Volume 3 Supplement 2
21st European Workshop for Rheumatology Research
Global analysis of gene expression in unseparated and CD8+ cells from bronchoalveolar lavage of patients with scleroderma lung disease
© BioMed Central Ltd 2001
Received: 15 January 2001
Published: 26 January 2001
The molecular mechanisms that lead to lung fibrosis following lung inflammation in patients with scleroderma are unknown. The objective of this study was to identify patterns of abnormal gene expression in unfractionated bronchoalveolar lavage (BAL) cells from scleroderma patients. DNA microarrays were used to assess expression of over 4000 genes in BAL cells from 17 scleroderma patients and 7 controls. Hierarchical matrices were constructed and showed that BAL cell samples from patients with lung inflammation segregated into one cluster, whereas BAL cell samples from patients without lung inflammation and controls clustered in another. Next, 372 genes were identified that were expressed at least two- fold higher or lower in BAL samples from patients without lung inflammation, compared to controls. These genes, which may represent a scleroderma phenotype independent of tissue inflammation, clustered into eight groups. One cluster of note included receptors for several chemokines,IL-1, IL-13, IL-18,and IFN-gamma receptors, as well as IL-10, IL-12, macrophage stimulating factor, VEGF, IGF binding protein and TXK tyrosine kinase. Fibroblast growth factors, other cytokines, and intracellular signaling molecules were among the genes in other clusters. Finally, 238 genes were identified that were over- or under- expressed in BAL cells from patients with greater risk of lung fibrosis, that is, patients with lung inflammation, compared to both patients without lung inflammation and controls. These genes clustered into 3 groups which included genes induced by stress (such herne oxygenase, complement components, and heat shock proteins), multiple chemokines (such as MCP-1, MIP-1, and PARC), and genes associated with several intracellular signaling pathways (such as JNK2 kinase, diacylglycerol kinase, and phosphatidylinositol 4,5 bisphosphate 5-phosphatase). Similar studies of global gene expression have begun with CD8+ T cells isolated from BAL samples. Preliminary data suggest abnormal expression of lymphotoxin beta, endothelin-2, fibroblast growth factors, and TGF-beta RII. In summary, scleroderma patients with lung inflammation have distinct patterns of gene expression in BAL cells, compared to patients without lung inflammation and healthy controls. Cluster analyses of genes that are abnormally expressed in different patient groups may shed light on new mechanisms that contribute to the development of the scleroderma phenotype, including genes likely to be involved in the inflammatory process and subsequent development of fibrosis in this autoimmune illness.