Systemic sclerosis (SSc or scleroderma) is a multisystem, uncommon disease characterized by fibrosis in skin and internal organs, immune dysregulation, and vasculopathy. Its pathogenesis remains poorly understood, however the disease is thought to arise from an interaction between genetic factors and environmental triggers. Case-control candidate gene genome wide association studies (GWAS) have identified several robust SSc susceptibility loci that have been validated in subsequent independent studies. Some of the confirmed SSc susceptibility loci show a stronger association with its serological or clinical (limited versus diffuse) subtypes than the overall disease. Besides the conformation of HLA genes as the strongest SSc risk loci, these studies have shown that the majority of non-HLA SSc genes such as IRF5, STAT4, CD247, BANK1 or BLK belong to pathways involved in immune regulation, mainly in genes related to innate immunity, as well as B- and T-cell activation, highlighting the important role of an altered immune response in the pathogenesis of Sc.
Interestingly, the majority of these gene variants are also risk loci for other autoimmune diseases, especially for systemic lupus erythematosus (SLE). This indicates that SSc has a shared immune pathogenesis with other autoimmune diseases providing further support for the concept of quantitative thresholds in immune-cell signaling. It is noteworthy that the gene variants of interest do not operate in isolation as they are parts of intertwined biological pathways. Therefore, examination of gene-gene or gene-environment interactions can lead to better understanding of SSc pathogenesis. Lastly, mechanistic studies are needed to elucidate how these immune system gene variants contribute to the cross-talk among immune, vascular and fibrotic pathways leading to the unique phenotype of SSc. Beyond identification of new therapeutic targets, the significant advances in SSc genetics represent an opportunity for biomarker development since the genetic information can potentially lead to identification of genetic markers that predict disease severity and response to treatment in SSc.
Disclosure of Interest None Declared