Epstein-Barr virus-specific intrathecal oligoclonal IgG production in relapsing-remitting multiple sclerosis is limited to a subset of patients and is composed of low-affinity antibodies.

Massimiliano Castellazzi,Carlo Contini,Gloria Roversi,Roberta Rizzo,Maria Rosaria Tola,Carmine Tamborino,Enrico Granieri,Eleonora Baldi,Francesca Fasolo,Tiziana Bellini,Enrico Fainardi,Silva Seraceni

doi:10.1186/s12974-014-0188-1

Abstract

BackgroundThe purpose of this study was to investigate intrathecal production and affinity distributions of Epstein-Barr virus (EBV)-specific antibodies in multiple sclerosis (MS) and controls.MethodsCerebrospinal fluid (CSF) and serum concentrations, quantitative intrathecal synthesis, oligoclonal bands (OCB) patterns and affinity distributions of anti-Epstein Barr virus (EBV) antibodies were evaluated in 100 relapsing-remitting MS (RRMS) patients and 200 age- and sex-matched controls with other inflammatory neurological disorders (OIND) and other noninflammatory neurological disorders (NIND).ResultsLevels of anti-EBNA-1 and anti-viral capsid antigen (VCA) IgG were different in both the CSF (P <0.0001 and P <0.01, respectively) and serum (P <0.001 and P <0.05, respectively) among the RRMS, OIND and NIND. An intrathecal synthesis of anti-EBNA-1 IgG and anti-VCA IgG, as indicated by the antibody index, was underrepresented in the RRMS, OIND and NIND (range 1 to 7%). EBV-specific OCB were detected in 24% of the RRMS patients and absent in the controls. High-affinity antibodies were more elevated in the RRMS and in the OIND than in the NIND for CSF anti-EBNA-1 IgG (P <0.0001) and anti-VCA IgG (P <0.0001). After treatment with increasing concentrations of sodium thiocyanate, the EBV-specific IgG OCB had low affinity in all 24 RRMS patients analyzed.ConclusionsOur findings do not support the potential role of an EBV persistent brain chronic infection in MS and suggest that an EBV-specific intrathecal oligoclonal IgG production can occur in a subset of MS patients as part of humoral polyreactivity driven by chronic brain inflammation.

Highlights

The purpose of this study was to investigate intrathecal production and affinity distributions of Epstein-Barr virus (EBV)-specific antibodies in multiple sclerosis (MS) and controls
It is crucial to determine the exact nature of EBV-specific intrathecal humoral immune response since the key feature of chronic central nervous system (CNS) infections is the presence of targeted intrathecaly produced high-affinity oligoclonal antibodies, of which only 20% are specific to the causative agent [2]
Cerebrospinal fluid and serum levels and intrathecal synthesis of anti-Epstein Barr virus immunoglobulin G (IgG) in relapsing-remitting multiple sclerosis patients and controls Detectable cerebrospinal fluid (CSF) levels of anti-Epstein Barr nuclear antigen 1 (EBNA-1) IgG were statistically more frequent in RRMS than in noninflammatory neurological disorders (NIND) (P

Summary

Introduction

The purpose of this study was to investigate intrathecal production and affinity distributions of Epstein-Barr virus (EBV)-specific antibodies in multiple sclerosis (MS) and controls. Disease etiology remains largely unknown, epidemiological observations suggest the potential implication of an infectious organism as a causative agent of MS [2] In this setting, an ideal candidate is represented by Epstein-Barr. The actual relevance of EBV in MS still remains to be elucidated In this regard, it is crucial to determine the exact nature of EBV-specific intrathecal humoral immune response since the key feature of chronic CNS infections is the presence of targeted intrathecaly produced high-affinity oligoclonal antibodies, of which only 20% are specific to the causative agent [2]. To address the question of whether an EBV persistent brain infection exists in MS, in this study we sought to verify the frequency of EBV-specific oligoclonal IgG restricted to CSF and their affinity distributions in a large number of MS patients and controls

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