Progressive MS is a T cell Problem?

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Kaufmann M, Evans H, Schaupp AL, Engler JB, Kaur G, Willing A, Kursawe N, Schubert C, Attfield KE, Fugger L, Friese MA. Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis. Med (N Y). 2021 Mar 12;2(3):296-312.e8.

  • Multimodal single-cell profiling of blood and spatial RNA sequencing of brain tissue
  • VLA4 blockage mobilizes CD161+/LTB+ Th17/Tfh cells to the blood early in MS
  • Identification of these Th17/Tfh as brain-resident cells in progressive MS patients
  • Targetable surface markers on Th17/Tfh include AQP3 (Water channel expressed on cells lining the lung and skin cells and T cells) , TNFRSF25 (death receptor 3), ICOS (CD278 and a marker of T regulatory cells), and VLA4 (target for natalizumab)

According to one long-standing theory, the therapeutic resistance might arise due to infiltration and lasting residence of blood immune cells behind the blood-brain barrier, beyond the reach of most therapeutics. 

Figure thumbnail fx1

Background: Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), can be suppressed in its early stages but eventually becomes clinically progressive and unresponsive to therapy (This is not true, based on the ASCEND natalizumab and OPERATA ocrelizumab trial data) . Here, we investigate whether the therapeutic resistance of progressive MS can be attributed to chronic immune cell accumulation behind the blood-brain barrier (BBB).

Methods: We systematically track CNS-homing immune cells in the peripheral blood of 31 MS patients and 31 matched healthy individuals in an integrated analysis of 497,705 single-cell transcriptomes and 355,433 surface protein profiles from 71 samples. Through spatial RNA sequencing, we localize these cells in post mortem brain tissue of 6 progressive MS patients contrasted against 4 control brains (20 samples, 85,000 spot transcriptomes).

They looked in the blood for immune cell signatures and looked at cases where cells were trapped in the blood due to natalizumab and found a number of them, but being T cell immunologists they focussed on T cells:-). They found an increase in effector memory T cells, which we know are concetrated in the CNS. These cells were reduced in MS blood but were enriched in the CNS. They hunted for the signature in the brains of MS and found them

Findings: We identify a specific pathogenic CD161+/lymphotoxin beta (LTB)+ T cell population that resides in brains of progressive MS patients. Intriguingly, our data suggest that the colonization of the CNS by these T cells may begin earlier in the disease course, as they can be mobilized to the blood by usage of the integrin-blocking antibody natalizumab in relapsing-remitting MS patients.

H = control and MS 1=4 = 4 MS samples and yellow dots equal in brain slices indicate cells with the signature of homing cells

Guess what these T cells are TH17 like by also Tfh (T follicle helper cells than help B cells to make antibodies) like. They express CD161

Conclusions: As a consequence, we lay the groundwork for a therapeutic strategy to deplete CNS-homing T cells before they can fuel treatment-resistant progression.

Now I have to say I do not share their optimism that this is the central problem in treating progressive MS. But they now have the sequences of thousands of these T cells and their antigen receptor. What are their targets?

However, have they missed an obvious target because you and I know that the cell types that are massively increased with natalizumab treatment are not memory T cells but memory B cells. This has been shown repeatedly, but it was not reported here. It suggests it was not looked for or they are hiding something. The B cells were put in one cluster and the T cells were put inot 11 clusrers. The important T cells produce LTB and express ICOS or CD278. This is an immune check point protein thought to be important in Th2 cells. ICOS is stimulated by ICOS ligand = CD275.

Lymphotoxin beta (LTB) is interesting because this is a cytokine that is involved in the development of B cell follicles within lymph glands. Ipilimumab  targets CTLA4 and increases ICOS T cells and this type of agent is associated with the development of demyelination as a side effect. So do the T cells promote the development of B cell follicles, which may be an important driver of glial cell activation and chronic nerve damage.

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MouseDoctor

6 comments

  • Rather shocked MD about fingo think how we feel! Actually I feel quite devastated as I have had both doses and so has my mum fortunately so we have resumed hugs. Not to mention all the plans to go to gigs .

    Now we have to decide whether we can go in to battle with our Neurologists to change treatments and all the relapse worry of coming off fingo balanced against a Covid risk.

    Thanks for the blog even when it’s bad news

    • It is better to know and adapt but we have to see what the AZ/Moderna vaccine does There is 3 times the RNA in moderna and the titres of antobody are highrer. and we have to see what they do to T cell response. I have wondered with the adenovirus drugs if the imuune response is blunted the virus isn’t removed as fast surely the payload of antigen hangs around for longer…more chance of immune response?

      I appreciated the worry, I would say to anyone thinking about starting fingolimod to think about the exit strategy if it doesn’t work, likelwise I would apply this thought natalizumab and indeed any other agents , e.g. the concern that fingolimod stops alemtzumab working in some people.

      Gigs what are they?

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