Postulated Vasoactive Neuropeptide Autoimmunity in Fatigue‐Related Conditions: A Brief Review and Hypothesis

Abstract

Disorders such as chronic fatigue syndrome (CFS) and gulf war syndrome (GWS) are characterised by prolonged fatigue and a range of debilitating symptoms of pain, intellectual and emotional impairment, chemical sensitivities and immunological dysfunction. Sudden infant death syndrome (SIDS) surprisingly may have certain features in common with these conditions. Post-infection sequelae may be possible contributing factors although ongoing infection is unproven. Immunological aberration may prove to be associated with certain vasoactive neuropeptides (VN) in the context of molecular mimicry, inappropriate immunological memory and autoimmunity. Adenylate cyclase-activating VNs including pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) act as hormones, neurotransmitters, neuroregulators, immune modulators and neurotrophic substances. They and their receptors are potentially immunogenic. VNs are widely distributed in the body particularly in the central and peripheral nervous systems and have been identified in the gut, adrenal gland, blood cells, reproductive system, lung, heart and other tissues. They have a vital role in maintaining cardio-respiratory function, thermoregulation, memory, concentration and executive functions such as emotional responses including social cues and appropriate behaviour. They are co-transmitters for a number of neurotransmitters including acetylcholine and gaseous transmitters, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system against toxic assault as well as being important in the maintenance of homeostasis. This paper describes a biologically plausible mechanism for the development of certain fatigue-related syndromes based on loss of immunological tolerance to these VNs or their receptors following infection, other events or de novo resulting in significant pathophysiology possibly mediated via CpG fragments and heat shock (stress) proteins. These conditions extend the public health context of autoimmunity and VN dysregulation and have implications for military medicine where radiological, biological and chemical agents may have a role in pathogenesis. Possible treatment and prevention options are considered.

Altered functional B cell subset populations in patients with chronic fatigue syndrome compared to healthy controls

“…A small number of studies show an increased frequency of low‐level autoantibodies directed against nuclear, thyroid and other antigens in CFS patients . Others have proposed autoimmunity to neuropeptide antigens . Alternatively, depletion of B cells may have resulted in the removal of the reservoir of lymphotrophic B cell viruses such as EBV.…”

Review of immunological and virological aspects as contributory factors in Sudden Unexpected Death in Infancy (SUDI)

“…Infants may thus be less able to compensate for inflammatory responses and more susceptible to the damaging effects of pro-inflammatory cytokines [51]. Mutations causing lower expression of anti-inflammatory cytokines have been detected in some SUDI cases, together with increased pro-inflammatory cytokines [44]. Surprisingly, despite a functionally immature immune system, production of proinflammatory cytokines can be detected very early in life.…”

Postulated Role of Vasoactive Neuropeptide‐Related Immunopathology of the Blood Brain Barrier and Virchow‐Robin Spaces in the Aetiology of Neurological‐Related Conditions

“…VN autoimmunity has been postulated as a contributing cause for some fatigue-related conditions [ 28 ]. The present paper explores the possible role VN immune dysregulation may have on VRS function and CNS activity as this anatomical pathway may have a significant bearing on disease aetiology.…”