Introduction: The Etiopathogenesis of Systemic Sclerosis—An Integrated Overview

The multifaceted and interactive links in the pathogenesis of systemic sclerosis are attractive features to study disease mechanisms providing challenges that are both intellectually stimulating and scientifically rewarding. Heterogeneity in genetics, organ complication, natural history (pace, tempo, and severity), and outcome, adds extra intricacies to the exploration of pathogenesis and places systemic sclerosis in the very top tier of disorders in rheumatic disease research. Evidence points to complex interactions between environmental factors, host genetics, and response in the development of disease and desultory events leading to the presentation of key pathogenic phenotypes. Critical dynamic interactions between the dominant pathobiological processes characterized by vasculopathy, immune dysregulation, and fibrosis drive disease pathogenesis and define the phenotypic expression of clinical endotypes. Early pathogenic events involving endothelial and perivascular cells that alter angiogenesis and are exacerbated by hypoxia and reactive oxygen species (ROS) impact upon cell viability and blood vessel integrity. Endothelial dysfunction and aberrant apoptosis underlie the deployment of innate immune cells and the influx of activated neutrophils and macrophages. Defective phagocytosis of cell debris favoring the persistence of nuclear antigens is likely to present as targets for autoantibodies. Diverse mechanisms lead to the activation of the adaptive immune system and the inflammatory environment impact T and B cell activation and their differentiation programs, and polarization of macrophages. Pro-fibrotic signals are integrated by fibroblasts and myofibroblasts altering their metabolism, inducing pro-survival and senescent phenotypes that enhance extracellular matrix production and stiffness. Here, we provide an integrated view of systemic sclerosis and highlight emerging areas of scientific interest.