A couple of years ago we were awakened to the prospect of EBV being the cause of multiple sclerosis, at least part of the causal route. It was based on two papers one that it was shown that people who develop MS were infected with Epstein Bar Virus before, maybe years, they got MS. The other was that antibodies directed against EBV, cross reacted with a protein found in the brain. This changed the focus that MS was a CD4, TH17 mediated disease built up by the same people over decades. Now the protein found was unlikely to be a good candidate for a number of reasons and it was more likely to be a consequence than a cause and the original observations havn’t really been properly and considently replicated.
How could and when could EBV cause MS? Was it a trigger, meaning that treating MS with anti-EBV maybe too late or perhaps a target and gung-ho off we go…trials in MS here we come. Now without waiting to get an answer the trials are being done…ProfG has gone off in the neurology sunset to give it a go. More recently there have been papers to suggest that there maybe a suggestion that there is viral reactivation in MS focusing the mind that it may be a useful target….Today it is more T time and this is to suggest that T cells in the brain of MS notably CD8 T cells are targeting EBV….Now this doesn’t surprise me as CD8 T cells are designed to target virally infected cells but again it says the dogma of decades was not the right focus as it still isn’t CD4, TH17 T cells. Yep I keep saying this to wind-up the blinkered T cell immunologists that don’t accept that B cells are important. Is starts with the premise that the T cells that enter the CNS tissues is more commonly CD8 than CD4 T cells. But what do they respond to? For years we were told that T cells entering the CNS were targeting myelin basic protein to target oligodendrocytes. The problem with this idea is that CD4 T cells need to see their target in the context of a thing called MHC class II (which is part of the “you” identifying mechanism and what is not you is an invader i.e. infection and needs to be removed), but oligodendrocytes do not express MHC class II…so they ain’t going to be directly killed by CD4 T cells. CD8 T cells however recognise a different bid of the “you” detection system and this is called MHC class I and here every cells essentially has the capacity to express MHC class I and viral proteins formed when a virus infects a cell are loaded into MHC class I and exported to the cell surface. The CD8 sees you (the MHC class I) and the virus and gets the message cell infected with virus…destroy it.
What do the T cells see lets go to AI google and yep it makes stuff -up it says “CD8+ T cells in Multiple Sclerosis (MS) primarily target components of the central nervous system (CNS), contributing to inflammation, demyelination, and axonal damage. Key targets include mylein antigens blah blah blah. We get the usual intro blah blah blah this is unknown and I think havent sequencing been done already and I cast my mind back to find
Mittl K, et al. Antigen specificity of clonally-enriched CD8+ T cells in multiple sclerosis. bioRxiv [Preprint]. 2024 Oct 17:2024.09.07.611010. doi: 10.1101/2024.09.07.611010
actually first posted on 7 Sepetemeber 2024
https://www.biorxiv.org/content/10.1101/2024.09.07.611010v1.article-info
I now realise that this is the same paper as todays post and spare a thought for poor old Kirstie (Mittl) who has been kicked off being the first authour and it shows you it takes an age to get stuff published. This again shows why the publication model is rather broken as the info was there 2 years ago….What’s the real story now?
The sequences of B cells were examined years ago when they looked the antigen receptors of B cells Ramesh et al. A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis. Proc Natl Acad Sci U S A. 2020 Sep 15;117:22932-22943 and in them they say that “No viral transcripts, including from Epstein-Barr virus, were detected”. Was it because they had all been destroyed or how they looked for it?
Anyway back to the paper they extracted T cells and with single cell sequencing they got antigen receptor pairs and these could be probled for specificity they put 100 million random peptides into MHC class I and looked for T cell responses. They find T cells that respond to EBV.
They pull out CSERNPWTFY as a sequence recognised. Searching (Blastp) for this I get an unnamed protein from a beetle and some proteins from a spadefoot toad and blow me firmicutes…are these the micobiota from gut backeria I was joking about a few days ago. They pull out another peptide FLRGRAYGL which is found in Epstein Barr Virus (EBNA3) but again we find bacteria and firmicutes (Clostridum bacteria 89% of sequence with 100% identity)…Next sequence EPLPQGQLTAY found in EBV. They find other people reacting to EBV but they do not appear to be targeting cross reactive targets. They also find EBV in the samples. So more ammo for the stop EBV brigade . Does it support targeting CD8 T cells? Would that be a good or a bad thing. I have some views but that’s for another day
Hayashi F, Mittl K, Dandekar R, Gerdts J, Hassan E, Schubert RD, Oshiro L, Loudermilk R, Greenfield A, Augusto DG, Havton G, Anumarlu S, Surapaneni A, Ramesh A, Tran E, Koshal K, Kizer K, Dreux J, Cagalingan AK, Schustek F, Flood L, Moore T, Kirkemo LL, Fisher IJ, Cooper T, Harms M, Gomez R; University of California, San Francisco MS-EPIC Team; Clelland CD, Sibener L, Cree BAC, Hauser SL, Hollenbach JA, Gee M, Wilson MR, Zamvil SS, Sabatino JJ Jr. Antigen specificity of clonally enriched CD8+ T cells in multiple sclerosis. Nat Immunol. 2026 Feb 5. doi: 10.1038/s41590-025-02412-3.
CD8+ T cells are the dominant lymphocyte population in multiple sclerosis (MS) lesions where they are highly clonally expanded. The clonal identity, function, and antigen specificity of CD8+ T cells in MS are not well understood. Here we report a comprehensive single-cell RNA-seq and T cell receptor (TCR)-seq analysis of the cerebrospinal fluid (CSF) and blood from a cohort of treatment-naïve MS patients and control participants. A small subset of highly expanded and activated CSF-enriched CD8+ T cells were abundant in people with MS and displayed high cytotoxicity and tissue-homing transcriptional profiles. Using a combination of unbiased and targeted antigen discovery approaches, several MS-derived CD8+ T cell clonotypes recognizing Epstein-Barr virus (EBV) antigens and novel mimotopes were identified. These findings shed insight into the functions of CD8+ T cells in MS and may serve as potential disease biomarkers and therapeutic targets.
Source: multiple-sclerosis-research.org