Systemic Sclerosis Pathogenesis and Emerging Therapies, beyond the Fibroblast

Abstract

Systemic sclerosis (SSc) is a complex rheumatologic autoimmune disease in which inflammation, fibrosis, and vasculopathy share several pathogenic pathways that lead to skin and internal organ damage. Recent findings regarding the participation and interaction of the innate and acquired immune system have led to a better understanding of the pathogenesis of the disease and to the identification of new therapeutic targets, many of which have been tested in preclinical and clinical trials with varying results. In this manuscript, we review the state of the art of the pathogenesis of this disease and discuss the main therapeutic targets related to each pathogenic mechanism that have been discovered so far.

Figure 1

Scheme of the pathogenesis of systemic sclerosis. Participation of the immune system, epithelium, endothelium, and fibroblasts. Theoretically, an unknown self or foreign antigen (Ag) starts an autoimmune response in a susceptible individual, producing damage to endothelial and/or epithelial cells. The abnormal activation of the innate and adaptive immune system leads to the production of proinflammatory and profibrotic cytokines and to autoantibody production. Endothelial cells may undergo apoptosis, activation, or endothelial to mesenchymal transdifferentiation, while epithelial cells may undergo either epithelial to mesenchymal transdifferentiation or inflammation and injury. Then, myofibroblasts recruited from different sources (fibrocytes, bone marrow stem cells, tissue fibroblasts, or endothelial/epithelial transdifferentiation) concentrate at the extracellular matrix and produce excessive fibrosis that leads to organ damage. In addition, blood vessel injury promotes in situ thrombosis, subendothelial fibrosis, and muscular proliferation, leading to the vascular manifestations of the disease. ET-1: endothelin 1, TGFβ: transforming growth factor beta, TNFα: transforming growth factor alpha, αSMA: alpha smooth muscle actin, Ab: antibodies, ROS: reactive oxygen species, ICAM: intercellular adhesion molecules, VCAM-1: type 1 vascular cell adhesion molecules, Ag: antigens, Col 1: collagen type 1, VE: vascular endothelial, vWF: Von Willebrand factor, BM: bone marrow, TLR: Toll-like receptor, M1: type 1 macrophage, M2: type 2 macrophage, MDC: myeloid dendritic cell, IL: interleukin, IFNγ: interferon gamma, MCP-1: monocyte chemoattractant protein type 1, MCP-2: monocyte chemoattractant protein type 2, Th: T helper lymphocyte, and Treg: T regulator lymphocyte.