system, including a local humorally mediated response with B and T helper cell muscle infiltration, antibody and complement-mediated injury of capillaries, and perifascicular atrophy of muscle fibers caused by ischemia. To further understand the pathophysiology of dermatomyositis, we used microarrays, computational methods, immunohistochemistry and electron microscopy to study muscle specimens from 67 patients, 54 with inflammatory myopathies, 14 with dermatomyositis. In dermatomyositis, genes induced by interferon-alpha/beta were highly overexpressed, and immunohistochemistry for the interferon-alpha/beta inducible protein MxA showed dense staining of perifascicular, and, sometimes all myofibers in 8/14 patients and on capillaries in 13/14 patients. Of 36 patients with other inflammatory myopathies, 1 patient had faint MxA staining of myofibers and 3 of capillaries. Plasmacytoid dendritic cells, potent CD4+ cellular sources of interferon-alpha, are present in substantial numbers in dermatomyositis and may account for most of the cells previously identified as T helper cells. In addition to an adaptive immune response, an innate immune response characterized by plasmacytoid dendritic cell infiltration and interferon-alpha/beta inducible gene and protein expression may be an important part of the pathogenesis of dermatomyositis, as it appears to be in systemic lupus erythematosus.
SourceAvailable from: Olga Krystufkova[Show abstract] [Hide abstract]
ABSTRACT: IntroductionAnti-Jo-1 and anti-Ro52 autoantibodies are common in patients with myositis, but the mechanisms for their production are not known. Survival of autoantibody producing cells is dependent on B cell activating factor of the TNF family (BAFF). BAFF levels are elevated in serum of anti-Jo-1+ myositis patients and are influenced by type I interferon (IFN). IFN producing cells and BAFF mRNA expression are present in myositis muscle. We investigated expression of the receptors for BAFF in muscle tissue in relation to anti-Jo-1 and anti-Ro52/anti-Ro60 autoantibodies and type I IFN markers.Methods Muscle biopsies from 23 myositis patients, selected by autoantibody profile and seven healthy controls were investigated for expression of BAFF receptor (BAFF-R), B cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI). Nineteen of these were assessed for plasma (CD138) and B cell (CD19) markers. Positively stained cells per area were compared with expression of plasmacytoid dendritic cell (pDC) marker blood dendritic cell antigen-2 (BDCA-2) and IFN¿/ß-inducible myxovirus resistance-1 protein (MX-1).ResultsBAFF-R, BCMA and TACI were expressed in five, seven and seven patients respectively and more frequently in anti-Jo-1+ and/or anti-Ro52/anti-Ro60+ patients compared to patients without these autoantibodies and controls (P¿=¿BAFF-R: 0.007, BCMA: 0.03 and TACI: 0.07). A local association of receptors with B and plasma cells in serial sections was confirmed by confocal microscopy. The numbers of CD138+ and BCMA+ cells correlated (rs¿=¿0.79; P¿=¿0.001).Expression of BDCA-2 correlated with numbers of CD138+ and marginally with BCMA+ cells (rs¿=¿0.54 and 0.42; P¿=¿0.04 and 0.06). There was a borderline correlation between the number of TACI+ cells and MX-1+ areas (rs¿=¿0.38; P¿=¿0.08).Conclusions The expression pattern of BAFF receptors on B and plasma cells in muscle suggests a local role for BAFF in autoantibody production in muscle tissue of myositis patients with anti-Jo-1 or anti-Ro52/anti-Ro60 autoantibodies. BAFF production could be influenced by type I IFN produced by pDCs. Thus B cell related molecular pathways may have a role in the pathogenesis in this subset of myositis patients.Arthritis Research & Therapy 10/2014; 16(5):454. DOI:10.1186/s13075-014-0454-8 · 4.12 Impact Factor
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ABSTRACT: Purpose of review This review discusses the spectrum of diseases associated with a necrotizing muscle biopsy. Although patients with toxic myopathies, endocrine dysfunction, and heritable myopathies may have prominent necrosis on muscle biopsy, immune-mediated myopathies are emphasized here. Recent findings A decade ago, immune-mediated necrotizing myopathy was recognized as a distinct form of myositis. Recent evidence now suggests that immune-mediated necrotizing myopathy is not one disease, but can be divided on the basis of the presence of distinct autoantibodies recognizing either the signal recognition particle or 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Anti-HMG-CoA reductase-positive patients can be further subdivided into those with and without statin exposure, the latter of which may be particularly refractory to immunosuppressive therapy. Summary A significant number of patients with autoimmune myopathy have a predominantly necrotizing muscle biopsy with minimal lymphocytic infiltration. This biopsy finding occurs in various forms myositis, including the antisynthetase syndrome, scleroderma-associated myopathy, antisignal recognition particle-associated myopathy, statin-associated anti-HMG-CoA reductase-positive autoimmune myopathy, and statin-naive anti-HMG-CoA reductase-positive myopathy. Future progress in elucidating pathogenic mechanisms and defining optimal treatment strategies may depend upon recognizing these distinct forms of myositis and analyzing them as separate entities.Current Opinion in Rheumatology 09/2014; 26(6). DOI:10.1097/BOR.0000000000000106 · 5.07 Impact Factor
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ABSTRACT: This review outlines the progress that has been made in understanding the genetics of the idiopathic inflammatory myopathies in the previous 2 years, with a particular focus on dermatomyositis and polymyositis. A recent genome-wide association study in dermatomyositis has confirmed the importance of the major histocompatibility region in this disease, and has suggested a shared genetic etiology with other autoimmune disorders. This has led to an ongoing study of additional immune-related loci using the Immunochip array. Candidate gene studies have identified novel risk associations in non-Europeans, such as STAT4 and HLA-DRB1 in the Japanese population. Evidence for gene-environment interactions has come from two recent studies implicating smoking status and statin use with HLA alleles. This review also touches on future approaches to genetic research in myositis, including bioinformatics tools to identify causal variants, HLA imputation from existing genetic data and statistical methods to investigate shared effects between subgroups of myositis.Current Rheumatology Reports 10/2014; 16(10):446. DOI:10.1007/s11926-014-0446-3 · 2.45 Impact Factor