Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis
James C. Lee, … , Miles Parkes, Kenneth G.C. Smith
James C. Lee, … , Miles Parkes, Kenneth G.C. Smith
Published September 26, 2011
Citation Information: J Clin Invest. 2011;121(10):4170-4179. https://doi.org/10.1172/JCI59255.
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Research Article

Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis

Abstract

Crohn disease (CD) and ulcerative colitis (UC) are increasingly common, chronic forms of inflammatory bowel disease. The behavior of these diseases varies unpredictably among patients. Identification of reliable prognostic biomarkers would enable treatment to be personalized so that patients destined to experience aggressive disease could receive appropriately potent therapies from diagnosis, while those who will experience more indolent disease are not exposed to the risks and side effects of unnecessary immunosuppression. Using transcriptional profiling of circulating T cells isolated from patients with CD and UC, we identified analogous CD8+ T cell transcriptional signatures that divided patients into 2 otherwise indistinguishable subgroups. In both UC and CD, patients in these subgroups subsequently experienced very different disease courses. A substantially higher incidence of frequently relapsing disease was experienced by those patients in the subgroup defined by elevated expression of genes involved in antigen-dependent T cell responses, including signaling initiated by both IL-7 and TCR ligation — pathways previously associated with prognosis in unrelated autoimmune diseases. No equivalent correlation was observed with CD4+ T cell gene expression. This suggests that the course of otherwise distinct autoimmune and inflammatory conditions may be influenced by common pathways and identifies what we believe to be the first biomarker that can predict prognosis in both UC and CD from diagnosis, a major step toward personalized therapy.

Authors

James C. Lee, Paul A. Lyons, Eoin F. McKinney, John M. Sowerby, Edward J. Carr, Francesca Bredin, Hannah M. Rickman, Huzefa Ratlamwala, Alexander Hatton, Tim F. Rayner, Miles Parkes, Kenneth G.C. Smith

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Figure 1

Overlapping CD8 T cell gene expression signatures divide patients with CD and UC into 2 distinct subgroups.

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Overlapping CD8 T cell gene expression signatures divide patients with C...
Consensus clustering heat maps, demonstrating the merged output of 5,000 iterations of hierarchical and k-means clustering of (A) patients with CD and (B) patients with UC. Patient samples are arranged in the same order along the x and y axes. The colors of the intersecting squares represent the frequency with which samples cluster together, both within individual consensus clustering analyses and also between analyses using different methods of clustering. The color ranges from red (patients always cluster together) to blue (patients never cluster together). (C) Venn diagram illustrating the overlap between the gene signatures that distinguish the respective subgroups in CD, UC, and SLE/AAV (15). The statistical significance of each overlap was determined using a hypergeometric test. Numbers in the diagram refer to numbers of genes. Those inside the circles refer to the genes that are within each respective signature. The number outside the circles refers to the remaining genes expressed in CD8 T cells, which were not differentially expressed in any of the signatures. (D) The clusters of CD patients that were produced by k-means clustering for this cohort using the gene signature generated in the UC patients and (E) vice versa. The colored bar beneath each dendrogram corresponds to the original IBD1/2 subgroup membership.