Systemic sclerosis (SSc) is a chronic connective tissue disease characterized by vascular damage, autoimmunity, and excessive collagen deposition. Despite advances in disease-specific treatment of other rheumatologic diseases, disease-targeted treatment in SSc continues to be elusive. In this review, our goal was to place the contemporary immunobiology of SSc in the perspective of clinical medicine.
We performed a PubMed search for the period from 1989 to 2007, using the keyword, "systemic sclerosis," resulting in a total of 9099 publications, including 1252 reviews. Articles were then selected based on their discussion of recent advances in the elusive pathogenesis of SSc. A final total of 259 articles were chosen for the review.
The SSc hallmarks of vascular damage, immunologic activation, and collagen deposition can be traced to 4 major factors: T-cells, fibroblasts, B-cells, and cytokines/chemokines. T-cells are a major component of the infiltrate in skin and lung, exhibiting increased expression of activation markers and showing signs of antigen-driven expansion. Preliminary data indicate that induction of oral tolerance with collagen, a target of SSc T-cell responses, is associated with clinical benefits. Although this suggests that T-cells participate in the pathogenesis of SSc, their precise role and antigen specificity largely remain to be elucidated. Defective numbers and functions of certain T-cell subsets, such as natural killer and gammadelta T-cells, may be involved in the failure to maintain tolerance. Other data suggest that gammadelta T-cells may themselves be effector cells in endothelial cell cytotoxicity. There are several lines of evidence for a pathogenic role of B-cells in SSc, in particular, through the production of autoantibodies. Antibody-dependent cell-mediated cytotoxicity is a primary pathogenic event in an animal model of SSc and is likely to be involved in human SSc. Nonetheless, there is as yet no convincing evidence for the pathogenicity of SSc-specific antibodies. SSc fibroblasts exhibit a specific phenotype characterized not only by excessive collagen production but also by increased responsiveness to and production of cytokines and chemokines. This phenotype is induced by a complex network of cytokines and chemokines but appears to be maintained in the absence of exogenous stimuli via the autocrine production of some of these factors by SSc fibroblasts themselves, particularly transforming growth factor, platelet-derived growth factor, monocyte chemoattractant protein 1, and interleukin-1.
Significant variations in laboratory data among patients suggest that the pathology reflects a heterogeneous disease. Nonetheless, the possibility of achieving clinical benefits by inducing oral tolerance highlights the importance of characterizing SSc T-cell antigens. It is hoped that the identification of some of the key players in the induction and maintenance of the SSc fibroblast phenotype may yield new disease-targeted treatment regimens for patients with SSc.