I’m wrong…it’s all T cells


A new study finds a another T cell subtype for MS

This time the cell expresses Granulocycte macrophage growth factor and a chemokine recepter called CXCR4. There is a relatively new detection system and they have looked in the MS brain and found this one.

Yes yes its T cells, It’s T cells I give up.

They found a CD4 T cell is that surprising?

So off we go and do a new set of EAE studies, although it must be said this has already been down with blocking GM-CSF and CXCR4 and a clinical trial in the making…perhaps.

So here is the paper

Galli, E et al. GM-CSF and CXCR4 define a T helper cell signature in multiple sclerosis. Nature Medicine https://doi.org/10.1038/s41591-019-0521-4

Cytokine dysregulation is a central driver of chronic inflammatory diseases such as multiple sclerosis (MS). Here, we sought to determine the characteristic cellular and cytokine polarization profile in patients with relapsing–remitting multiple sclerosis (RRMS) by high-dimensional single-cell mass cytometry (CyTOF). Using a combination of neural network-based representation learning algorithms, we identified an expanded T helper cell subset in patients with MS, characterized by the expression of granulocyte–macrophage colony-stimulating factor and the C-X-C chemokine receptor type 4. This cellular signature, which includes expression of very late antigen 4 in peripheral blood, was also enriched in the central nervous system of patients with relapsing–remitting multiple sclerosis. In independent validation cohorts, we confirmed that this cell population is increased in patients with MS compared with other inflammatory and non-inflammatory conditions. Lastly, we also found the population to be reduced under effective disease-modifying therapy, suggesting that the identified T cell profile represents a specific therapeutic target in MS.

So they went on a fishing trip (a non-hypothesis -driven look-see) to find cells they found (New T cell enriched in CNS) and then they show it disappears with treatment…….Yeah.

OK, I suspect any effective treatment would do this because any effective treatment will reduce cells from the CNS. But them what does the study say.

The past story of Th17 is all wrong? We now have ThGM? I bet that isn’t a take home message, but isn’t that surely what it does says? You can’t have it both ways. Will the T cell EAEoloists embrace this? We have seen the Th3 and Th9 arrive and is not really discussed.

So there you have it, CD4 T cells are the target for MS. I’m wrong, I’m always wrong:-(

I wonder if the referees said hey by what about Response to Therapy what about that CD4 depletion trial that didn’t work too good (They didn’t deplete enough and the wrong type of cells were depleted?) and what about the CD20 therapy and have you thought about this paper

Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. EBioMedicine. 2017 Feb;16:41-50.  (OK I am cynically keeping the altmetric up:-).

I am sure this thought never arrives when someone mentions a T cells, but if one mentions B cells without T cells, in the same breathe, one is told of course I am wrong. T cells are the top dog. “While substantial evidence suggests that MS is mainly a T cell driven disease, the quite remarkable efficacy of B cell depleting therapies demonstrates that B cells play a non-redundant accessory role somewhere in the disease process.” . However is it really the B cell. “We all know CD20 depletion works beacuse” it (a) Blocks T cell activation (b) CD20 is present on T cells (c) CD20 depletion increases T regs (of course it will if 20% of the blood population decreases, the percentage of T regs will go up). It’s T cells, T cells, T cells. So in the interests of balance there you have it it’s T cells, T cells, T cells.

Why is this important?. It is important because it determines where you go next.

Target CD27 get the memory B cells but also get the memory T cells, stick on T cell only targets and hope they work, like they haven’t in the past or focus on the B cell as the main target and avoid side-effects. In reality we know where old-school academics are putting their effort, it is on T cell. Big Pharma on the other hand are probably having a bit of a laugh as they but their money elsewhere.

Let’s see. So here we have it a new T cell, it was replicated in an independent cohort in this paper, but remember we have been here before with the Kir 4.1 antibody story as the cause of MS. Internally replicated but not replicated by other groups (No wonder the B cells were ditched). This could and should be confirmed in nano seconds by the people doing the single cell RNAseq in MS. If this is the target, let the trials begin. What will they do? Target GM-CSF get a result and thats it proven.

Oh maybe not. The “last” fishing trip found a different catch

Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Li R, Rezk A, Miyazaki Y, Hilgenberg E, Touil H, Shen P, Moore CS, Michel L, Althekair F, Rajasekharan S, Gommerman JL, Prat A, Fillatreau S, Bar-Or A; Canadian B cells in MS Team. Sci Transl Med. 2015 Oct 21;7(310):310ra166.

Dimethyl Fumarate Treatment Mediates an Anti-Inflammatory Shift in B Cell Subsets of Patients with Multiple Sclerosis. Li R, Rezk A, Ghadiri M, Luessi F, Zipp F, Li H, Giacomini PS, Antel J, Bar-Or A. J Immunol. 2017 Jan 15;198(2):691-698.

Keep your mind open and read, read, read. I may be wrong, but I am big enought to admit it and keep an open mind about it, however I suspect some labs are “too-big” to contemplate change. Time will tell. For this story, is it a few minutes or a few years. Time will tell.

The immune system is a system and of course nothing works in isolation you don’t have an effective B cell without a T cell and B cells help T cells

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  • The autoimmune profile of MS is one of the most complex there is. I have lost hope that any treatment will halt this disease. There are too many players, cells, chemokines, cytokines, antibodies, genetic profiles, etc etc. Too many variables and not enough computational power to make a dent into the cellular pathophysiology of this disease. We are perhaps only 10% closer (my statistics) to understanding this debilitating disease since it was first characterized. I am 48 and will unlikely see any stoppage of progression much less reversal of established disability. How many times have we read about “hope” for what is essentially a hopeless condition? The best we can do is something like this: a patient on ocrevus will delay using a wheelchair for 7 years. Wow. Terrific. In other words, we will all eventually end up using one. Depressing

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