HLA alleles modulate EBV viral load in multiple sclerosis

Simone Agostini,Sandra D’Alfonso,Cristina Agliardi,Milena Zanzottera,Maurizio A Leone,Franca R Guerini,Ambra Hernis,Roberta Mancuso,Marco Rovaris,Nadia Barizzone,Mario Clerici,Domenico Caputo

doi:10.1186/s12967-018-1450-6

Abstract

BackgroundThe etiopathology of multiple sclerosis (MS) is believed to include genetic and environmental factors. Human leukocyte antigen (HLA) alleles, in particular, are associated with disease susceptibility, whereas Epstein Barr Virus (EBV) infection has long been suspected to play a role in disease pathogenesis. The aim of the present study is to evaluate correlations between HLA alleles and EBV infection in MS.MethodsHLA alleles, EBV viral load (VL) and serum anti-EBV antibody titers were evaluated in EBV-seropositive MS patients (N = 117) and age- and sex-matched healthy controls (HC; N = 89).ResultsSignificantly higher DNA viral loads (p = 0.048) and EBNA-1 antibody titer (p = 0.0004) were seen in MS compared to HC. EBV VL was higher in HLA-B*07+ (p = 0.02) and HLA-DRB1*15+ (p = 0.02) MS patients, whereas it was lower in HLA-A*02+ (p = 0.04) subjects. EBV VL was highest in HLA-A*02−/B*07+/DRB1*15+ patients and lowest in HLA-A*A02+/B*07−/DRB1*15− individuals (p < 0.0001). HLA-B*07 resulted the most associated allele to EBV VL after multiple regression analysis considering altogether the three alleles, (p = 0.0001). No differences were observed in anti-EBV antibody titers in relationship with HLA distribution.ConclusionsHost HLA-B*07 allele influence EBV VL in MS. As HLA-class I molecules present antigens to T lymphocytes and initiate immune response against viruses, these results could support a role for EBV in MS.

Highlights

The etiopathology of multiple sclerosis (MS) is believed to include genetic and environmental factors
Results showed that the highest Epstein Barr Virus (EBV) viral load (37.5; 2.1–72.1 copies/μg) was detected in Human leukocyte antigen (HLA)-B*07+/HLADRB1*15+/HLA-class I (HLA-A)*02− patients (N = 23); the 25 HLA-B*07−/ HLA-DRB1*15−/HLA-A*A02+ patients were characterized by the lowest EBV viral load (2.0; 2.0–2.0 copies/μg) (p < 0.0001) (Fig. 5a)
These data suggest that the risk effects of the HLA-B*07 allele are stronger than the “protective” ones attributed to the HLA-A*02 allele and than the “risk” ones attributed to the HLA-DRB1*15 allele

Summary

Introduction

The etiopathology of multiple sclerosis (MS) is believed to include genetic and environmental factors. Human leukocyte antigen (HLA) alleles, in particular, are associated with disease susceptibility, whereas Epstein Barr Virus (EBV) infection has long been suspected to play a role in disease pathogenesis. Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), is the most common cause of neurological disability in adults, and it affects over 2.5 million people worldwide [1]. The etiopathogenesis of the disease is still unclear and is believed to include both environmental and genetic factors, whose interplay leads to chronic activation of immune cells and neuronal damage. Chronic viral infections, including those supported by Epstein Barr virus (EBV), are suspected to be involved in the initiation of Agostini et al J Transl Med (2018) 16:80. EBV replicates in oropharyngeal epithelial cells during primary disease and subsequently establishes a latent infection in circulating B lymphocytes

Objectives

Methods

Results

Discussion

Conclusion