http://www.twitlonger.com/show/n_1rt43lk THE 2nd INTERNATIONAL SYMPOSIUM FOR CFS/ME December 2013, Gold Coast, Australia. I felt privileged to be invited to attend this symposium, which was combined with the opening of the National Centre for Neuroimmunoloy and Emerging Diseases (NCNED) at Griffith University. The campus at Griffith is new and adjacent to the new 750-bed Gold Coast Hospital. The programme for the day began at Griffith University with the Opening Ceremony for the National Centre for Neuroimmunoloy and Emerging Diseases (NCNED). We were welcomed by Professor Sonya Marshall-Gradisnik, Co-director. She then introduced Professor Allan Cripps, Pro Vice Chancellor Health, Griffith University, who welcomed us, and he then introduced Dr Elizabeth Unger (USA), who gave a brief opening address before they both unveiled the plaque. Hugh Perry (Southampton, UK) gave the inaugural Alison Hunter Memorial Foundation address. However he began his address pointing out that neuro-immunology has a large role to play in the understanding and research associated with ME/CFS. He reiterated how much Christine Hunter (AMHF) had raised so much the awareness of the illness. The first part of his talk explained the Medical Research Council (MRC) mission. The MRC has been established for 100 years. The mission is to encourage research, produce skilled researchers, disseminate knowledge and bring dialogue to the table. ME/CFS research has been supported since 2003. A strategy document was produced in 2008 – leading to an expert group incorporating external researchers for collaboration. The idea was to bring in new people, new research and new technologies. One of the big challenges was the unmet clinical need (up to 600,000 sufferers in the UK). Grants were initially low as there was no clear pathology and no targeted therapies. Treatment has been geared towards support and symptom control. There is need to define phenotypes and sub-phenotypes and embrace new technology. He then outlined a prioritization of topics for research: Autonomic dysfunction, cognitive symptoms, fatigue, immune dysregulation, pain and sleep. There is a need to bring in external expertise. In the medium term there is need to encompass comorbidity and chronicity, susceptibility and resilience, mitochondrial function, use of well characterized cohorts and development of intervention (eg cytokine inhibition). In the longterm there should be development of imaging technologies, assessment of genetic risk and review of neurobiological changes (eg cerebral activity). The MRC is currently funding new research looking into the mechanism of ME/CFS (1.6 million pounds). There needs to be partnership with new researchers to qualify for grants, and a focus on one of the 6 topics listed above. So far the following awards have been made: Mitochondrial function, Autonomic dysfunction, Biological fingerprints of fatigue, Slow-wave sleep and daytime function, persistent fatigue induced by interferonα (a new model for ME/CFS). The MRC role is to support excellent and innovative research. There is increased emphasis on translation, and increased commitment to develop research for application to new therapies. This needs a “bottom-up” researcher –led approach. This has led to the establishment of the UK ME/CFS Research collaborative launched in April 2013, associated with Dr Stephen Holgate. This brings together funders and ME Charities. The MRC acts as an observer. The aim is to collaborate the ME charities and to increase awareness with the research community. The key to success is that research should drive the agenda, the “bottom-up” approach and the engagement of researchers outside the field. This has led to the First UK CMRC Research conference to be held in Bristol in September 2014. The second part of the address focused on the Impact of Systemic Inflammation on the Brain. He described how diseases “talk” to the brain, and how infection makes you feel “sick”. Inflammation changes behavior. These symptoms can be the same as those experienced by those with ME/CFS. This highly organized strategy is critical to survival if living in the wild. Systemic inflammation activates selective brain regions. Infection causes a localized inflammatory response, with release of pro-inflammatory cytokines, which then communicate with the brain. The cytokines act on the endotheliail cells, which in turn affect the macrophages in the brain (microglia) – and microglia play a key role in immune/brain communication. This is tightly regulated by the brain/micro-environment. The microglia may become dysregulated, escaping from CNS control, and this leads to massive pathology and symptoms equivalent to microglial activation. The activated microglia may proliferate, leading to neuro-degeneration. The microglia may be primed by decline (eg Alzheimer’s disease). Macrophages are primed by exposure to ɣinterferon and then triggered by infection, which is the secondary stimulus. In a younger population the microglia can be primed by the environment – living in dirty conditions (animal model) predisposes the brain to give a more robust response to infection, which can lead to microglial activation for months. Smoking and obesity lead to higher levels of cytokines and this in turn leads to more activation of the microglia as if a peripheral disease exists. Lifestyle, systemic infection and genetics all prime the microglia. The final conclusion/hypothesis was that systemic infection and inflammation, that normally leads to sickness behavior in an individual with a healthy brain, is a homeostatic mechanism with no long term consequences, is distorted and maladaptive in an individual with primed microglia. The question is to find “inhibitors” to penetrate the brain and downregulate the microglia. Elena Gonzalez-Rey (Granada,Spain) was the next presenter who addressed the issue of therapeutic and physiological relevance of cortistatin as a key molecule in the development and progression of inflammatory and autoimmune diseases. Cortistatin is a cyclic-neuropeptide produced by the brain cortex and immune cells, with unique function, that shows potent anti-inflammatory activity. She reiterated that homeostasis leads to survival, and that immune homeostasis is protective. The immune system “talks” to the neuroendocrine system via cytokines and neuropeptides. The therapeutic effect of cortistatin gives a good response. She had looked at mouse models and found a good response in MS (EAE). Cortistatin improves symptoms, reduces inflammatory response, inhibits demyelination, inhibits Th1/Th17 responses and induces regulatory T cells. It also induces the production of trophic factors, modulates the immune response of resident cells and protects against oxidative stress. Severe disease leads to decrease in cortistatin levels. Low cortistatin leads to anxiety and fear behaviours, affects neurogenic processes and induces cognitive problems. (article published in Arthritis and Rheumatism May 2013). This is a potential treatment for ME/CFS. The therapeutic potential of Vasoactive Intestinal Peptide (in auto-immunology) was discussed by Mario Delgado (Granada,Spain). VIP is widely distributed in the body, produced from many organs. It has a plethora of functions. It has been found to be a pleiotropic immunomodulatory factor with potential for use in inflammatory and auto-immune disorders. It is a key factor. Various auto-immune diseases have been studied. It has been found to reduce experimental auto-immune endocarditis in mice, decreases severity of EAE and restores immune tolerance. Questions asked were: Is VIP needed for a healthy immune system, is it ready for clinical use and could it play a role in ME/CFS? Endogenous VIP and its signalling are critically involved in maintenance of immune tolerance. Clinical use of VIP (Aviptadil) includes treatment of erectile dysfunction, idiopathic pulmonary hypertension and acute systemic respiratory disease. Inhaled Aviptadil is used for alleviation of lung inflammation in sarcoidosis (Treg cells increase). A published article on ciguatera poisoning (Shoemaker May 2010) found that VIP was decreased leading to many symptoms. In another open label study, patients exposed to contaminated buildings had reduced symptoms with inhaled VIP treatment. Inflammation was corrected, Treg cells were normalized and there was enhanced quality of life in all patients. We need to look to see if VIP is decreased in ME/CFS and also whether a VIP infusion could be helpful. Gilles Guillemin (Sydney, Australia) presented his work looking at the involvement of the tryptophan mechanism in neuro-inflammation. He explained that the kynurenine pathway is a major route of tryptophan catabolism resulting in the production of several neuro-active intermediates. Tryptophan is one of 20 amino acids and is diet sourced. It is a “calming” neurotransmitter and a sleep inducing hormone. The kynurenine pathway is induced during inflammatory brain diseases leading to tryptophan catabolism, and then production of various neuroactive metabolites , including quinolinic acid (QUIN.) This field of research is growing and there is now a Journal of Tryptophan Research. The foetus protects itself against rejection via this pathway. Human microglia and macrophages produce QUIN, which acutely can lead to neuronal death and chronically to neuronal dysfunction and neurotoxicity. Neuroinflammation can lead to suicidal ideology, (there may be an imbalance with elevated QUIN). QUIN can induce apoptosis in human primary astrocytes. It also induces oligodendrite apoptosis, and affects chemokine production and expression by astrocytes. It is not specific for any particular neurological diseases. The kynurenine pathway is activated and QUIN rises in neuroinflammation. QUIN also rises in various neurological diseases. This pathway is potentially modifiable, and may be a therapeutic option.