Building a Cellular and Genetic Atlas of Systemic Sclerosis for a Roadmap Toward a Cure
Dinesh Khanna, MD, MS
University of Michigan
Johann Gudjonsson, MD, PhD
University of Michigan
Project Overview
Systemic Sclerosis (SSc) is a multi-system fibrotic disease characterized by hard, thickened (fibrotic) skin and involvement of multiple internal organs, with a major impact on morbidity, mortality, and quality of life. The pathogenesis of SSc is complex, with contributions from genetic predisposition, striking female predominance, associated vascular alterations (vasculopathy), immune system dysregulation, and aberrant tissue fibrosis.
Recent genome-wide association studies have identified over 30 genetic risk loci showing involvement of various genetic loci involved in multiple immune functions such as for the Fc gamma receptor (FCGR), Th1 responses (STAT4/IL12RB1), NFkb-signaling (TNFAIP3, NFKB1), cytotoxic responses (GSDMB), Tcell/B-cell responses (TNFSF4), and interferon responses (IRF5, IRF8). However, the number of genetic loci in SSc is dwarfed by that of SLE, where over 80 susceptibility loci have been identified, suggesting that we have barely scratched the surface of the immune and profibrotic mechanisms contributing to SSc susceptibility.
In addition, there remains a large gap between the identification of predisposing genetic variants and how these variants contribute to the immunopathogenesis of SSc. The central hypothesis of Dr. Khanna’s and Dr. Gudjonsson’s project is that genetic susceptibility variants shape the cellular network in SSc skin in a cell-type and context-specific manner to promote disease mechanisms and immune activation. To address this, they will create a cellular atlas of SSc pathogenesis.
