As the countdown to B cell week at Charcot Meeting (a meeting aiming at training young neurologists) occurs, I had a gripe that I had been given a miss as far as this meeting is concerned. I will be sat at home licking my wounds, as young new minds are manipulated and learn all things MS.
However, what you learn depends on what you get taught.
There are a series of company sponsored symposia at the Charcot Meeting
Anyway, I had the pleasure in doing a teaching course at ECTRIMS. However, I wonder what Gremlins were at work. I had handed my slides in before the meeting only to arrive in the morning in Stockholm to find the system had been wiped and the the slides gone. These were quickly loaded in a bit of a panic and I got to the session with a few minutes to spare. I was ready to give my 30 minute talk, I had practised it it was going to be abit of a gallop but I could get through it with time to spare for some questions. So there I was 10 minutes in and it’s going good. Then the computer system crashed. I could of stood there like a lemon or I could crack-on and I had to do the rest of the talk with no slides or other teaching aids. ProfK had to do his whole talk like that. So my message was not really delivered.
Later in the day, I saw what Dr Lemon looked like as the slides crashed on a key opinion leader…Not a pretty sight:-)
I now look at the Charcot programme and ask where are the memory B cell talks? A couple of years ago, we suggested that all drugs that work in relapsing MS target this sub-population of B cells.
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.
The drugs that work the best, target this subpopulation the best. If you deplete memory B cells you inhibit MS, if you don’t, you don’t ,and natalizumab traps them in the blood so they can’t get in the brain. There it is, MS treatments are so easy to explain and you can make it T cell dependent or independent, depending on how mischevious you want to be. The choices for you and your neuro become in my opinion…. very simples.
However, pharma and the MS Community don’t want simple, they want you to think every thing is different and it is all so complicated so “Trust Me I’m a Doctor”. However, they can make it so complicated, you don’t know where to look . Sadly neuros then don’t know what to do and some treatments get left in the maggot pile…..rotting. The memory B cell idea is forgotten. I’m airbrushed from History:-(
In recent comments You said and asked
“Why is there so much resistance to your theory concerning memory B cells? Are you the smelly kid that nobody wants to play with or is it because you call a turd a turd (and we all know they can’t be polished)”.
“What do your colleagues in immunology think? Personally, I’m starting to think they should be leading the charge against MS, not neurologists”.
Well I suspect we will see a lot of rubbing, but I’m not sure the Genie of Enlightenment is due to appear. As for leading the Charge, be careful what you wish for, because I wonder if the Charge of the Light Bridage is the charge that you will get. We all know what happened to the 600.
In this week’s study published by Immunologists, what do we get? A charge into the Valley of Death or a Charge into the Path of Enlightment.
It says ” Based on the earlier assumption that the pathophysiology of MS is mainly mediated by T cells, the majority of established MS medications have been designed and trialed to target pro-inflammatory T cell properties. As a consequence, relatively little is known on how these MS drugs may influence B cells, and if so, how this may contribute to their therapeutic efficacy”.
Really? Is there really little known, or are they just saying that to make their data seem interesting? It is important to say that you will know a lot more if you read. There is no mention of our memory B cell idea:-(. So what do we make of the data? It is open access . Go-on, have a read!
Why do I do this? Well we talked about the memory B cell idea and it is approriate to fit all data into the idea or reject it, if need be.
In this study they looked at 4 different drugs and compared them to each other and to untreated MS and hoped to gain insight. What did they get? A fingolimod group showed a reduced B cell frequency, natalizumab increased B cells and dimethyl fumarate had no effect. So do we think that fingolimod would inhibit MS, dimethyl fumarate and glatiramer acetate won’t work and natalizumab would make things worse. But this doesn’t fit with the clinical experience. So back to the drawing board
Dimethyl fumarate and fingolimod increase transitional (immature B cells). They are about as good as each other. Is this the reason? However memory B cells go down is that the reason? Natalizumab increase them. Where do we look? Do we hear “It’s behind you?” They so “Oh no it isn’t”, Maybe I say “Oh yes it is” and so on goes the science pantomime. Widow Twangky seems to say one thing and but let’s look at the data. What do you see?
They say “Glatiramer acetate treatment exerted no detectable effect on B cells”. I say “Say no more”. Maybe that’s all we need to say.
In this study they report there is a predominant increase in pro-inflammatory B cell subsets (CD25+, CD40+, CD80+, CD69+, CD86+, TNF+) upon natalizumab treatment. They then study the immune stimulatory effect by adding natalizumab to white blood cells and TNF and IL-6 were produced and CD40, CD69 and CD95 were increased and proliferation and cell death are unaffected.
They add the antibody and see some of the changes they see in the blood. But without linking it to efficacy I guess you can ask is it related to the mechanism of action, but if it is making memory B cells is this a problem?
So there you have it….we have no clue on how we explain the 4 drugs and you are left wondering why natalizumab doesn’t make MS worse? Natalizumab has effects on B cells, T cells and monocytes, where should we look? “It’s behind you!”…..Really “It’s behind you!!!”
So in conclusion the study says “Established MS therapeutics exert fundamentally opposing effects on B cells, reaching from their inhibition (DMF, FTY) to substantial activation (NAT). Possible clinical consequences of these complex alterations yet need to be established”.
So as your head explodes whilst not knowing where to look as the immunologists have confused us all. We ask Mighty mouse who asked the question above? Should immunologist lead the charge?
Just remember memory B cells express CD27, CD40, CD80, CD86 and CD69 and CD95 are activation and regulation markers, natalizumab traps cells in blood and stops them getting in the brain, dimethyl fumarate and fingolimod stop them accumulating in the blood and so they can’t get into the brain. If they don’t arrive in the brain they can’t trigger MS attack. Now this may be wrong, but why try suggest something so complicated that no one can understand, or take the easy approach that I think anyone can understand. Then explain your results when you know where to look.
So when you polish your work, you don’t smell a stink but the Aire of Enlightenment.
What do you think?
After this I am sure I will be seen as Mr. Stinky, as I am sure some people will be calling me an “a-hole”. But I hope this post educates and enlightens. I am happy to be proved wrong, because that is what science is about
Sermon Endeth Amen!
P.S. Remember I may be wrong because in contrast to what our commenter suggested….. apparently you can polish them…..Gross!
Natalizumab promotes activation and pro-inflammatory differentiation of peripheral B cells in multiple sclerosis patients. Traub JW, Pellkofer HL, Grondey K, Seeger I, Rowold C, Brück W, Husseini L, Häusser-Kinzel S, Weber MS. J Neuroinflammation. 2019 Nov 16;16(1):228.
Background. In the past, multiple sclerosis (MS) medications have been primarily designed to modulate T cell properties. Based on the emerging concept that B cells are equally important for the propagation of MS, we compared the effect of four commonly used, primarily T cell-targeting MS medications on B cells.
Methods. Using flow cytometry, we analyzed peripheral blood mononuclear cells (PBMC) of untreated (n = 19) and dimethyl fumarate (DMF; n = 21)-, fingolimod (FTY; n = 17)-, glatiramer acetate (GA; n = 18)-, and natalizumab (NAT; n = 20)-treated MS patients, focusing on B cell maturation, differentiation, and cytokine production.
Results. While GA exerted minor effects on the investigated B cell properties, DMF and FTY robustly inhibited pro-inflammatory B cell function. In contrast, NAT treatment enhanced B cell differentiation, activation, and pro-inflammatory cytokine production when compared to both intraindividual samples collected before NAT treatment initiation as well as untreated MS controls. Our mechanistic in vitro studies confirm this observation.
Conclusion. Our data indicate that common MS medications have differential, in part opposing effects on B cells. The observed activation of peripheral B cells upon NAT treatment may be instructive to interpret its unfavorable effect in certain B cell-mediated inflammatory conditions and to elucidate the immunological basis of MS relapses after NAT withdrawal