INTERFERON-? CORRELATES WITH DISEASE ACTIVITY IN PEDIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS AND POTENTIATES THE PRODUCTION AND THE ACTIVITY OF TYPE I INTERFERONS

Introduction: Pediatric systemic lupus erythematosus (pSLE) is an autoimmune disease characterized by the production of autoantibodies against self-antigens and immune dysregulation, resulting in tissue damage. Standard treatments of pSLE are high-dose glucocorticoids and immunosuppressive agents; however, a sustained response is still not achieved in a significant proportion of patients. In the last decade, several studies showed an up-regulation of genes induced by type I interferons in peripheral blood and tissues of pSLE patients. The expression of this group of genes, known as the interferon signature, correlates with disease activity. More recently the type II interferon has been implicated in pSLE; however, its precise role has not been extensively investigated yet. Objectives: To investigate the role of type II IFN, IFN?, in the pathogenesis of pSLE evaluating: 1) the expression levels of IFN-related genes and serum levels of IFN-related chemokines in the peripheral blood of pSLE patients; 2) the cross-talk between type II and type I IFNs. Methods: Expression levels of type I IFN-induced genes (IFI27, IFI44L, IFIT1, RSAD2, ISG15, SIGLEC1) and type II IFN-induced genes (CXCL9, CXCL10, IDO1) in peripheral blood of pSLE patients was evaluated by quantitative PCR (qPCR). Serum levels of IFN?-related chemokines were measured by ELISA. For each patient, SLEDAI score was calculated. Human peripheral blood mononuclear cells (PBMCs) from 6 HD were stimulated in vitro with recombinant human IFN? and IFN?2b and gene expression was evaluated by qPCR. Results: Expression levels of both IFN?-induced genes and IFN?- induced genes were increased in the peripheral blood of pSLE patients with active disease (n=12) compared to healthy donors (HD) (n=10) and pSLE patients with inactive disease (n=13). We developed a type II IFN score similarly to the type I IFN score described by Crow et al. Type I and type II IFN scores were calculated for each pSLE patient. The type II IFN score significantly correlated with the SLEDAI (r=0.64, p<0.01); as previously reported, also the type I IFN score significantly correlated with SLEDAI (r=0.67, p<0.01). To confirm the gene expression data, we evaluated the serum levels of two cytokines induced by IFN?, CXCL9 and CXCL10, and we found that both were increased in pSLE patients compared to HD. We, then, investigated a possible crass-talk between type I and type II IFNs: we found that IFN? induced the expression of type I IFN-related genes in human PBMCs in a dose-dependent manner. Moreover, IFN? upregulated the expression of both TLR7 and TLR9, two potent inducer of IFN? by pDC. Finally, human PBMCs stimulated with recombinant IFN?2b strongly up-regulated the expression of IFN?, thus, once activated, IFN? can potentiate the production of IFN?. Conclusion: Our data suggest a potential role of IFN? in the pathogenesis of pSLE. IFN?-induced genes in whole blood and serum levels of IFN?-induced chemokines are increased in patients with pSLE patients; moreover, a type II IFN score correlates with disease activity. We show that type I interferon and IFN? establish a positive crosstalk that can potentiate their reciprocal biological activity in SLE. Disclosure of Interest None Declared achieved in a significant proportion of patients. In the last decade, several