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Abnormal gene expression in CD8 T cells from the lungs of scleroderma patients

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Activated CD8+ T cells in bronchoalveolar lavage (BAL) samples are associated with progressive lung fibrosis in scleroderma. The hypothesis of this work is that CD8+ T cells from a subset of scleroderma patients, especially those with lung inflammation, have an abnormal pattern of gene expression that can promote fibrosis. Freshly isolated BAL CD8+ T cells from 26 individuals were tested for expression of cytokines, chemokines, growth factors, and receptor genes, using DNA microarrays. Hierarchical cluster analyses showed two groups of arrays. Group 1 included all 10 patients with lung inflammation and two patients without. Arrays from the other 7 patients without lung inflammation clustered with all 7 arrays from controls in group 2. Differences in gene expression indicated that CD8+ T cells in group 1, compared to group 2, were more likely to be activated, express type 2 cytokines, and stimulate extracellular matrix deposition, and less likely to undergo activation-induced cell death. T-cell activation was suggested by increased expression of LIGHT, neurotropin-4, CD100, CD6, integrin b1 and decreased expression of VIP R1 genes. Type 2 cytokine production was suggested by increased expression of CCR4, G-CSFR and IL-13 Ra and decreased expression of TRANCE and TNF R1 genes. Reduced expression of TNF R1, TNF R11, TRAIL R1, CD30 L and Fas genes suggested that CD8+ T cells from Group 1 were less likely to die following activation. Increased gene expression of oncostatin M, which simulates fibroblast proliferation and collagen production, integrin b6, which can activate TGF-β, FGF17, FGF4, and membrane type-1 and -2 matrix metallopro-teinases was seen. To confirm some of these results, increased IL-4 mRNA had been reported in our previous work, and increases in oncostatin M and activated TGF-β proteins in BAL fluids from patients with lung inflammation were confirmed by ELISA. These findings suggest that activated CD8+ T cells are part of a pathway that leads to lung fibrosis in scleroderma.

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Keywords

  • Integrin
  • Scleroderma
  • Hierarchical Cluster Analysis
  • Lung Inflammation
  • Lung Fibrosis