Table 2.

EBV Hypotheses: Mechanisms, Evidence For, and Evidence Against

Hypothesis	Mechanism	Evidence	Evidence against	Refs
EBV-infected autoreactive B cells (Pender hypothesis)	EBV exposure is essential for MS onset in genetically susceptible individuals. EBV-infected autoreactive B cells accumulate in the CNS where they produce pathogenic antibodies and provide co-stimulatory survival signals to autoreactive T cells that would otherwise die in the CNS by apoptosis. Loss of EBV control due to a defective EBV-specific CD8+ T cell response. Sunlight/vitamin D may protect against MS by increasing EBV-specific cytotoxic T cells.	EBV-infected B cells and plasma cells are present in MS brain. Presence of EBV-infected autoreactive plasma cells in the synovium in rheumatoid arthritis and in the salivary glands in Sjögren’s syndrome. Defective T cell control of EBV infection in MS. Beneficial effect of B cell depletion in MS. Beneficial effect of EBV-specific T cell therapy in MS. Higher frequency of EBV seropositivity in MS patients compared with controls. No MS in the absence of EBV serology. Blood samples collected from US military personnel before the onset of MS showed that high titers of serum IgG antibodies to EBNA1 increase the risk of developing MS. History of IM predisposes to MS.	CMV, VZV, HHV6, and HERV are also implicated in MS. Evidence for the presence of EBV in MS brain has been challenged. No virus has been unequivocally associated with lesion formation in MS.	[8,24,25,50,114,86,87]
EBV bystander damage	Inflammation in the CNS in MS primarily directed against EBV results in bystander damage.	Bystander T cells contribute to EAE pathogenesis. Virus infections can lead to significant activation of APCs such as dendritic cells which could activate autoreactive T cells, thus initiating autoimmune disease.	The mechanism of bystander killing of uninfected neighboring cells in MS brain remains unclear and requires further study.	[47]
αB-Crystallin 'mistaken self'	Exposure to infectious agents induces the expression of αB-crystallin, a small heat-shock protein, in lymphoid cells. The immune system mistakes self αB-crystallin for a microbial antigen and generates a CD4+ T cell response, attacking αB-crystallin in oligodendrocytes, causing inflammatory demyelination.	αB-Crystallin is reported to be an immunodominant antigen in the CNS. αB-Crystallin is the dominant myelin-associated activator of human T cells and accumulates in oligodendrocytes. EBV induces the expression of αB-crystallin in B cells, which present the protein to CD4+ T cells in an HLA-DR-restricted manner.	A connection between initial development and persistent CNS inflammation related to αB-crystallin reactivity is not clearly accounted for by this hypothesis.	[39]
Molecular mimicry, EBV crossreactivity	T cells primed by exposure to EBV antigens crossreact with and attack CNS antigens.	3–4% of EBNA1-specific CD4+ T cells in healthy subjects and MS patients react with peptides derived from myelin proteins. IgGs recognizing peptides from EBV and MBP 85–98 are elevated in MS patients.	Detailed mechanisms of molecular mimicry are limited by prolonged periods of disease latency, lack of statistical power in epidemiological studies, the potential role of genetics, and limited understanding of T cell repertoire and B cell responses.	[115, 116, 117]
HHV6A/EBV; potential astrocyte involvement	EBV infection of astrocytes activates HERV-W/MSRV/syncytin-1. HHV-6A actives latent EBV in B cells in MS lesions. HHV-6A is a neurotropic virus that infects astrocytes. HHV-6A and EBV may both be fundamental to the pathogenetic processes in MS. Infection with neurotropic HHV-6A leads to transformation of latent EBV-infected B cells in the CNS.	Induces human endogenous retrovirus HERV-K18-encoded superantigen. MS subjects that fail to suppress HHV-6 during IFN-β treatment show a poor clinical response.	The prevalence of viral coinfection and their combined effects in MS are unknown.	[27,49]
EBI2; EBV-induced G protein-coupled receptor 2 (GPR183)	EBI2 is a mediator of CNS autoimmunity and contributes to the migration of lymphocytes. Not a B cell versus T cell hypothesis.	Highly expressed in MS lesions. Promotes early CNS migration of encephalitogenic CD4 T cells and B cell migration within secondary lymphoid organs. EBI2 receptor regulates myelin development and inhibits lysophosphatidylcholine (LPC, lysolecithin)-induced demyelination. EBI2 mediates the oxysterol–EBI2 pathway that is involved in immune regulation, and differential expression of this receptor mediates B and T-dependent antibody responses.	Knowledge of the role of EBI2 in EBV infection is incomplete. Studies are limited to animal models.	[42, 43, 44, 45]
EBV-induced B cell cytokine response	EBV infection of B cells induces the expression of proinflammatory cytokines. Success of B cell therapies may lie in restoring and maintaining a favorable balance between pro- and anti-inflammatory B cell activities in patients.	Proinflammatory cytokines play a key role in MS pathology. EBV infection may interfere with the downregulatory function of innate IL-10, potentially through the production of vIL-10. Cytokine-secreting B cells in the periphery may influence new disease activity and play a role disease activity in the CNS.	Functional heterogeneity in the B cell pool is poorly understood, as are the activities of B cells in the CNS.	[40,41,118]