Investigation of Cellular and Genetic Mechanisms Required for Natural Killer Cell Cytotoxic Activity in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract

Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) is a complex disorder associated with disabling and unremitting fatigue, flu-like symptoms, muscle and joint pain, post-exertional malaise and cognitive impairments. CFS/ME is a heterogeneous illness and the cause of CFS/ME is currently unknown. Consequently, there is no biological marker to diagnose the illness, and case definitions are used to identify CFS/ME patients. CFS/ME is a multi-system disorder that has been associated with impairments in the functions of the endocrine, immune, central and autonomic nervous systems. Evidence for chronic immune dysfunction in CFS/ME has been reported by several groups, where significantly reduced Natural Killer (NK) cell cytotoxic activity has been the most predominant and consistent finding. NK cells consist of CD56brightCD16dim/- NK cells which produce immunoregulatory cytokines, and CD56dimCD16+ NK cells which induce cytotoxic lysis of target cells infected by viruses, bacteria and parasites, or cells that have been malignantly transformed. The granule secretory pathway mediates NK cell cytotoxic activity and includes contact, adhesion, activation, granule polarisation and degranulation. Cytotoxic lysis of target cells is predominantly induced by the granule secretory pathway and, as such, has been associated with the cytotoxic dysfunction reported in CFS/ME patients. The aim of this thesis was to investigate cellular and genetic components required for NK cell cytotoxic activity to identify a potential mechanism of reduced cytotoxic activity in CFS/ME patients.