T Cell Polarization Identifies Distinct Clinical Phenotypes in Scleroderma Lung Disease

Arthritis Rheum. 2008 Apr;58(4):1165-74. doi: 10.1002/art.23406.

Abstract

Objective: Lung involvement is the leading cause of morbidity and mortality in systemic sclerosis (SSc; scleroderma), and interstitial lung disease (ILD) is the most common pulmonary manifestation. An abnormal profibrotic Th2/Tc2-polarized T cell response is postulated to mediate tissue damage and fibrosis. The aim of this study was to investigate whether a polarized T cell phenotype in SSc is associated with lung disease or other clinical manifestations of SSc.

Methods: Circulating T cells were characterized by flow cytometry in 62 patients with SSc and 36 healthy control subjects, using antibodies against CD3, CD4, CD8, chemokine receptor CCR5 (Th1/Tc1-specific), and prostaglandin D2 receptor CRTH2 (Th2/Tc2-specific). The ratio between CCR5 and CRTH2 T cell frequencies was used to quantify type 1 (high-ratio) or type 2 (low-ratio) immune polarization.

Results: Patients with SSc exhibited lower CCR5/CRTH2 T cell ratios than those exhibited by control subjects (P<0.0001), indicating a Th2/Tc2-polarized phenotype. Markedly reduced CCR5/CRTH2 T cell ratios were observed in SSc patients with ILD compared with SSc patients without ILD (P<0.0001), particularly in patients with active ILD (P<0.0001) compared with those with stable lung function. Lower CCR5/CRTH2 ratios were strongly associated with a lower value for the percent predicted forced vital capacity (P<0.0001). In patients with an estimated right ventricular systolic pressure>35 mm Hg, suggestive of pulmonary vascular disease, a lower value for the percent predicted diffusing capacity (DLCO) was associated with higher CCR5/CRTH2 T cell ratios (Th1/Tc1) (P=0.009), while in those with right ventricular systolic pressure<35 mm Hg, a lower value for the percent predicted DLCO correlated with lower ratios (Th2/Tc2) (P<0.0001), as observed for ILD.

Conclusion: T cell polarization in SSc is strongly associated with specific manifestations of lung disease. Measurement of T cell polarization may represent a valuable tool to monitor disease activity and predict clinical outcomes in SSc patients with lung disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers / blood
  • Case-Control Studies
  • Female
  • Humans
  • Lung Diseases, Interstitial / complications
  • Lung Diseases, Interstitial / immunology*
  • Lymphocyte Count
  • Male
  • Middle Aged
  • Phenotype
  • Scleroderma, Systemic / classification*
  • Scleroderma, Systemic / complications
  • Scleroderma, Systemic / immunology*
  • Severity of Illness Index
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes, Cytotoxic
  • Th1 Cells
  • Th2 Cells

Substances

  • Biomarkers