MS is a chronic inflammatory and demyelinating disease of the CNS with as yet unknown etiology.
A hallmark of this disease is the occurrence of oligoclonal IgG antibodies in the cerebrospinal fluid (CSF).
To assess the specificity of these antibodies, we screened protein expression arrays containing 37,000 tagged proteins.
The 2 most frequent MS-specific reactivities were further mapped to identify the underlying high-affinity epitopes.
In both cases, we identified peptide sequences derived from EBV proteins expressed in latently infected cells.
Immunoreactivities to these EBV proteins, BRRF2 and EBNA-1, were significantly higher in the serum and CSF of MS patients than in those of control donors.
Oligoclonal CSF IgG from MS patients specifically bound both EBV proteins.
Also, CD8+ T cell responses to latent EBV proteins were higher in MS patients than in controls.
In summary, these findings demonstrate an increased immune response to EBV in MS patients, which suggests that the virus plays an important role in the pathogenesis of disease.
Discussion
Despite intense research efforts over the last decades, the cause of MS remains unknown.
Although many findings support the view of a highly selective acquired immune response in the CNS of MS patients, it has not been possible to determine the target(s) of this localized immune response within the CNS.
In the current study, we used a broad screening approach to investigate the specificity of IgG antibodies in the CSF of MS patients.
Starting from a human cDNA expression library, we identified several protein sequences that showed higher reactivity in MS patients than in controls.
The 2 epitopes that showed the highest IgG reactivity in MS patients in comparison with those of control patients were mapped to obtain high-affinity ligands.
In both cases, we identified peptide sequences from EBV proteins.
The genes that coded for the 2 proteins are adjacently located in the EBV genome and expressed in latently EBV-infected cells.
Humoral immune responses to these proteins were elevated in the serum and CSF of MS patients compared with that of controls.
Intrathecal synthesis and binding to the OCBs were confirmed for both proteins.
The relevance of this finding was further strengthened by the observation that MS patients show increased CD8 T cell responses to EBV proteins expressed in latently infected cells.
These responses were mainly found in the CD8+CD28+ population, which is most relevant for the control of latent infection of EBV (27, 28).
Since CD28+ memory cells are dominant in the CSF compartment in MS and other infectious diseases, it is conceivable to assume that this population of cells plays an important role in the CNS immune response (5, 29, 30).
Our findings are in line with previous epidemiological studies on the role of EBV in the pathogenesis of MS (31).
EBV titers in serum are higher in MS patients than in control donors.
Almost all MS patients are seropositive whereas between 5 and 10% of the general population are seronegative.
Children who develop MS differ from controls by their higher immunoreactivity to EBV but not to other common viral pathogens (32).
MS patients more frequently have a history of mononucleosis than controls (33).
A 2- to 3-fold increased risk of developing MS after late EBV infection has been observed (34, 35).
Studies have demonstrated that immunoreactivity to EBV was higher in donors who later developed MS than in those who did not (36, 37).
Latent proteins have been suggested as bearing primary responsibility for the differences in immunoreacitivty to EBV (38).
Recently, an association between EBV reactivation and disease activity was reported whereas no association was found with other herpes viruses (39, 40).
Another study found elevated EBV DNA levels in the blood of MS patients during relapses (41).
While our study provides evidence for increased humoral and cellular immunity to EBV in MS, the mechanisms through which EBV contributes to the pathogenesis of MS remains uncertain.
Theoretically, 3 scenarios can be envisioned to explain the role of EBV in MS.
First, EBV may persist in a niche in the central nervous system and periodically become reactivated.
Glia cells, which seem to carry the EBV entry receptor CD21, can be infected with the virus under certain conditions (42-44).
However, EBV RNA has not been detected in the lesions of MS patients by hybridization methods (45); this argues against permanent CNS infection. Second, the virus may periodically spread from infected B cells to CNS tissue, resulting in a local antiviral immune response.
In this case, EBV may only be detectable in the CNS during a narrow window preceding the appearance of inflammatory lesions.
Third, EBV-infected peripheral B cells may trigger a crossreactive autoimmune response against CNS antigens.
Reactivation of the virus in infected B cells that are potent antigen-presenting cells may periodically boost an autoimmune response in the CNS that involves antibodies and HLA-class I restricted T cell responses.
Indeed, CD8+ T cells dominate MS lesions and are more often clonotypic than CD4+ T cells in MS tissue and CSF (4, 5).
T cell cross-recognition between virus (e.g., EBV peptides) and myelin antigens was demonstrated on the cellular (46, 47) and structural levels (48).
Cross-reactivity with viral antigens can trigger autoimmunity in animal models of MS (49).
Given the lifelong persistence of EBV in immunocompetent cells and its periodic reactivation, the virus has all the features which are required for a sustained cross-reactive autoimmune response.
Although we provide strong evidence for the role of EBV in the pathogenesis of MS, we are far from understanding the mechanisms leading to disease development and progression.
Further studies are necessary to clarify whether targeting EBV or the immune response against the virus may become therapeutic options in MS.
-------------------- Note: I'm NOT a medical professional. The information I share is from my own personal research and experience. Please do not construe anything I share as medical advice, which should only be obtained from a licensed medical practitioner. Posts: 4881 | From Middlesex County, NJ | Registered: Jul 2006
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