Cytokines in Systemic Sclerosis: Focus on IL-17 PDF Print E-mail
Saturday, 18 February 2012 11:48
Julie Baraut, Dominique Farge, Elena Ivan-Grigore, Franck Verrecchia, and Laurence Michel

Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive sclerosis of the skin and internal organ dysfunction. Cytokine production and release are key events in SSc pathogenesis as they are involved in T and B cell activation leading to inflammation, auto-antibodies production, microvascular damage and fibrosis (Katsumoto et al. 2011). The Th1/Th2/Th17/Treg balance is one of the hallmarks of SSc pathogenesis, as the Th2 and Th17 cytokines response leads to tissue fibrosis, whereas Th1 and Th17 cytokines promote inflammation in SSc patients. In our previous review, we analyzed the relationship between cytokine release and SSc pathogenesis, based on experimental and clinical data. We concluded that circulating or in situ cytokine levels could be assessed as diagnostic and prognostic markers in SSc patients (Baraut et al. 2010).

The precise pathogenesis of SSc is still poorly understood. The use of microarray technology showed significant differences of gene patterns in skin biopsies from diffuse scleroderma (dSSc) and limited scleroderma (lSSc) patients, which also differed from normal controls (Milano et al. 2008). An immune signaling cluster was evidenced, suggestive for a role of B and T cells in SSc pathogenesis. Interleukin IL-1α, IL-4, tumor necrosis factor-α (TNF- α), connective tissue growth factor (CTGF), and transforming growth factor-β (TGF-β) have been identified as some relevant genes related to SSc disease. More recently, major contributions were made by experiments using genome-wide screening technology, which identified specific nucleotide polymorphisms (SNPs) in relevant genes related to SSc disease, including genes coding for cytokines and growth factors (Agarwal et al. 2008).

The first genome-wide association study (GWAS), performed in Korean patients and confirmed in US Caucasians population, indicated that specific SNPs of HLA-DPB1 and/or DPB2 were strongly associated with SSc patients who had anti-DNA topoisomerase I or anticentromere autoantibodies (X. Zhou et al. 2009). More recently, a larger GWAS identified a new susceptibility locus for SSc susceptibility, previously found in systemic lupus erythematosus, at CD247 (T cell receptor T3 zeta chain). The role of Major Histocompatibility complex (MHC), Interferon regulatory factor 5 (IRF5) and STAT4 gene regions as SSc genetic risk factors has also been confirmed in this recent GWAS study (Radstake et al. 2010). GWAS approaches have identified multiple genetic markers related to innate and adaptive immunity as SSc susceptibility, such as HLA class II, STAT-4, IRF5, B cell scaffold protein BANK1, B lymphocyte kinase (BLK), Tumor necrosis factor ligand super-family member 4 (TNFSF4) and CD247 genes (Romano et al. 2011). However no GWAS have been preformed to clarify the role of genes involved in vascular and fibrotic processes in SSc susceptibility.

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