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How long are memory B cell depleted?. Can we learn from other conditions

Discussion in 'Other Health News and Research' started by Ecoclimber, Oct 10, 2017.

  1. Ecoclimber

    Ecoclimber Senior Member

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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[​IMG]


    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.

    [​IMG]

    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.
    [​IMG]


    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.


    [​IMG]

    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

    [​IMG]

    [​IMG]

    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%

    [​IMG]

    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?.

    [​IMG]

    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.
    [​IMG]

    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.

    [​IMG]


    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

    [​IMG]

    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
    Reactions:
    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.
    Reply
    Alex HansenSaturday, October 07, 2017 1:09:00 pm

    Great post, thank you for all the effort that clearly went into this ��
    Reply
    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.
    Reply
    Replies
    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.
    Reply
    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?
    Reply
    Replies
    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.
    Reply
    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?
    Reply
    Replies
    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.
    Reply
    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!
    Reply
    Replies
    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.
    Reply
    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.
    Reply
    Replies
    MouseDoctorSunday, October 08, 2017 8:18:00 am

    The MS Society has just supported us to be able to look at this very aspect
    Reply
    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


    Reply
    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

    Reply
     

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  2. Ecoclimber

    Ecoclimber Senior Member

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    #ClinicSpeak & #ResearchSpeak: how close are we to pinning down EBV as being the cause of MS?

    Causation theory is essential to frame the EBV problem in MS.
    #ClinicSpeak #ResearchSpeak

    Summary
    : This post sets the scene for revisiting the Bradford-Hill criteria around EBV being the cause of MS.
    Are we any closer to proving EBV is the cause of MS? I have posted on this topic many times before, but one of the Bradford-Hill criteria we use for establishing causation is 'Coherence with Biological Background and Previous Knowledge'. We now have at least nine classes of DMTs that have been shown to work in MS. Over the last few months, we have been making the case that they work via B-cells in particular memory B-cells. It may be a coincidence that the memory B cell is the main cell where EBV resides in a latent state. The challenge now is how to work this knowledge into what we know about the pathogenesis of MS and the other factors that are in the causal pathway, for example, smoking, vD and UVB sunlight exposure, female sex and the genetic pathways identified from the whole genome association studies. We have so much to do and so little time. Regardless of this work, we need to start our proposed infectious mononucleosis and EBV vaccination studies sooner than later. Causation will only be proved when we show that preventing, or treating infectious mononucleosis or preventing EBV infection reduces the incidence of MS.
    The British Statistician, Sir Austin Bradford-Hill, has formulated more general and appropriate criteria of causation; the following are the Bradford-Hill criteria:
    1. CONSISTENCY AND UNBIASEDNESS OF FINDINGS

    2. STRENGTH OF ASSOCIATION

    3. TEMPORAL SEQUENCE

    4. BIOLOGICAL GRADIENT (DOSE-RESPONSE RELATIONSHIP)

    5. SPECIFICITY

    6. COHERENCE WITH BIOLOGICAL BACKGROUND AND PREVIOUS KNOWLEDGE

    7. BIOLOGICAL PLAUSIBILITY

    8. REASONING BY ANALOGY

    9. EXPERIMENTAL EVIDENCE

    1. AnonymousSunday, October 08, 2017 10:57:00 am
      Yes please! It is too late for us patients, but it is much more important than we though. Cancer is another reason for this vaccine.

      Sunday, October 08, 2017 11:56:00 am
      It would seem EBV is associated with higher risk of other autoimmune disorders too especially dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome.

      Autoimmune disease: A role for new anti-viral therapies?
      Autoimmunity Reviews, Volume 11, Issue 2, Pages 88-97
      David H. Dreyfus. 2011.

      Klaus SchmiererSunday, October 08, 2017 3:43:00 pm
      I agree EBV may well be a rather generic contributor to risk of several "auto-immune" diseases. Our steep learning curve about the role of memory B cells in MS certainly suggests this: http://www.sciencedirect.com/science/article/pii/S2352396417300452?via=ihub



    2. [​IMG]
      Nissan GrifterSunday, October 08, 2017 5:45:00 pm
      Dr. Schmierer, or Dr. Baker, is there any evidence for cladribine trials for progressive MS that cladribine is killing these EBV-controlled memory cells in follicles in the brain that may control MS relapses and progression?



    3. [​IMG]
      MouseDoctorSunday, October 08, 2017 8:31:00 pm
      Not yet. There is a suggestion that cladribine can influence OCB in some studies. However these studies need doing and we will try to do them.

      As for evidence that cladribine blocks relapsing disease in relapsing and advanced MS. I would say yes is the answer.




      luis fernandoSunday, October 08, 2017 3:32:00 pm
      "Conclusions
      While these findings confirm the association of EBV infection with early MS, neither EBNA-1 nor VCA IgG antibodies in serum nor EBV DNA load in saliva were associated with radiological or clinical disease activity in patients with CIS/early RRMS. These data are compatible with the concept that EBV may be a trigger for MS acting very early during the development of the disease."

      http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175279.

      If ebv infected B cells are the bad guys and

      Leflunomide/teriflunomide is very good at killing those

      infected b cell ,why its only 30% efficacy in ms (mainly relapses reduction )?

      Along with your reasoning Leflunomide/teriflunomide should be 2the

      mother of all Dmds"

      Am I missing something?

      https://www.ncbi.nlm.nih.gov/pubmed/28574826
      https://www.ncbi.nlm.nih.gov/pubmed/16534472
      https://www.ncbi.nlm.nih.gov/pubmed/27494108

      http://www.nejm.org/doi/full/10.1056/NEJMoa1014656#t=article


      Obrigado Luis

      Nissan GrifterSunday, October 08, 2017 5:37:00 pm
      If you believe, Dr. G, that these EBV controlled memory B-cells in the follicles in the brain are directing MS relapses and progression and not one treatment currently is proven to destroy them then isn't every current therapy DMD treating a downstream effect (i.e. peripheral B or T-cells) and not the cause of relapses and progression of MS? Hence maybe why every current treatment have a far less than perfect NEDA outcome?

      MouseDoctorSunday, October 08, 2017 8:24:00 pm
      I am not sure the relapses are caused by the B feel follicles. The fact that the ms drugs that block relapse but don't get into the brain argues against this.


      • [​IMG]
        bearmsTuesday, October 10, 2017 8:35:00 am
        "isn't every current therapy DMD treating a downstream effect (i.e. peripheral B or T-cells) and not the cause of relapses and progression of MS"

        ... Yes. And that's why DMDs don't work. All the evidence over decades of dmd's, entirely fits your above thought

      steve sSunday, October 08, 2017 8:12:00 pm
      Are any virologists on board? Are you out there?

      MouseDoctorSunday, October 08, 2017 8:19:00 pm
      Simply put leflunomide is not good at killing the memory B and there lies it's efficacy I think.. I have seen a poster on this.

      luis fernandoSunday, October 08, 2017 9:01:00 pm
      "EBV infects cells in both latent and lytic
      forms. EBV-infected humans sustain life-long latent
      viral infection within the memory B cell compartment,
      and periodically shed infectious viral particles into the
      saliva [2]"

      In summary, our investigations here, using both in
      vitro as well as in vivo systems to model the effects of
      the FDA-approved leflunomide metabolite teriflunomide
      on latent and lytic EBV B-cell infection, suggest that
      these drugs may be surprisingly effective for treating
      both latent and lytic EBV infection in humans

      I found this study here on the blog and it says that Ebv infects memory B cells, and Teri/leflunomide are good at killing those infected memory b cells

      https://www.ncbi.nlm.nih.gov/pubmed/28574826

      Obrigado
      Luis


      • [​IMG]
        luis fernandoMonday, October 09, 2017 12:17:00 am
        This one:1. The virus will enter any resting B cell and cause it to proliferate, guaranteeing efficient access of
        the virus to the B cell pool and amplifying the viral genome copy number. In doing so, it uses a set of
        genes that recapitulates what is necessary to cause a B cell to become a blast on the way to
        differentiating to a plasma or memory cell.
        2. The virus will infect any resting B cell, but in vivo it ends up in a very specific subset, the resting
        memory B cell - precisely the best place to be for long term persistence. When there, it shuts off gene
        expression so the cells cannot be immunosurveilled. Instead the cells are maintained at stable levels
        for long periods of time as though they were normal memory B cells - precisely the state required for
        benign, long term persistence in a healthy host.
        3. The memory cells appear to go through an activated state when they enter mucosal epithelium where
        they express only the minimal viral information necessary for survival, the LMPl/Th surrogate, the
        LMP2a/BCR surrogate and EBNAl(Qp) to be sure the viral genome is maintained.
        4. When the cells become activated in the mucosal epithelium they behave like normal memory B cells
        in a secondary response. Most of the cells produced undergo terminal differentiation to become plasma cells. The virus responds by reactivating and producing infectious virus so that it can be released into
        the saliva.
        https://www.ncbi.nlm.nih.gov/pubmed/10530796

      Sunday, October 08, 2017 9:22:00 pm
      "...that are in the causal pathway, for example, smoking, vD and UVB sunlight exposure"

      There is at least a link: IL-6 levels.
      Did you notice that all well working DMTs also target IL-6?
      IL-6 knock out mice can't develop EAE...
      IL-6 elevated mixe have more severe EAE symptomes

      EBV enhances the secretion of IL-6 and so on.

      MouseDoctorSunday, October 08, 2017 10:58:00 pm
      IL-6 B cell growth and differntiation factor?


      • [​IMG]
        AnonymousSunday, October 08, 2017 11:03:00 pm
        In Cambridge they are working on the IL-6

        "Neurodegenerative diseases are often preceded by inflammation. Inflammation perturbs the normal dynamic equilibrium of the neuron altering its environment and causing adverse metabolic changes. When the inflammation becomes chronic, a vicious cycle of inflammatory damage predisposes to death of neurons as their ability to function correctly is compromised, leading to neurodegeneration. We know that both LIF and IL-6 play key roles in the CNS, appearing to act in concert to maintain the healthy environment of the brain. However, too much IL-6 - as may occur in inflammation - may suppress LIF. To recover the normal dynamic equilibrium between LIF and IL-6, delivery of LIF via LIFNano therapy may break the vicious cycle of chronic inflammation within the CNS. "

        They start from degeneration but if the immune system is not corrected the problem will still be there I guess. The idea has not been tested on human.

      • [​IMG]
        adam bombMonday, October 09, 2017 9:05:00 am
        "Causation will only be proved when we show that preventing, or treating infectious mononucleosis or preventing EBV infection reduces the incidence of MS."

        EBV vaccination study would take how many decades..?
        If you treat PPMS for EBV and it stops progression
        and removes brain lesions in one year you'd know the score.

        All these drugs and not one can clear lesions or stop
        progressive ms.

      • [​IMG]
        AnonymousMonday, October 09, 2017 12:24:00 pm
        "If you treat PPMS for EBV and it stops progression
        and removes brain lesions in one year you'd know the score." This assumes it is the virus acting directly and not something the virus accidentally modifies, acting indirectly. If you do not remove what it changed when you kill the virus it will not work. Some sub types of Hodgkin's Lymphoma are caused by EBV but killing the virus would be unlikely to cure the Lymphoma. It would, however, stop it happening in the first place.

      CinaraTuesday, October 10, 2017 5:52:00 am
      Prof. Michael Pender could give a light and show how EBV can act in MS and how a pwMS with PPMS can be treated in fact by EM in combating EBV.

      Tuesday, October 10, 2017 9:58:00 am
      Could MS be caused by number of virus and bacteria infections? Dr David wheldon thinks the cause maybe chlamydia pneumoniae? His wife was sick with 2nd progressive MS. After years course of antibiotics she recovered, including lost function. That should not happen right?

      MouseDoctor2Tuesday, October 10, 2017 10:44:00 am
      I would view any n=1 "study" with extreme caution, proper studies would need to be done before any firm conclusion could be drawn.



      Reply
     
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  3. Alvin2

    Alvin2 If humans were rational...

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    Can someone post a 1 paragraph summary, i can't get through this :cry:
     
  4. Gingergrrl

    Gingergrrl Senior Member

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    USA
    I was literally just going to ask the same thing @Alvin2! I don't have the background to comprehend this but am extremely interested if anyone out there is able to post a summary for the scientifically challenged.
     
    Alvin2 likes this.
  5. Alvin2

    Alvin2 If humans were rational...

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    I might be able to figure it out but its far, far too long, i can't process that much these days. :bang-head:
     
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  6. wastwater

    wastwater Senior Member

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    Professor ulf Klein researches B cell disorders
     
  7. Ecoclimber

    Ecoclimber Senior Member

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    I'll do a better job. It was while I was posting on here that I saw the dustup and the flaming cauldron of anger, people living, resigning. I didn't know what was happening as I was away for 8 mos working om another proejct. So Cautious about putting research on now.if the forum blowsup. I will try to shorten in a couple of days as longer one needs to be posted. I will break them up but for now they are what they are

    @Gingergrrl @wastwater
     
  8. Ecoclimber

    Ecoclimber Senior Member

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    Friday, 29 September 2017


    Education: B cells are not a single subpoulation


    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 as a B-Cell mediated disease

    Gavin Giovannoni is shifting the paradigm after 80-90 decades that it is a B-Cell mediated disease

    Permission to post Prof.



    Friday, 29 September 2017


    Education: B cells are not a single subpoulation


    Lehmann-Horn K, Kinzel S, Weber MS. Deciphering the Role of B Cells in Multiple Sclerosis-Towards Specific Targeting of Pathogenic Function.Int J Mol Sci. 2017 Sep 23;18(10). pii: E2048. doi: 10.3390/ijms18102048.
    B cells, plasma cells and antibodies may play a key role in the pathogenesis of multiple sclerosis (MS).

    This notion is supported by various immunological changes observed in MS patients, such as activation and pro-inflammatory differentiation of peripheral blood B cells, the persistence of clonally expanded plasma cells producing immunoglobulins in the cerebrospinal fluid, as well as the composition of inflammatory central nervous system lesions frequently containing co-localizing antibody depositions and activated complement.

    In recent years, the perception of a respective pathophysiological B cell involvement was vividly promoted by the empirical success of anti-CD20-mediated B cell depletion in clinical trials; based on these findings, the first monoclonal anti-CD20 antibody-ocrelizumab-is currently in the process of being approved for treatment of MS.

    In this review, we summarize the current knowledge on the role of B cells, plasma cells and antibodies in MS and elucidate how approved and future treatments, first and foremost anti-CD20 antibodies, therapeutically modify these B cell components. We will furthermore describe regulatory functions of B cells in MS and discuss how the evolving knowledge of these therapeutically desirable B cell properties can be harnessed to improve future safety and efficacy of B cell-directed therapy in MS.

    B cells, the persistence of clonally expanded plasma cells producing immunoglobulins in the cerebrospinal fluid, as well as the composition of inflammatory central nervous system lesions frequently containing co-localizing antibody depositions and activated complement.

    In recent years, the perception of a respective pathophysiological B cell involvement was vividly promoted by the empirical success of anti-CD20-mediated B cell depletion in clinical trials; based on these findings, the first monoclonal anti-CD20 antibody-ocrelizumab-is currently in the process of being approved for treatment of MS.

    In this review, we summarize the current knowledge on the role of B cells, plasma cells and antibodies in MS and elucidate how approved and future treatments, first and foremost anti-CD20 antibodies, therapeutically modify these B cell components.

    We will furthermore describe regulatory functions of B cells in MS and discuss how the evolving knowledge of these therapeutically desirable B cell properties can be harnessed to improve future safety and efficacy of B cell-directed therapy in MS.




    [​IMG]


    I am doing a presentation and am trying to see where the road blocks are to the understanding of MS.

    Reading through this review on B cells, which you can read if you are interested, it gives me the feeling that I am banging my head against a brick wall.

    I think there is a failure to appreciate that you cannot simply view B cells as a single population. Because if you do you cannot hope to understand what is going on.

    For years we have been viewing T cells as a mixed group of cells, T helper cells (CD4), cytotoxic (CD8) and regulator cells and more, but the biggest road block to understanding MS is viewing B cells as a single cell population, which many studies do.


    As a card carrying T cell immunologists, I must admit I do not understand the complexities of the B cell response, but I am trying to learn. So maybe you can learn too.

    There are many, many subtypes of B cells and here are a few[​IMG]




    B cells are born in the bone marrow from stem cells and then go through a series changes in their coats and expressing some markers. The graph below is simplified as is much more complex [​IMG]


    It is clear that pre-B cells form immature B cells in the Bone Marrow, these change into mature B cells, which shuttle between the bone marrow and lymphoid tissue, such as the spleen and lymph nodes.

    In some studies they are called follicular cells. Following stimulation, they proliferate in structures called germinal centres.

    Germinal centre cells differentiate into either memory B cells or plasmablasts that can turn into antibody forming..plasma cells,....

    When B cells are depleted they repopulate in a stereotyped way.

    The immature cells enter the blood to fill the space and then there is maturation This masks the very slow repopulation of memory cells, from the lymphoid organs, which is where we have said the action is. All drugs that work in MS deplete memory B cells, except natalizumab which get trapped in the blood so they can't get into the brain.



    Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis.


    Clearly not many people buy it...until they do. They may be clutching at straws

    [​IMG]


    I will explain how this happens, but I hope you can see that alemtuzumab wipes out memory B cells, but if you look at the CD19 population it is relatively meaningless in terms of understanding what is going on. So MS B cells are not a single population
    Mouse doctor

    COMMENTS

    68 comments:

    1. [​IMG]
      AnonymousFriday, September 29, 2017 11:33:00 am
      Isn't an anti-cd19 drug under trial for NMO that doesn't work well on MS?
      Reply
      Replies
      1. Reply

    2. MouseDoctorFriday, September 29, 2017 11:35:00 am
      Gibberish....Indeed.
      Maybe T cell immunologists are reading:).

      However, I see the the blog administrators are tinkering again.

      Originally you could tick something like "bad", "OK" and "good", but it was clear that the trolls were simply ticking "bad" every day.

      So to foil this behaviour we got rid of "bad", and "OK" to only give positive choices were simply "good", "very good" or "excellent".

      I see this issue has been forgotten, obviously it going to be used to say how bad the posts are:-(...Will it change how we write?
      Reply
    3. MD2
      MouseDoctor2Friday, September 29, 2017 11:54:00 am
      "Gibberish....Indeed.
      Maybe T cell immunologists are reading:)."

      Also our favourite commenter from Leicester? ;-)
      Reply
      Replies
      1. Reply
    4. [​IMG]
      AnonymousFriday, September 29, 2017 12:07:00 pm
      The issue I have with these posts is that they are irrelevant to me - I'm not a researcher or scientist, just a patient. It's a bit like when I take my laptop in for repair, I don't need to know the ins and outs of all the hardware and software - just get it working properly again. I am interested in trial results based on this sort of work, but lots of colourful blobs marked up with different names don't help my condition at all. Please keep the gibberish option in as some of your posts are gibberish.
      Reply
      Replies

        • MouseDoctorFriday, September 29, 2017 2:31:00 pm
          It is not irrelevant and here is why.

          This post perhaps gets to the core of why MS drugs work and if you accept that the central purpose of each MS treatment is to remove the memory B cells, then when a treatment comes along, you can ask what does it do in terms of memory cell depletion.

          If treatment doesn't kill them very well, then it is likely that the treatment is not going to work very well.

          Therefore it helps with making the right choice.

          You don't believe it.....you can ask what evidence supports an alternative view.

          Maybe you like the "neuro knows best" approach....

          Maybe they have read the post and are enlighted, but if they haven't and are lazy, they will stick you on a DMT that requires no monitoring and you will be OK, whilst you burn up your neurological research, by which time you options have become more severely limited..

          So you either take the rubbishy drug and hope that you are one of the lucky few where the rubbishy drug works (you could monitor to see if it is working) or you select one where the chances of memory B cell depletion is better and so it has a better chance of it working.

          If the action is at the level of the B cell, why on earth would you want to take an anti-T cell drug....you wouldn't do that...Maybe you wouldn't but the literature is full of people who have been involved in T cell trials that haven't worked and had limited chances of working.

          Another example Ocrelizumab is given every 6 months because the CD19 population is depleted for 6 months and then it returns. It returns because the space in the blood is filled with immatutre and mature B CD19+ cells but there is not a memory B cell in sight maybe for 18 months - 5 years. So you are paying $30,000 every 6 months to kill a cell that is not even there so maybe you would save £240,000 from your purse or for the NHS. Not bothered about that...but if you keep your B cells permanently depleted you will probably suffer the consequence of infections from having no B cells. Maybe if you monitored your B cells you would know it it is worth having another dose

        • MouseDoctorFriday, September 29, 2017 2:40:00 pm
          It is jibberish be you have not understood the post...maybe we have pitched the level to high....maybe you have not done any home work to get up to speed and we cannot do back to basics over and over again.

          Does this subject need a basic explanation, e.g the car park ad train analogy to explain the difference between relapsing and progressive MS. This takes time to prepare.
        • B
          FiFriday, September 29, 2017 5:00:00 pm
          The opposite perspective: driving home from hospital this afternoon repeatedly saying to myself 'Thank god for Bart's Blog, and they're telling it the way it is!'
          I'm a patient and don't have a scientific cell ('cuse the pun) in my body. Much of what is posted and the replies are beyond me. What is true is that I benefit from getting a handle on the key underlying pieces of information. Due to your posts MD, I asked about testing for neutralising antibodies today (due second round of Alemtuzumab) to be told they don't test for them. So guess what if/when I require a second lot of Alemtuzumab I'll be requesting the test!
          And now I'll know to check out any future possible DMT for the capacity to destroy B cells.
          I'm going to cause some amusement, scoffing, and incredulity by adding this, but it's my truth: the Blog is a life-line and I wouldn't be in the place I am physically and psychologically without the incredible contribution it has made!
          Hope the whole team has a great weekend.

        • MouseDoctorFriday, September 29, 2017 8:08:00 pm
          The second round of alemtuzumab should not be a major problem for the majority of people but could be more of a problem on round three. But they can be tested for by the manufacturer as they have done it but to do that first there needs to an acknowledgement that they exist and that they are an issue. They have the data they just need to be transparent.

        • Annonie MouseFriday, September 29, 2017 11:26:00 pm
          Hi Fi 5.00pm Well said! re possible future dmt to destroy B cells, you mean memory B cells of course?
          And yes, Me 9.16pm, that sounds like a great idea! Save all that unnecessary drug, loss of immunity and not to mention cost!

          Have a great weekend everyone :)
        Reply

    5. Vasilis VasilopoulosFriday, September 29, 2017 4:38:00 pm
      MDs, you say that MS pathology might be driven by memory B cells. However, when brain damage takes place, like in AIS, all kinds of immune cells, T & B, enter the brain for restoration purposes.

      Does this mean that within an early MS lesion some damaging B cells co-exist and act together with some other protective B cells? Are B cells Janus-cells?
      Reply
      Replies

        • MouseDoctorFriday, September 29, 2017 8:12:00 pm
          Yes there are regulatory B cells and damaging B cells. It is a hole in the idea. Why do B cells accumulate to n the CNS, what makes this special to MS and how is it done.

          I haven't matured the ideas enough...however in my defense when you ask the question about how would a CD4 kill an oligodendrocyte...the answer is equally vague.

        • Vasilis VasilopoulosFriday, September 29, 2017 8:29:00 pm
          "how would a CD4 kill an oligodendrocyte"

          You know that i would never ask that question.
          But, don't you think that the contradiction of regulatory and damaging B cells acting side by side, in the light of the indisputable regulatory activity following brain damage, is enough proof that there is no prior damaging activity of B cells whatsoever?

        • Vasilis VasilopoulosSaturday, September 30, 2017 8:16:00 pm
          Oligos are dead before inflammation starts, remember? Your B-memory cells have killed them, but blood-borne B-cells that inflame the lesion site collect the garbage. Why don't they contribute to the damage instead? They are all supposed to be EBV-infected.

        • MouseDoctorSunday, October 01, 2017 12:49:00 am
          If you look in MS tissue there are sick looking oligos surrounded by microglia, they are not necessarily dead and the B cell toxins (e.g antibodies or the high molecular weight toxin reported by Lisak et al.are soluble and so act at some distance from the cells.

        • Vasilis VasilopoulosSunday, October 01, 2017 1:54:00 pm
          I guess Lisak et al used B-cells taken from blood directly. Couldn't those toxins be just the manifestation of the regulatory B-cell function? Since oligos are constantly ill anywhere in the CNS, why wouldn't the immune system keep on producing those toxins?

          For your theory to hold, you have to prove that oligos are in perfect health prior to toxin production. However, nothing in the facts available so far can even remotely insinuate that. Activated microglia, B-cell toxins and everything else are always reported with clear damage in sight.

        • MouseDoctorSunday, October 01, 2017 8:14:00 pm
          What do you suggest we use two photon microscopy on people infected with fluorescent virus to track oligodendrocytes and microglia.

          Activated microglia always has damage in sight, not so sure
        Reply

    6. The Wheelchair KamikazeFriday, September 29, 2017 6:31:00 pm
      If the working theory regarding CD 20 B cell depletion is that these cells (specifically the memory B cells) is that the cells harbor EBV, wouldn't a drug targeting CD 19 be even more effective, since EBV is also harbored in plasmablast and plasma cells? These cells are not targeted by the CD 20 drugs, correct?

      Or, would depleting all CD 19 cells be too dangerous, opening the patient up to all kinds of opportunistic infections?

      Interesting that the Intrathecal Rituxamab trials failed, as it would seem that compartmentalized B cells in the CNS would be candidates as primary drivers of the MS disease process. Any thoughts on the failure of these trials (conducted by the NIH, I believe).
      Reply
      Replies

        • MouseDoctorFriday, September 29, 2017 7:51:00 pm
          EBV infects via CD21 which is a late stage mature cell
          marker I think that this then drives the mature cells to differentiate into Germinal centre cells that proliferate and turn into memory cells or plasmablasts. The plasmablasts don't express CD20 and so won't be wiped out by rituximab however it looks like the virus stops the cells turning into plasmablasts and drive the B cell to become a memory cell. Therefore there is no need to evoke the cD19 .However cladribine is a chemical anti cd19.

          The virus lives in the memory B cell doing nothing until it reactivates to create infectious virus.

        • MouseDoctorFriday, September 29, 2017 7:57:00 pm
          Why didn't rituximab work. It was put into the spinal fluid to get rid of plasma cells in the brain. (A) plasma cells do not express any CD20 and so will never be depleted by the antibody and (b) the flow of the cerebrospinal fluid was down and out into the blood so the rituximab didn't touch the rain b cells and simply wiped out the B cells in the blood. It was known that this approach was not good enough to target non active ms. So it failed in all studies.

          So next they will want to put it in the ventricles and to get a better flow but it still won't kill plasma cells. Why do it I don't know.

          5minutes of thought verse experiments costing thousands..but hey I'm just a heretic who doesn't know any better:-(
        Reply

    7. The Wheelchair KamikazeSaturday, September 30, 2017 9:49:00 am
      MD, thanks for the replies. I suspected that part of the reason for the Intrathecal Rituxan failures might be due to the drug being washed out of the CNS before it could be effective. Hadn't considered that it doesn't target the cells that needed targeting.

      So, EBV only resides in memory B cells? Interesting. Any work being done on ways to specifically target only these cells?
      Reply
      Replies

        • Nissan GrifterSaturday, September 30, 2017 6:57:00 pm
          WK here is some work going on by Dr. Pender on this critical issue and correct me if I am wrong MD.

          http://www.medscape.com/viewarticle/879140

          It will be the answer for progressive MS if these EBV laden memory cells are driving progression of MS. I do not think that there is any proof that any current peripheral B-cell immunotherapy, including ocrezulimab or siponimod, currently affects these EBV laden memory B cells in follicles in the brain and perhaps this is why current therapies are not helping or minimally helping progressive patients (<25% at best) and probably why the NEDA for all current therapies, minus HSCT, are less than 50%.

          Here is a pharma group that I think is focusing on destruction of EBV driven B-cells in the follicles in the brain by CD8 T-cells:

          https://multiplesclerosisnewstoday....lights-including-ata188-t-cell-immunotherapy/

          PS: Brilliant post Steve S thanks. It provides further proof that current therapies will not alleviate progression of MS as the EBV controlled memory B-cellls in follicles of the brain are not affected by current DMDs. In other words, we currently are treating a downstream effect of these EBV laden memory B-cells in follicles of the brain by diminishing peripheral B-cells but not the cause, which is these EBV laden memory B-cells in follicles in the brain.
        Reply

    8. luis fernandoSaturday, September 30, 2017 5:19:00 pm
      Great work Md

      "However cladribine is a chemical anti cd19"

      Do you mean cladribine kills memory B cell ? Or only cd 19+?

      Obrigado
      Reply
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        • [​IMG]
          MouseDoctorSunday, October 01, 2017 12:19:00 am
          The specificity of cells targeted by cladribine is likely broader than anti-CD20 antibodies and should hit the pro-B population. It certainly hits memory B cells as we will be presenting at ECTRIMS along with target profiling
        Reply
    9. [​IMG]
      luis fernandoSaturday, September 30, 2017 5:50:00 pm
      EBV infects via CD21 which is a late stage mature cell
      marker I think that this then drives the mature cells to differentiate into Germinal centre cells that proliferate and turn into memory cells or plasmablasts. The plasmablasts don't express CD20 and so won't be wiped out by rituximab however it looks like the virus stops the cells turning into plasmablasts and drive the B cell to become a memory cell


      EBV is transmitted via oral secretions, enters through the epithelium that lines the oropharynx
      (Waldeyer's ring) and infects naïve B cells, which differentiate through a germinal center
      reaction into memory B cells, where EBV persists for the lifetime of the host [28]. Upon returning
      of EBV-infected memory B cells to the oropharynx these can differentiate into plasma cells
      that subsequently initiate viral replication and release virions that are shed into the saliva [29].

      http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175279


      This article has sought to cast EBV in the role of a stealth virus that has adapted to the biology of the
      normal B cell in order to establish life long, persistent infection. Although the details of the model will
      need refining, the data at hand make such a model virtually inescapable. Most striking is that the virus
      has specific gene transcription patterns uniquely designed for each stage of the process:

      "In this paper we demonstrate that the cells which initiate replication of Epstein-Barr virus (EBV) in the tonsils of healthy carriers are plasma cells (CD38hi, CD10−, CD19+, CD20lo, surface immunoglobulin negative, and cytoplasmic immunoglobulin positive)"

      http://jvi.asm.org/content/79/2/1296


      This article has sought to cast EBV in the role of a stealth virus that has adapted to the biology of the
      normal B cell in order to establish life long, persistent infection. Although the details of the model will
      need refining, the data at hand make such a model virtually inescapable. Most striking is that the virus
      has specific gene transcription patterns uniquely designed for each stage of the process:
      1. The virus will enter any resting B cell and cause it to proliferate, guaranteeing efficient access of
      the virus to the B cell pool and amplifying the viral genome copy number. In doing so, it uses a set of
      genes that recapitulates what is necessary to cause a B cell to become a blast on the way to
      differentiating to a plasma or memory cell.
      2. The virus will infect any resting B cell, but in vivo it ends up in a very specific subset, the resting
      memory B cell - precisely the best place to be for long term persistence. When there, it shuts off gene
      expression so the cells cannot be immunosurveilled. Instead the cells are maintained at stable levels
      for long periods of time as though they were normal memory B cells - precisely the state required for
      benign, long term persistence in a healthy host.
      3. The memory cells appear to go through an activated state when they enter mucosal epithelium where
      they express only the minimal viral information necessary for survival, the LMPl/Th surrogate, the
      LMP2a/BCR surrogate and EBNAl(Qp) to be sure the viral genome is maintained.
      4. When the cells become activated in the mucosal epithelium they behave like normal memory B cells
      in a secondary response. Most of the cells produced undergo terminal differentiation to become plasma cells. The virus responds by reactivating and producing infectious virus so that it can be released into
      the saliva.

      Life Scieaces, Vol. 65, No. 14. pp. 1433-1453, 1999

      Is this contradictory to your reasoning?

      Obrigado
      Reply

    10. MouseDoctorSunday, October 01, 2017 12:35:00 am
      Thanks for the quotes and for the reader viewing these comments naive cells are the same as mature cells http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175279.

      No I don't think this is contradictory at all.

      To us it indicates the virus has co evolved with humans. It survives to live another day and hijacks the B cells, it makes B cell growth and differentiation factors and immortalises B cells and it drives cells to house the silent virus and activates to create live virus.

      We think the advantage to the human is that this provides for long lasting immunity, the price is a few cancers, glandular fever and autoimmunity, but as the autoimmunity often occurs at an age post reproductive age remembering most people would be teenagers in our history, it would not be selected against. A testable hypothesis but by no means
      Reply
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        • MouseDoctorSunday, October 01, 2017 8:17:00 pm
          Why is lefunamide good at killing virus but not MS, I suspect it is because the cells & virus is proliferating in the assays used. It will be using pyrimidines which leflunamide and teriflunamide block, bet it doesn't touch latent virus.
        Reply

    11. CinaraSunday, October 01, 2017 8:37:00 am
      Since we are talking about B cells and have cited EBV, a latent infection of EBV in African Americans and Latinos? This is what this study points out.

      http://www.neurology.org/content/early/2017/08/30/WNL.0000000000004412
      Reply
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      1. Reply

    12. Annonie MouseSunday, October 01, 2017 10:08:00 am
      Thanks everyone for all this ebv info. I'm doing my best to keep up and getting there slowly. Bought a good book too:

      https://books.google.co.uk/books/ab...=frontcover&source=kp_read_button&redir_esc=y

      (not sure if that counts as advertising and will be deleted? But I see author John Oxford is a fellow Barts prof so maybe that's allowed)

      Sounds like ECTRIMS quite the place to be this year, look forward to learning more about cladribine thanks MD (rare trip out of the mousehole, you'll have to be nice to all those important neuros and smooth pharma reps) and ATA188 too.

      Re ATA188 it's a tad ironic that after all these years of trying to deplete T cells someone is (hopefully) getting good results doing the polar opposite with CD8. Oh, talking of which, isn't there this big T v B debate too?

      Re MD 12.35 ebv co-evolved with humans and lifelong immunity. Do people produce memory B cells at all without ebv? If so, what is the difference between a normal mem B and ebv mem B?

      Thanks again MD, Luis and Nissan.

      Reply
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        • MouseDoctorSunday, October 01, 2017 8:23:00 pm
          what is the difference between a normal mem B and ebv mem B?
          I don't know by I suspect longevity.

          There are people without EBV, they will have B cell memory but will it be the same...we have the hypothesis and are trying to test this, we have bloods coming.

        • luis fernandoMonday, October 02, 2017 12:10:00 am
          "I don't know by I suspect longevity."

          For example, 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 virus50

          doi:10.1038/nri3802
        Reply

    13. luis fernandoSunday, October 01, 2017 1:42:00 pm
      Do people produce memory B cells at all without ebv?

      Sure ,if you catch an infection (other than ebv):
      Memory B cells are a B cell sub-type that are formed within germinal centers following primary infection and are important in generating an accelerated and more robust antibody-mediated immune response in the case of re-infection (also known as a secondary immune response)
      .[1][2]

      " what is the difference between a normal mem B and ebv mem B?"

      "EBV is transmitted via oral secretions, enters through the epithelium that lines the oropharynx
      (Waldeyer's ring) and infects naïve B cells"

      Mem b are, not infected with ebv

      Reply
      Replies
        • [​IMG]
          adam bombSunday, October 01, 2017 3:30:00 pm
          "Mem b are, not infected with ebv"

          http://www.msard-journal.com/article/S2211-0348(17)30118-9/fulltext

          "EBV episome replication during B cell division is now known to be inefficient, resulting in some descendant B cells becoming EBV-free after a few dozen divisions. EBV-free memory B cells in the CNS may thus have descended from a memory B cell which matured while containing EBV episomes, enabling its B cell receptor to recognize “forbidden” MS-causing antigens in the CNS, even if EBV is absent from this site."

          •Epstein–Barr virus (EBV) is involved in the pathogenesis of MS.
          •EBV DNA generally cannot be detected in central nervous system.
          •EBV may enable the recognition of “forbidden” antigens by memory B cells (Pender's hypothesis).
          •Inefficient EBV episome replication during B cell division results in some descendant B cells becoming EBV-free.
          •Memory B cells in the CNS are mostly EBV-free and can recognize “forbidden” MS-causing antigens in the CNS.

        • MouseDoctor2Monday, October 02, 2017 11:41:00 am
          It's a bit of a leap to extrapolate from the freshwater hydra to the human but there's obviously a lot of work going on investigating the microbiome and disease. Whether anything useful results is another matter, I try to keep an open mind but to me it's the latest bandwagon to be jumped on.
        Reply
    14. [​IMG]
      AnonymousTuesday, October 03, 2017 3:31:00 pm
      Being a beginner and trying to make a sense from it all... I understand that you believe that there is only B cell involvement in the autoimmuninity and there is no role for T cells and their interaction. And that B cell depleting therapies such as ocrelizumab and cladribine are successful in the way that they approach the resolution of the disease but fail because the CNS is very complex. Is that so? Why B cell therapies are not 100% successful to other autoimmmune diseases? Is it because it is hard to remove all memory B cells, do we need a wider B cell depletion agent or does it mean that there are other factors in the immune system that stay untouched by only Bcell targeting therapies? Is it ever possible to achieve a wider depletion that is not harmful to the overal health?
      Reply
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        • MouseDoctorWednesday, October 11, 2017 8:39:00 am
          I am open to T cells being involved and would be unusual if they were not but at present we ask the question are they critical.
          We have made the suggestion at all MS drugs work the same way and the more efficient they are at depleting memory B cells the more efficient they are. They are very effective at controlling relapsing disease

          The potential failings is how much of each agent gets in the brain.

          No treatment is 100% effective and B cell therapies do work in other diseases.

          We dont't need to remove all B cells we need to be more surgical in what we remove
        • [​IMG]
          adam bombWednesday, October 11, 2017 9:20:00 am
          "the more efficient they are at depleting memory B cells the more efficient they are."

          Do higher does deplete more B cells?..beta-seron is supposed to be once every 48 hours but seems better 24-36 hours.

        • MouseDoctorWednesday, October 11, 2017 12:21:00 pm
          I don't know it would be interesting to see the differences

          Immunology and Cell Biology (2016) 94, 886–894; doi:10.1038/icb.2016.55; published online 5 July 2016
          Interferon-β therapy specifically reduces pathogenic memory B cells in multiple sclerosis patients by inducing a FAS-mediated apoptosis

          In that study they looked at beteraferon and rebif but did not distinguidh between the two
        Reply

    15. luis fernandoWednesday, October 11, 2017 1:07:00 am
      " Is it because it is hard to remove all memory B cells, do we need a wider B cell depletion agent or does it mean that there are other factors in the immune system that stay untouched by only Bcell targeting therapies"

      Long-lived plasma cells (LLPCs) are an unmet therapeutic challenge, and developing strategies
      for their targeting is an emerging goal of autoantibody-mediated diseases such as
      systemic lupus erythematosus (SLE). It was previously shown that plasma cells can be
      depleted by agents such as bortezomib (Bz) or by blocking LFA-1 and VLA-4 integrins.
      However, they regenerate quickly after depletion due to B cell hyperactivity in autoimmune
      conditions. Therefore, we compared different therapies for the elimination of LLPCs combined
      with selective B-cell targeting in order to identify the most effective treatment to eliminate
      LLPCs and prevent their regeneration in lupus-prone NZB/WF1 mice.

      Our data indicate that effective depletion of long-lived and autoreactive plasma cells can
      only be achieved by depletion regimens containing the proteasome inhibitor bortezomib. The
      combination of bortezomib with integrin blockade does not seem to provide an additional synergistic
      effect

      http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0135081
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      1. Reply

    16. luis fernandoWednesday, October 11, 2017 3:51:00 pm
      Sharing is caring

      Thanks a lot... glad to be helping

      Especially because you have no Coi

      Also they did a SLE trial


      The proteasome inhibitior bortezomib depletes
      plasma cells and ameliorates clinical manifestations
      of refractory systemic lupus erythematosus

      https://www.ncbi.nlm.nih.gov/pubmed/25710470

      (Its open source)

      They have this b an plasma cells populations followup recovery ,in

      graphs, i think it relates to your work

      Obrigado

      Luis
      Reply
      Replies

        • luis fernandoWednesday, October 11, 2017 10:06:00 pm
          Thanks

          It s not only Hsct...lolllll

          In contrast,
          mice conditionally deleted for Mcl-1 in activation-
          induced cytidine deaminase producing
          cells were able neither to form GC, nor
          to produce memory B cells and GC-derived
          plasma cells. Antigen-specific B cells did notexpand even before the onset of the GC
          reaction, indicating that Mcl-1 dependency
          precedes GC formation

          anti-apoptotic molecule myeloid cell leukemia sequence 1 (Mcl-1

          http://www.nature.com/icb/journal/v89/n2/full/icb2010159a.html?foxtrotcallback=true

          Obrigado
          precedes GC formation. However, immunization
          of mice, in which Mcl-1 was deleted in
          either one or both alleles demonstrated that
          GC B cells are even more sensitive to Mcl-1
          deletion than activated B cells present before
          GC induction.

        • luis fernandoWednesday, October 11, 2017 11:40:00 pm
          Dont know

          Being involved in systemic inflammation and regulator of

          imumne cells, blocking it would send dangers signal to others

          cells to make maters worse in auto immunne disease context

          (i am speculating really) Cytokines are tricky


          It has been suggested that TNFα antagonists may increase the risk of demyelinating diseases in patients with RA by about 30% [32], however, these data are not supported by others [38]. The overall prevalence of RA and MS is 0.6% and 0.05% respectively [23]. The occurrence of both diseases in the same patient has been reported [51]. This coincidence should be not surprising because both RA and MS share pathogenetic and genetic similarities [51]. In this context patients having one autoimmune disease are at increased risk of developing another. In favor of this, is the existence in our study of two patients with preexisting MS-like lesions.

          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229940/

          obrigado
        Reply
     

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