Elsevier

Clinical Immunology

Volume 120, Issue 3, September 2006, Pages 319-325
Clinical Immunology

MxA gene expression in juvenile dermatomyositis peripheral blood mononuclear cells: Association with muscle involvement

https://doi.org/10.1016/j.clim.2006.05.011Get rights and content

Abstract

Juvenile dermatomyositis (JDM), a systemic vasculopathy, is characterized by inflammation of skin and muscle. Muscle biopsies from untreated JDM patients show upregulation of type I interferon (IFN)-inducible genes, including myxovirus resistance protein A (MxA). The present study examines whether MxA mRNA expression in peripheral blood mononuclear cells (PBMC) from JDM patients: (1) is elevated compared to healthy controls, (2) reflects disease activity, and (3) changes with the onset of clinically effective treatment. MxA mRNA expression in JDM PBMC obtained at the initial clinic visit was elevated compared to controls and was positively correlated with Disease Activity Score (DAS) for muscle, but not with DAS for skin, suggesting that damage to skin and muscle in JDM may each have a discrete pathophysiology. During the course of clinically effective treatment, decrease in muscle symptoms was associated with a decrease in PBMC MxA mRNA expression.

Introduction

Although juvenile dermatomyositis (JDM) is a rare disease, it is the most common pediatric inflammatory myopathy, with an incidence of 3.2 cases/million children/year [1]. The mean age of disease onset (the time of the first symptom of JDM — rash or weakness) was 6.9 years and 25% of newly diagnosed children with JDM are younger than 4 years of age. Clinically, JDM is characterized by cutaneous manifestations, including the hallmark vasculitic rash, and progressive proximal muscle weakness. While the rash is requisite to meet the Bohan and Peter criteria for diagnosis [2], [3], traditional assessments of disease activity have focused on muscle strength and do not quantify levels of cutaneous involvement. To address these issues, a validated Disease Activity Score (DAS), comprised of both patient-derived dermatological and musculoskeletal criteria [4], was developed to assess clinical observations of system-related disease activity individually (DAS skin and DAS muscle) or in total (DAS total). Such a categorization has permitted our group to observe associations between disease activity in the specific tissue compartments and laboratory and/or clinical measurements. For example, we have recently reported that abnormal nailfold capillary blood vessels are associated with DAS skin but not DAS muscle [5]. Conversely, a decrease in the absolute count of circulating natural killer (NK) cells is associated with DAS muscle but not DAS skin [6]. These observations suggest that there may be divergent disease mechanisms in the different tissue compartments (i.e., skin versus muscle).

Although JDM and adult-onset dermatomyositis may have distinct pathogeneses, gene expression profiling revealed increased expression of many type I interferon (IFN)-inducible genes in muscle biopsies from both untreated JDM and adult-onset dermatomyositis patients as compared to healthy age-matched controls [7], [8], [9]. Type I IFN, which includes IFN-α and -β, is difficult to measure in biological samples. Thus, several assays have been developed to detect type I IFN activity by assessing the expression of type I IFN-inducible genes in various cell types, including peripheral blood mononuclear cells (PBMC) [10], [11], [12], [13]. Increased levels of type I IFN-inducible genes indicate that the cells have been exposed to type I IFN in vivo. Myxovirus resistance protein A (MxA), one of the genes found to be upregulated in JDM muscle biopsies, is unique in that its expression is specifically and tightly regulated by type I IFN and not other cytokines, including type II IFN (i.e., IFN-γ) [12], [14]. In fact, MxA mRNA expression in PBMC has been successfully used as a marker of type I IFN activity in a variety of settings, including the assessment of the bioavailability of therapeutically administered IFN-α and -β in hepatitis C virus and multiple sclerosis patients, respectively [12], [13], [15].

It is not known whether the type I IFN activity observed in JDM patients parallels JDM disease activity or if evidence of type I IFN activity in children with JDM will be suppressed by clinically effective treatment. Given the near impossibility of collecting sequential muscle biopsies from children, we chose to assess the type I IFN response in JDM by examining MxA mRNA expression in PBMC. There are several clinical factors that may impact MxA mRNA expression in JDM, including age, previous therapy, and disease activity. Because many components of the immune response, including circulating lymphocytes subset distribution and cytokine production, are modified by the age of the child, age-matched, control data are essential in studies of children with JDM. Thus, the purpose of these studies was to determine whether: (1) MxA mRNA expression in PBMC from JDM patients is higher than in healthy age-matched controls, similar to the MxA mRNA expression in muscle biopsies; (2) MxA mRNA expression in PBMC is associated with disease severity at the initial visit; and (3) MxA mRNA expression decreases with the initiation of clinically effective treatment.

Section snippets

Study population

The first study examined 14 children who attended the pediatric Immunology/Rheumatology clinic at Children's Memorial Hospital (CMH; Chicago, Illinois) between August 1997 and March 2001 and, subsequently, had been followed at the CMH clinic for at least 36 months. Seven patients received some immunosuppressive therapy prior to their first visit to the CMH clinic, and seven were untreated. All 7 previously treated patients had been given oral prednisone, a subset had received methotrexate (n

MxA expression PBMC at initial visit

Within the group of 14 JDM patients with clinical symptoms of active JDM (rash, weakness), 7 patients had been given immunosuppressive therapy prior to their initial visit to the CMH Immunology/Rheumatology Clinic. However, MxA mRNA expression in PBMC from previously treated children with active JDM did not significantly differ from MxA mRNA expression in PBMC from untreated children with active JDM (p = 0.503; Fig. 1). Consequently, the 7 JDM patients who were treated prior to their initial

Discussion

These results confirm that JDM, like other rheumatic diseases, is associated with activation of the type I interferon system [17], [18], [19], [20]. Furthermore, these results show that the type I interferon response (as assessed by MxA mRNA expression) observed in JDM is not restricted to muscle and may be monitored in PBMC. However, the type I IFN response in JDM appears to be associated with muscle symptoms, rather than with skin symptoms, suggesting that damage to skin and muscle in JDM may

Acknowledgments

The authors wish to acknowledge the contribution of Violet Kula, Susan Spiropoulos, and Joyce Sundberg, who performed the invaluable task of collecting and processing blood samples. Supported in part by grants from: The Myositis Association, NIAMS: RO1-AR48289-02, and The Arthritis Foundation.

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