This theory makes just as much sense if not more than xmrv and should be investigated fully by any scientist truly passionate about solving this mystery!!

Postulated vasoactive neuropeptide autoimmunity in fatigue-related
conditions: A brief review and hypothesis

DONALD R. STAINES
Gold Coast Public Health Unit, 10-12 Young Street, Southport, Qld 4215, Australia

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.

Excerpts

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.

VNs belong to the secretin-glucagon super-family, exerting significant control over carbohydrate and lipid metabolism. They have important roles in vasodilation, neurotrophism, nociception, neuroregulation and neurotransmission including thermoregulation, cardio-respiratory control, balance and vestibular function, emotional and intellectual functioning including memory and concentration, and immunological and hormonal modulation.

They exert their effects at high level in controlling central and peripheral nervous systems and hypothalamic–pituitary–adrenal axis functions. Other vital functions regulated in the brain include olfaction, feeding and reproductive behaviours, circadian rhythm, and sleep–wake cycles. They and their receptors are expressed at important peripheral sites such as heart, gut, blood, lung, pancreas, liver and urogenital systems (Ishizuka et al. 1992, Arimura 1998, Sherwood et al. 2000, Hannibal 2002, Hashimoto 2002, Ganea et al. 2003). Compromise of their function is likely to have serious consequences for homeostasis.

Endogenous opioid activity is functionally related to cytokine and VN activity suggesting that pain mediation and perception may be altered in conditions where endogenous opioid function is mpaired through VN mechanisms (Wilderman and Armstead 1997, Peterson et al. 1998). Nitric oxide (NO) metabolism is implicated in immunomodulation as well as possibly mediating chemical sensitivity in these conditions suggesting a plausible mechanism for some concurrent symptoms in CFS and GWS (Pall 2002, Onoue et al. 2002). Synaptic plasticity and pain behaviours are critically mediated by CGRP in the amygdala (Han et al. 2005).

As these antibodies may be polyclonal with varying degrees of blocking capacity, this may explain heterogeneity in phenotypic expression of VN autoimmune fatigue disorders. In other words fatigue disorders of varying degrees of severity and duration may result.

Ancient DNA sequences mimicking bacterial and viral genomes containing higher proportions of CpG elements have become incorporated into mammalian DNA as human endogenous retrovirus (HERV). These genetic components have become methylated over time making them mostly benign components of mammalian DNA. However, these DNA components may undergo hypomethylation through a range of stimulating factors, making them able to regulate transcriptional activity and expression of the HERV family (Lavie et al. 2005) with implications for a range of pathologies.

The known association of VPAC2 receptors with acetylcholine and muscle function (Hinkle et al. 2005) suggests a patho-mechanism crudely analogous with autoimmune dysfunction in Myasthenia Gravis and may provide a useful model to explore. Hence treatment options such as pyridostigmine and thymectomy may be considered. In a series of three case reports, Kawamura et al. (2003) describe successful use of oral pyridostigmine in the treatment of CFS. This is an interesting finding given the possible association of pyridostigmine with the aetiology of GWS (Abou-Donia et al. 2004, Staines 2005b).

Conclusion

The autoimmune hypothesis of VNs suggests that relatively minor infection or inflammation results in predictable pro-inflammatory cytokine and other responses which may have subsequent serious effects involving VN dysfunction. Other pro-inflammatory effects such as NO release and possible chemical sensitivities may also result. Modulation and termination of these inflammatory responses is required by VNs. Autoimmune effects, e.g. on PACAP/VIP or the PAC1/VPAC1/VPAC2 receptors will have a negating effect on VN function and also subsequent effects on intracellular mechanisms. While some inflammatory or infectious events may be trivial, compromise of the functions of VNs such as PACAP/VIP/CGRP is not. Brain, cardiac and other organs known to exhibit similar PACAP/VIP receptor function would also be expected to demonstrate dysfunction somewhat simultaneously. Prevention of SIDS and other disorders if shown to be VN autoimmune conditions may evolve from these concepts. Public health implications may exist if “epidemics” or simply seasonal circulating organisms have particular molecular mimicry with VNs or their receptors. Short term relatively benign IgM may shift to a more pathogenic IgG phenotype as autoimmune responses to VNs/receptors and result in longer-term profound impairment and disability. These VN autoimmune processes may also have implications for military medicine where radiological, chemical and biological agents may play an important role in pathogenesis.

Further understanding of possible autoimmune dysfunction of these VNs and their receptors may
elucidate the mechanisms of disabling fatigue-related syndromes such as CFS and GWS, and possibly SIDS, and open the way for routine laboratory investigations and prevention options. VN and receptor reactivation may prove to become successful interventions. A spectrum of interventions including genomic, immunological and biochemical/drug therapies may prove to be possible in VN autoimmune fatigue-related disorders. Interventions such as phosphodiesterase inhibitors, immunotherapy, VN replacement or VN receptor reactivation may prove to be useful in these conditions but are not yet tested.