Background Juvenile dermatomyositis (JDM) is the most common autoimmune inflammatory myopathy of childhood, with a still not fully clarified immunopathogenesis. There is substantial evidence for an involvement of interferons (IFNs) in the chronic inflammation that characterizes JDM. A better characterization of their role may provide promising targets for new therapies. The aim of this study was to investigate the 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 in these patients. Methods In a retrospective cohort of patients diagnosed with JDM (n=22), mRNA expression levels of specific genes induced by IFN?/? (IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1), by IFN? (CXCL9, CXCL10, CXCL11, CIITA), and IFN? itself, were analyzed from muscle biopsies and compared with samples from Duchenne muscular dystrophy (DMD) patients (n=24). We also analyzed mRNA expression of pro-inflammatory cytokines such as TNF-?, IL-6, and IL-1?. 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), ESR, CRP 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, fibrosis) on tissue sections of the muscle biopsies. Results Since steroid therapy strongly reduced expression levels of cytokines, JDM patients treated before biopsy were excluded from final statistics. The mRNA expression of type I IFN signature genes ("I-IFN score") was higher in untreated JDM patients (n=16) compared with DMD patients (p<0.0001). Expression levels of IFN?, CIITA, CXCL9, CXCL10, and CXCL11 (p<0.01, p<0.01, p<0.01, p<0.0001, p<0.0001) were significantly higher in biopsies of untreated JDM patients compared with those of DMD patients. Expression levels of TNF-?, but not IL-6 and IL-1?, were higher in untreated JDM samples compared with those of DMD patients (p<0.01). I-IFN score correlated with ESR, time to inactive disease and number of immunosuppressants of untreated JDM patients (p<0.05, p<0.05, p<0.01). IFN? mRNA levels correlated with time to inactive disease and polycyclic disease course (p<0.05, p<0.01). Moreover, we performed histological analysis of JDM patient biopsies to evaluate quantity of muscle inflammatory infiltrate, necrosis, perifascicular atrophy and fibrosis. We also found that type I-IFN score correlated with inflammatory infiltrate and necrosis (p<0.01), while IFN? correlated with inflammatory infiltrate, perifascicular atrophy and fibrosis (p<0.05, p<0.05, p<0.01). 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;
2017
Abstract
Background Juvenile dermatomyositis (JDM) is the most common autoimmune inflammatory myopathy of childhood, with a still not fully clarified immunopathogenesis. There is substantial evidence for an involvement of interferons (IFNs) in the chronic inflammation that characterizes JDM. A better characterization of their role may provide promising targets for new therapies. The aim of this study was to investigate the 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 in these patients. Methods In a retrospective cohort of patients diagnosed with JDM (n=22), mRNA expression levels of specific genes induced by IFN?/? (IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1), by IFN? (CXCL9, CXCL10, CXCL11, CIITA), and IFN? itself, were analyzed from muscle biopsies and compared with samples from Duchenne muscular dystrophy (DMD) patients (n=24). We also analyzed mRNA expression of pro-inflammatory cytokines such as TNF-?, IL-6, and IL-1?. 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), ESR, CRP 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, fibrosis) on tissue sections of the muscle biopsies. Results Since steroid therapy strongly reduced expression levels of cytokines, JDM patients treated before biopsy were excluded from final statistics. The mRNA expression of type I IFN signature genes ("I-IFN score") was higher in untreated JDM patients (n=16) compared with DMD patients (p<0.0001). Expression levels of IFN?, CIITA, CXCL9, CXCL10, and CXCL11 (p<0.01, p<0.01, p<0.01, p<0.0001, p<0.0001) were significantly higher in biopsies of untreated JDM patients compared with those of DMD patients. Expression levels of TNF-?, but not IL-6 and IL-1?, were higher in untreated JDM samples compared with those of DMD patients (p<0.01). I-IFN score correlated with ESR, time to inactive disease and number of immunosuppressants of untreated JDM patients (p<0.05, p<0.05, p<0.01). IFN? mRNA levels correlated with time to inactive disease and polycyclic disease course (p<0.05, p<0.01). Moreover, we performed histological analysis of JDM patient biopsies to evaluate quantity of muscle inflammatory infiltrate, necrosis, perifascicular atrophy and fibrosis. We also found that type I-IFN score correlated with inflammatory infiltrate and necrosis (p<0.01), while IFN? correlated with inflammatory infiltrate, perifascicular atrophy and fibrosis (p<0.05, p<0.05, p<0.01). 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.
