BTLA, A T Cell Co-Inhibitory Receptor, Is A Potential Biomarker For Progressive Idiopathic Pulmonary Fibrosis

IPF has a heterogeneous course of disease in which some patients experience a slow or more stable course while others RATIONALE: experience rapid decline and early mortality. Currently we lack understanding of the mechanisms that underlie the pathogenesis responsible for the differences between stable IPF (S-IPF) and rapidly progressive IPF (RP-IPF). Previous studies examining whole genome expression arrays in PBMCs of IPF patients have demonstrated a signature that is predictive of progressive disease. The predominant pathways identified were altered gene expression in T cell activity and receptors. is to link these markers of The objective of our study progressive IPF to actual protein expression on peripheral lymphocytes, thereby determining potential mechanisms involved in disease progression. METHODS: We collected patient's peripheral blood mononuclear cells (PBMC) and classified patients as S-IPF or RP-IPF based on physiologic measures taken as part of their usual clinical care. We examined mRNA levels and cell surface protein expression by flow cytometry and correlated our findings with IPF severity, using the diffusing capacity of carbon monoxide (DLCO) as the physiological measurement. RESULTS: From our previous data sets, one of the T cell receptors with the highest alteration in gene expression patterns between S-IPF and RP-IPF was Band T-lymphocyte attenuator (BTLA), a surface co-inhibitory receptor on lymphocytes. A significant association was found between decreased BTLA mRNA levels and decreased predicted DLCO levels. Analysis of all samples demonstrated a significant and dramatically decreased BTLA surface expression on both peripheral CD4 and CD8 T cells, but not B cells, from RP-IPF patients compared to controls or S-IPF patients. CONCLUSION: Our data demonstrate that BTLA protein expression and mRNA levels are potential biomarkers and may have a predictive value for determining the patients most likely to rapidly progress. Decreased BTLA protein expression on peripheral blood T cells, may either be a cause of, or a result of, disease progression. Further, our data imply that the adaptive immune system, and T cells specifically, play a key role in the progression of IPF. Peripheral blood T cell biomarkers of rapid progression developed as a result of these efforts may be used in the development of personalized diagnostics. Furthermore, understanding these pathways may identify potential therapeutic targets and explain why the variability of disease course exists.