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Full Text, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Medical Science, Griffith Health, Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a disabling condition characterised by unexplained chronic fatigue that is associated with immune, neurological (including autonomic), musculoskeletal, cardiovascular and gastrointestinal symptoms [1, 2]. Currently, accurate diagnosis remains challenging in the absence of a clinical or laboratory test. Although the aetiology of ME/CFS remains undefined, a significant reduction in natural killer (NK) cell cytotoxicity is consistently reported in ME/CFS patients compared with healthy controls (HC) [3-6]. NK cells are effector lymphocytes of the innate immune system principally responsible for recognising and responding to pathogen invasion [7]. Approximately 90% of peripheral NK cells are CD56DimCD16+ which are highly cytotoxic and kill infected, tumour or ‘missing self’ cells through cytotoxic processes [8]. Conversely, the CD56BrightCD16Dim/- subset is responsible for immunosurveillance and cytokine production [9]. Importantly, NK cells require calcium (Ca2+) to regulate various cellular functions, such as cell differentiation, cell division, apoptosis, transcription, and cytotoxicity [10]. Transient Receptor Potential (TRP) channels are a group of unique ion channels whereby majority are highly selective to Ca2+ [11]. Functionally, TRP ion channels regulate “threat” stimuli, such as pain, thermosensation, mechanosensation, pathogens, and chemicals, via sensory transduction pathways. TRPM2 and TRPM3 are cation channels ubiquitously expressed throughout the human body and expressed in almost all cell types, such as NK cells. Both TRPM members are highly permeable to Ca2+, therefore are critical regulators of Ca2+-dependent pathways, such as NK cell cytotoxicity. TRPM2 is activated by adenine dinucleotides (ADPR, cADPR, NAADP, ꞵ-NAD), reactive oxygen species (hydrogen peroxide and OH-), and intracellular ([Ca2+]i). Conversely, TRPM3 is potently activated by neural steroids, such as pregnenolone sulphate (

Donald R Staines1,2, Ekua W Brenu2, Sonya Marshall-Gradisnik21Queensland Health, Gold Coast Population Health Unit, Southport, Gold Coast, Queensland, Australia; 2Faculty of Health Science and Medicine, Population Health and Neuroimmunology Unit, Bond University, Robina, Queensland, AustraliaAbstract: Neuropsychiatric symptoms occur in a number of neurological fatigue-related conditions including multiple sclerosis (MS), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and chronic fatigue syndrome (CFS). These conditions have been attributed variably to neuroinflammatory and neurodegenerative processes. While autoimmune pathology, at least in part, has long been suspected in these conditions proof has been elusive. Autoimmune pathomechanisms affecting the blood–brain barrier (BBB) or blood–spinal barrier (BSB) may predispose the BBB/BSB to ‘leakiness’ and be a precursor to additional autoimmune events resulting in neuroinflammatory or neurodegenerative processes. The aim of the paper is to postulate immunopathology of the cerebrospinal perivascular compartment involving certain vasoactive neuropeptides, specifically pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP), in the etiology of certain neuropsychiatric fatigue-related conditions such as MS, ALS, PD, and CFS. Vasoactive neuropeptides (VNs) such as PACAP and VIP have critical roles as neurotransmitters, vasodilators including perfusion and hypoxia regulators, and immune and nociception modulators. PACAP and VIP are widely distributed in the central nervous system (CNS) and have key roles in CNS blood vessels including maintaining functional integrity of the BBB and BSB. Autoimmunity affecting these VNs would likely have a detrimental effect on BBB and BSB functioning arguably predisposing to further pathological processes. Virchow–Robin spaces (VRS) are perivascular compartments surrounding