Ecoclimber
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There are some in the ME/CFS medical field that believe ME/CFS is 'MS Light' or 'Atypical MS'. The reason I post these articles is the fact that research in one area may spill over into another area of research or the fact that researchers reviewing a site may look at the research in another disease category that could be related to theirs and it might raise their interest level.
Futhermore, research may be further ahead in another field that ME/CFS researchers wish to explore if they had the funding and the researchers to explore such as EBV, HERVs, Autoimmune diseases, Fibromyalgia, Lyme etc.
Permission to post Prof.
How long are memory B cell depleted?. Can we learn from other conditions
Understandingyourtreatmentsspeak
We have been making the case that memory B cells are a central player in the treatment target for all drugs in MS.
As we saw yesterday many people don't buy this idea (see below) or perhaps don't even know about this idea because they: (a) don't read the blog; (b) Don't read papers (c) cannot assimilate knowledge or (d) all of the above or (e) I'm wrong.
Yesterday I was sad, because it confirmed what I wrote above.
So I want to put more meat on the idea
I was talking about B cells and the fact there were are more than one type of cell that make up the CD19 population.
Some didn't like my slide
You (at least one of you) said I was talking "jibberish" and it is unrelated to people with MS and it was more relevant to scientists and doctors.
I said "nonsense" because, it is important in understanding the choices that you may need to make.
Is the level pitched wrongly...the answer will be yes and perhaps no...however virtually every part of the post has been explained in the past and so look at the education posts to help you get up to speed.
If you look at alemtuzumab, the CD19 B cell population (in green below) is back to normal levels within 3 months. But alemtuzumab is still working years later...so it can't be the B cell? Can it?
This is the view if you see CD19 B cells as a single population as is usually portrayed.
So can it be the B cell?
Yes it can, because that repopulation is occurring because of immature and then mature (also called naive B cells) cell subsets come rushing out of the bone marrow to fill the space vacated by the lymphocytes that are killed. This masks the fact that memory B cells are being depleted long-term.
See our picture from Baker et al. 2017 (below). This is the pattern you see with rituximab, and HSCT so there is nothing special going on.
The blue (Total CD19+) is a composite response of the (green, pink and the baby blue). The antibody is given at 0 and 12 months and shows percentage change from baseline (-80 = 80% depletion)
This is the default pathway for B cell repopulation and will occur for all drugs that kill B cells. However, with HSCT and alemtuzumab, this occurs in the relative absence of effective T cell regulation by CD8 T cells and maybe CD4 T regs. The default pathway of T cells is the immediate repopulation comes from expansion of the memory cells, this is seen in humans and mice. There is nothing special going on. However back to the B cells.
We have suggested that this B celll hyper-population could be the basis for the secondary B cell autoimmunities that can occur with alemtuzumab and HSCT (lower proportion than alemtuzumab) in a person with the genetic background that allows autoimmunity to develop as this does not occur when alemtuzumab is used in cancer. So the change in proportions per se is not the answer.
As I do "Grant of the month" when I give ideas away for free.
Here is my new installment which is/has been written up and you are getting a sneak preview.
The most effective agents at depleting memory B cells are in my opinion: alemtuzumab, cladribine, and ocrelizumab (and HSCT), with fingo and tecfidera in the next rung and then the CRABS. We need to see MS data for daclizumab and teriflunomide but they will be in the range of fingo or below. There is a poster with leflunomide so we know the ball-park figure and there is transplant data with daclizumab.
CoI: None
With ocrelizumab, memory B cells are hit ever 6 months, with alemtzumab and claribine, they are hit essentially twice a year apart and then you wait to see what happens. With HSCT they are hit twice once with the agent that mobilises the stem cells from the bone marrow (usually cyclophosphamide) and then again during the immune ablation.
Why do induction therapies last so long?
First question is
How long does it take for memory cells to get back to normal?
There is not enough long-term data on cladribine to talk about it...I know... this makes a change.
This is also the case for ocrelizumab (anti-CD20) too, however we have rituximab and as it is being used off-label in a variety of immune conditions it can and I think has told us how these other agents probably work.
Yes, rituximab can delete CD20 positive T cells, but they remain within normal limits.
Lavielle M, Mulleman D, Goupille P, Bahuaud C, Sung HC, Watier H, Thibault G. Repeated decrease of CD4+ T-cell counts in patients with rheumatoid arthritis over multiple cycles of rituximab treatment. Arthritis Res Ther. 2016 ;18:253.
Yes, this happens in MS also
Palanichamy A, Jahn S, Nickles D, Derstine M, Abounasr A, Hauser SL, Baranzini SE, Leppert D, von Büdingen HC. Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J Immunol. 2014; 193:580-586.
So depletion of T cells by 20% is enough for some people to think that this is how rituximab works.
But you have to say "come on people"....."Think outside your T cell box"
Why take the the most difficult idea to support a blinkered world view, and throw away a simpler hence more plausible one?
But that is what is done by the majority of MSologists/EAEers as they are convinced that it is all T cells.
Sure EAE is all T cells but you have to ask...
What does the response to treatment tell you?
I may be wrong and the pathogenic cell is actually in the tiny population affected by rituximab and that this was missed by the large population wiped out by CD4-specific monoclonal antibody.
However, in the same paper, where Palanichamy et al. 2014 showed a tiny effect on T cells they showed a massive effect on memory B cells. These were depleted for at least a year.
So back to the question how long are the B memories gone for?
The data is not there in MS (OK it probably is, but controlled by pharma, but we can learn from other conditions where B cell depletion is used.
Anolik JH, Barnard J, Owen T, Zheng B, Kemshetti S, Looney RJ, Sanz I. Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy. Arthritis Rheum. 2007;56:3044-56.
Whilst the number of samples could be bigger, this paper tells us that people who respond well to CD20 depletion have low memory B cell levels, 5 years after the last dose of rituximab.
They showed 6.3 ± 0.9% memory B cells in the blood compared to normal where there are 30.5 ± 6.9% memory B cells. The failers with poor response have a total memory cells 51.1 ± 23.2% total.
For those interested it is due to loss of both immunoglobulin class switched (IgD- but IgG+ or IgM+ or IgA+) or unswitched (IgD+) memory B cells (see below).
STOP FOR EDUCATION.
When a B cell is activated it hypermutates the target binding region (red bit on the diagram below) of the antibody molecules to make it bind its target more strongly. It also changes its tail (blue bit below) for be IgG, IgA, IgM etc
As the memory B cell subset is also a mixed population to help compare with other publications (below) there were 3.6 ± 0.5% immunoglobulin class switched from IgD to IgM/IgA/IgG compared to 18.3 ± 5.89% in health and 2.7 ± 0.4% versus 12.2 ± 4% for the non-switched memory B cells.
So let's say its all T cells and forget such information .
However the B cell idea fits with other studies that link memory B cell numbers and plasmablasts (precursors to antibody producing cells) that can be derived from memory cells to disease activity
See
Vital EM, Dass S, Buch MH, Henshaw K, Pease CT, Martin MF, Ponchel F, Rawstron AC, Emery P. B cell biomarkers of rituximab responses in systemic lupus erythematosus. Arthritis Rheum. 2011; 63:3038-47
These studies also tell us that it is the degree of B cell depletion rather than the dose of antibody used to cause depletion that is important
Vital EM, Rawstron AC, Dass S, Henshaw K, Madden J, Emery P, McGonagle D. Reduced-dose rituximab in rheumatoid arthritis: efficacy depends on degree of B cell depletion. Arthritis Rheum. 2011; 63:603-8.
So this is important for MS because it suggests:
(a) Dosing every 6 months with ocrelizumab may be too frequent. This is probably especially the case, as ocrelizumab is more effective than rituximab (better depleter) and more ocrelizumab is dosed than used with rituximab. This is relevant because ocrelizumab is not inert and depleting B cells long-term leaves you open to infection.
(b) Anti-CD20 probably has induction therapy potential, just like we showed based on the phase II extension studies where efficacy was maintained 18 months after the last dose in the majority of people.
This supports the idea that the drug maybe being dosed too frequently.
Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K.Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017;16:41-50.
A trial needs to be done to confirm/refute this.
This indicates that once depleted, memory B cell stay depleted and stay depleted for a long, long-time, in some people. This perhaps should not be surprising because it looks like after depletion
Memory B cell repopulation, reflects ontogeny (development), and is very slow. It takes 10 or more years for your B cell memory to fully mature.
If you look at memory B numbers moving from birth to adulthood, the accumulation of memory B cells into the blood is very slow as least in Western Europe
Morbach H, Eichhorn EM, Liese JG, Girschick HJ. Reference values for B cell subpopulations from infancy to adulthood.
Clin Exp Immunol. 2010;162:271-9.
Duchamp M, Sterlin D, Diabate A, Uring-Lambert B, Guérin-El Khourouj V, Le Mauff B, Monnier D, Malcus C, Labalette M, Picard C.B-cell subpopulations in children: National reference values. Immun Inflamm Dis. 2014 Nov;2(3):131-40
see the bottom line is at about 2.5% anthe one above is at about 5%
You can see (above) based on development it takes between 18 months to 4 years to develop 3.6% class switched memory B cells. So the fact that there are 3.6% class-switched B cells 5 years after rituximab suggest it takes years to get a normal complement of cells. At 5 years there should be about 10-15% memory cells so the repopulation process is slower and with ocrelizumab this may be because plasma cells are not destroyed, because they do not express CD20. It means you do not need to make responses to childhood infections again as they may no be lost.
Therefore Induction therapy may simply be long-term memory B cell depletion.
If it is not a reboot then will disease return?
However, based on the alemtuzumab NEDA data it would indicate that there is some disease activity in most people, but it is also clear that some people do very well. Are they the best responders let's find out.
Studies in childhood MS indicate that they have more memory cells
What is the difference in the B memory cell repertoire of the responders verses the failers?.
For the people responding well,,,, you don't need to retreat for years, maybe never, if they are effectively regulated.
For the failures one monitors blood levels and retreats to a target memory B cell level. As is done in a number of Non-MS conditions. So in some people the memories come back quickly..why?
That's another post.
The memory B cells get destroyed because they express the drug targets for alemtuzumab (CD52), orcrelizumab (CD20) and cladribine (deoxycytidine kinase).
This it true of the mature cells too, but the difference is that they repopulate from different places.
The immature/mature are repopulating from the bone marrow. Whereas, the memory cells are repopulating from the lymphoid tissue. I think this is important.
It looks like alemtuzumab may not effectively purge the bone-marrow based on the suggestion that fingolimod can sequester cells away from the actions of alemtuzumab to stop it working (Willis et al. 2017). Maybe the protein does not penetrate as well and it needs complement and natural killer cells to kill.
Ocrelizumab is also an antibody and less will penetrate the bone marrow than the blood and it does not target pro-B cells (precursor B cells), which do no express CD20 and so the B cell precursors may not be hit as much as in the blood so they can repopulate easier.
We know from studies with rituximab that bone marrow is affected but it is less affected than the peripheral blood.
Nakou M, Katsikas G, Sidiropoulos P, Bertsias G, Papadimitraki E, Raptopoulou A, Koutala H, Papadaki HA, Kritikos H, Boumpas DT.Rituximab therapy reduces activated B cells in both the peripheral blood and bone marrow of patients with rheumatoid arthritis: depletion of memory B cells correlates with clinical response.Arthritis Res Ther. 2009;11(4):R131
So in arthritis in the blood the level of memory B cells dropped from 30% to 9% in the responders compared to an increase to 39% in the non-responders and in the bone marrow they dropped to 26% in the responders. So further evidence for the link between memory B cells and disease activity...How much more evidence do we need?
Memory B cells may not repopulate quickly because they repopulate slowly and importantly because the precursors of the memory cell are destroyed in the lymph glands and so this probably adds to a slow repopulation, therefore these anti-B cell treatments last a long time.
We know this because again following rituximab treatment some people have had their spleens removed or they have had lymph node or tonsil biopsies.
In the cases above on the right the B cell follicles (in brown) are removed and on the left the follicle structure is gone leaving only some plasma cell follicles but the memory cells are gone.
In fact in Anolik et al 2007 above they did lymph node biopsies 5 years after treatment and they were still affected and there were less CD27+ cells after rituximab (31.5 +/ 4.9%) as compared with untreated SLE patients (58.3 +/- 15%) and the treatment failers (76% +/- 11.3%). Showing long term effects on lymph glands that may contribute to the more marked depletion (remember it memory cels were only 9% of CD19+ cells) in blood
These are going to contribute to the slow repopulation of memory B cells.
However ,with time memory B cells appear to return because at 12 and 20 years the memory cell levels are back up after alemtuzumab
Immunity 12 years after alemtuzumab in RA: CD5⁺ B-cell depletion, thymus-dependent T-cell reconstitution and normal vaccine responses. Rheumatology. 2012: 51:1397-406.
FA, Anderson AE, Drayton T, Harry RA, Diboll J, Munro L, Thalayasingham N, Östör AJ, Isaacs JD. Arthritis Res Ther. 2016;18(1):302 Immune reconstitution 20 years after treatment with alemtuzumab in a rheumatoid arthritis cohort: implications for lymphocyte depleting therapies.
So in summary the scenario for B cell depleting treatments is that after depletion immature B cell repopulate followed by mature B cells with ocrelizumab they repeat this cycle every 6 months (yellow circular arrow). Will the daily treatments the matures won,t return.
With alemtuzumab and probably cladribine the memory cells are going to take 18 months to 5-6 years to repopulate. If the pathogenic cells are regulated effectively, disease is gone if not there will be disease-reactivation Other drugs do the same but they are less effective at B cell depletion. This is how they all work.
Here, I have left the B cells in the brain intact but CNS penetrable agents may get them. and also agents that clear the bone marrow may also repopulate slower. However the brain clusters may need memory B and T to survive
Do you still think it is T cell mediated?
COI. This idea has not been peer reviewed yet so maybe I have missed something.....but I am sure Luis and Steve S will be on the case
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Posted by MouseDoctor at 07:00
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22 comments:
FiSaturday, October 07, 2017 8:43:00 am
Thank you MD for providing such a comprehensive and accessible post - even with my extremely limited capacity for anything scientific I have found so much of this accessible and easy to understand.
I have been asked why Alemtuzumab works for some and not others and why the number of years of its effectiveness vary and I may now be able to explain (though if you heard it in my terms I'm sure I'd make you wince!)
As I'm due my three days of Alemtuzumab in a couple of weeks time I'm gonna be saying my Hail Marys that them there memory B cells stay well and truly done for!
Best wishes for your efforts to have this perspective accepted and endorsed by others in your scientific community.
Have a good weekend.
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Alex HansenSaturday, October 07, 2017 1:09:00 pm
Great post, thank you for all the effort that clearly went into this ��
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adam bombSaturday, October 07, 2017 3:16:00 pm
If Alemtuzumab does not get rid of brain lesions
won't someone always have a chance of disease resumption.
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MouseDoctorSunday, October 08, 2017 8:20:00 am
If we look at the NEDA rates recently presented about 60% or more people had some activity.
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AnonymousSaturday, October 07, 2017 4:27:00 pm
Great post, MD.
I am missing something important: Do you need to mount a new response to infection in order to repopulate memory Bcells?
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MouseDoctorSaturday, October 07, 2017 8:54:00 pm
I think this may be part of the slow repopulation but as drug is gone nothing to stop repopulation occuring. After alemtuzumab you can be vaccinated. After HSCT you have to be vaccinated as you have a new repertoire. I think that if the planes cells Sur I've you existing immunity survives so maybe not much of a driving force for new b cells.
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AnonymousSaturday, October 07, 2017 6:29:00 pm
Ok I'm sold. Makes sense, data fits, sounds logically. However. Unless I'm being dumb, why does Alemtuzumab produce superior brain atrophy then b depleting agents? Granted alemtuzumab works on two front. One makes immune less tolerant of the original infection. 2nd depleting memory cells. Surely inspite of the first effect b cell still drives the progression as the disease as your paper explains. But inspite this Ocrelizumab should have superior brain atrophy data?
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AnonymousSaturday, October 07, 2017 11:39:00 pm
Ok. We are comparing apples and pears. Because we Don't have real world data for ocrelizumab since its just been approved in March 2017 so the need to look at clinical trial data. However, the real world data for alemtuzumab is still good in terms of brain atropy. Where as the neda for ocrelizumab is almost excellent. Reducing inflammation by 98%. Inspite the difference in patient selection between the two, it seems ocrelizumab brain atrophy should be in the highs given it's efficacy in total suppression on inflammation? Where as neda for alemtuzumab is okay.
MouseDoctorSunday, October 08, 2017 8:37:00 am
Good point becuase they should be the same. However are we comparing like for like?
In the alemtuzumab trials people i think people were on treatment within two years but looking at the cladribine it takes four years to be on drug and for ocrelizumab it was about 3.8 years so is the difference due 2 extra years of loss of brain reserve.
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AnonymousSaturday, October 07, 2017 6:58:00 pm
For sure noone argues that B cells play a leading role in autoimmune diseases, but the arguement is if they are the soldiers or the generals. One unanswered question that cannot be ignored is that where the selection of organs comes from, if it is just the memory B cells. One could imagine many reasons apart from that it stems from the different types of T cells involved, but the secondary autoimmunity that emerges from Lemtrada deletes many of them I think...
The predisposition for Lemtrada's s.autoimmunity is only a theory also.
The involvement of CD4-CD8 is weak since DMF depletes those for long term after treatment yet the disease is not improved. So, DMF is probably all about the Bcells. Still that doesn't dispove of the idea of T cell involvement.
I see in one of the papers that you have posted here that another subtype of T cells is depleted together with RTX, which is the CD3 in MS and it is different than the one in RAs RTX. Does this have something to say to us?
Also, the non responders are patients that created antibodies or there are other reasons involved? A different anti20 drug can answer that.
Also, how long does a memory b cell live? Even if the drugs cannot reach the brain, since these agents affect both the blood and the lymph glands, wouldn't eventually, after some reasonable time, the B cells accumulated in the brain die and not be replaced?
Thank you very much for your article, really appreciated!
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MouseDoctorSaturday, October 07, 2017 8:20:00 pm
Where is the selection for the organs very good question. I don't know I can give the lame answer and say it is a specific antibody to something in the CNS,which is about as good as it gets for the T cell.
CD3 is a T cell it is expressed by cd4 and CD8.
MouseDoctorSaturday, October 07, 2017 8:42:00 pm
How long do memory cells live is another great question and also we need to ask how long do plasma cell live
B cells in culture tend to die very quickly or within a couple of weeks
I don't know enough about b cells to answer these and profG and I was talking about this on Friday.
Annonie MouseSaturday, October 07, 2017 10:11:00 pm
Anon 6.58
I think CD3 is all T cells? ie no subset?
Re memory B, I've got a horrible feeling that the ones with ebv in might live forever? Even worse, my brain is stuffed full of 'em
luis fernandoSunday, October 08, 2017 1:14:00 am
"b cells are the cockroachs of the immune system"
one study found
IgG1+ memory B cells specific for the 1918 pandemic
strain of influenza virus circulating in the blood of survivors
90 years after primary exposure to the virus.
luis fernandoSunday, October 08, 2017 1:20:00 am
"How long do memory cells live"
Longevity. To determine which types of cells and which
types of molecules are required for memory B cell survival,
previous studies have used IgG+ memory B cells
as a target. IgG+ memory B cells can persist in the
absence of T cells or input from precursor cells, but
experiments using mice with follicular dendritic cells
(FDCs) in which the gene encoding complement receptor
2 (Cr2) has been knocked out have suggested that
there is a requirement for FDCs for the maintenance
of IgG+ memory B cells44. In these mice, the primary
IgG response was unaffected, but the secondary antibody
response was significantly decreased. Notably,
the impaired memory response corresponded with the
reduced frequency of antigen-specific memory B cells.
Thus, one straightforward interpretation is that CR2 on
FDCs promotes the survival of IgG+ memory B cells,
directly or indirectly, possibly by functioning as a depot
for antigen–antibody–complement complexes; however,
the role of antigen persistence in memory responses
is debated (see below).
Inducible deletion of phospholipase Cγ2 (PLCγ2)
after the generation of IgG1+ memory B cells substantially
decreased the size of the memory B cell
compartment, which suggests a requirement for
BCR signalling for IgG1+ memory B cell survival45.
Memory B cells doi:10.1038/nri3802
Obrigado
Luis
luis fernandoSunday, October 08, 2017 1:39:00 am
PLC-γ2 is essential for formation and maintenance of memory B cells
Abstract
Resting antigen-experienced memory B cells are thought to be responsible for the more rapid and robust antibody responses after antigen reencounter, which are the hallmark of memory humoral responses. The molecular basis for the development and survival of memory B cells remains largely unknown. We report that phospholipase C (PLC) γ2 is required for efficient formation of germinal center (GC) and memory B cells. Moreover, memory B cell homeostasis is severely hampered by inducible loss of PLC-γ2. Accordingly, mice with a conditional deletion of PLC-γ2 in post-GC B cells had an almost complete abrogation of the secondary antibody response. Collectively, our data suggest that PLC-γ2 conveys a survival signal to GC and memory B cells and that this signal is required for a productive secondary immune response.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699133/
MouseDoctorSunday, October 08, 2017 2:10:00 pm
Thanks for this. I'll have a look. The CR2 = EBV receptor...ProfG asked how long does antigen persist on the follicular dendritic cell (a cell that keeps B cells going).
AnonymousSunday, October 08, 2017 3:24:00 pm
This was released earlier this year but I can't have access to it.
First Atlas of B-cell Clones in Human Body Forms New Foundation for Infectious Disease Research
https://www.pennmedicine.org/news/n...ew-foundation-for-infectious-disease-research
"Our fantasy for the future is to create organ-specific immune monitoring assays. If we can define features of the antibody repertoire that are unique to particular tissues, we may be able to monitor tissue-specific immune responses using blood-based clinical lab tests.”
Such tests might be used to monitor immune responses to vaccines or inappropriate antibody responses in organ-specific autoimmune diseases; however, the first step towards that is knowing the location of B-cell clones.
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Annonie MouseSaturday, October 07, 2017 9:56:00 pm
Well, this is some post MD! Like Fi this morning, I'm stunned by how much I've understood so well done indeed, top marks for accessibility
Thank heavens for SLE and RA research, profiling B cells for the last 10 years. 'Clinical response to rituximab is associated with depletion of CD19+CD27+ memory B cells' lost track of which excellent paper I've copied that from ;-)
So who are the responders? How on earth can we know if we don't profile B cells whilst on dmt?
That's the best line ever 'treat infrequently and monitor' get it printed on a T-shirt and wear it to ECTRIMS.
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MouseDoctorSunday, October 08, 2017 8:18:00 am
The MS Society has just supported us to be able to look at this very aspect
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luis fernandoSaturday, October 07, 2017 11:38:00 pm
Excellent post Md
One of the best i have ever seen (wonder how manny hours it took to complete)
As a true scientific assay it raises more questions than provides
answers
According to this review tfh and also Dendritic folicular cells are needed for a robust B cell memory response
"In summary, there are multiple pathways for generating
B cell memory. Although T cell-independent memory
B cells can be generated as discussed above, it seems
that their recall response is quantitative, rather than
qualitative, in nature. Thus, aside from the increased frequency
of antigen-specific B cells, it is unclear whether
T cell-independent memory B cells have an intrinsic
advantage compared with their naive B cell counterparts
to respond more rapidly and more robustly to antigen,
as is seen in T cell-dependent B cell memory. Therefore,
we hereafter focus on several aspects of canonical,
T cell‑dependent memory B cells."
IgG+ memory B cells can persist in the
absence of T cells or input from precursor cells, but
experiments using mice with follicular dendritic cells
(FDCs) in which the gene encoding complement receptor
2 (Cr2) has been knocked out have suggested that
there is a requirement for FDCs for the maintenance
of IgG+ memory B cells44. In these mice, the primary
IgG response was unaffected, but the secondary antibody
response was significantly decreased. Notably,
the impaired memory response corresponded with the
reduced frequency of antigen-specific memory B cells.
Thus, one straightforward interpretation is that CR2 on
FDCs promotes the survival of IgG+ memory B cells,
directly or indirectly, possibly by functioning as a depot
for antigen–antibody–complement complexes; however,
the role of antigen persistence in memory responses
is debated (see below).
Although virusspecific
memory B cells can be activated in the absence
of T cells57, T cell help is a strict requirement for the
reactivation of memory B cells that are specific for monomeric
protein antigens
Memory B cells doi:10.1038/nri3802
Anyway I dont think its only t cells or memory B (even follicular dendritic)
Maybe they are all working togheter
Anyway i see your post have some aditions to your previous woork
Ps: Good luck with your Ectrims adventure hope you get thru those
skeptical looking neuros
Glad to be helping
Obrigado
Luis
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luis fernandoMonday, October 09, 2017 2:29:00 am
After all those dreadfull long lived plasma b cells can be knock down (hopefully)
Just found this
Proteasome Inhibition with Bortezomib
Depletes Plasma Cells and Autoantibodies in
Experimental autoimmune myasthenia gravis.
https://www.ncbi.nlm.nih.gov/pubmed/21239719
Long-lived plasma cells are early and constantly
generated in New Zealand Black/New Zealand
White F1 mice and their therapeutic depletion
requires a combined targeting of autoreactive
https://www.ncbi.nlm.nih.gov/pubmed/25889236
Obrigado
plasma cells and their precursors
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Futhermore, research may be further ahead in another field that ME/CFS researchers wish to explore if they had the funding and the researchers to explore such as EBV, HERVs, Autoimmune diseases, Fibromyalgia, Lyme etc.
Permission to post Prof.
How long are memory B cell depleted?. Can we learn from other conditions
Understandingyourtreatmentsspeak
We have been making the case that memory B cells are a central player in the treatment target for all drugs in MS.
As we saw yesterday many people don't buy this idea (see below) or perhaps don't even know about this idea because they: (a) don't read the blog; (b) Don't read papers (c) cannot assimilate knowledge or (d) all of the above or (e) I'm wrong.
Yesterday I was sad, because it confirmed what I wrote above.
So I want to put more meat on the idea
I was talking about B cells and the fact there were are more than one type of cell that make up the CD19 population.
Some didn't like my slide
You (at least one of you) said I was talking "jibberish" and it is unrelated to people with MS and it was more relevant to scientists and doctors.
I said "nonsense" because, it is important in understanding the choices that you may need to make.
Is the level pitched wrongly...the answer will be yes and perhaps no...however virtually every part of the post has been explained in the past and so look at the education posts to help you get up to speed.
If you look at alemtuzumab, the CD19 B cell population (in green below) is back to normal levels within 3 months. But alemtuzumab is still working years later...so it can't be the B cell? Can it?
This is the view if you see CD19 B cells as a single population as is usually portrayed.
So can it be the B cell?
Yes it can, because that repopulation is occurring because of immature and then mature (also called naive B cells) cell subsets come rushing out of the bone marrow to fill the space vacated by the lymphocytes that are killed. This masks the fact that memory B cells are being depleted long-term.
See our picture from Baker et al. 2017 (below). This is the pattern you see with rituximab, and HSCT so there is nothing special going on.
The blue (Total CD19+) is a composite response of the (green, pink and the baby blue). The antibody is given at 0 and 12 months and shows percentage change from baseline (-80 = 80% depletion)
This is the default pathway for B cell repopulation and will occur for all drugs that kill B cells. However, with HSCT and alemtuzumab, this occurs in the relative absence of effective T cell regulation by CD8 T cells and maybe CD4 T regs. The default pathway of T cells is the immediate repopulation comes from expansion of the memory cells, this is seen in humans and mice. There is nothing special going on. However back to the B cells.
We have suggested that this B celll hyper-population could be the basis for the secondary B cell autoimmunities that can occur with alemtuzumab and HSCT (lower proportion than alemtuzumab) in a person with the genetic background that allows autoimmunity to develop as this does not occur when alemtuzumab is used in cancer. So the change in proportions per se is not the answer.
As I do "Grant of the month" when I give ideas away for free.
Here is my new installment which is/has been written up and you are getting a sneak preview.
The most effective agents at depleting memory B cells are in my opinion: alemtuzumab, cladribine, and ocrelizumab (and HSCT), with fingo and tecfidera in the next rung and then the CRABS. We need to see MS data for daclizumab and teriflunomide but they will be in the range of fingo or below. There is a poster with leflunomide so we know the ball-park figure and there is transplant data with daclizumab.
CoI: None
With ocrelizumab, memory B cells are hit ever 6 months, with alemtzumab and claribine, they are hit essentially twice a year apart and then you wait to see what happens. With HSCT they are hit twice once with the agent that mobilises the stem cells from the bone marrow (usually cyclophosphamide) and then again during the immune ablation.
Why do induction therapies last so long?
First question is
How long does it take for memory cells to get back to normal?
There is not enough long-term data on cladribine to talk about it...I know... this makes a change.
This is also the case for ocrelizumab (anti-CD20) too, however we have rituximab and as it is being used off-label in a variety of immune conditions it can and I think has told us how these other agents probably work.
Yes, rituximab can delete CD20 positive T cells, but they remain within normal limits.
Lavielle M, Mulleman D, Goupille P, Bahuaud C, Sung HC, Watier H, Thibault G. Repeated decrease of CD4+ T-cell counts in patients with rheumatoid arthritis over multiple cycles of rituximab treatment. Arthritis Res Ther. 2016 ;18:253.
Yes, this happens in MS also
Palanichamy A, Jahn S, Nickles D, Derstine M, Abounasr A, Hauser SL, Baranzini SE, Leppert D, von Büdingen HC. Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J Immunol. 2014; 193:580-586.
So depletion of T cells by 20% is enough for some people to think that this is how rituximab works.
But you have to say "come on people"....."Think outside your T cell box"
Why take the the most difficult idea to support a blinkered world view, and throw away a simpler hence more plausible one?
But that is what is done by the majority of MSologists/EAEers as they are convinced that it is all T cells.
Sure EAE is all T cells but you have to ask...
What does the response to treatment tell you?
I may be wrong and the pathogenic cell is actually in the tiny population affected by rituximab and that this was missed by the large population wiped out by CD4-specific monoclonal antibody.
However, in the same paper, where Palanichamy et al. 2014 showed a tiny effect on T cells they showed a massive effect on memory B cells. These were depleted for at least a year.
So back to the question how long are the B memories gone for?
The data is not there in MS (OK it probably is, but controlled by pharma, but we can learn from other conditions where B cell depletion is used.
Anolik JH, Barnard J, Owen T, Zheng B, Kemshetti S, Looney RJ, Sanz I. Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy. Arthritis Rheum. 2007;56:3044-56.
Whilst the number of samples could be bigger, this paper tells us that people who respond well to CD20 depletion have low memory B cell levels, 5 years after the last dose of rituximab.
They showed 6.3 ± 0.9% memory B cells in the blood compared to normal where there are 30.5 ± 6.9% memory B cells. The failers with poor response have a total memory cells 51.1 ± 23.2% total.
For those interested it is due to loss of both immunoglobulin class switched (IgD- but IgG+ or IgM+ or IgA+) or unswitched (IgD+) memory B cells (see below).
STOP FOR EDUCATION.
When a B cell is activated it hypermutates the target binding region (red bit on the diagram below) of the antibody molecules to make it bind its target more strongly. It also changes its tail (blue bit below) for be IgG, IgA, IgM etc
As the memory B cell subset is also a mixed population to help compare with other publications (below) there were 3.6 ± 0.5% immunoglobulin class switched from IgD to IgM/IgA/IgG compared to 18.3 ± 5.89% in health and 2.7 ± 0.4% versus 12.2 ± 4% for the non-switched memory B cells.
So let's say its all T cells and forget such information .
However the B cell idea fits with other studies that link memory B cell numbers and plasmablasts (precursors to antibody producing cells) that can be derived from memory cells to disease activity
See
Vital EM, Dass S, Buch MH, Henshaw K, Pease CT, Martin MF, Ponchel F, Rawstron AC, Emery P. B cell biomarkers of rituximab responses in systemic lupus erythematosus. Arthritis Rheum. 2011; 63:3038-47
These studies also tell us that it is the degree of B cell depletion rather than the dose of antibody used to cause depletion that is important
Vital EM, Rawstron AC, Dass S, Henshaw K, Madden J, Emery P, McGonagle D. Reduced-dose rituximab in rheumatoid arthritis: efficacy depends on degree of B cell depletion. Arthritis Rheum. 2011; 63:603-8.
So this is important for MS because it suggests:
(a) Dosing every 6 months with ocrelizumab may be too frequent. This is probably especially the case, as ocrelizumab is more effective than rituximab (better depleter) and more ocrelizumab is dosed than used with rituximab. This is relevant because ocrelizumab is not inert and depleting B cells long-term leaves you open to infection.
(b) Anti-CD20 probably has induction therapy potential, just like we showed based on the phase II extension studies where efficacy was maintained 18 months after the last dose in the majority of people.
This supports the idea that the drug maybe being dosed too frequently.
Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K.Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017;16:41-50.
A trial needs to be done to confirm/refute this.
This indicates that once depleted, memory B cell stay depleted and stay depleted for a long, long-time, in some people. This perhaps should not be surprising because it looks like after depletion
Memory B cell repopulation, reflects ontogeny (development), and is very slow. It takes 10 or more years for your B cell memory to fully mature.
If you look at memory B numbers moving from birth to adulthood, the accumulation of memory B cells into the blood is very slow as least in Western Europe
Morbach H, Eichhorn EM, Liese JG, Girschick HJ. Reference values for B cell subpopulations from infancy to adulthood.
Clin Exp Immunol. 2010;162:271-9.
Duchamp M, Sterlin D, Diabate A, Uring-Lambert B, Guérin-El Khourouj V, Le Mauff B, Monnier D, Malcus C, Labalette M, Picard C.B-cell subpopulations in children: National reference values. Immun Inflamm Dis. 2014 Nov;2(3):131-40
see the bottom line is at about 2.5% anthe one above is at about 5%
You can see (above) based on development it takes between 18 months to 4 years to develop 3.6% class switched memory B cells. So the fact that there are 3.6% class-switched B cells 5 years after rituximab suggest it takes years to get a normal complement of cells. At 5 years there should be about 10-15% memory cells so the repopulation process is slower and with ocrelizumab this may be because plasma cells are not destroyed, because they do not express CD20. It means you do not need to make responses to childhood infections again as they may no be lost.
Therefore Induction therapy may simply be long-term memory B cell depletion.
If it is not a reboot then will disease return?
However, based on the alemtuzumab NEDA data it would indicate that there is some disease activity in most people, but it is also clear that some people do very well. Are they the best responders let's find out.
Studies in childhood MS indicate that they have more memory cells
What is the difference in the B memory cell repertoire of the responders verses the failers?.
For the people responding well,,,, you don't need to retreat for years, maybe never, if they are effectively regulated.
For the failures one monitors blood levels and retreats to a target memory B cell level. As is done in a number of Non-MS conditions. So in some people the memories come back quickly..why?
That's another post.
The memory B cells get destroyed because they express the drug targets for alemtuzumab (CD52), orcrelizumab (CD20) and cladribine (deoxycytidine kinase).
This it true of the mature cells too, but the difference is that they repopulate from different places.
The immature/mature are repopulating from the bone marrow. Whereas, the memory cells are repopulating from the lymphoid tissue. I think this is important.
It looks like alemtuzumab may not effectively purge the bone-marrow based on the suggestion that fingolimod can sequester cells away from the actions of alemtuzumab to stop it working (Willis et al. 2017). Maybe the protein does not penetrate as well and it needs complement and natural killer cells to kill.
Ocrelizumab is also an antibody and less will penetrate the bone marrow than the blood and it does not target pro-B cells (precursor B cells), which do no express CD20 and so the B cell precursors may not be hit as much as in the blood so they can repopulate easier.
We know from studies with rituximab that bone marrow is affected but it is less affected than the peripheral blood.
Nakou M, Katsikas G, Sidiropoulos P, Bertsias G, Papadimitraki E, Raptopoulou A, Koutala H, Papadaki HA, Kritikos H, Boumpas DT.Rituximab therapy reduces activated B cells in both the peripheral blood and bone marrow of patients with rheumatoid arthritis: depletion of memory B cells correlates with clinical response.Arthritis Res Ther. 2009;11(4):R131
So in arthritis in the blood the level of memory B cells dropped from 30% to 9% in the responders compared to an increase to 39% in the non-responders and in the bone marrow they dropped to 26% in the responders. So further evidence for the link between memory B cells and disease activity...How much more evidence do we need?
Memory B cells may not repopulate quickly because they repopulate slowly and importantly because the precursors of the memory cell are destroyed in the lymph glands and so this probably adds to a slow repopulation, therefore these anti-B cell treatments last a long time.
We know this because again following rituximab treatment some people have had their spleens removed or they have had lymph node or tonsil biopsies.
In the cases above on the right the B cell follicles (in brown) are removed and on the left the follicle structure is gone leaving only some plasma cell follicles but the memory cells are gone.
In fact in Anolik et al 2007 above they did lymph node biopsies 5 years after treatment and they were still affected and there were less CD27+ cells after rituximab (31.5 +/ 4.9%) as compared with untreated SLE patients (58.3 +/- 15%) and the treatment failers (76% +/- 11.3%). Showing long term effects on lymph glands that may contribute to the more marked depletion (remember it memory cels were only 9% of CD19+ cells) in blood
These are going to contribute to the slow repopulation of memory B cells.
However ,with time memory B cells appear to return because at 12 and 20 years the memory cell levels are back up after alemtuzumab
Immunity 12 years after alemtuzumab in RA: CD5⁺ B-cell depletion, thymus-dependent T-cell reconstitution and normal vaccine responses. Rheumatology. 2012: 51:1397-406.
FA, Anderson AE, Drayton T, Harry RA, Diboll J, Munro L, Thalayasingham N, Östör AJ, Isaacs JD. Arthritis Res Ther. 2016;18(1):302 Immune reconstitution 20 years after treatment with alemtuzumab in a rheumatoid arthritis cohort: implications for lymphocyte depleting therapies.
So in summary the scenario for B cell depleting treatments is that after depletion immature B cell repopulate followed by mature B cells with ocrelizumab they repeat this cycle every 6 months (yellow circular arrow). Will the daily treatments the matures won,t return.
With alemtuzumab and probably cladribine the memory cells are going to take 18 months to 5-6 years to repopulate. If the pathogenic cells are regulated effectively, disease is gone if not there will be disease-reactivation Other drugs do the same but they are less effective at B cell depletion. This is how they all work.
Here, I have left the B cells in the brain intact but CNS penetrable agents may get them. and also agents that clear the bone marrow may also repopulate slower. However the brain clusters may need memory B and T to survive
Do you still think it is T cell mediated?
COI. This idea has not been peer reviewed yet so maybe I have missed something.....but I am sure Luis and Steve S will be on the case
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22 comments:
FiSaturday, October 07, 2017 8:43:00 am
Thank you MD for providing such a comprehensive and accessible post - even with my extremely limited capacity for anything scientific I have found so much of this accessible and easy to understand.
I have been asked why Alemtuzumab works for some and not others and why the number of years of its effectiveness vary and I may now be able to explain (though if you heard it in my terms I'm sure I'd make you wince!)
As I'm due my three days of Alemtuzumab in a couple of weeks time I'm gonna be saying my Hail Marys that them there memory B cells stay well and truly done for!
Best wishes for your efforts to have this perspective accepted and endorsed by others in your scientific community.
Have a good weekend.
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Alex HansenSaturday, October 07, 2017 1:09:00 pm
Great post, thank you for all the effort that clearly went into this ��
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adam bombSaturday, October 07, 2017 3:16:00 pm
If Alemtuzumab does not get rid of brain lesions
won't someone always have a chance of disease resumption.
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MouseDoctorSunday, October 08, 2017 8:20:00 am
If we look at the NEDA rates recently presented about 60% or more people had some activity.
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AnonymousSaturday, October 07, 2017 4:27:00 pm
Great post, MD.
I am missing something important: Do you need to mount a new response to infection in order to repopulate memory Bcells?
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MouseDoctorSaturday, October 07, 2017 8:54:00 pm
I think this may be part of the slow repopulation but as drug is gone nothing to stop repopulation occuring. After alemtuzumab you can be vaccinated. After HSCT you have to be vaccinated as you have a new repertoire. I think that if the planes cells Sur I've you existing immunity survives so maybe not much of a driving force for new b cells.
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AnonymousSaturday, October 07, 2017 6:29:00 pm
Ok I'm sold. Makes sense, data fits, sounds logically. However. Unless I'm being dumb, why does Alemtuzumab produce superior brain atrophy then b depleting agents? Granted alemtuzumab works on two front. One makes immune less tolerant of the original infection. 2nd depleting memory cells. Surely inspite of the first effect b cell still drives the progression as the disease as your paper explains. But inspite this Ocrelizumab should have superior brain atrophy data?
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AnonymousSaturday, October 07, 2017 11:39:00 pm
Ok. We are comparing apples and pears. Because we Don't have real world data for ocrelizumab since its just been approved in March 2017 so the need to look at clinical trial data. However, the real world data for alemtuzumab is still good in terms of brain atropy. Where as the neda for ocrelizumab is almost excellent. Reducing inflammation by 98%. Inspite the difference in patient selection between the two, it seems ocrelizumab brain atrophy should be in the highs given it's efficacy in total suppression on inflammation? Where as neda for alemtuzumab is okay.
MouseDoctorSunday, October 08, 2017 8:37:00 am
Good point becuase they should be the same. However are we comparing like for like?
In the alemtuzumab trials people i think people were on treatment within two years but looking at the cladribine it takes four years to be on drug and for ocrelizumab it was about 3.8 years so is the difference due 2 extra years of loss of brain reserve.
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AnonymousSaturday, October 07, 2017 6:58:00 pm
For sure noone argues that B cells play a leading role in autoimmune diseases, but the arguement is if they are the soldiers or the generals. One unanswered question that cannot be ignored is that where the selection of organs comes from, if it is just the memory B cells. One could imagine many reasons apart from that it stems from the different types of T cells involved, but the secondary autoimmunity that emerges from Lemtrada deletes many of them I think...
The predisposition for Lemtrada's s.autoimmunity is only a theory also.
The involvement of CD4-CD8 is weak since DMF depletes those for long term after treatment yet the disease is not improved. So, DMF is probably all about the Bcells. Still that doesn't dispove of the idea of T cell involvement.
I see in one of the papers that you have posted here that another subtype of T cells is depleted together with RTX, which is the CD3 in MS and it is different than the one in RAs RTX. Does this have something to say to us?
Also, the non responders are patients that created antibodies or there are other reasons involved? A different anti20 drug can answer that.
Also, how long does a memory b cell live? Even if the drugs cannot reach the brain, since these agents affect both the blood and the lymph glands, wouldn't eventually, after some reasonable time, the B cells accumulated in the brain die and not be replaced?
Thank you very much for your article, really appreciated!
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MouseDoctorSaturday, October 07, 2017 8:20:00 pm
Where is the selection for the organs very good question. I don't know I can give the lame answer and say it is a specific antibody to something in the CNS,which is about as good as it gets for the T cell.
CD3 is a T cell it is expressed by cd4 and CD8.
MouseDoctorSaturday, October 07, 2017 8:42:00 pm
How long do memory cells live is another great question and also we need to ask how long do plasma cell live
B cells in culture tend to die very quickly or within a couple of weeks
I don't know enough about b cells to answer these and profG and I was talking about this on Friday.
Annonie MouseSaturday, October 07, 2017 10:11:00 pm
Anon 6.58
I think CD3 is all T cells? ie no subset?
Re memory B, I've got a horrible feeling that the ones with ebv in might live forever? Even worse, my brain is stuffed full of 'em
luis fernandoSunday, October 08, 2017 1:14:00 am
"b cells are the cockroachs of the immune system"
one study found
IgG1+ memory B cells specific for the 1918 pandemic
strain of influenza virus circulating in the blood of survivors
90 years after primary exposure to the virus.
luis fernandoSunday, October 08, 2017 1:20:00 am
"How long do memory cells live"
Longevity. To determine which types of cells and which
types of molecules are required for memory B cell survival,
previous studies have used IgG+ memory B cells
as a target. IgG+ memory B cells can persist in the
absence of T cells or input from precursor cells, but
experiments using mice with follicular dendritic cells
(FDCs) in which the gene encoding complement receptor
2 (Cr2) has been knocked out have suggested that
there is a requirement for FDCs for the maintenance
of IgG+ memory B cells44. In these mice, the primary
IgG response was unaffected, but the secondary antibody
response was significantly decreased. Notably,
the impaired memory response corresponded with the
reduced frequency of antigen-specific memory B cells.
Thus, one straightforward interpretation is that CR2 on
FDCs promotes the survival of IgG+ memory B cells,
directly or indirectly, possibly by functioning as a depot
for antigen–antibody–complement complexes; however,
the role of antigen persistence in memory responses
is debated (see below).
Inducible deletion of phospholipase Cγ2 (PLCγ2)
after the generation of IgG1+ memory B cells substantially
decreased the size of the memory B cell
compartment, which suggests a requirement for
BCR signalling for IgG1+ memory B cell survival45.
Memory B cells doi:10.1038/nri3802
Obrigado
Luis
luis fernandoSunday, October 08, 2017 1:39:00 am
PLC-γ2 is essential for formation and maintenance of memory B cells
Abstract
Resting antigen-experienced memory B cells are thought to be responsible for the more rapid and robust antibody responses after antigen reencounter, which are the hallmark of memory humoral responses. The molecular basis for the development and survival of memory B cells remains largely unknown. We report that phospholipase C (PLC) γ2 is required for efficient formation of germinal center (GC) and memory B cells. Moreover, memory B cell homeostasis is severely hampered by inducible loss of PLC-γ2. Accordingly, mice with a conditional deletion of PLC-γ2 in post-GC B cells had an almost complete abrogation of the secondary antibody response. Collectively, our data suggest that PLC-γ2 conveys a survival signal to GC and memory B cells and that this signal is required for a productive secondary immune response.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699133/
MouseDoctorSunday, October 08, 2017 2:10:00 pm
Thanks for this. I'll have a look. The CR2 = EBV receptor...ProfG asked how long does antigen persist on the follicular dendritic cell (a cell that keeps B cells going).
AnonymousSunday, October 08, 2017 3:24:00 pm
This was released earlier this year but I can't have access to it.
First Atlas of B-cell Clones in Human Body Forms New Foundation for Infectious Disease Research
https://www.pennmedicine.org/news/n...ew-foundation-for-infectious-disease-research
"Our fantasy for the future is to create organ-specific immune monitoring assays. If we can define features of the antibody repertoire that are unique to particular tissues, we may be able to monitor tissue-specific immune responses using blood-based clinical lab tests.”
Such tests might be used to monitor immune responses to vaccines or inappropriate antibody responses in organ-specific autoimmune diseases; however, the first step towards that is knowing the location of B-cell clones.
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Annonie MouseSaturday, October 07, 2017 9:56:00 pm
Well, this is some post MD! Like Fi this morning, I'm stunned by how much I've understood so well done indeed, top marks for accessibility
Thank heavens for SLE and RA research, profiling B cells for the last 10 years. 'Clinical response to rituximab is associated with depletion of CD19+CD27+ memory B cells' lost track of which excellent paper I've copied that from ;-)
So who are the responders? How on earth can we know if we don't profile B cells whilst on dmt?
That's the best line ever 'treat infrequently and monitor' get it printed on a T-shirt and wear it to ECTRIMS.
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MouseDoctorSunday, October 08, 2017 8:18:00 am
The MS Society has just supported us to be able to look at this very aspect
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luis fernandoSaturday, October 07, 2017 11:38:00 pm
Excellent post Md
One of the best i have ever seen (wonder how manny hours it took to complete)
As a true scientific assay it raises more questions than provides
answers
According to this review tfh and also Dendritic folicular cells are needed for a robust B cell memory response
"In summary, there are multiple pathways for generating
B cell memory. Although T cell-independent memory
B cells can be generated as discussed above, it seems
that their recall response is quantitative, rather than
qualitative, in nature. Thus, aside from the increased frequency
of antigen-specific B cells, it is unclear whether
T cell-independent memory B cells have an intrinsic
advantage compared with their naive B cell counterparts
to respond more rapidly and more robustly to antigen,
as is seen in T cell-dependent B cell memory. Therefore,
we hereafter focus on several aspects of canonical,
T cell‑dependent memory B cells."
IgG+ memory B cells can persist in the
absence of T cells or input from precursor cells, but
experiments using mice with follicular dendritic cells
(FDCs) in which the gene encoding complement receptor
2 (Cr2) has been knocked out have suggested that
there is a requirement for FDCs for the maintenance
of IgG+ memory B cells44. In these mice, the primary
IgG response was unaffected, but the secondary antibody
response was significantly decreased. Notably,
the impaired memory response corresponded with the
reduced frequency of antigen-specific memory B cells.
Thus, one straightforward interpretation is that CR2 on
FDCs promotes the survival of IgG+ memory B cells,
directly or indirectly, possibly by functioning as a depot
for antigen–antibody–complement complexes; however,
the role of antigen persistence in memory responses
is debated (see below).
Although virusspecific
memory B cells can be activated in the absence
of T cells57, T cell help is a strict requirement for the
reactivation of memory B cells that are specific for monomeric
protein antigens
Memory B cells doi:10.1038/nri3802
Anyway I dont think its only t cells or memory B (even follicular dendritic)
Maybe they are all working togheter
Anyway i see your post have some aditions to your previous woork
Ps: Good luck with your Ectrims adventure hope you get thru those
skeptical looking neuros
Glad to be helping
Obrigado
Luis
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luis fernandoMonday, October 09, 2017 2:29:00 am
After all those dreadfull long lived plasma b cells can be knock down (hopefully)
Just found this
Proteasome Inhibition with Bortezomib
Depletes Plasma Cells and Autoantibodies in
Experimental autoimmune myasthenia gravis.
https://www.ncbi.nlm.nih.gov/pubmed/21239719
Long-lived plasma cells are early and constantly
generated in New Zealand Black/New Zealand
White F1 mice and their therapeutic depletion
requires a combined targeting of autoreactive
https://www.ncbi.nlm.nih.gov/pubmed/25889236
Obrigado
plasma cells and their precursors
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