Peripheral Blood Mononuclear Cell Gene Expression Profiles Predict Poor Outcome in Idiopathic Pulmonary Fibrosis

Abstract

We aimed to identify peripheral blood mononuclear cell (PBMC) gene expression profiles predictive of poor outcomes in idiopathic pulmonary fibrosis (IPF) by performing microarray experiments of PBMCs in discovery and replication cohorts of IPF patients. Microarray analyses identified 52 genes associated with transplant-free survival (TFS) in the discovery cohort. Clustering the microarray samples of the replication cohort using the 52-gene outcome-predictive signature distinguished two patient groups with significant differences in TFS. We studied the pathways associated with TFS in each independent microarray cohort and identified decreased expression of “The costimulatory signal during T cell activation” Biocarta pathway and, in particular, the genes CD28, ICOS, LCK, and ITK, results confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A proportional hazards model, including the qRT-PCR expression of CD28, ICOS, LCK, and ITK along with patient’s age, gender, and percent predicted forced vital capacity (FVC%), demonstrated an area under the receiver operating characteristic curve of 78.5% at 2.4 months for death and lung transplant prediction in the replication cohort. To evaluate the potential cellular source of CD28, ICOS, LCK, and ITK expression, we analyzed and found significant correlation of these genes with the PBMC percentage of CD4+CD28+ T cells in the replication cohort. Our results suggest that CD28, ICOS, LCK, and ITK are potential outcome biomarkers in IPF and should be further evaluated for patient prioritization for lung transplantation and stratification in drug studies.

Autoimmunity to Vimentin Is Associated with Outcomes of Patients with Idiopathic Pulmonary Fibrosis

“…Thus, there are numerous biological precedents that could plausibly explain the development of autoimmunity in IPF as a secondary consequence of another, distinctly different lung injury(ies) that actually triggers the disease. Nonetheless, at least some of the many autoimmune responses that have been discovered in IPF patients, in addition to the antivimentin in this study, seem to play important roles in disease severity and progression (2,(4)(5)(6)(7)(8)(9)(10)(13)(14)(15)(16). In addition, pathogenic secondary immune responses could cause or contribute to the well-known resistance of IPF to conventional therapies, because many other autoantibody-mediated lung diseases are similarly refractory to nonspecific agents, including glucocorticoids (8).…”

“…T cell-related genes and proteins, such as CD28 and LCK, have been identified as prognostic biomarkers in IPF (13,16). Furthermore, T cell depletion attenuates fibroblast proliferation and extracellular matrix (ECM) accumulation in experimental models of pulmonary fibrosis (17).…”

Thyroid Disease Is Prevalent and Predicts Survival in Patients With Idiopathic Pulmonary Fibrosis

“…A gene expression analysis of peripheral blood mononuclear cells in patients with IPF using an RNA microarray platform identifi ed several diff erentially expressed genes, including CTLA-4 , ICOS , and CD28 , within the T-cell biocarta pathway. 34 Reduced expression of each of these genes was associated with an increased hazard of death in two IPF cohorts. Genes encoding CTLA-4 , ICOS , and CD28 lie within 300kb on the long arm of chromosome 2, and polymorphisms at this locus have been linked previously to autoimmune thyroid disease.…”

Idiopathic pulmonary fibrosis biomarkers: clinical utility and a way of understanding disease pathogenesis

“…103 These findings were supported further by genomic analysis of peripheral blood mononuclear cells from two separate IPF cohorts that showed that low expression of four genes, LCK, ITK, ICOS, and CD28, was associated with increased IPF mortality. 104 These four genes all map to the T-cell costimulatory signal pathway and suggest that repeated cycles of T-cell stimulation are associated with the development of a pathologic T-cell phenotype and a significantly worsened prognosis in IPF. 103 …”

“…Newer studies will likely focus on the data that are obtainable from peripheral blood mononuclear cells. 104 Another potential source of information may be the isolation of circulating microRNA species. 122,123 How should biomarkers be studied?…”