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Postulated Vasoactive Neuropeptide Autoimmunity in fatigue-related Conditions

Discussion in 'Other Health News and Research' started by Marco, Mar 13, 2010.

  1. Marco

    Marco Grrrrrrr!

    Near Cognac, France
    Apologies for the length of this post but the full paper is a very dense 15 pages. I've selected out some of the 'juicy bits'. Those with a better scientific grounding may get more out of this but what I take from it is :

    Vasoactive neuropeptides (VN) play many roles in the body and are associated with functions commonly compromised in ME/CFS;

    Relatively minor infection, trauma etc may cause the body to mount an autoimmune response against endogenous VNs leading to the widespread pathology seen in 'chronic fatigue conditions';

    No specific trigger is required, ongoing infection may not be necessary and both clusters and sporadic cases can be explained;

    Resulting 'fatigue states' may be expressed heterogenously;

    Treatments are speculative but possible.

    Not a new paper but fascinating.

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

    Gold Coast Public Health Unit, 10-12 Young Street, Southport, Qld 4215, Australia


    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.

    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 hypothalamicpituitaryadrenal axis functions. Other vital functions regulated in the brain include olfaction, feeding and reproductive behaviours, circadian rhythm, and sleepwake 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).


    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.

    Full Paper
    cigana, leela and Enid like this.
  2. leelaplay

    leelaplay member

    Thanks for this Marco. So interesting - seems it could possibly explain many of the symptoms.

    The paper came out in 2006 (in Clinical & Developmental Immunology, March 2006; 13(1): 25–39 in case anyone is wondering).

    I wonder if anything has been done since.
  3. Alesh

    Alesh Senior Member

    Czech Republic, EU
    One of the best articles on ME/CFS I have ever seen. Thank you. I have to read it thoroughly. If I am right they mention increasing cAMP as a potential treatment. Then forskolin would be safe and cheap option. I think it is banned in EU as a supplement but it should not be a problem to obtain it in the USA.
  4. kurt

    kurt Senior Member

    This paper should get a big re-read, given the new Mella & Fuge finding of possible autoimmunity... has anybody tried Forskolin?
  5. mellster

    mellster Marco

    San Francisco
    Marco, thanks - I agree this is one of the best reads I have seen in a while. Maybe Cort can bring it on the front page. cheers
  6. Lynne B

    Lynne B Senior Member

    sydney, australia
    Marco, the Don Staines paper on vasoactive neuropeptide autoimmunity looks fascinating, as it seems to cover all our symptom categories. I can't say I understand it yet, but do you think it may point to a simpler explanation and solution to our condition than previous theories have? I wonder how it correlates with the Bond Uni Marshall/Staines interim report. regards, Lynne.
  7. Enid

    Enid Senior Member

    A very interesting paper indeed - thanks Marco.
  8. Marco

    Marco Grrrrrrr!

    Near Cognac, France
    Hi Lynne.

    It may offer a more unified explanation as he suggests that VN autoimmunity can account for most of not all of our symptoms but I doubt it offers an easier route to a cure as this appears to be quite speculative or at least cutting edge and with VNs being so ubiquitous and fundamental to our health anything that interferes with them is likely to have unanticipated consequences.

    As for the interim report it appears to me that understanding the immune system is very much like peeling an onion with deeper and deepr layers interacting with and controlling others. VN's appear to be at quite a deep layers compared to the usual immune markers we're familiar with like NK cells.

    I've just skimmed the interim report though and they report findings for both 'standard' immune markers and for a few of these VNs and they are reported as being at least in the predicted direction.

    What I find slightly frustrating about the interim report is that they don't demonstrate that the immune pattern they find in ME/CFS patients that may be used as a biomarker is distinct and unique. Nor do they state whether the pattern supports or refutes an association with a virus/retrovirus/bacteria or an autoimmune disorder. I don't mind the latter as I'd prefer more effort was spent in confirming the pathology and getting that accepted rather than chasing the pathogen. Longer term though it would help at least point researchers in the right direction.

    PS - If this is the interim report, is there more to the study?
  9. Sing

    Sing Senior Member

    New England
    I wonder if anyone can ask Nancy Klimas about this paper? Or ask any of our other doctors who focus a great deal on the immune system. I am thinking like a soccer/football player who sees an opportunity with the ball and wants to shoot it to one of the better players to take it down the field. Wish I could understand and contribute more on the science but get lost in the complexities.
  10. grosolo


    Can we bump this up and find out the latest on it? And has anyone tried forskolin because of this and if so, what were the results?
  11. Ema

    Ema Senior Member

    Midwest USA
    I think this is a really interesting paper and would also like to see the follow up.

    I did try forskolin and didn't notice anything in particular unfortunately.
  12. Ema

    Ema Senior Member

    Midwest USA
  13. wastwater

    wastwater Senior Member

    The 2010 paper on me/cfs covered a lot of keywords for me Atp cAMP and glial.I'd not seen it before and not really heard of it since,I think it maybe important.The 2010 paper needs it's own thread if it doesn't already have one.
    Last edited: Apr 22, 2015

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