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

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.