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An Interferon Signature in the Peripheral Blood of Dermatomyositis Patients Is Associated with Disease Activity

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An Interferon Signature in the Peripheral Blood of Dermatomyositis Patients Is Associated with Disease Activity An Interferon Signature in the Peripheral Blood of Dermatomyositis Patients is Associated with Disease Activity Emily C Baechler,1 Jason W Bauer,1 Catherine A Slattery,1 Ward A Ortmann,1 Karl J Espe,1 Jill Novitzke,1 Steven R Ytterberg,2 Peter K Gregersen,3 Timothy W Behrens,1,4 and Ann M Reed2 1University of Minnesota Medical School, 312 Church St. SE, Minneapolis, MN 55455; 2Mayo Clinic and Medical School, Division of Rheumatology, Departments of Medicine and Pediatrics, 200 First Street SW, Rochester, MN, 55902; 3The Feinstein Institute for Medical Research, North Shore Long Island Jewish Research Institute, 350 Community Drive, Manhasset, NY, 11030; 4Current address: Genentech, Inc., S. San Francisco, CA 94080 Recent studies have shown increased expression of interferon (IFN)-regulated genes in the peripheral blood cells of patients with systemic lupus erythematosus. A similar interferon signature has been observed in affected muscle tissue from patients with dermatomyositis (DM), but it has not yet been determined if this signature extends to the peripheral blood in DM. We performed global gene expression profiling of peripheral blood cells from adult and juvenile DM patients and healthy controls. Several in- teresting groups of genes were differentially expressed in DM, including genes with immune function, and others that function in muscle or are involved in mitochondrial/oxidative phosphorylation. Investigation of type I IFN-regulated transcripts revealed a striking interferon signature present in most DM patients studied. Levels of type I IFN-regulated proteins were also elevated in DM serum samples. Furthermore, both the transcript and serum protein IFN signatures were associated with disease activity. These data suggest that the IFN signature may be a useful marker for DM disease activity, and that sampling peripheral blood may be a more practical alternative to muscle biopsy for measuring this signature. Online address: http://www.molmed.org doi: 10.2119/2006–00085.Baechler INTRODUCTION evidence suggests that the vasculature light chains and IgG heavy chains, were Juvenile and adult dermatomyositis and perifascicular regions in muscle also found at elevated levels in two sepa- (DM) are rare autoimmune diseases be- are targets for both humoral- and cell- rate studies (7,9). longing to the group of idiopathic in- mediated autoimmunity. It has been pro- Interestingly, interferon (IFN) pathway flammatory myopathies (IIM), which are posed that viral infection is a trigger for activation was observed in all reported characterized by proximal muscle weak- initiation of juvenile DM (4), but this has studies and was largely specific to DM as ness and muscle inflammation. In cases not yet been convincingly demonstrated. opposed to other types of IIM (5,7–9). of adult and juvenile DM, patients also Several studies have recently reported Greenberg et al. further documented the present with a characteristic skin rash the results of gene expression profiling presence of an IFN-inducible protein, (1). Juvenile dermatomyositis is the most from muscle biopsies of patients with MxA, in muscle fibers and capillaries of common pediatric IIM. Although the adult and juvenile DM (5–9). The emerg- DM patients (5). cause of IIM is unknown, it is believed ing data suggest that cells from affected Recently, much attention has been fo- that a combination of genetic and envi- muscle tissue carry distinct immune fin- cused on type I IFN for its potential role ronmental factors contribute to disease. gerprints which may be useful for moni- in the autoimmune disease systemic Juvenile DM is known to be associated toring disease status and may provide lupus erythematosus (SLE) (10,11). Pe- with the HLA class II region genes HLA- new targets for disease modifying ripheral blood cells from SLE patients ex- DQA1*0501, and polymorphisms in agents. Two of these studies reported up- hibit a striking pattern of up-regulation TNFα are associated with disease sever- regulation of genes related to antigen of IFN-induced genes (12–14). Approxi- ity (2). In both adult and juvenile DM, processing (7,8). Immunoglobulin tran- mately 50-75% of adult patients carry the associations exist with DR3 (2,3). Current scripts, particularly those encoding Igλ IFN signature, and it is strongly corre- lated with disease activity and certain clinical manifestations of SLE, including Address correspondence and reprint requests to Ann M. Reed, E15 Rheumatology, Mayo anti-dsDNA antibodies and low comple- Clinic, 200 1st St. SW, Rochester, MN, 55902. Phone: 507-284-3522; Fax: 507-284-0564; E-mail: ments (15,16). Interestingly, evidence [email protected]. for IFN pathway activation is also found Submitted October 5, 2006; Accepted for publication December 7, 2006. in individual glomeruli isolated from MOL MED 13(1-2)59-68, JANUARY-FEBRUARY 2007 | BAECHLER ET AL. | 59 INTERFERON SIGNATURE IN DERMATOMYOSITIS the kidneys of patients with lupus JDM (21,22). Clinical data were collected the SLE group had mild/moderate dis- nephritis (17). Plasmacytoid dendritic for each patient, including duration of ease activity on the day of the blood cells (PDC), the primary producers of disease (average 23 ± 25 months, range draw (SLE disease activity index range type I IFN, are recruited to inflamed 1–84 months), muscle biopsy (available 0-10). Current symptoms/organ involve- lupus skin lesions (18,19) and are also for eight patients), and medications (11 ment included rash (25% of patients), found in substantial numbers in affected patients on oral prednisone, average 20 ± arthritis (30%), renal disease (18%), and adult and juvenile DM muscle tissue (5). 19 mg/day; three patients on hydroxy- hematologic manifestations (18%). Med- IFN signatures have also been observed chloroquine; eight patients on immuno- ications included oral prednisone (52% in Sjögren’s syndrome and psoriasis, but suppressive therapy, including of patients; average 8.8 ± 6.8 mg/day), not in rheumatoid arthritis or multiple methotrexate, azathioprine, or mycophe- hydroxychloroquine (63% of patients), sclerosis (20). nolate mofetil). Standard clinical lab tests and immunosuppressive drugs (37% of Although several interesting signa- were also performed, in addition to mea- patients). tures have been reported in muscle tissue surement of autoantibodies and specific from adult and juvenile DM, it has not enzymes (creatine kinase, or CK; al- Sample Processing for Microarray yet been determined whether these or dolase; aspartate aminotransferase, or Analysis other signatures are present in the blood. AST; and alanine aminotransferase, or For RNA isolation, blood was drawn To address this, we examined global ALT). One patient exhibited unusually into PAXgene tubes (PreAnalytix, gene expression patterns in peripheral high levels of these enzymes; for pur- Franklin Lakes, NJ). Total RNA was iso- blood cells of DM patients and healthy poses of analysis, these outlier values lated according to the manufacturer’s controls using Affymetrix GeneChips. were truncated to a clinically relevant protocol with on-column DNAse treat- Several interesting groups of differen- maximum (CK, 500 units/L; aldolase, 15 ment. RNA yield and integrity were as- tially expressed transcripts were ob- units/L; AST, 100 units/L; ALT, 75 sessed using an Agilent Lab-on-a-Chip served in DM, including genes that func- units/L). Four patients had measurable Bioanalyzer (Agilent Technologies, Inc., tion in muscle, and others involved in autoantibodies (one positive for ANA; Palo Alto, CA). cRNA probes were gen- mitochondrial/oxidative phosphoryla- one positive for anti-Jo1; one positive for erated using the MessageAmp cRNA kit tion and immune function. We also iden- anti-SSA and anti-RNP; one positive for (Ambion, Austin, TX) and hybridized to tified a prominent type I IFN gene and ANA, anti-SSA, and anti-Jo1). Current Affymetrix U133 2.0 + GeneChips ac- protein signature in most of the adult disease activity was evaluated using re- cording to standard Affymetrix protocols and juvenile DM patients studied, which cently published measures (23,24), in- (Expression Analysis Technical Manual, correlated with disease activity. These cluding the childhood myositis assess- Affymetrix, Santa Clara, CA). After scan- data suggest that the IFN signature may ment scale (CMAS, used in the JDM ning the arrays, Expressionist Refiner serve as a marker for DM disease activity patients), the (childhood) health (GeneData, Basel, Switzerland) was used in adult and juvenile subjects, and that assessment questionnaires (HAQ/ to generate expression (or “signal”) val- identification of the signature in periph- CHAQ), manual muscle testing, eleva- ues for each gene using the Affymetrix eral blood samples is an alternative to tion of muscle enzymes, and the extra- Microarray Suite 5.0 condenser and scal- the more invasive technique of muscle muscular activity measure. Disease activ- ing the overall intensity of each chip to biopsy. ity was given a rating of 0–2 based on 1500. All chips passed both the Microar- the combination of these measures. ray Suite and Refiner quality control MATERIALS AND METHODS Biological samples collected at each measures. visit included RNA from whole blood Study Participants and Sample (using the PAXgene system from Qiagen/ Microarray Data Analysis Collection Becton-Dickinson), DNA, serum, plasma, Uncharacterized genes were removed The study protocol was approved by and peripheral blood mononuclear cells from the dataset before performing the the Human
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