More T cells stuff, is the B cell idea wrong?

M
If MS is a T cell mediated disease how does ocrelizumab (CD20 B cell depleting antibody) work


Simple because T cells express CD20


Is this a blow for the B cell idea?

von Essen MR, Ammitzbøll C, Hansen RH, Petersen ERS, McWilliam O, Marquart HV, Damm P, Sellebjerg F. Pro-inflammatory CD20+ T cells in the pathogenesis of multiple sclerosis. Brain. 2018 Dec 17. doi: 10.1093/brain/awy301. [Epub ahead of print]

With the discovery that the highly effective anti-CD20 antibody therapies developed to deplete CD20+ B cells deplete CD20+ T cells equally well, a great interest in the biological properties of CD20+ T cells has emerged. In this study we show that CD20+ T cells have a proinflammatory Th1/Tc1 phenotype with a high proliferative capacity to CNS antigens. We also found that the percentage of CD20+ T cells is increased in the blood of patients with multiple sclerosis and are enriched in the CSF of the patients. Furthermore, we found a positive correlation between CD20+ T cells in the CSF and multiple sclerosis disease severity and see that regulation of CD20+ T cells likely contributes to the positive treatment effect of the multiple sclerosis treatment alemtuzumab. These data represent an important contribution to the understanding of the nature of CD20+ T cells and strongly suggests a role of CD20+ T cells in the pathogenesis of multiple sclerosis.


Is this study they show that the frequency of CD20+ T cells was significantly increased in blood from patients with RRMS; both in the CD4+ (P = 0.0006) and CD8+ (P = 0.0017) compartment

The cells produce gamma interferon, tumor necrosis factor  GM-CSF) and CD4 variants also produce IL-4 and IL-13 so is this really Th1-like? as IL-4 and IL-13 are TH2 cytokines. This is more Th0)


The cells form after Birth and they recovered very slowly in people treated with alemtuzumab. I
s this why alemtuzumab lasts so long?





So this study suggests it is T cells all the way.  


The circumstantial argument is there. 

However, are these authors deluding themselves?

Well they do say that there are no B cells in the thymus “ CD20+ T cells have been found in the thymus where B cells are not present” but the literature would suggest this fact ain’t correct, so they can convinced themsleves of stuff that isn’t right. 


The finger is pointed at CD8, CD20+ T cells which produce pro-inflammatory cytokines and they outnumber B cells.


They also react to myelin (but to a similar level as healthy people).


So the question is whether this population is the central pathogenic mediator. At present we have this circumstantial evidence. They make up about 10% of CD4 T cells and 10-15% of CD8 T cells and they accumulate in CNS. 


You need to get rid of them and MS goes away. However you need to do this without depleting CD20+ memory B cells to be convincing.


These results are essentially the same as that reported previously.
What’s different..well about 5 points on the impact factor scale and 2 years later:-). Have a look for yourself. Schuh et al. J. Immunol 2016 197:1111 .


Monoclonal Abs against CD20 reduce the number of relapses in multiple sclerosis (MS); commonly this effect is solely attributed to depletion of B cells. Recently, however, a subset of CD3(+)CD20(+) T cells has been described that is also targeted by the anti-CD20 mAb rituximab. Because the existence of cells coexpressing CD3 and CD20 is controversial and features of this subpopulation are poorly understood, we studied this issue in detail. In this study, we confirm that 3-5% of circulating human T cells display CD20 on their surface and transcribe both CD3 and CD20. We report that these CD3(+)CD20(+) T cells pervade thymus, bone marrow, and secondary lymphatic organs. They are found in the cerebrospinal fluid even in the absence of inflammation; in the cerebrospinal fluid of MS patients they occur at a frequency similar to B cells. Phenotypically, these T cells are enriched in CD8(+) and CD45RO(+) memory cells and in CCR7(-) cells. Functionally, they show a higher frequency of IL-4-, IL-17-, IFN-γ-, and TNF-α-producing cells compared with T cells lacking CD20CD20-expressing T cells respond variably to immunomodulatory treatments given to MS patients: they are reduced by fingolimod, alemtuzumab, and dimethyl fumarate, whereas natalizumab disproportionally increases them in the blood. After depletion by rituximab, they show earlier and higher repopulation than CD20(+) B cells. Taken together, human CD3(+)CD20(+) T cells pervade lymphatic organs and the cerebrospinal fluid, have a strong ability to produce different cytokines, and respond to MS disease modifying drugs.


So pretty much saying the same thing, drugs make tham go down so great, but then they say they recovery quickly after rituximab



However if CD20 depletion has immune reconstituion activity in MS as seems to be the case then this would argue against the idea that CD20 T cells are being important.  The retreatment is based on repopulation of CD19 cells, so would treatment need to be more frequent than every 6 months if you base efficacy on T cells.

Importantly, if you use this T cell argument you have then to ask how does CD19, another B cell depleting antibody, work?


There has been a trial and it is just as good at stopping MRI lesions as CD20.


CD20+ T cells would have to express CD19 also.


When I asked one person forwarding the CD20 argument this very question, they said that T cells do express CD19! 


But on abit of reading and looking at pictures the data says they don’t. (Therefore, if you mushroom food convincingly enough, people buy it without question…Sad)

Have a look. Here is a mouse staining looking at cells that express CD3 (a T cell marker)  and CD19 (a B cell marker) look in the top right hand square and there are a few dots, but not many and you always get some crud appearing as cells with this machine.

Now human blood cells
So about 9 dots (Cells) probably out of  10,000, draw the lines abit differently to include CD19-ve and CD3-ve better and it drops to no dots. So human and mouse cells do not express much CD19.

How about another

In this one  I think about 3 dots only,  as the CD19 negative line is in the wrong place (too far to left).

Now, you can find the occassional flow cytometry plot with CD19+, CD3+ T cells (or are they CD3+ B cells) and there are some cancers that express both but on the whole we say no.


But it has been examined by Schuh et al. J. Immunol 2016 197:1111   and they demonstrate at the protein level and message level that that CD20 T cells don’t do this.


So as CD20+ T cells do not express CD19,  the argument topples.


To be fair,  I have to say the company developing anti-CD19 dropped interest in MS after the phase I trial (Was it the death and infection risk?) and went for NMO, why? 


Are the results in MS not as good as I think, but the MRI lesion load was dropped.

Maybe it is a conspiracy by the T cell immunologists to keep their idea  afloat:-)






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MouseDoctor

4 comments

  • phase 1 trial completed using ppms and spms patients all improved except one person stayed the same. epstein barr virus targeted using cd8 t cells. guess the culprit was a virus all along. now phase 2.

  • MD, am confused, maybe I need to read again when I get home. The black text above mentions CD20 depletion in the same breath as alemtuzumab. Isn’t alemtuzumab a CD52 target?

  • Yes alemtuzumab is anti CD52. TheTblack text says CD20 T cells are depleted by alemtuzumab so these cells are CD52+ CD20+, CD3+

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