From Molecular Neurobiology, 15 December 2016.
Humoral Immunity Profiling of Subjects with MyalgicEncephalomyelitis Using a Random Peptide MicroarrayDifferentiates Cases from Controls with High Specificity and Sensitivity
Sahajpreet Singh(1), Phillip Stafford(2), Karen A. Schlauch(3,4), Richard R. Tillett(4) Martin Gollery(5), Stephen Albert Johnston(2), Svetlana F. Khaiboullina(1,6 )Kenny L. De Meirleir(1), Shanti Rawat(1), Tatjana Mijatovic(7) Krishnamurthy Subramanian(1), András Palotás(6,8), Vincent C. Lombardi(1,9)
1) Nevada Center for Biomedical Research,1664 N Virginia St. MS 0552, Reno, NV 89557-0552, USA
2) The Biodesign Institute Center for Innovations in Medicine atArizona State University, Tempe, AZ, USA
3) Department of Biochemistry and Molecular Biology,University of Nevada, Reno, NV, USA
4) Nevada INBRE Bioinformatics Core, University of Nevada,Reno, NV, USA
5) Tahoe Bioinformatics, Incline Village, Reno, NV, USA
6) Kazan Federal University, Kazan, Russian Federation
7) R.E.D. Laboratories, Zellik, Belgium
8) Asklepios-Med (private medical practice and research center),Kossuth Lajos sgt. 23, Szeged 6722, Hungary
9) Department of Pharmacology, University of Nevada, Reno,School of Medicine, Reno, NV, USA
Myalgic encephalomyelitis (ME) is a complex, heterogeneous illness of unknown etiology.
The search for bio-markers that can delineate cases from controls is one of the most active areas of ME research; however, little progress has been made in achieving this goal. In contrast to identifying biomarkers that are directly involved in the pathological process, an immunosignature identifies antibodies raised to proteins expressed during, and potentially involved in, the pathological process.
Although these proteins might be unknown,it is possible to detect antibodies that react to these proteins using random peptide arrays.
In the present study, we probe a custom 125,000 random 12-mer peptide microarray with serafrom 21 ME cases and 21 controls from the USA and Europe and used these data to develop a diagnostic signature.
We further used these peptide sequences to potentially uncover the naturally occurring candidate antigens to which these antibodies may specifically react with in vivo.
Our analysis revealed a subset of 25 peptides that distinguished cases and controls with high specificity and sensitivity. Additionally, Basic Local Alignment Search Tool (BLAST) searches suggest that these peptides primarily represent human self-antigens and endogenous retroviral sequences and, to a minor extent, viral and bacterial pathogens.
From the Journal of Translational Medicine, 20 December 2016.
Association of mitochondrial DNA variants with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms
Maureen R. Hanson(1), Zhenglong Gu(2), Alon Keinan(3), Kaixiong Ye(3), Arnaud Germain(1) and Paul Billing-Ross(2)
1) Department of Molecular Biology and Genetics, Cornell University
2) Division of Nutritional Sciences, Cornell University
3) Department of Biological Statistics and Computational Biology, Cornell University
Earlier this year, we described an analysis of mitochondrial DNA (mtDNA) variants in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) patients and healthy controls.
We reported that there was no significant association of haplogroups or singe nucleotide polymorphisms (SNPs) with disease status.
Nevertheless, a commentary about our paper appeared (Finsterer and Zarrouk-Mahjoub. J Transl Med14:182, 2016) that criticized the association of mtDNA haplogroups with ME/CFS, a conclusion that was absent from our paper. The aforementioned commentary also demanded experiments that were outside of the scope of our study, ones that we had suggested as follow-up studies.
Because they failed to consult a published and cited report describing the cohorts we studied, the authors also cast aspersions on the method of selection of cases for inclusion. We reiterate that we observed statistically significant association of mtDNA variants with particular symptoms and their severity, though we observed no association with disease status.
From the Journal of Neuroimmunology, 13 December 2016.
Poor sleep quality is associated with greater circulating pro-inflammatory cytokines and severity and frequency of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) symptoms in women
Sara F. Milrad(1), Daniel L. Hall(2), Devika R. Jutagir(1), Emily G. Lattie(3), Gail H. Ironson(1), William Wohlgemuth(4), Maria Vera Nunez(5), Lina Garcia(6), Sara J. Czaja(6), Dolores M. Perdomo(6), Mary Ann Fletcher(5), Nancy Klimas(5), Michael H. Antoni(1)
1) Department of Psychology, University of Miami, 5665 Ponce de Leon Blvd., Miami, FL 33133, USA
2) Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, 55 Fruit St., Boston, MA 02114, USA
3) Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N Lake Shore Dr. Suite 1400, Chicago, IL 60611, USA
4) Department of Sleep Medicine, Miami Veteran Affairs Hospital, 1201 NW 16th St, Miami, FL 33125, USA
5) Institute for Neuro Immune Medicine, Nova Southeastern University, 8501 SW 124th Ave #111, Miami, FL 33183 , USA
6) Department of Psychiatry and Behavioral Sciences, University of Miami, 1120 NW 14th St., Miami, FL 33136, USA
• Sleep quality, inflammation, and CFS/ME symptoms were analyzed.
• Poor sleep quality predicted pro-inflammatory cytokines IL-1β, IL-6, and TNF-α.
• Worse sleep quality related to greater fatigue severity and daily interference.
• Worse sleep quality related to more severe and frequent CFS/ME symptoms.
• Further research is needed to identify the etiology of sleep disruptions in CFS/ME.
Poor sleep quality has been linked to inflammatory processes and worse disease outcomes in the context of many chronic illnesses, but less is known in conditions such as chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). This study examines the relationships between sleep quality, pro-inflammatory cytokines, and CFS/ME symptoms.
Sixty women diagnosed with CFS/ME were assessed using the Pittsburgh Sleep Quality Index (PSQI), Fatigue Symptom Inventory (FSI) and Center for Disease Control and Prevention (CDC)-based CFS/ME symptom questionnaires. Circulating plasma pro-inflammatory cytokine levels were measured by ELISA. Multiple regression analyses examined associations between sleep, cytokines and symptoms, controlling for age, education, and body mass index.
Poor sleep quality (PSQI global score) was associated with greater pro-inflammatory cytokine levels: interleukin-1β (IL-1β) (β = 0.258, p = 0.043), IL-6 (β = 0.281, p = 0.033), and tumor necrosis factor-alpha (TNF-α) (β = 0.263, p = 0.044). Worse sleep quality related to greater fatigue severity (β = 0.395, p = 0.003) and fatigue-related interference with daily activities (β = 0.464, p < 0.001), and more severe and frequent CDC-defined core CFS/ME symptoms (β = 0.499, p < 0.001, and β = 0.556, p < 0.001, respectively). CONCLUSIONS Results underscore the importance of managing sleep-related difficulties in this patient population. Further research is needed to identify the etiology of sleep disruptions in CFS/ME and mechanistic factors linking sleep quality to symptom severity and inflammatory processes.
From the JOurnal of Clinical Investigation Insight, 22 December. Full text available.
Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome
Øystein Fluge(1), Olav Mella(1,2), Ove Bruland(1,3), Kristin Risa(1) Sissel E. Dyrstad(4), Kine Alme(1), Ingrid G. Rekeland(1), Dipak Sapkota(1), Gro V. Røsland(4), Alexander Fosså(5) Irini Ktoridou-Valen(1) Sigrid Lunde(1) Kari Sørland(1), Katarina Lien(6), Ingrid Herder(6), Hanne Thürmer(7), Merete E. Gotaas(8), Katarzyna A. Baranowska(8), Louis M.L.J. Bohnen(9) Christoph Schäfer(9), Adrian McCann(10), Kristian Sommerfelt(11), Lars Helgeland(12), Per M. Ueland(2,10) Olav Dahl(12), and Karl J. Tronstad(4).
1) Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
2) Department of Clinical Science, University of Bergen, Bergen, Norway.
3) Department of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
4) Department of Biomedicine, University of Bergen, Bergen, Norway.
5) Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
6) CFS/ME Center, Division of Medicine, Oslo University Hospital, Oslo, Norway.
7) Telemark Hospital, Department of Medicine, Notodden, Norway.
8) Department of Pain and Complex Disorders, St. Olav’s Hospital, Trondheim, Norway.
9) Division of Rehabilitation Services, University Hospital of Northern Norway, Tromsø, Norway.
10) Bevital AS, Bergen, Norway.
11) Department of Pediatrics and
12) Department of Pathology, Haukeland University Hospital, Bergen, Norway.
Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown etiology, with hallmark symptoms including postexertional malaise and poor recovery. Metabolic dysfunction is a plausible contributing factor.
We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS.
Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients.
Serum 3-methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male patients.
The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4; sirtuin 4; and PPARδ in peripheral blood mononuclear cells from both sexes.
Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion.
The amino acid changes could not be explained by symptom severity, disease duration, age, BMI, or physical activity level among patients.
These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion.