The role of inflammation in systemic sclerosis

Abstract

Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology. It is a rare disorder with an incidence in adults of approximately 20 new cases per million per year (1). Genetic and environmental factors such as toxins and infections have been identified to be associated with SSc (2, 3). Its pathogenesis is characterized by vasculopathy, autoimmunity, and cytokine dysbalance, altogether leading to fibrosis of the skin and inner organs (4). These features vary between patients, but it seems clear that SSc pathogenesis is characterized by a complex interplay between these factors. There is a high heterogeneity in clinical presentation of SSc e.g. limited versus diffuse SSc, early vs. chronic disease, or early vs. late onset SSc, that have to be taken into consideration when studying this disease (5). Along the important progress in inflammation research that has been made during the last decade in general, inflammation has also attracted increasing attention in SSc (6). Both the innate and adaptive immune system participates in SSc pathogenesis. The importance of the immune system in SSc has also been demonstrated in cases where SSc patients underwent autologous or allogeneic stem cell transplantation. Conditioning e.g. with cyclophosphamide followed by reinfusion of stem cells markedly improved the disease course (7). Cell infiltrates in SSc affected dermis mainly consist of T- and B lymphocytes, macrophages, and mast cells. These cells release profibrotic mediators which then stimulate fibroblasts to secrete extracellular matrix (ECM) proteins (8-10). The inflammatory cells are responsible for a profibrotic cytokine milieu, typically characterized by Th2 cytokines (11). Humoral autoimmunity in the form of autoantibodies has been postulated to contribute to SSc progression, e.g. by autoantibodies against endothelial cells or fibroblasts (12). Although B-cells clearly occur in the inflamed SSc tissue and certainly are of importance, the pathogenic relevance of autoantibodies in SSc remains controversial (13). This work contributes to the understanding of SSc by further analyses of the cellular pathogenesis and cytokines involved in SSc. Both experimental and clinical studies have been performed in this thesis, analysing different inflammatory cell types and cytokines and patient subgroups, respectively.