Immune Markers of Pulmonary Arterial Hypertension
Edwards, Adrienne Laura
Pulmonary arterial hypertension (PAH) is a rare, but fatal disease of the pulmonary arteries that evades early diagnosis. Although modern targeted therapies have improved symptoms and outcomes in PAH, lung transplantation remains the only cure. Identification of new biomarkers of PAH would facilitate early diagnosis and enable prompt targeted therapy that could halt the dire outcome. Immune markers of PAH are under intense scrutiny given the substantial evidence implicating inflammatory processes in PAH pathogenesis. T-lymphocytes and NK cells are known to play important roles in animal models of PAH. Decreased circulating cytotoxic CD8+ T lymphocytes and natural killer (NK) cells are reported in IPAH patients but the effect of their depletion on disease outcome is unknown. Elevated cytokine levels are reported to predict adverse outcome in IPAH patients but the underlying mechanism for this remains unknown. Non-immune markers of PAH such as plasma Brain Natiuretic Peptide (BNP), cardiac troponins and endothelin have been under investigation for some time. Plasma BNP is currently the favoured prognostic biomarker and is the only marker recommended by international guidelines. Method: This prospective study analysed the lymphocyte and cytokine profiles of patients with idiopathic PAH (IPAH), connective tissue disease associated PAH (CTD-APAH) and matched healthy controls. CD4+ (Helper T-cell marker), CD8+ (Cytotoxic T-cell marker), CD56/CD16 (NK cell marker) and CD19+ (mature B-cell marker) cell numbers were assessed together with the immunofluorescence levels of 507 inflammatory cytokines using a commercially available cytokine array. Lymphocyte counts and cytokine profiles were then correlated with clinical outcome and with the plasma BNP. Finally, the utility of cardiac troponin I and endothelin-1 as prognostic markers was explored. Results: Fourteen PAH patients (9 IPAH, 5CTD) were recruited. Three patients were deceased at one year follow up; all had elevated BNP levels, elevated CD4:CD8 ratios and deficiencies of NK cells and cytotoxic CD8+ T-lymphocytes at recruitment. Patients with normal lymphocyte profiles at recruitment were all alive a year later and none on the active transplant list. Deficiency of NK and CD8+ cells was associated with increased interleukin (IL)-23 and decreased IL-21 immunofluorescence levels. As univariate markers of survival cytotoxic CD8+ T-cell and NK cell counts (and the associated cytokine profile) appear to be more powerful predictors of short term survival than the currently recommended biomarker, BNP. Cardiac troponin I was an insensitive prognostic marker in both IPAH and CTD-APAH patients. Endothelin-1 levels were predictive of adverse outcome in IPAH patients but not CTD-APAH. Conclusion: NK cell and cytotoxic CD8+ T-cell depletion in IPAH and CTD-APAH patients is associated with elevated BNP levels and an increased risk of death. An altered cytokine profile (elevated IL-23 and depleted IL-21 immunofluorescence levels) is associated with combined deficiency of NK and CD8+ cells. Further research is required to elucidate the mechanism of these findings and could lead to new NK and CD8+ directed immunotherapy.
Advisor: Beckert, Lutz E. L.; Robinson, B. A.; Gunningham, S. P.
Degree Name: Master of Medical Science
Degree Discipline: Internal Medicine
Publisher: University of Otago
Keywords: Pulmonary arterial hypertension; Lymphocytes; Biomarkers
Research Type: Thesis