http://www.tandfonline.com/doi/full/10.1080/17513758.2012.704083 2.2. Chronic fatigue syndrome The literature on CFS is very broad with hundreds of analysis carried out and a rich collection of data, yet the clinical implications of such findings remain uncertain and a unifying, globally accepted, picture of its etiology and pathophysiology is still missing 22. Afari, N. and Buchwald, D. 2003. Chronic fatigue syndrome: A review. Am. J. Psychiatry , 160: 221–236. [CrossRef], [PubMed], [Web of Science ®], [CSA] View all references 1818. Dinos, S., Khoshaba, B., Ashby, D., White, P. D., Nazroo, J., Wessely, S. and Bhui, K. S. 2009. A systematic review of chronic fatigue, its syndromes and ethnicity: Prevalence, severity, co-morbidity and coping. Int. J. Epidemiol. , 38: 1554–1570. [CrossRef], [Web of Science ®] View all references 2020. Gerritya, R. T., Papanicolaoub, A. D., Amsterdamc, J. D., Binghamd, S., Grossmane, A., Hedrickf, T., Herbermang, R. B., Kruegerh, G., Levinei, S., Mohagheghpourj, N., Moorek, R. C., Oleskel, J. and Snellm, C. R. 2004. Immunologic aspects of chronic fatigue syndrome. Neuroimmunomodulation , 11: 351–357. [CrossRef] View all references 2626. Lorusso, L., Mikhaylova, S. V., Capelli, E., Ferrari, D., Ngonga, G. K. and Ricevuti, G. 2009. Immunological aspects of chronic fatigue syndrome. Autoimmun. Rev. , 8: 287–291. [CrossRef], [Web of Science ®] View all references 2828. Lyalla, M., Peakmanb, M. and Wessely, S. 2003. A systematic review and critical evaluation of the immunology of chronic fatigue syndrome. J. Psychosom. Res. , 55: 79–90. [CrossRef], [Web of Science ®], [CSA] View all references. Current theories are looking at the possibilities of neuroendocrine dysfunction, virus geneses, environmental toxins, genetic predisposition, or a combination of these. Several researches suggest that EBV, by prompting a chronic immune reaction in the body, might cause CFS. Indeed, the phenomenology reported is consistent with the idea that the syndrome may follow the occurrence of an infection yielding a massive immune response, which, for causes not yet completely clarified, may persist for a long time, although the underlying infection is no longer in course. In fact, a CFS state is usually associated with an abnormal concentration and/or functioning of B cells, T cells and cytokines. Another interesting and robust immunological fact found in patients with CFS is an unusually high (more than 67%) increase of activated CD8+ cytotoxic T lymphocytes with MHC-II activation markers 99. Caligiuri, M., Murray, C., Buchwald, D., Levine, H., Cheney, P., Peterson, D., Komaroff, L. and Ritz, J. 1987. Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome. J. Immunol. , 139: 3306–3313. [Web of Science ®], [CSA] View all references 1010. Carlo-Stella, N., Badulli, C., De Silvestri, A., Bazzichi, L., Martinetti, M., Lorusso, L., Bombardieri, S., Salvaneschi, L. and Cuccia, M. 2006. A first study of cytokine genomic polymorphism in CFS: Positive association of TNF-857 and IFN-874 rare alleles. Clin. Exp. Rheumathol. , 24: 179–182. [Web of Science ®] View all references 1717. Devanur, L. D. and Kerr, J. R. 2006. Chronic fatigue syndrome. J. Clin. Virol. , 37: 139–150. [CrossRef], [PubMed], [Web of Science ®] View all references 2525. Klimas, N. G., Salvato, F. R., Morgan, R. and Fletcher, M. A. 1990. Immunologic abnormalities in chronic fatigue syndrome. J. Clin. Microbiol. , 28: 1403–1410. [PubMed], [Web of Science ®], [CSA] View all references. This will be a key point of our speculation. From a symptomatology viewpoint, fatigue is a common symptom, but CFS is a multi-systemic disease including even post-exertional malaise, unrefreshing sleep, widespread muscle, joint pain, cognitive difficulties, chronic (often severe) mental and physical exhaustion, muscle weakness, hypersensitivity, orthostatic intolerance, digestive disturbances and more. 2.3. The Epstein–Bar virus EBV is one of the most successful viruses, infecting over 90% of humans and persisting for the lifetime of the person in a non-pathogenic way4 Strictly speaking, EBV is also associated with serious diseases such as the Burkitt lymphoma, but its incidence is irrelevant with respect to its average behaviour, which is the typical outcome from a many-body theory as statistical mechanics. View all notes 3232. Robertson, E. S. 2005. Epstein–Barr Virus , Edited by: Robertson, E. S. Norfolk : Caister Academic Press. View all references 3333. Young, S. L. and Rickinson, A. B. 2004. Epstein–Barr virus: 40 years on. Nat. Rev. Cancer , 4: 757–768. [CrossRef], [PubMed], [Web of Science ®] View all references. The infection can follow different pathways, in particular, it can turn in AIM (in up to 25% cases 88. Buchwald, D. S., Rea, T. D., Katon, W. J., Russo, J. E. and Ashley, R. L. 2000. Acute infectious mononucleosis: Characteristics of patients who report failure to recover. Am. J. Med. , 109: 531–537. [CrossRef], [Web of Science ®], [CSA] View all references) or it can simply introduce the virus in the host organism in a non-apparent way. The virus aims to enter B cells and, if successful, two outcomes are possible. In the first case, the EBV begins a viral replication cycle (the so-called ‘lytic phase’, a common feature of most viral infections), which induces the death of the infected cell, followed by the complete release of new virus particles, which are going to infect other cells; in the second case, a state of latency (latent phase) is established where the ‘disguised’ virus multiplies and stands by inside the cell, while no extracellular phenomena are observed, in such a way that no tackling by the immune system is evidenced. During the primary infection, the latent cycle and the lytic cycle proceed in parallel and the immune system addresses most of its resources to the lytic cycle of viral replication; the infection can be asymptomatic, have non-specific symptoms, or be so massive to result in AIM. The acute phase can last up to several months and it ceases when the lytic cycle is interrupted by the immune responses or by the virus itself, then, the infection becomes latent and the host becomes a healthy carrier. The possible persistence of the acute phase, despite a potent immune response against it, indicates that the virus has evolved strategies to elude the immune system. Among the different hypothesis, one has received particular attention 2323. Hsu, D. H., de Waal Malefyt, R., Fiorentino, D. F., Dang, M. N., Vieira, P., de Vries, J., Spits, H., Mosmann, T. R. and Moore, K. W. 1990. Expression of interleukin-10 activity by Epstein–Barr virus protein BCRF1. Science , 250: 830–832. [CrossRef], [PubMed], [Web of Science ®], [CSA] View all references: the antigen BCRF15 The BCRF1 antigen is a Lytic Antigen sharing 70% of the human IL-10R, which is the membrane bound receptor for IL-10, see also 32. View all notes can simulate the signal produced by IL-10 cytokines (which normally prompts leukocytes specialized against small-sized threatening agents, like EBV's antigens) and determine a delay in the immune response. More precisely, the signal from BCRF1 inhibits the production of real IL-10; the lack of IL-10 polarizes the cellular immune response in the activation of a different kind of leukocyte, specialized in fighting against bigger-sized pathogens. We finally report an interesting study 77. Bharadwaj, M., Burrows, S. R., Burrows, J. M., Moss, D. J., Catalina, M. and Khanna, R. 2001. Longitudinal dynamics of antigen specific CD8+ cytotoxic T lymphocytes following primary Epstein–Barr virus infection. Blood , 98: 258–259. [CrossRef] View all references on T-cell responses, in the cases of a relatively brief (2–3 weeks) and of a protracted (4 months) acute phase. Although expansions of antigen-specific T cells were observed in both situations, the T cells reactivity occurred to be broad (i.e. addressed to several, both lytic and latent, antigens) and narrowly focused (i.e. mainly addressed to a singular antigen, the early BMLF1), respectively.6 An investigation on the link between BCRF1 and BMLF1 can be found in 24. View all notes Summarizing, a significant presence of antigen BCRF1 can determine a delay in the immune response. As a result, the immune activity may take a long time for the clearance of the infection; during this time, the concentration of TK cells remains high and polarizes against BMLF1 antigen as if an internal self-reinforcement has occurred.