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

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

Author information

1
Neuroimmunology Unit, The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Department of Clinical Neuroscience, Karolinska Institute, 171 76 Stockholm, Sweden; katarina.tengvall@ki.se.
2
Centrum for Molecular Medicine, Karolinska University Hospital, 171 76 Stockholm, Sweden.
3
Neuroimmunology Unit, The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Department of Clinical Neuroscience, Karolinska Institute, 171 76 Stockholm, Sweden.
4
Division of Affinity Proteomics, Department of Protein Science, SciLifeLab, KTH - Royal Institute of Technology, 171 21, Solna, Sweden.
5
Infections and Cancer Epidemiology, Infection, Inflammation and Cancer Research Program, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
6
Department of Pharmacology and Clinical Neuroscience, Umeå University, 901 85 Umeå, Sweden.
7
Division of Cellular and Clinical Proteomics, Department of Protein Science, SciLifeLab, KTH - Royal Institute of Technology, 171 21, Solna, Sweden.
8
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, 171 76 Stockholm, Sweden.
9
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
10
deCODE Genetics, Amgen, IS-101 Reykjavik, Iceland.
11
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
12
Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
13
Institute of Environmental Medicine, Karolinska Institute, 171 77 Stockholm, Sweden.
14
Centre for Occupational and Environmental Medicine, Stockholm County Council, 171 77 Stockholm, Sweden.

Abstract

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

PMID:
31375628
PMCID:
PMC6708327
[Available on 2020-02-02]
DOI:
10.1073/pnas.1902623116

Conflict of interest statement

Conflict of interest statement: Outside this work, T.O. has received unrestricted MS research grants, lecture and/or advisory board honoraria from: Biogen, Novartis, Merck, Sanofi, and Roche. Outside this work, P.K. is working at Roche Diagnostics in unrelated projects.

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