Epstein-Barr Virus Induced Gene-2 Upregulation Identifies a Particular Subtype of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a chronic multisystem disease characterized by a variety of symptoms, and exhibits various features of an autoimmune-like disease. Subtypes are well recognized but to date are difficult to identify objectively. The disease may be triggered by infection with a variety of micro-organisms, including Epstein-Barr virus (EBV). A subset of CFS/ME patients exhibit up regulation of EBV virus induced gene 2 (EBI2) mRNA in peripheral blood mononuclear cells (PBMC), and these patients appear to have a more severe disease phenotype and lower levels of EBNA1 IgG. EBI2 is induced by EBV infection and has been found to be upregulated in a variety of autoimmune diseases. EBI2 is a critical gene in immunity and central nervous system function; it is a negative regulator of the innate immune response in monocytes. Its heterogeneous expression in CFS/ME could explain the variable occurrence of a variety of immune and neurological abnormalities which are encountered in patients with CFS/ME. The EBI2 subtype occurred in 38-55% CFS/ME patients in our studies. Further work is required to confirm the role of EBV and of EBI2 and its oxysterol ligands in CFS/ME, and to identify the most practical means to identify patients of the EBI subtype. There are two EBI2 antagonists currently in development, and these may hold promise in the treatment of CFS/ME patients of the EBI subtype.

Keywords: Chronic Fatigue Syndrome; Epstein-Barr virus; Epstein-Barr virus induced gene 2; Myalgic Encephalomyelitis; autoimmune; microarray; real-time polymerase chain reaction.

Figure 1

Expression of Epstein-Barr Virus (EBV) induced gene 2 (EBI2) (open ellipse) and Neuropathy Target Esterase (NTE) (asterisk) genes in 40 healthy blood donors (shown on the Left) and 31 Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients (shown on the Right). Upregulated EBI2 mRNA expression was demonstrated in 12 of 31 CFS/ME patients, and in none of the controls.

Figure 2

(A) Medical Outcomes Survey Short Form-36 (SF36) domain and total scores for each chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) subtype: physical function (PF), physical role (RP), bodily pain (BP), general health (GH), vitality (VIT), social functioning (SF), emotional role (RE), mental health (MH), and total score (Total). (B) Scores indicating occurrence and severity of 11 clinical symptoms for each CFS/ME subtype: headache (HA), sore throat (ST), swollen glands (GLA), cognitive defect (COG), muscle pain (MP), joint pain (JP), muscle weakness (MW), post-exertional malaise (PEM), sleep problems (SLE), fainting/dizziness (F/D), gastrointestinal complaints (GI), numbness/tingling (N/T), spatial span (SSP), verbal recognition memory (VRM). (C) Histogram showing the numbers of CFS/ME patients of each subtype occurring in each of the six geographical locations. (D) Epstein-Barr virus (EBV) antibody titers [viral capsid antigen (VCA) IgM, VCA IgG, early antigen (EA) IgG, Epstein-Barr nuclear antigen (EBNA) IgG] in each CFS/ME subtype and the normal comparison group. (E) Distribution of categories of EBV serostatus (seronegative, primary/re-activation, late phase of infection) in the CFS/ME subtypes, A-H, in CFS/ME (all subtypes combined) and in normal controls. (F) Log (base 2) of fold-difference values of 10 human genes known to be important in EBV infection, in eight CFS subtypes (A-H). Reproduced from Figure 1 of reference no. 34 with permission from BMJ Publishing Group Ltd. (License number 4413611406714).