pattismith
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Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk
Katarina Tengvall, Jesse Huang, Cecilia Hellström, Patrick Kammer, Martin Biström, Burcu Ayoglu, Izaura Lima Bomfim, Pernilla Stridh, Julia Butt, Nicole Brenner, Angelika Michel, Karin Lundberg, Leonid Padyukov, Ingrid E. Lundberg, Elisabet Svenungsson, Ingemar Ernberg, Sigurgeir Olafsson, Alexander T. Dilthey, Jan Hillert, Lars Alfredsson, Peter Sundström, Peter Nilsson, Tim Waterboer, Tomas Olsson, and Ingrid KockumPNAS
August 20, 2019
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 1.8).
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.
Katarina Tengvall, Jesse Huang, Cecilia Hellström, Patrick Kammer, Martin Biström, Burcu Ayoglu, Izaura Lima Bomfim, Pernilla Stridh, Julia Butt, Nicole Brenner, Angelika Michel, Karin Lundberg, Leonid Padyukov, Ingrid E. Lundberg, Elisabet Svenungsson, Ingemar Ernberg, Sigurgeir Olafsson, Alexander T. Dilthey, Jan Hillert, Lars Alfredsson, Peter Sundström, Peter Nilsson, Tim Waterboer, Tomas Olsson, and Ingrid KockumPNAS
August 20, 2019
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 1.8).
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.
