T Cells in Systemic Sclerosis

A Reappraisal

Steven O'Reilly; Thomas Hügle; Jacob M. van Laar

Disclosures

Rheumatology. 2012;51(9):1540-1549. 

In This Article

Abstract and Introduction

Abstract

SSc is an autoimmune disease characterized by inflammation and extracellular matrix deposition that ultimately leads to loss of organ function. T cells appear to play a prominent role in its pathogenesis. The evidence for this comes from their being at the site of fibrosis, their activated phenotype and alteration in their number and frequency in peripheral blood. This review examines the role of T cells in the pathogenesis of SSc and specifically examines the key soluble profibrotic mediators (IL-4, IL-6, IL-13) secreted by Th2 cells and their interactions with fibroblasts that deposit excess extracellular matrix leading to fibrosis. We finally examine possible therapeutic options in targeting T-cell mediators to disrupt the cellular interactions between T cells and fibroblasts that serve to drive the fibrotic response. One of the factors driving fibrosis is IL-6 and this can be neutralized in vivo not only to limit IL-6-driven tissue fibrosis but concomitantly to suppress switching of Tregs to Th17 T cells that will provide more IL-6, thus perpetuating the fibrosis. Taken together, these data implicate the role of T cells in SSc and suggest that Th2-polarized T cells and the fibrotic mediators subsequently released directly induce fibrosis. Targeting such cytokines may be therapeutic not only in SSc but more generally in diseases where fibrosis is directed by inflammatory signals.

Introduction

SSc is an idiopathic CTD that is characterized by the presence of autoantibodies, inflammation, vascular abnormalities and fibrosis of skin and inner organs. Raised inflammatory markers such as CRP or IL-6 in peripheral blood are typically observed in early phases of the disease, with the final result being excessive extracellular matrix material deposition, primarily collagen types I and III.

Affected skin is infiltrated by mononuclear cells, mainly macrophages and activated T cells. The cell infiltration correlates with skin thickening, suggesting a relation between inflammation and fibrosis.[1] A definite cause for this inflammation has not been established but is similar to other autoimmune diseases; loss of tolerance to self-antigens, failure to resolve inflammation or both are thought to be involved.[2]

Activation of the innate and acquired immune system is of importance in the early stages of the disease. This is shown by mast cell infiltration and degranulation, macrophage infiltration and an activated phenotype of circulating monocytes in the peripheral blood.[3,4] Furthermore, autoantibodies such as anti-centromere and anti-Scl70 or against other targets are associated with disease subtypes and can predict disease progression.[5]

Substantial progress in the knowledge of T-cell differentiation has been achieved in the past two decades (Fig. 1). In SSc, differentiation towards Th-2 lymphocytes has been reported.[6] This review examines the role of T cells in SSc with a specific focus on the role of T-cell-derived mediators that are pro-fibrogenic. A greater understanding of the interplay between T cells, their pro-fibrotic mediators and fibroblasts will contribute to improved drug development.

Figure 1.

CD4 T-cell differentiation pathway.

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