Molecular mimicry agent finally found? ANO2 and EBNA1

A forum to discuss research on the origins of MS and its development.
Post Reply
User avatar
frodo
Family Elder
Posts: 1749
Joined: Wed Dec 02, 2009 3:00 pm
Contact:

Molecular mimicry agent finally found? ANO2 and EBNA1

Post by frodo »

Both EBNA-1 and Anoctamin-2 have been previously implicated. EBNA-1 is a protein of the EBV virus and ANO-2 us a protein of the family TMEM16 (anoctamins) called "chloride channel". See image:

Image

(Source https://www.creative-biolabs.com/ano2-m ... ction.html)

The paper:

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

https://www.pnas.org/content/early/2019 ... sT1z7tgxSD

Significance

We have previously demonstrated an increased autoantibody reactivity to Anoctamin 2 (ANO2), an ion channel expressed in the central nervous system (CNS), in multiple sclerosis (MS). We now show that ANO2 antibodies recognize a fragment of Epstein-Barr virus (EBV) nuclear antigen 1, thereby constituting an example of molecular mimicry. In this way, the immune response toward EBV may take part in and promote CNS inflammation, likely through T cells reactive with the same protein. In our very large case-control cohort, we demonstrate that the presence of ANO2 reactivity associates with a high MS risk, in particular together with HLA risk variants and high EBNA1 antibody titers, which we consider a strong argument for its relevance in MS ethiopathogenesis

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 1.80)

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 34.80)

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.
User avatar
frodo
Family Elder
Posts: 1749
Joined: Wed Dec 02, 2009 3:00 pm
Contact:

Re: Molecular mimicry agent finally found? ANO2 and EBNA1

Post by frodo »

Update: This theory has been reviewed:

https://pubmed.ncbi.nlm.nih.gov/31375628/

but currently seems unlikely:

https://www.sciencedirect.com/science/a ... via%3Dihub

Highlights

• Most of genetic variants affecting the mimicked ANO2 peptide are rare in the human population.
• The mimicking EBNA1 peptide has only two variants on reference Epstein-Barr virus strains.
• Bionformatic analysis did not suggest any association between different variants of ANO/EBNA1 peptides and the HLA allele DRB1*15:01.
Post Reply
  • Similar Topics
    Replies
    Views
    Last post

Return to “MS Etiology and Pathogenesis”