The role of immune responses, focussing on herpes virus specificity and interferon-gamma, in Myocardial Infarction with reperfusion and in Chronic Fatigue Syndrome, by Santosh Murali. Doctoral thesis, Northumbria University, 14 January 2020


Research thesis abstract:

Immune responses targeting microbes can contribute to chronic inflammation, particularly when the microbes are persistent such as herpes-family Cytomegalovirus (CMV) and EpsteinBarr virus (EBV). Such persistence of antigens can cause T cell exhaustion characterized by loss of appropriate effector functions, expression of inhibitory
receptors, as well as failure to return to homeostatic pre-inflammatory conditions. This results in immune senescence and dysregulation which may cause disrupted cell populations, homing and cytokine productions that mediate immunopathology and compromise anti-microbial defences.

The aim of the study was to determine whether microbe specific particularly, interferon gamma immune responses measured in 2 disease states, where a herpes viral inflammatory aetiology and immune dysregulation are suggested, acute Myocardial Infarction (MI) with reperfusion and Chronic Fatigue Syndrome (CFS), are indicative of
disease presence and severity.

MI occurs due to blockage of the coronary artery, and treatment involves stent insertion, allowing reperfusion (R), which has associated immunopathology due to T cell homing. A total of 52 MI patients were studied. Blood samples were taken before and after reperfusion to investigate the dynamics of specific T cell homing to the heart, that may contribute to disease severity (reperfusion damage). For 50 CFS patients with measured disease levels, blood samples were taken to examine immune responses including those against microbes implicated in disease (CMV & EBV) compared to healthy controls.

T cell immunity was measured by ELIspot and flow cytometry, and cytokine levels in cell culture supernatants were measured using multiplextechnology. Statistical analyses were carried out for normality in data sets. The Mann-Whitney test or unpaired t test was used to determine the difference between two unrelated groups. Differences between repeat or
paired measurements were determined by Wilcoxon signed rank tests or paired t tests. Associations between measurements were investigated using Spearman correlation.

Results and Discussion:
In MI patients, compared to before reperfusion, levels of the following cell populations fell significantly after reperfusion: terminally-differentiated CD8+ PD-1+ effector memory cells (p=0.016) and CMV-specific IFNg-secreting CD4+ T cells (p=0.002) the latter also being associated with injury. This suggests specific pathogenic T cell homing to the heart during reperfusion. In CFS patients, increased disease severity was associated with increased non-specific IFNy production (p=0.008), and reduced percentage of NK cells (p=0.0047). NK cell deficiency may reduce antiviral defences and allow detrimental viral

T cell responses against CMV appeared to have greater involvement in MI + R than CFS. Immune responses involving IFN-gamma are demonstrated in both conditions as being associated with disease, and so this cytokine may be considered a disease biomarker and a therapeutic target for both.

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