Elsevier

Medical Hypotheses

Volume 102, May 2017, Pages 8-15
Medical Hypotheses

The spread of EBV to ectopic lymphoid aggregates may be the final common pathway in the pathogenesis of ME/CFS

https://doi.org/10.1016/j.mehy.2017.02.011Get rights and content

Abstract

According to the hypothesis presented here, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) develops over 3 steps: Step 1 is characterized by the aggregation of lymphoid cells in dorsal root ganglia or other nervous structures. The cause of this formation of ectopic lymphoid aggregates may be an acute infection, asymptomatic reactivations of a common neurotropic virus, exposure to a neurotoxin, or physical injury to peripheral nerves. In step 2, Epstein-Barr virus (EBV)-infected lymphocytes or monocytes bring EBV from the circulation to one or several of these lymphoid aggregates, whereupon cell-to-cell transmission of EBV and proliferation of latently EBV-infected lymphocytes lead to the presence of many EBV-infected cells in the lymphoid aggregates. The EBV-infected cells in the aggregates ignite an inflammation in the surrounding nervous tissue. This local inflammation elicits, in turn, a wave of glial cell activation that spreads from the EBV-infected area to parts of the nervous system that are not EBV-infected, disturbing the neuron-glial interaction in both the peripheral – and central nervous system. In step 3, immune cell exhaustion contributes to a consolidation of the pathological processes. There might be a cure: Infusions of autologous EBV-specific T-lymphocytes can perhaps remove the EBV-infected cells from the nervous system.

Section snippets

Background

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disorder (or perhaps two or more disorders) that is characterized by severe fatigue and several other symptoms, such as pain, concentration problems, post-exertional malaise, and a persistent or recurrent ‘flu-like’ feeling [1], [2], [3], [4], [5], [6]. It usually starts in adolescence or young adulthood [5]. The etiology is unclear, but many hypotheses have been set forth [7], [8], [9], [10], [11], [12], [13], [14], [15], [16],

Hypothesis

According to the hypothesis that is posited here, ME/CFS develops over 3 steps:

Comparison with some other hypotheses

In a hypothesis about the cause of autoimmune disorders, set forth by Michael Pender [65], [66], EBV and ectopic lymphoid structures play important roles. Pender does not mention ME/CFS, but some of the pathophysiological mechanisms he describes might be relevant also for ME/CFS. However, there are important differences between his hypothesis and the one presented here. In Pender’s hypothesis, autoimmunity (immune processes elicited and orchestrated by autoreactive lymphocytes) plays a central

Formation of ectopic lymphoid aggregates

Ectopic lymphoid aggregates are aggregates of lymphoid cells (B-lymphocytes, T-lymphocytes, dendritic cells) in non-lymphoid tissues [51], [56]. Some of these aggregates are only gatherings of lymphoid cells within a certain area, whereas other aggregates are organized structures with germinal centers. The ectopic lymphoid aggregates seem to form in response to antigenic stimuli [51], [56]. They often develop in tissues that are inflamed because of infectious, autoreactive, or neoplastic

Final remarks

The hypothesis presented here can explain all ME/CFS symptoms. It is also consistent with important research findings. This does not necessarily mean that the hypothesis is valid, however. Future testing is required.

One way to test the hypothesis may be to examine the effects of transferring ex vivo-expanded autologous EBV-specific T-lymphocytes to the patients. There is increasing evidence that EBV-specific T-cell infusions may have good effects on several EBV-related disorders, including

Conflict of interest

No conflict of interest declared.

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