{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T10:47:02Z","timestamp":1783334822731,"version":"3.54.6"},"reference-count":45,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T00:00:00Z","timestamp":1653436800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Government of the Russian Federation","award":["14.W03.31.0009"],"award-info":[{"award-number":["14.W03.31.0009"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathophysiology"],"abstract":"<jats:p>Chronic fatigue syndrome\/myalgic encephalomyelitis (CFS\/ME) is considered to be associated with post-viral complications and mental stress, but the role of autoimmunity also remains promising. A comparison of autoimmune profiles in chronic fatigue of different origin may bring insights on the pathogenesis of this disease. Thirty-three patients with CFS\/ME were divided into three subgroups. The first group included Herpesviridae carriers (group V), the second group included stress-related causes of chronic fatigue (distress, group D), and the third group included idiopathic CFS\/ME (group I). Were evaluated thirty-six neural and visceral autoantigens with the ELISA ELI-test (Biomarker, Russia) and compared to 20 healthy donors, either without any fatigue (group H), or \u201chealthy but tired\u201d (group HTd) with episodes of fatigue related to job burnout not fitting the CFS\/ME criteria. \u03b22-glycoprotein-I autoantibodies were increased in CFS\/ME patients, but not in healthy participants, that alludes the link between CFS\/ME and antiphospholipid syndrome (APS) earlier suspected by Berg et al. (1999). In CFS\/ME patients, an increase in levels of autoantibodies towards the non-specific components of tissue debris (double-stranded DNA, collagen) was shown. Both CFS and HTd subgroups had elevated level of autoantibodies against serotonin receptors, glial fibrillary acidic protein and protein S100. Only group V showed an elevation in the autoantibodies towards voltage-gated calcium channels, and only group D had elevated levels of dopamine-, glutamate- and GABA-receptor autoantibodies, as well as NF200-protein autoantibodies. Therefore, increased autoimmune reactions to the multiple neural antigens and to adrenal medullar antigen, but not to other tissue-specific somatic ones were revealed. An increase in autoantibody levels towards some neural and non-tissue-specific antigens strongly correlated with a CFS\/ME diagnosis. Autoimmune reactions were described in all subtypes of the clinically significant chronic fatigue. Visceral complaints in CFS\/ME patients may be secondary to the neuroendocrine involvement and autoimmune dysautonomia. CFS may be closely interrelated with antiphospholipid syndrome, that requires further study.<\/jats:p>","DOI":"10.3390\/pathophysiology29020016","type":"journal-article","created":{"date-parts":[[2022,5,29]],"date-time":"2022-05-29T23:43:03Z","timestamp":1653867783000},"page":"187-199","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Chronic Fatigue Exhibits Heterogeneous Autoimmunity Characteristics Which Reflect Etiology"],"prefix":"10.3390","volume":"29","author":[{"given":"Olga","family":"Danilenko","sequence":"first","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, Saint Petersburg State University, Universitetskaya emb, 7\u20139, 199034 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Gavrilova","sequence":"additional","affiliation":[{"name":"Department of Faculty Therapy, Faculty of Medicine, Saint Petersburg State University, Universitetskaya emb, 7\u20139, 199034 St. Petersburg, Russia"},{"name":"Department of Pulmonology, Saint Petersburg Research Institute of Phthisiopulmonology, Ligovskii pr., 2\u20134, 191036 St. Petersburg, Russia"},{"name":"Research Institute of Phthisiopulmonology, St. Petersburg State University Hospital, Fontanka River Emb., 154, 190103 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6359-0026","authenticated-orcid":false,"given":"Leonid","family":"Churilov","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, Saint Petersburg State University, Universitetskaya emb, 7\u20139, 199034 St. Petersburg, Russia"},{"name":"Department of Experimental Tuberculosis and Innovative Technologies, Saint Petersburg Research Institute of Phthisiopulmonology, Ligovskii pr., 2\u20134, 191036 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1007\/s10067-018-4009-2","article-title":"On chronic fatigue syndrome and nosological categories","volume":"37","author":"Sharif","year":"2018","journal-title":"Clin. Rheumatol."},{"key":"ref_2","unstructured":"Institute of Medicine (2015). Beyond Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome: Redefining the Illness, National Academies Press."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1515\/reveh-2015-0026","article-title":"Review of Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome: An evidence-based approach to diagnosis and management by clinicians","volume":"30","author":"Bested","year":"2015","journal-title":"Rev. Environ. Health"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1080\/10852352.2014.973240","article-title":"An investigation of symptoms predating CFS onset","volume":"43","author":"Evans","year":"2015","journal-title":"J. Prev. Interv. Community"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1186\/s12967-020-02455-0","article-title":"Review of case definitions for myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS)","volume":"18","author":"Lim","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1001\/jama.2019.8312","article-title":"Advances in understanding the pathophysiology of chronic fatigue syndrome","volume":"322","author":"Komaroff","year":"2019","journal-title":"JAMA\u2014J. Am. Med. Assoc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.autrev.2018.01.009","article-title":"European Network on ME\/CFS (EUROMENE). Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome\u2014Evidence for an autoimmune disease","volume":"17","author":"Sotzny","year":"2018","journal-title":"Autoimmun Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3389\/fimmu.2018.00229","article-title":"Infection Elicited Autoimmunity and Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome: An Explanatory Model","volume":"9","author":"Blomberg","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"206","DOI":"10.3389\/fped.2019.00206","article-title":"Genetic Predisposition for Immune System, Hormone, and Metabolic Dysfunction in Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome: A Pilot Study","volume":"7","author":"Perez","year":"2019","journal-title":"Front. Pediatr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.psym.2017.04.010","article-title":"Comorbidity in Chronic Fatigue Syndrome\/Myalgic Encephalomyelitis: A Nationwide Population-Based Cohort Study","volume":"58","author":"Faro","year":"2017","journal-title":"Psychosomatics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.bbi.2015.09.013","article-title":"Antibodies to \u03b2 adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome","volume":"52","author":"Loebel","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Scheibenbogen, C., Loebel, M., Freitag, H., Krueger, A., Bauer, S., Antelmann, M., Doehner, W., Scherbakov, N., Heidecke, H., and Reinke, P. (2018). Immunoadsorption to remove \u03b22 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS\/ME. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0193672"},{"key":"ref_13","first-page":"784520","article-title":"A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome","volume":"2013","author":"Tomas","year":"2013","journal-title":"Int. Sch. Res. Not."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6806","DOI":"10.1007\/s12035-016-0170-2","article-title":"Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)\/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways","volume":"54","author":"Morris","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"945","DOI":"10.2967\/jnumed.113.131045","article-title":"Neuroinflammation in Patients with Chronic Fatigue Syndrome\/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study","volume":"55","author":"Nakatomi","year":"2014","journal-title":"J. Nucl. Med."},{"key":"ref_16","unstructured":"Zaichik, A.S., and Churilov, L.P. (1999). Fundamentals of General Pathology. Fundamentals of General Pathophysiology, ELBI Publishers."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1124\/jpet.118.250845","article-title":"Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome\u2014Metabolic Disease or Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus?","volume":"367","author":"Hatziagelaki","year":"2018","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_18","first-page":"589","article-title":"Glial Activation and Expression of the Serotonin Transporter in Chronic Fatigue Syndrome","volume":"9","author":"Noda","year":"2018","journal-title":"Front. Psychol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s11055-010-9250-3","article-title":"Activity in the Hypothalamo-Hypophyseal-Adrenocortical System on Experimental Induction of Chronic Fatigue Syndrome","volume":"40","author":"Fomicheva","year":"2010","journal-title":"Neurosci. Behav. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.clinthera.2019.04.001","article-title":"Searching for Serum Antibodies to Neuronal Proteins in Patients with Myalgic Encephalopathy\/Chronic Fatigue Syndrome","volume":"41","author":"Giannoccaro","year":"2019","journal-title":"Clin. Ther."},{"key":"ref_21","first-page":"26","article-title":"Immunoreactivity in chronic fatigue syndrome during remission. exacerbation and virus carriage","volume":"25","author":"Churilov","year":"2019","journal-title":"Clin. Pathophysiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1002\/jcla.20217","article-title":"Acute phase phospholipids related to the cardiolipin of mitochondria in the sera of patients with chronic fatigue syndrome (CFS), chronic Ciguatera fish poisoning (CCFP), and other diseases attributed to chemicals, Gulf War, and marine toxins","volume":"22","author":"Hokama","year":"2008","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1002\/jcla.20325","article-title":"Anticardiolipin antibodies in the sera of patients with diagnosed chronic fatigue syndrome","volume":"23","author":"Hokama","year":"2009","journal-title":"J Clin Lab. Anal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2058738418812342","DOI":"10.1177\/2058738418812342","article-title":"A compromised paraventricular nucleus within a dysfunctional hypothalamus: A novel neuroinflammatory paradigm for ME\/CFS","volume":"32","author":"Mackay","year":"2018","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Yamamoto, S., Ouchi, Y., Nakatsuka, D., Tahara, T., Mizuno, K., Tajima, S., Onoe, H., Yoshikawa, E., Tsukada, H., and Iwase, M. (2012). Reduction of [11C](+)3-MPB binding in brain of chronic fatigue syndrome with serum autoantibody against muscarinic cholinergic receptor. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0051515"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pashnina, I.A., Krivolapova, I.M., Fedotkina, T.V., Ryabkova, V.A., Chereshneva, M.V., Churilov, L.P., and Chereshnev, V.A. (2021). Antinuclear Autoantibodies in Health: Autoimmunity Is Not a Synonym of Autoimmune Disease. Antibodies, 10.","DOI":"10.3390\/antib10010009"},{"key":"ref_27","unstructured":"WHO (2020, November 03). ICD-11\u2014Mortality and Morbidity Statistics 2020. Available online: https:\/\/icd.who.int\/browse11\/l-m\/en#\/http%3A%2F%2Fid.who.int%2Ficd%2Fentity%2F569175314."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"387","DOI":"10.7326\/0003-4819-108-3-387","article-title":"Chronic fatigue syndrome: A working case definition","volume":"108","author":"Holmes","year":"1988","journal-title":"Ann. Intern. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"953","DOI":"10.7326\/0003-4819-121-12-199412150-00009","article-title":"The chronic fatigue syndrome: A comprehensive approach to its definition and study","volume":"121","author":"Fukuda","year":"1994","journal-title":"Ann. Intern. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1300\/J092v11n01_02","article-title":"Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome","volume":"11","author":"Carruthers","year":"2003","journal-title":"J. Chronic Fatigue Syndr."},{"key":"ref_31","first-page":"16","article-title":"Chronic fatigue syndrome: From symptom\u2014to diagnosis","volume":"8","year":"2010","journal-title":"Tr. Patsient."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"120","DOI":"10.4088\/PCC.v10n0206","article-title":"A systematic review of chronic fatigue syndrome: Don\u2019t assume it\u2019s depression","volume":"10","author":"Griffith","year":"2008","journal-title":"Prim. Care Companion J. Clin. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1111\/j.1600-0447.1983.tb09716.x","article-title":"The hospital anxiety and depression scale","volume":"67","author":"Zigmond","year":"1983","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_34","first-page":"75","article-title":"The relationship between chronic fatigue syndrome. burnout. job satisfaction. social support and age among academics at a tertiary institution","volume":"32","author":"Coetzee","year":"2019","journal-title":"Int. J. Occup Med. Environ. Health"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1111\/j.1600-0897.2007.00479.x","article-title":"Application of ELI-P Complex method in clinical obstetrics","volume":"57","author":"Poletaev","year":"2007","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_36","unstructured":"Poletaev, A., and Rizzo, C. (2019). New Approaches to Early Detection of Pathological Changes in the Human Body. ELI-Viscero-Test (Molecular Clinical Examination). Guidelines for Physicians, MIC Immunculus Publisher."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"18005","DOI":"10.1038\/nrdp.2018.5","article-title":"Antiphospholipid syndrome","volume":"4","author":"Schreiber","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1097\/00001721-199910000-00006","article-title":"Chronic fatigue syndrome and\/or fibromyalgia as a variation of antiphospholipid antibody syndrome: An explanatory model and approach to laboratory diagnosis","volume":"10","author":"Berg","year":"1999","journal-title":"Blood Coagul. Fibrinolysis"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"108384","DOI":"10.1016\/j.clim.2020.108384","article-title":"Complex syndromes of chronic pain. fatigue and cognitive impairment linked to autoimmune dysautonomia and small fiber neuropathy","volume":"214","author":"Shoenfeld","year":"2020","journal-title":"Clin. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.jaut.2007.02.005","article-title":"Clearance deficiency and systemic lupus erythematosus (SLE)","volume":"28","author":"Gaipl","year":"2007","journal-title":"J. Autoimmun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13075-019-1818-x","article-title":"Reduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-TNF drugs","volume":"21","author":"Vomero","year":"2019","journal-title":"Arthritis Res. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1038\/nm939","article-title":"TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases","volume":"9","author":"Feldmann","year":"2003","journal-title":"Nat. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/nrrheum.2015.8","article-title":"Rheumatoid arthritis therapy reappraisal: Strategies, opportunities and challenges","volume":"11","author":"Smolen","year":"2015","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"701419","DOI":"10.3389\/fneur.2021.701419","article-title":"A Paradigm for Post-COVID-19 Fatigue Syndrome Analogous to ME\/CFS","volume":"12","author":"Mackay","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"102792","DOI":"10.1016\/j.autrev.2021.102792","article-title":"The SARS-CoV-2 as an instrumental trigger of autoimmunity","volume":"20","author":"Dotan","year":"2021","journal-title":"Autoimmun. Rev."}],"container-title":["Pathophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1873-149X\/29\/2\/16\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:18:40Z","timestamp":1760138320000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1873-149X\/29\/2\/16"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,25]]},"references-count":45,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["pathophysiology29020016"],"URL":"https:\/\/doi.org\/10.3390\/pathophysiology29020016","relation":{},"ISSN":["1873-149X"],"issn-type":[{"value":"1873-149X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,25]]}}}