From the Journal of Affective Disorders, 5 September 2013.
In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation
Michael Maes(a,b,c), Karl Ringel(d), Marta Kubera(e), George Anderson(f), Gerwyn Morris(g), Piotr Galecki(h), Michel Geffard(i)
a) Maes Clinics @ TRIA, Bangkok, Thailand
b) Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand
c) Department of Psychiatry, Deakin University, Geelong, VIC, Australia
d) Immunologischen Laboratorien, Aachen, Germany
e) Department of Experimental Endocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
f) CRC, Rm 30, Glasgow, Scotland
g) Tir Na Nog, Pembrey, Llanelli, UK
h) Department of Adult Psychiatry, Medical University of Lódź and Babinski Memorial Hospital, Lódź, Poland
i) Association Institute for Research & Development in Human Pathology and Therapy, Talence, France
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is accompanied by activation of immuno-inflammatory pathways, increased bacterial translocation and autoimmune responses to serotonin (5-HT). Inflammation is known to damage 5-HT neurons while bacterial translocation may drive autoimmune responses. This study has been carried out to examine the autoimmune responses to 5-HT in ME/CFS in relation to inflammation and bacterial translocation.
We examined 5-HT antibodies in 117 patients with ME/CFS (diagnosed according to the centers for disease control and prevention criteria, CDC) as compared with 43 patients suffering from chronic fatigue (CF) but not fulfilling the CDC criteria and 35 normal controls. Plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)α, neopterin and the IgA responses to Gram-negative bacteria were measured. Severity of physio-somatic symptoms was measured using the fibromyalgia and chronic fatigue syndrome rating scale (FF scale).
The incidence of positive autoimmune activity against 5-HT was significantly higher (p<0.001) in ME/CFS (61.5%) than in patients with CF (13.9%) and controls (5.7%). ME/CFS patients with 5-HT autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise. DISCUSSION The results show that, in ME/CFS, increased 5-HT autoimmune activity is associated with activation of immuno-inflammatory pathways and increased bacterial translocation, factors which are known to play a role in the onset of autoimmune reactions. 5-HT autoimmune activity could play a role in the pathophysiology of ME/CFS and the onset of physio-somatic symptoms. These results provide mechanistic support for the notion that ME/CFS is a neuro-immune disorder.
From Acta Psychiatrica Scandinavica, 17 August 2013 (e-published first).
Biological phenotypes underpin the physio-somatic symptoms of somatization, depression, and chronic fatigue syndrome
G. Anderson(1), M. Berk(2,3,4,5), M. Maes(2,6,7,*)
1) CRC, Glasgow, UK
2) School of Medicine, Deakin University, Melbourne, Vic., Australia
3) Orygen Youth Health Research Centre, and the Centre for Youth Mental Health, Parkville, Vic., Australia
4) The Florey Institute for Neuroscience and Mental Health, Parkville, Vic., Australia
5) Department of Psychiatry, Melbourne University, Parkville, Vic., Australia
6) Department of Psychiatry, Faculty of Medicine, Pathumwan, Bangkok, Thailand
7) Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand
* Prof. Dr. M. Maes, MD, PhD, Department of Psychiatry, Faculty of Medicine, 1873 Rama 4 Road, Pathumwan, Bangkok 10330, Thailand.
Somatization is a symptom cluster characterized by ‘psychosomatic’ symptoms, that is, medically unexplained symptoms, and is a common component of other conditions, including depression and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This article reviews the data regarding the pathophysiological foundations of ‘psychosomatic’ symptoms and the implications that this has for conceptualization of what may more appropriately be termed physio-somatic symptoms.
This narrative review used papers published in PubMed, Scopus, and Google Scholar electronic databases using the keywords: depression and chronic fatigue, depression and somatization, somatization and chronic fatigue syndrome, each combined with inflammation, inflammatory, tryptophan, and cell-mediated immune (CMI).
The physio-somatic symptoms of depression, ME/CFS, and somatization are associated with specific biomarkers of inflammation and CMI activation, which are correlated with, and causally linked to, changes in the tryptophan catabolite (TRYCAT) pathway. Oxidative and nitrosative stress induces damage that increases neoepitopes and autoimmunity that contribute to the immuno-inflammatory processes. These pathways are all known to cause physio-somatic symptoms, including fatigue, malaise, autonomic symptoms, hyperalgesia, intestinal hypermotility, peripheral neuropathy, etc.
Biological underpinnings, such as immune-inflammatory pathways, may explain, at least in part, the occurrence of physio-somatic symptoms in depression, somatization, or myalgic encephalomyelitis/chronic fatigue syndrome and thus the clinical overlap among these disorders.
From BMC Central, 25 July 2013.(Open access journal)
Cutting edge: issues in automimmunity
Hospital admissions for vitamin D related conditions and subsequent immune-mediated disease: record-linkage studies
Sreeram V Ramagopalan(1,2), Raph Goldacre(3), Giulio Disanto(1), Gavin Giovannoni(2) and Michael J Goldacre(3*)
1) Department of Physiology, Anatomy and Genetics and Medical Research Council Functional Genomics Unit, University of Oxford, Oxford, UK
2) Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
3) Unit of Health-Care Epidemiology, Nuffield Department of Population Health, University of Oxford, Oxford, UK
* Corresponding author: Michael J Goldacre firstname.lastname@example.org
Previous studies have suggested that there may be an association between vitamin D deficiency and the risk of developing immune-mediated diseases.
We analyzed a database of linked statistical records of hospital admissions and death registrations for the whole of England (from 1999 to 2011). Rate ratios for immune-mediated disease were determined, comparing vitamin D deficient cohorts (individuals admitted for vitamin D deficiency or markers of vitamin D deficiency) with comparison cohorts.
After hospital admission for either vitamin D deficiency, osteomalacia or rickets, there were significantly elevated rates of Addison’s disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, celiac disease, Crohn’s disease, diabetes mellitus, pemphigoid, pernicious anemia, primary biliary cirrhosis, rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus, thyrotoxicosis, and significantly reduced risks for asthma and myxoedema.
This study shows that patients with vitamin D deficiency may have an increased risk of developing some immune-mediated diseases, although we cannot rule out reverse causality or confounding. Further study of these associations is warranted and these data may aid further public health studies.
From the Journal of Medical Virology, 19 August 2013.
Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome
Jose G. Montoya(1,2,*), Andreas M. Kogelnik(2,†), Munveer Bhangoo(2,‡), Mitchell R. Lunn(2,3,§,‖), Louis Flamand(4), Lindsey E. Merrihew(2,3), Tessa Watt(2,¶), Jessica T. Kubo(1,3,5), Jane Paik(1,3,5), Manisha Desai(1,3,5)
1) Department of Medicine, Stanford University School of Medicine, Stanford, California
2) Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California
3) Stanford University School of Medicine, Stanford, California
4) Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, Laval University, Québec, Canada
5) Division of General Medicine Disciplines and Quantitative Sciences Unit, Stanford University School of Medicine, Stanford, California
†) Open Medicine Institute, Mountain View, CA
‡) University of California-San Diego School of Medicine, La Jolla, CA
§) Department of Medicine, Brigham and Women's Hospital, Boston, MA
¶) University of Michigan Medical School, Ann Arbor, MI
‖) Harvard Medical School, 25 Shattuck Street, Boston, MA 02115.
* Correspondence to: Jose G. Montoya, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305. E-mail: email@example.com
There is no known treatment for chronic fatigue syndrome (CFS). Little is known about its pathogenesis. Human herpesvirus 6 (HHV-6) and Epstein–Barr virus (EBV) have been proposed as infectious triggers.
Thirty CFS patients with elevated IgG antibody titers against HHV-6 and EBV were randomized 2:1 to receive valganciclovir (VGCV) or placebo for 6 months in a double-blind, placebo-controlled trial.
Clinical endpoints aimed at measuring physical and mental fatigue included the Multidimensional Fatigue Inventory (MFI-20) and Fatigue Severity Scale (FSS) scores, self-reported cognitive function, and physician-determined responder status. Biological endpoints included monocyte and neutrophil counts and cytokine levels.
VGCV patients experienced a greater improvement by MFI-20 at 9 months from baseline compared to placebo patients but this difference was not statistically significant. However, statistically significant differences in trajectories between groups were observed in MFI-20 mental fatigue subscore (P = 0.039), FSS score (P = 0.006), and cognitive function (P = 0.025).
VGCV patients experienced these improvements within the first 3 months and maintained that benefit over the remaining 9 months. Patients in the VGCV arm were 7.4 times more likely to be classified as responders (P = 0.029).
In the VGCV arm, monocyte counts decreased (P < 0.001), neutrophil counts increased (P = 0.037) and cytokines were more likely to evolve towards a Th1-profile (P < 0.001). Viral IgG antibody titers did not differ between arms. VGCV may have clinical benefit in a subset of CFS patients independent of placebo effect, possibly mediated by immunomodulation and/or antiviral effect. Further investigation with longer treatment duration and a larger sample size is warranted.