Journal Article

Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk

Michel, Angelika, Ayoglu, Burcu, Padyukov, Leonid, Brenner, Nicole, Kockum, Ingrid, Svenungsson, Elisabet, Waterboer, Tim, Olafsson, Sigurgeir, Ernberg, Ingemar, Sundström, Peter, Nilsson, Peter, Huang, Jesse, Kammer, Patrick, Hellström, Cecilia, Biström, Martin, Lundberg, Karin, Tengvall, Katarina, Hillert, Jan, Bomfim, Izaura Lima, Stridh, Pernilla, Butt, Julia, Alfredsson, Lars, Dilthey, Alexander T., Olsson, Tomas, Lundberg, Ingrid E.

2019

Overview

Multiple sclerosis (MS) is a chronic inflammatory, likely autoimmune disease of the central nervous system with a combination of genetic and environmental risk factors, among which Epstein-Barr virus (EBV) infection is a strong suspect. We have previously identified increased autoantibody levels toward the chloride-channel protein Anoctamin 2 (ANO2) in MS. Here, IgG antibody reactivity toward ANO2 and EBV nuclear antigen 1 (EBNA1) was measured using bead-based multiplex serology in plasma samples from 8,746 MS cases and 7,228 controls. We detected increased anti-ANO2 antibody levels in MS (P = 3.5 × 10−36) with 14.6% of cases and 7.8% of controls being ANO2 seropositive (odds ratio [OR] = 1.6; 95% confidence intervals [95%CI]: 1.5 to 1.8). The MS risk increase in ANO2-seropositive individuals was dramatic when also exposed to 3 known risk factors for MS: HLA-DRB1*15:01 carriage, absence of HLA-A*02:01, and high anti-EBNA1 antibody levels (OR = 24.9; 95%CI: 17.9 to 34.8). Reciprocal blocking experiments with ANO2 and EBNA1 peptides demonstrated antibody cross-reactivity, mapping to ANO2 [aa 140 to 149] and EBNA1 [aa 431 to 440]. HLA gene region was associated with anti-ANO2 antibody levels and HLA-DRB1*04:01 haplotype was negatively associated with ANO2 seropositivity (OR = 0.6; 95%CI: 0.5 to 0.7). Anti-ANO2 antibody levels were not increased in patients from 3 other inflammatory disease cohorts. The HLA influence and the fact that specific IgG production usually needs T cell help provides indirect evidence for a T cell ANO2 autoreactivity in MS. We propose a hypothesis where immune reactivity toward EBNA1 through molecular mimicry with ANO2 contributes to the etiopathogenesis of MS.

• Publisher: National Academy of Sciences
• Subject: ANO2 / Anoctamin 2 / Anoctamins - genetics / Anoctamins - immunology / Antigens / Autoantibodies / Autoantibodies - immunology / Autoimmune diseases / Biological Sciences / Central nervous system / Chloride ions / Confidence intervals / Cross Reactions - genetics / Cross-reactivity / Drb1 protein / Environmental risk / Epstein-Barr virus / Epstein-Barr Virus Nuclear Antigens - genetics / Epstein-Barr Virus Nuclear Antigens - immunology / Female / Gene mapping / Haplotypes / Herpesvirus 4, Human - genetics / Herpesvirus 4, Human - immunology / Histocompatibility antigen HLA / HLA-A2 Antigen - immunology / HLA-DRB1 Chains - genetics / HLA-DRB1 Chains - immunology / Humans / IgG antibody / Immunoglobulin G / Immunoglobulin G - immunology / Immunology and Inflammation / Inflammatory diseases / Ion channels / Lymphocytes / Lymphocytes T / Male / Mimicry / Models, Immunological / Molecular Mimicry / Multiple sclerosis / Multiple Sclerosis - genetics / Multiple Sclerosis - immunology / Multiple Sclerosis - pathology / Peptide mapping / Peptides / Reactivity / Risk analysis / Risk Factors / Serology / Viruses