Gender influence in EBV antibody response in multiple sclerosis patients from Kuwait Rabeah Al-Temaimi a, ⁎, Raed Alroughani b,c , Sindhu Jacob d , Fahd Al-Mulla d a Human Genetics Unit, Department of Pathology, Faculty of Medicine, Kuwait University, Kuwait b Division of Neurology, Department of Medicine, Amiri Hospital, Kuwait, Kuwait c Neurology Clinic, Department of Medicine, Dasman Diabetes Institute, Kuwait d Molecular Pathology Unit, Department of Pathology, Faculty of Medicine, Kuwait University, Kuwait abstract article info Article history: Received 2 March 2015 Received in revised form 18 May 2015 Accepted 20 May 2015 Available online xxxx Keywords: Multiple sclerosis Kuwait Epstein–Barr virus EBNA1 VCA HLA-DRB1*1501 Background: Epstein–Barr virus (EBV) infection is implicated with multiple sclerosis (MS) risk, exacerbation, and progression. The HLA-DRB1*1501 haplotype is a strong MS risk factor consistently documented in MS popula- tions. There are no studies of EBV infections and HLA-DRB1*1501 haplotype associating with MS from Kuwait where MS prevalence has increased significantly. Objectives: To determine the association of EBV infection with MS incidence, and to investigate HLA-DRB1*1501 as a potential genetic risk factor for MS in Kuwait. Methods: This is a case–control study involving 141 MS patients and 40 healthy controls. Antibody titers against EBV antigens' viral capsid antigen (VCA) and Epstein–Barr nuclear antigen 1 (EBNA1) were measured using enzyme-linked immunosorbent assays. HLA-DRB1*1501 haplotype assessment was done using rs3135005 TaqMan genotyping assay. Results: Antibody titers against EBV were significantly elevated in MS patients compared to healthy controls (anti-EBNA1, p = 0.008; anti-VCA, p = 0.028). MS males had higher antibody titers to EBNA1 than healthy male controls (p = 0.005) and female MS patients (p = 0.03). HLA-DRB1*1501 haplotype genotypes failed to generate a risk association with MS or EBV antibody titers (p = 0.6). Conclusion: An increased immune response to EBV infection is associated with MS incidence influenced by the type of antigen and sex. HLA-DRB1*1501 haplotype is not associated with MS risk in our Kuwaiti MS cohort. © 2015 Elsevier B.V. All rights reserved. 1. Introduction Multiple sclerosis (MS) is an inflammatory demyelinating disorder resulting from an autoimmune reaction against myelin and myelin as- sociated antigens in the central nervous system (CNS), however the exact etiology remains unknown. Repeated demyelination events in the white matter result in subsequent neuro-axonal degeneration and oligodendrocyte cell death in the CNS manifesting primarily as lesions in the white matter of the brain and spinal cord causing perturbed cen- tral sensory and motor nerve conduction. MS incidence is 2:1 female:male ratio at a typical age of onset between 20–40 years of age (Liguori et al., 2000). MS is considered a multi-factorial complex disor- der where genetic and environmental factors play a role in MS patho- genesis and relapse risk (Milo and Kahana, 2010). Kuwait has become a high-risk area for MS, its prevalence has increased from 4.4 in 1990 to 85 cases per 100,000 individuals in 2014 (Al-Din et al., 1990; Alroughani et al., 2014). One of the most consistently reported association with MS risk is the association of viral infections, specifically Epstein–Barr virus (EBV) infection (Owens and Bennett, 2012; Lucas and Taylor, 2012). EBV is a human gamma-herpes virus that specifically infects nasopharyngeal epithelial cells and resting B-lymphocytes. EBV has the ability to activate or persist in a latent phase within the cells of infected individuals throughout their lives. EBV can mimic the stimuli of antigens and T-cell receptors in activating naïve B-lymphocytes into antigen specific memory B-cells. As infected memory B-cells differenti- ate into plasma cells EBV switches to lytic reproductive phase to pro- duce new EBV particles (Laichalk and Thorley-Lawson, 2005). Human immune response against flourishing EBV production is to eliminate production houses; mainly EBV-infected plasma cells, effectively via the action of cytotoxic CD8 + T-cells (Hislop et al., 2007). EBV infection specificity to immune cells has resulted in its association with the inci- dence of several autoimmune disorders and malignancies in individuals predisposed to such disorders. Systemic lupus erythematosus, rheuma- toid arthritis, Burkitt's lymphoma, and Hodgkin's lymphoma are examples of such disorders (Toussirot and Roudier, 2008; Saha and Robertson, 2011). In recent years, the role of EBV infections as an MS risk factor prelud- ing MS incidence in susceptible individuals has become a field of Journal of Neuroimmunology 285 (2015) 57–61 ⁎ Corresponding author at: Human Genetics Unit, Dept. of Pathology, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait. E-mail address: rabeah@hsc.edu.kw (R. Al-Temaimi). http://dx.doi.org/10.1016/j.jneuroim.2015.05.021 0165-5728/© 2015 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim