Introduction: Juvenile dermatomyositis (JDM) is the most common juvenile inflammatory myopathy, with a still not fully clarified immunopathogenesis. However, there is relevant evidence for an involvement of interferons (IFNs) in the chronic inflammation that characterizes JDM, and a better characterization of their role may provide promising targets for new therapies. Objectives: The aim of this study was to investigate muscle expression of type I (IFN?/?) and type II (IFN?) IFN inducible genes in muscle biopsies of JDM patients and their correlations with clinical and histological aspects of the disease. Methods: In a retrospective cohort of patients diagnosed with JDM (n=22), expression of specific genes induced by IFN?/? (IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1), the so called "type I IFN signature", by IFN? (CXCL9, CXCL10, CXCL11, CIITA), and IFN? itself, were analysed by real-time PCR on snap frozen muscle biopsies and compared with samples from Duchenne muscular dystrophy (DMD) patients (n=24). We also analysed mRNA expression of pro-inflammatory cytokines such as interleukin-1? (IL-1?), tumor necrosis factor-? (TNF?) and interleukin-6 (IL-6). For each patient charts were reviewed to record clinical features at diagnosis, physician's global assessment of the patient's overall disease activity, serum levels of muscle enzymes (CK, ALT, AST, LDH), erythrocyte sedimentation rate (ESR), C-reactive protein level, antinuclear antibodies status, time to inactive disease, number of immunosuppressants used over disease course and relapses. We also evaluated typical histological aspects of JDM (inflammatory infiltrate, necrosis, perifascicular atrophy and fibrosis) on tissue sections of the muscle biopsies. Results: Since glucocorticoid therapy strongly reduced muscle expression of cytokines, JDM patients treated before biopsy were excluded from analysis. The mRNA expression of type I IFN signature genes (type I-IFN score) was significantly higher in untreated JDM patients (n=16) compared with DMD patients (p <0.0001). Expression of IFN? and IFN? related genes (CXCL9, CXCL10, CXCL11, CIITA) were significantly higher in biopsies of untreated JDM patients compared with those of DMD patients (p <0.01, p <0.01, p <0.01, p <0.0001, p <0.0001, p <0.01, respectively). Expression of TNF?, but not of IL-1? and IL-6, was significantly higher in untreated JDM muscles compared with those of DMD patients (p <0.01). IFN? expression significantly correlated with CIITA, CXCL9, CXCL10 and CXCL11 mRNA levels (p <0.05, p <0.0001, p <0.01, p <0.01, respectively).Type I-IFN score significantly correlated with ERS, CK, time to inactive disease and number of immunosuppressants (p <0.05, p <0.05, p <0.05, p <0.01, respectively). IFN? mRNA levels significantly correlated with time to inactive disease and relapse after remission (p <0.05, p <0.01, respectively). We also found that type I-IFN score correlated with inflammatory infiltrate and necrosis (p <0.05), while IFN? correlated with inflammatory infiltrate, perifascicular atrophy and fibrosis (p <0.01, p <0.05, p <0.05 respectively ). Conclusion: The increased expression of IFN related genes in muscle biopsies of JDM patients and their association with clinical and histological features suggest a pathogenic role of IFNs in muscle damage and inflammation in JDM. Thus, both type I and type II IFNs pathways may represent therapeutic targets in JDM.
EXPRESSION OF TYPE I AND TYPE II INTERFERONS IS INCREASED IN MUSCLE BIOPSIES OF JUVENILE DERMATOMYOSITIS PATIENTS AND RELATED TO CLINICAL AND HISTOLOGICAL FEATURES
Luisa BracciLaudiero;
2016
Abstract
Introduction: Juvenile dermatomyositis (JDM) is the most common juvenile inflammatory myopathy, with a still not fully clarified immunopathogenesis. However, there is relevant evidence for an involvement of interferons (IFNs) in the chronic inflammation that characterizes JDM, and a better characterization of their role may provide promising targets for new therapies. Objectives: The aim of this study was to investigate muscle expression of type I (IFN?/?) and type II (IFN?) IFN inducible genes in muscle biopsies of JDM patients and their correlations with clinical and histological aspects of the disease. Methods: In a retrospective cohort of patients diagnosed with JDM (n=22), expression of specific genes induced by IFN?/? (IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1), the so called "type I IFN signature", by IFN? (CXCL9, CXCL10, CXCL11, CIITA), and IFN? itself, were analysed by real-time PCR on snap frozen muscle biopsies and compared with samples from Duchenne muscular dystrophy (DMD) patients (n=24). We also analysed mRNA expression of pro-inflammatory cytokines such as interleukin-1? (IL-1?), tumor necrosis factor-? (TNF?) and interleukin-6 (IL-6). For each patient charts were reviewed to record clinical features at diagnosis, physician's global assessment of the patient's overall disease activity, serum levels of muscle enzymes (CK, ALT, AST, LDH), erythrocyte sedimentation rate (ESR), C-reactive protein level, antinuclear antibodies status, time to inactive disease, number of immunosuppressants used over disease course and relapses. We also evaluated typical histological aspects of JDM (inflammatory infiltrate, necrosis, perifascicular atrophy and fibrosis) on tissue sections of the muscle biopsies. Results: Since glucocorticoid therapy strongly reduced muscle expression of cytokines, JDM patients treated before biopsy were excluded from analysis. The mRNA expression of type I IFN signature genes (type I-IFN score) was significantly higher in untreated JDM patients (n=16) compared with DMD patients (p <0.0001). Expression of IFN? and IFN? related genes (CXCL9, CXCL10, CXCL11, CIITA) were significantly higher in biopsies of untreated JDM patients compared with those of DMD patients (p <0.01, p <0.01, p <0.01, p <0.0001, p <0.0001, p <0.01, respectively). Expression of TNF?, but not of IL-1? and IL-6, was significantly higher in untreated JDM muscles compared with those of DMD patients (p <0.01). IFN? expression significantly correlated with CIITA, CXCL9, CXCL10 and CXCL11 mRNA levels (p <0.05, p <0.0001, p <0.01, p <0.01, respectively).Type I-IFN score significantly correlated with ERS, CK, time to inactive disease and number of immunosuppressants (p <0.05, p <0.05, p <0.05, p <0.01, respectively). IFN? mRNA levels significantly correlated with time to inactive disease and relapse after remission (p <0.05, p <0.01, respectively). We also found that type I-IFN score correlated with inflammatory infiltrate and necrosis (p <0.05), while IFN? correlated with inflammatory infiltrate, perifascicular atrophy and fibrosis (p <0.01, p <0.05, p <0.05 respectively ). Conclusion: The increased expression of IFN related genes in muscle biopsies of JDM patients and their association with clinical and histological features suggest a pathogenic role of IFNs in muscle damage and inflammation in JDM. Thus, both type I and type II IFNs pathways may represent therapeutic targets in JDM.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
