Unveiling the two faces of immune dysregulation in Systemic Sclerosis : A multi-omics approach

Abstract

Systemic sclerosis (SSc) is a complex, heterogeneous autoimmune disease characterized by vascular abnormalities, immune involvement and extensive fibrosis of the skin and internal organs. Immune system dysregulation is recognized as one of the main culprits of SSc pathogenesis, however, it remains unclear what molecular mechanisms underlie this. By applying various high-throughput omics approaches, the studies presented in this thesis aim to uncover the molecular mechanisms contributing to immune cell dysregulation in SSc. We show that immune dysregulation in SSc can be attributed to aberrances at various levels of molecular organization. These include the regulation of TLR signaling by lncRNAs, epigenomic imprinting of histone modifications and downregulation of immune regulatory transcription factors in monocytes and dendritic cells. Enhanced activation of these innate immune cells has the potential to cue the adaptive immune system and orchestrate the generation of highly clonal autoreactive T cell receptor repertoire. These insights offer new avenues for the development of novel therapeutics for SSc as well as other autoimmune diseases.