T time….Looking for MS targets


Is MS an autoimmune disease…It is difficult to confirm this view and disease needs to e controlled by antigen-specific means to e more compelling. This study hunted and found 4 antigens that could induce T cell responses and some showed the capacity to induce histological disease. The study seems to re-affirm that the typical myelin antigens favoured by many immunologists give no better responses than found with the new candidates. The conclusion is that T cells are more important than B cells in MS

Identification of four novel T cell autoantigens and personal autoreactive profiles in multiple sclerosis.
Bronge et al. .Sci Adv. 2022;8:eabn1823.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), in which pathological T cells, likely autoimmune, play a key role. Despite its central importance, the autoantigen repertoire remains largely uncharacterized. Using a novel in vitro antigen delivery method combined with the Human Protein Atlas library, we screened for T cell autoreactivity against 63 CNS-expressed proteins. We identified four previously unreported autoantigens in MS: fatty acid-binding protein 7, prokineticin-2, reticulon-3, and synaptosomal-associated protein 91, which were verified to induce interferon-γ responses in MS in two cohorts. Autoreactive profiles were heterogeneous, and reactivity to several autoantigens was MS-selective. Autoreactive T cells were predominantly CD4+ and human leukocyte antigen-DR restricted. Mouse immunization induced antigen-specific responses and CNS leukocyte infiltration. This represents one of the largest systematic efforts to date in the search for MS autoantigens, demonstrates the heterogeneity of autoreactive profiles, and highlights promising targets for future diagnostic tools and immunomodulatory therapies in MS.

Here “Antigens were chosen among proteins selectively expressed in the CNS but not previously described as established autoantigen….63 different proteins were….used to stimulate peripheral blood mononuclear cells (PBMCs) from natalizumab-treated persons with MS”.

When I see these types of papers I look to see where the target is expressed using public databates that anyone can look at.

http://www.brainrnaseq.org expression of FABP7 points towards astrocytes in mice less so in humans

http://www.allenbrain altas X10 expression of message in human brain (dark ble no expression), yellow expression. SNAP91 and RTN3 are nerve markers and low levels on gli,a PROK2 is essentially nothing in CNS and in BioGPS.org, PROK2 is on neutrophils and some lymphocytes and FABP7 is on a few nerves


And as for protein we can look at the protein atlas.org

Brown stain is positivity and the section is stained with blue in the brain. Limited brown = limited protein, but the protein expression reflects the RNA expression above.

So you need to ask yourself would you expect a prominant white matter lesional profile with loss of oligodendrocytes as seen in MS given the expression of protein above? However you also have to consider that in MS ssome proteins are upregulated and could then become targets

In the paper they found that “The responses were heterogeneous, and individual patients displayed unique autoreactivity profiles, with different magnitudes of response and combinations of autoantigens”. So there was a variety of responses to different proteins. But if people had responses to these proteins and also some myelin proteins it was more likely they had MS.

They looked for antibodies to the proteins and about 30% of people with MS and controls both responded to RTN3 but others were rare. So they can find some T cells that will respond to these proteins and next up they induce autoimmunity in mice, which develop histological disease. We have shown in the past that you can get disease in mie if you immunize then with CNS expresssed proteins.

Once you find autoantigens the key is to show they are important in humans can this be done…Its being tried.

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  • Does this mean that B cell targeting MS meds aren’t necessarily as effective as they’re currently considered to be? I only know that I did well on Tysabri. I later did horribly with ocrevus. For the first time since diagnosis, mri showed brain volume loss 🙁

    I’m left wondering if it’s crazy that brain volume loss alarms me so much more than new lesions would? I don’t really think so but I’m not an expert. It’s just depressing.

    In the US, most neurologists consider lemtrada the Hail Mary last ditch medication. Wish I’d just started with that to be honest. I guess it’ll sort of wipe out both B and T cells. At least for awhile.

    • Brain volume loss on ocrevus…could it be that ocrelizumab has worked so well that it has got rid of swelling in the brain, hence the apparent shrinkage. However maybe ocrelizumab does not work for you. There is a genetic variant that can influence whether ocrelizumab works well or not…this is not tested for because it is relatively rare…it is important however if you are the one with the rare variant. There may be other explanations too

      The Hail Mary should probably be my first pass and not the last one…stop the damage from occuring early because when it is set in motion it will have to play-out before benfit can be noted.

      • Thanks for answering. They couldn’t tell if I had new brain lesions because mine are large and entangled with each other. No one can tell if a lesion is just one huge expanding lesion or 20 small ones that are so close to each other that they look like one.

        The brain volume loss was a pretty extreme amount. It was hard not to cry when I looked at the images. I took gilenya in between Tysabri and ocrevus. Seemed to work pretty well until I had a relapse that felt pretty mild and didn’t leave lasting symptoms. But bam a large new lesion on my dang brain stem. So I had to change to ocrevus.

        Ocrevus definitely left me much worse off than before I started. My mobility, balance, vision, pretty much everything. It started after the very first half dose but I stupidly just went along with the plan for 2 years. So I’m definitely one of those people who don’t respond to that med.

        I just hope that I won’t get even worse after lemtrada. I know that it won’t improve my current symptoms (unless some miracle happens…my neurologist actually used the term Hail Mary hahaha, guess I’ll silently recite that during infusions even though I’m not catholic 🤷🏻‍♀️)

  • Several papers seem to do an untargeted search, I mean: let’s look at proteins in the brain, lets pick some of them and do the tests. Why not working the other way around? For example: what are the proteins highly expressed in a given cell type (eg oligodendrocytes) and on the outer membrane of the cell and test them? If MS is a one type of cell disease this approach should somewhat reduce the time to identification (that will still be huge given how many proteins with an extracellular domain can be expressed).

    • You are correct in science this is called a “fishing trip” where you go out hunting hoping to catch a big one….it used to be frowned on but with new sequencing technology it has made a comeback…sadly people catch tiddlers and claim they have a whopper…so the fishermans tale could be a scientists tale.

      The other way round is hypothesis based approaches where you focus on certain aspects. In MS a fishing trip caught another protein with was the most common protein recognised by the immune system, but because it was not a myelin antigen…the community did not pay much attention so maybe a crab was caught and not a fish. However, you have to careful not to show horn your observations into a grand design. In MS we do think the oligodendrocyte is a target…but it may not have to be on the surface…this may be the case for antibodies which cant get inside a cell, but T cells recognise fragments of proteins that are produced inside a cell before they are transported to the surface

      • Why do you say that the antigen may not be on the cell surface? How does a t cell recognise a protein or detect a protein within the cell? If it is within the cell there is no molecular contact between the t cell receptors and the antigen.

        • T cells do not recognise free antigen it must be processed inside the cell whereitis loaded in major histocompatibility complex that is expressed on self surface, so targets antigens don’t have to be cell surface

  • Was this study performed on mice where MS in mice is T- cell driven?

    Also if T cells play there part in driving MS progression which I’m sure they do, could it explain why treatments that effect T cells aswell as B cells act fairly well on progression

    And maybe you need to target both. As they work together on this

    • This humans and not mice….Name a treatment that works on T cells that does not work better on B cells…you will struggle to find on.
      I agree T and B cells will be the optimal but play the B cell card to make people think

      • I mean treatments such as IRTs that effect T cell populations better than just B cell depleters or some of the less effective medications. May be more effective against progression as they have an effect on T cells.

        Could it be that it’s a mixture of b and T cells and some people have more T cells that arm track myelin and some have more B cells that attack myelin.

        Something other than B cells in the blood is causing progression big chance it’s T cells. Maybe why ALA reduces brain atrophy, could it be it hinders T cells in the CNS?

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