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

Proc Natl Acad Sci U S A. 2019 Aug 20;116(34):16955-16960. doi: 10.1073/pnas.1902623116. Epub 2019 Aug 2.


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.

Keywords: ANO2; Anoctamin 2; Epstein-Barr virus; molecular mimicry; multiple sclerosis.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anoctamins* / genetics
  • Anoctamins* / immunology
  • Autoantibodies / immunology
  • Cross Reactions / genetics
  • Epstein-Barr Virus Nuclear Antigens* / genetics
  • Epstein-Barr Virus Nuclear Antigens* / immunology
  • Female
  • HLA-A2 Antigen / immunology
  • HLA-DRB1 Chains / genetics
  • HLA-DRB1 Chains / immunology
  • Haplotypes
  • Herpesvirus 4, Human* / genetics
  • Herpesvirus 4, Human* / immunology
  • Humans
  • Immunoglobulin G / immunology
  • Male
  • Models, Immunological*
  • Molecular Mimicry*
  • Multiple Sclerosis* / genetics
  • Multiple Sclerosis* / immunology
  • Multiple Sclerosis* / pathology
  • Risk Factors


  • ANO2 protein, human
  • Anoctamins
  • Autoantibodies
  • Epstein-Barr Virus Nuclear Antigens
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • HLA-DRB1 Chains
  • HLA-DRB1*15:01 antigen
  • Immunoglobulin G
  • EBV-encoded nuclear antigen 1