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Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2019 Aug 20; Vol. 116 (34), pp. 16955-16960. Date of Electronic Publication: 2019 Aug 02. - Publication Year :
- 2019
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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 <superscript>-36</superscript> ) 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.<br />Competing Interests: 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.
- Subjects :
- Autoantibodies immunology
Cross Reactions genetics
Female
HLA-A2 Antigen immunology
HLA-DRB1 Chains genetics
HLA-DRB1 Chains immunology
Haplotypes
Humans
Immunoglobulin G immunology
Male
Risk Factors
Anoctamins genetics
Anoctamins immunology
Epstein-Barr Virus Nuclear Antigens genetics
Epstein-Barr Virus Nuclear Antigens immunology
Herpesvirus 4, Human genetics
Herpesvirus 4, Human immunology
Models, Immunological
Molecular Mimicry
Multiple Sclerosis genetics
Multiple Sclerosis immunology
Multiple Sclerosis pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 116
- Issue :
- 34
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 31375628
- Full Text :
- https://doi.org/10.1073/pnas.1902623116