Brief report IgM-mediated autoimmune responses directed against multiple neoepitopes in depression: New pathways that underpin the inflammatory and neuroprogressive pathophysiology Michael Maes a, ⁎, Ivana Mihaylova b , Marta Kubera c , Jean-Claude Leunis d , Michel Geffard e a Maes Clinics @ TRIA, Bangkok, Thailand b Foundation Biological Psychiatry, Sofia, Bulgaria c Department of Experimental Endocrinology, Institute of Pharmacology, Polish Academy of Sciences, Poland d Laboratoire Ategis, Wavre, Belgium e Association Institute for Research & Development in Human Pathology and Therapy, Talence, France article info abstract Article history: Received 23 May 2011 Received in revised form 18 August 2011 Accepted 19 August 2011 Available online 17 September 2011 Background: There is evidence that depression is accompanied by oxidative and nitrosative stress (O&NS), as indicated by increased free radical levels, lipid peroxidation, and lowered an- tioxidant levels. The aims of the present study are to examine whether depression is accompa- nied by autoimmune responses directed against a) neoepitopes that are formed following O&NS damage; and b) the major anchorage molecules, i.e. palmitic and myristic acids and S- farnesyl-L-cysteine. Methods: We examined serum IgM antibodies to the conjugated fatty acids, palmitic and myr- istic acids; acetylcholine; S-farnesyl-L-cysteine; and NO-modified adducts in 26 depressed pa- tients and 17 normal controls. Severity of depression was measured with the Hamilton Depression Rating Scale and severity of fatigue and somatic (F&S) symptoms with the Fibro- myalgia and Chronic Fatigue Syndrome (FF) Rating Scale. Results: The prevalences and mean values for the serum IgM levels directed against conjugated palmitic and myristic acids, acetylcholine, S-farnesyl-L-cysteine; and the conjugated NO ad- ducts, NO-tyrosine, NO-phenylalanine, NO-aspartate, NO-histidine, and NO-creatine were sig- nificantly higher in depressed patients than in normal controls. The autoimmune responses were significantly related to FF symptoms, such as fatigue and a flu-like malaise, whereas the indicants of nitrosative stress were related to gastro-intestinal and autonomic symptoms. Discussion: Depression is characterized by IgM-related autoimmune responses directed against a) neoepitopes that are normally not detected by the immune system but that due to damage by O&NS have become immunogenic; and b) anchorage epitopes, i.e. palmitic and myristic acids, and S-farnesyl-L-cysteine. These autoimmune responses play a role in the inflammatory and O&NS pathophysiology of depression and may mediate the cellular dysfunctions that contribute to neuroprogression, e.g. aberrations in signal transduction, cellular differentiation and apoptosis. © 2011 Elsevier B.V. All rights reserved. Keywords: Depression Oxidative stress Chronic fatigue Inflammation Neuroprogression 1. Introduction There is evidence that depression is characterized by: a) an inflammatory response with an increased production of proin- flammatory cytokines (PICs), such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor-α (TNFα); b) activation of cell- Journal of Affective Disorders 135 (2011) 414–418 ⁎ Corresponding author at: Maes Clinics @ TRIA, Piyavate Hospital, 998 Rimklongsamsen Road, Bangkok 10310, Thailand. Tel.: + 66 26602728. URL's:URL: dr.michaelmaes@hotmail.com, http://www.michaelmaes.com (M. Maes). 0165-0327/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2011.08.023 Contents lists available at SciVerse ScienceDirect Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad