Therapeutic Targeting of T Cells in Systemic Sclerosis
Therapeutic Targeting of T Cells in Systemic Sclerosis
Systemic sclerosis is an autoimmune disorder with an unknown cause. The cardinal features of the disease are autoimmunity, vasculopathy, inflammation and fibrosis. There appears to be a link between inflammation and inflammatory cells and the uncontrolled deposition of the extracellular matrix. In particular, T cells appear to play a prominent role in disease initiation and propagation through the secretion of a myriad of cytokines and growth factors. These T-cell-dependent products may drive the proliferation and activation of resident fibroblasts, which ultimately leads to fibrosis. This review summarizes the current literature of the role of T cells in systemic sclerosis and suggests that therapeutic targeting of T cells is a promising new avenue.
Systemic sclerosis (SSc) is a rare, debilitating autoimmune disease of unknown origin characterized by inflammation and excessive deposition of extracellular matrix (ECM) components, particularly collagen. SSc is prevalent worldwide, primarily affecting females, and there is currently no effective treatment. Early activation of the immune system is thought to be involved in the pathogenesis, as reflected by the increased level of cytokines in the serum of patients and the infiltration of mononuclear cells in the dermis of patients, which is thought to stimulate the differentiation and proliferation of fibroblasts to myofibroblasts. The increased expression of myofibroblasts is a marker of SSc; these cells express the protein αSMA, which increases the contractile force of the cells, thus increasing the deposition of ECM. SSc patients can be classified into two subsets; limited and diffuse, each distinguishable by the level of fibrosis and the autoantibodies present in the serum of patients. Diffuse SSc has a rapid onset with fibrosis occurring within the skin and in one or more internal organs, whereas limited SSc is milder, with fibrosis limited to the skin.
Despite the unknown etiology of SSc, several inflammatory mediators have been identified in SSc patients. Analysis of the blood of patients has revealed the presence of autoantibodies, including anticentromere and anti-topoisomerase antibodies, an increase in the level of cytokines, including IL-1, IL-6 and IL-27, and the presence of activated immune cells, including macrophages, mast cells and T cells (Table 1). In addition, analysis of the inflammatory infiltrate in the affected tissue of SSc patients shows the presence of activated T cells and the increase in these cells correlates with the severity of disease and symptoms including skin thickening. Furthermore, examination of the peripheral blood of patients demonstrates a change in the composition of the T-cell population, with predominance for Th2 cells and a change in the phenotype of Tregs.
This review seeks to examine the role of T cells in the pathogenesis of SSc by looking into the origin of T cells and their role in the immune response; the authors will then review the evidence of an altered T-cell response in SSc patients and the possible role of the products of T cells in causing fibrosis. Finally, the authors will examine the therapeutic potential of targeting T cells in the treatment of this chronic disease, as there is currently no therapy to modify disease.
Abstract and Introduction
Abstract
Systemic sclerosis is an autoimmune disorder with an unknown cause. The cardinal features of the disease are autoimmunity, vasculopathy, inflammation and fibrosis. There appears to be a link between inflammation and inflammatory cells and the uncontrolled deposition of the extracellular matrix. In particular, T cells appear to play a prominent role in disease initiation and propagation through the secretion of a myriad of cytokines and growth factors. These T-cell-dependent products may drive the proliferation and activation of resident fibroblasts, which ultimately leads to fibrosis. This review summarizes the current literature of the role of T cells in systemic sclerosis and suggests that therapeutic targeting of T cells is a promising new avenue.
Introduction
Systemic sclerosis (SSc) is a rare, debilitating autoimmune disease of unknown origin characterized by inflammation and excessive deposition of extracellular matrix (ECM) components, particularly collagen. SSc is prevalent worldwide, primarily affecting females, and there is currently no effective treatment. Early activation of the immune system is thought to be involved in the pathogenesis, as reflected by the increased level of cytokines in the serum of patients and the infiltration of mononuclear cells in the dermis of patients, which is thought to stimulate the differentiation and proliferation of fibroblasts to myofibroblasts. The increased expression of myofibroblasts is a marker of SSc; these cells express the protein αSMA, which increases the contractile force of the cells, thus increasing the deposition of ECM. SSc patients can be classified into two subsets; limited and diffuse, each distinguishable by the level of fibrosis and the autoantibodies present in the serum of patients. Diffuse SSc has a rapid onset with fibrosis occurring within the skin and in one or more internal organs, whereas limited SSc is milder, with fibrosis limited to the skin.
Despite the unknown etiology of SSc, several inflammatory mediators have been identified in SSc patients. Analysis of the blood of patients has revealed the presence of autoantibodies, including anticentromere and anti-topoisomerase antibodies, an increase in the level of cytokines, including IL-1, IL-6 and IL-27, and the presence of activated immune cells, including macrophages, mast cells and T cells (Table 1). In addition, analysis of the inflammatory infiltrate in the affected tissue of SSc patients shows the presence of activated T cells and the increase in these cells correlates with the severity of disease and symptoms including skin thickening. Furthermore, examination of the peripheral blood of patients demonstrates a change in the composition of the T-cell population, with predominance for Th2 cells and a change in the phenotype of Tregs.
This review seeks to examine the role of T cells in the pathogenesis of SSc by looking into the origin of T cells and their role in the immune response; the authors will then review the evidence of an altered T-cell response in SSc patients and the possible role of the products of T cells in causing fibrosis. Finally, the authors will examine the therapeutic potential of targeting T cells in the treatment of this chronic disease, as there is currently no therapy to modify disease.
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