The picture gets more complex: ANO2 + GlialCam + CRYAB

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frodo
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The picture gets more complex: ANO2 + GlialCam + CRYAB

Post by frodo »

EBNA1 is a EBV protein with several interesting segments: Some of them mimic the human proteins ANO2, GlialCam or CRYAB. Maybe other segments mimic other proteins.

Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis

https://www.science.org/doi/full/10.1126/sciadv.adg3032

Excerpt:

"One study demonstrated cross-reactivity between EBNA1 amino acids 394 to 399 and GlialCAM (18), and we have previously demonstrated the same for EBNA1 amino acids 431 to 440 with ANO2 (17).

In addition, EBNA1 amino acids 411 to 426 and myelin basic protein cross-reactivity has been demonstrated in experimental autoimmune encephalomyelitis (EAE) (36), and EBNA1-specific T cells have been shown to react to a mixed myelin antigen pool (33).

We now demonstrate further cross-reactivity between EBNA1 amino acids 402 to 406 and CRYAB amino acids 11 to 15, with core sequence homology mapped to identical RRPFF residues within these fragments.

While many proteins contain this core amino acid RRPFF motif, amino acid residues that flank this sequence and are unique to CRYAB are also necessary for antibody binding. This is evidenced by the drop in signal after CRYAB amino acids 8 to 22, indicating that the shared proline at CRYAB position 8 (and at EBNA1 position 399) is critical to the epitope

Several different autoantigens may be involved in mimicry between MS and EBV, which could explain why each study to date has found autoreactivities in only ~20% of pwMS, despite essentially ubiquitous EBNA1 responses. In support of this, we saw a poor correlation between CRYAB and ANO2 IgG responses despite the shared EBNA1 link, which suggests that underlying factors such as human leukocyte antigen (HLA), previous antigen experience of the immune system, history of IM, or other perhaps undiscovered risk factors affect the different cross-reactivity patterns"
Last edited by frodo on Wed Sep 06, 2023 10:39 am, edited 1 time in total.
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Re: The picture gets more complex: ANO2 + GlialCam + CRYAB

Post by frodo »

https://www.science.org/doi/10.1126/science.abm7930

[...] showed serum antibodies from MS patients are cross-reactive between amino acids 411–440 of the viral protein EBV nuclear antigen 1 (EBNA-1) and the human chloride-channel protein, anoctamin 2 (ANO2), which is associated with electrical conduction in axons (11). MS serum antibodies targeting EBNA-1 residues 411–426 that cross-react with myelin basic protein have also been identified (12). Clonally expanded antibodies in the CSF of MS patients targeting EBNA-1 residues 386–405 that cross-react with the CNS cell adhesion molecule, glialCAM, have also been described (4).

It is intriguing that three contiguous regions of mimicry have been reported in a small region of the EBNA-1 protein; this may arise through immune surveillance in a process called epitope spreading.
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Re: The picture gets more complex: ANO2 + GlialCam + CRYAB

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Antibodies against the flotillin-1/2 complex in patients with multiple sclerosis

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10116574/

A long list of candidate antigens have been found, including the glial potassium channel KIR4.1, the flotillin-1/2 complex (FLOT1/2), anoctamin-2 (ANO2) or neurofascin-155 (NF155) and most recently, antibodies targeting hepatocyte cell adhesion molecule (GlialCAM/HEPACAM); although most of them have not been replicated in independent cohorts, and their clinical relevance remains uncertain.

Our study aims to analyse the presence of antibodies against NF155, ANO2 and FLOT-1/2 complex in our multiple sclerosis cohort, and to analyse if there are clinical features associated with these autoantibodies that could suggest that patients harbouring any of these antibodies constitute a differentiated multiple sclerosis subset.

Abstract

... We identified six multiple sclerosis patients with antibodies against the flotillin-1/2 complex (2.1%) and one multiple sclerosis patient with antibodies against anoctamin-2 (0.35%). All multiple sclerosis patients were negative for anti-neurofascin-155 antibodies. Three of the anti-flotillin-1/2 positive patients showed anti-flotillin-1/2 positivity in other serum samples extracted at different moments of their disease. Immunoglobulin G subclasses of anti-flotillin-1/2 antibodies were predominantly one and three. We confirm that antibodies targeting the flotillin-1/2 complex are present in a subgroup of patients with multiple sclerosis.

Roadmap for understanding mechanisms on how Epstein–Barr virus triggers multiple sclerosis

https://onlinelibrary.wiley.com/doi/ful ... /cti2.1438

It is important to note that at this point studies in the blood indicate that only about 15% of MS patients have detectable antibody to anoctamin 2,3 and about 25% of MS patients have antibody in blood to GlialCAM.
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