Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis

Abstract

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.

Intrathecal immune responses to EBV in early MS

“…However, in the blood of MS patients, authors have reported that EBNA-1 IgG are markedly increased whereas VCA IgG titers are normal [5][6][7][8]. Therefore, our findings, which are consistent with other reports [9,13,14], indicate that EBV may show more signs of reactivation in the CSF than in the blood at MS clinical onset. Corroborating the humoral immune response data, we found an enrichment in EBV-specific CD8 1 CTL in the CSF of patients with early MS as compared with paired blood.…”

“…Among the latter, the g-herpesvirus EBV has been repeatedly associated with this disease [2][3][4]. Large seroepidemiological studies [5][6][7][8] and cellular immune response assessments [9][10][11][12] have demonstrated enhanced EBV-specific immune responses in the blood of MS patients.…”

“…However, relatively few authors have examined the relationship between EBV and MS in this compartment. Increased Epstein-Barr nuclear antigen-1 (EBNA-1)-or viral capsid antigen (VCA)-specific IgG titers have been found in the cerebrospinal fluid (CSF) of MS patients [9,13,14]. Assessments of cellular immune responses are scarce owing to the low number of cells in the CSF.…”

Antibodies in multiple sclerosis oligoclonal bands target debris

“…Some earlier studies that evaluated whole CSF IgG from MS patients identified antibodies to several different viruses, such as measles, varicella zoster, human T-lymphocytic virus 1, and human hepatitis virus 6 (7), whereas other investigations found antibodies targeting major myelin proteins, myelin basic protein (MBP) and myelin oligodencrocyte glycoprotein (MOG) (8,9) as well as glycolipids, fatty acids, and neurofilament proteins (10). Similarly, more recent investigations that have applied single-cell PCR cloning to individual CSF B cells in MS have detected antibodies to certain viruses or myelin proteins (11)(12)(13). However, it has been impossible to match specificity of antibodies identified in CSF to OCB by studying whole CSF IgG or recombinant antibodies constructed from rearranged Ig heavy-and light-chain genes in individual B cells.…”

Multiple sclerosis genetics: leaving no stone unturned

“…Strong evidence for a role of EBV, in particular, has been indicated by epidemiologic 90 and laboratory studies. 91,92 Similar to other autoimmune diseases, exposure to cigarette smoke has also emerged as a potential environmental risk factor for MS. In a recent prospective A high prevalence of DR2 was observed in patients with acute unilateral optic neuritis.…”