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Astounding Norwegian research breakthrough with Rituximab can solve CFS mystery!!!

Discussion in 'Rituximab: News and Research' started by urbantravels, Oct 19, 2011.

  1. alex3619

    alex3619 Senior Member

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    Hi, the issue with NK cells is this: the kinds of monoclonal antibodies like Rituximab that target the B cells do so by activating another kind of cell. Guess which killing cell it is?

    http://bloodjournal.hematologylibrary.org/content/108/8/2648.short

    Rituximab might be working not by killing B cells, but by activating NK cells and other cytotoxic cells. That is an interesting possibility, and it suggests that activating the NK cells is critical. Of course we then have the question as to whether the actiivation carries over to fighting other pathogens or not. Perhaps it does in some, and not others ... just like what we see. Its intriguing enough that it should be kept in mind as an alternate possibility.

    Now in addition to this there is a little reported finding, not sure if its published or not, of soluble interleukin-2 receptor being very high in CFS. Mine was sky high, well on the way to lethal, typical of a severe autoimmune disease - sIL2r is a generic marker for autoimmune diseases, and CFS. Note that sIL2r is not directly lethal, its a surrogate marker for lethality. At a certain level (I lost my test results long ago, doh) it indicates imminent death, but the death is via autoimmune issues not sIL2r, its just a surrogate marker.

    Now IL-2 is bound by sIL2r and so it can't do its job. What is one of its jobs? Activating NK cells!

    So what is causing the increased sIL2r? Well for one thing the death of cells containing IL2r could release it into the blood stream, but thats just a guess. When I looked at this a decade ago nobody knew much about sIL2r. I am about to investigate it again.

    Bye
    Alex
     
  2. snowathlete

    snowathlete

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    Im seeing an imunologist soon, and given recent findings, i want to pass on the relevant information, and get the immunologist to run the right tests.

    Like many, i am convinced that EBV is a big part of my ME/CFS and my immune system is always on full alert now that i have ME/CFS. So, if anyone is able to help me identify which papers to show him/her, and which tests to suggest, then that would be really helpful!

    Best
    Joel
     
  3. ramakentesh

    ramakentesh Senior Member

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    The increased inflammation and oxidisive stress in CFS can also be explained by mechanisms other than the methylation cycle - in ways that are less complex and more obvious to me.

    Firstly, Autoimmunity:
    As an example, nearly all patients of chronic autoimmune or inflammatory conditions exhibit increased ROS (reactive oxygen species), increased serum assymetric dimethylarginine levels (a specific NO competitor), often increased endothelial nitric oxide (as found in a subset of POTS). Chronic elaboration of proinflammatory cytokines with potent vasoactive consequences such as TNF alpha have been associated with many autoimmune inflammatory conditions AND in CFS. In these cases the inflammation isnt a consequence of some theoretical concept but is the primary problem as associated with the patients histocompatibility.
    Do a search under RA, Lupus or Ankylosing Spondylitis and Endothelial or vascular and you will get LOTS of hits, most demonstrating increased ROS.

    Secondly, in POTS:

    If we concede for a moment that these are correct - in that most CFS patients have POTS:

    http://www.prohealth.com/library/showarticle.cfm?libid=16515

    Then we can see that a subset of POTS patients (many of whom were originally diagnosed with CFS) were found by Julian Stewart and Marvin Medow to have Elevated angiotensin II levels which results in reduced neuronal nitric oxide, excessive vasoconstriction, norepinephrine potentiation and above all, increased markers for inflammation (substance P, etc) and increased oxidisive stress with endothelial disfunction.

    this mechanism it alone can explain nearly all the features of CFS. Reduced cerebral hypoperfusion, increased ROS, sympathetic overactivity, abnormal blood flow etc.

    Im not saying that I think this applies to all CFS patients, but I am explaining a fully tested and definitively demonstrated pathophysiology that explains a subset of CFS through published studies in journals like Circulation, etc - reputable, respected, peer-reviewed journals.

    This demonstrates that there are at least two other mechanisms that I could successful argue and demonstrate to be clear candidates for explaining the increased ROS.

    THirdly I think the retrovirus angle has been overdone and distracted from broader research in areas with just as probable pathophysiologies. I am not saying that the retrovirus angle might not prove to be the ultimate truth behind this illness. But I think that research has too often focused to heavily in that direction to the detriment of other angles such as the autoimmune angle.

    I remember so many people arguing with total conviction that XMRV was a definate. if people can jump on that band wagon so blindly and with total conviction, then it can happen with other leads as well. XMRV was too good to be true from the start and if you stand back and read the story now its totally clear. Yet people wanted to believe so badly that they jumped the gun completely.

    Lastly, nearly every CFS patients Ive met has either suffered an autoimmune disease themselves or have a first degree relative that has.

    I developed POTS/CFS and Ankylosing Spondylitis in the same week. Out of the blue. They present by waxing and waning between one another - flare up of CFS, Flare up of AS, back and forth. The triggers that can cause a flare up of CFS/POTS, can cause a flare up of AS and vice versa. When As is really bad, I know that the POTS flare up afterwards will be worse, etc.

    And while this medication is potentially quite dangerous, if we can get certainty that CFS is an autoimmune disease, then we can examine some of the possible autoimmune targets (ace 2 receptor agonists? Norepinephrine transporter autoantibodies? A3 muscarinic receptor antibodies all implicated in POTS as examples), and potentially find safer medications to target the problem? Just a thought.
     
    fla and Jenny like this.
  4. ramakentesh

    ramakentesh Senior Member

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    Im always a big believer that the simple answer is often the correct one.
     
  5. alex3619

    alex3619 Senior Member

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    Hi ramakentesh, I more or less agree with your argument, but I think you are wrong about the prevalence of POTS. The paper you refered to does not say that at all. POTS by itself is a large minority of patients, not a majority. Orthostatic intolernce is found in the majority, but some have neurally mediated hypotension and not POTS. We also know that many patients have neither NMH nor POTS.

    The known inflammatory chemistry could indeed explain the oxidative stress in my view. Methylation cycle problems would exacerbate this, and possibly be a risk factor. However, improvement by boosting methylation may not be due to a deficiency, but simply higher production of methyl donors and glutathione - we dont need deficicncy for it to be of benefit.

    The question I am most focussing on at the moment is this: are our B cells or an NK cell or T cell subset dying? I think I can show if they are, and this has been alluded to, it could result in a decline in NK cell activation. I have been interested in sIL2r for over a decade, maybe since 1998, and lympocytes of all types have IL2 receptors. Dying lymphocytes might thus shed IL2r, making it sIL2r. I could be wrong about this, I am still looking for confirmation. sIL2r will bind interleukin-2 and so substantially decrease NK cell activation. Of course the obvious counter to this is that Rituximab kills B cells, so wouldn't it make NK cell function worse? I dont think so, as the monoclonal antibody acts to activate NK cells, thats how it kills the B cells. In addition the manner of death is likely to be different from, say, a B cell virus such as EBV.

    I have also pursued many other oxidative stress models over the years. There are many possibilities.

    One we always have to keep in mind is subgroups. These need to be identified and many of the models retested on specific subgroups.

    Bye
    Alex
     
  6. Kaoru

    Kaoru

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    I also that the fact that autoimmune diseases are also more prevalent in women is a good point in favor of an autoimmune component/origin in ME/CFS

    http://www.bsd-journal.com/content/pdf/2042-6410-2-1.pdf
     
  7. Kaoru

    Kaoru

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    A medical centre in Barcelona (Institut Ferran) announces on its website (http://www.institutferran.org/fatiga_cronica.htm) that they have prescribed Rituximab to some severe SFC patients on a compassionate basis and are currently preparing a clinical trial with similar agents.

    Original text "Este frmaco ya ha sido utilizado por nuestro equipo en algunos pacientes graves con SFC como tratamiento compasivo y actualmente estamos preparando un ensayo clnico sobre biosimilares al Rituximab en el contexto de la Fatiga Anormal y patologas inflamatorias."

    Also in their mailing list they specified that 5 patients have been followed now for more than 6 months and 3 of them improved "a lot".
     
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  8. redo

    redo Senior Member

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    +1 Kaoru. This is great news, especially for the people of Spain. Are you Spanish? I hope they could use the same symptom schemes as in the study (also discussed in the other thread). That would give them somewhat more substansial to report during and after the treatment. Accelerometeres as well. Perhaps you could tip them if you know the language?
     
  9. kurt

    kurt Senior Member

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    Definitely great news, maybe there are other small trials going on right now. Also, 3/5 is a similar ratio to the Mella & Fluge finding!
     
  10. sensing progress

    sensing progress Senior Member

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    does anyone know if any of the "responders" in the phase II trial had problems like MCS, food allergy/intolerances, etc? I would be very interested to know if those particular symptoms were affected.
     
  11. ramakentesh

    ramakentesh Senior Member

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    Most definately!

    http://circep.ahajournals.org/content/1/2/103.short

    Does the CFS diagnostic criteria used in the Norwegian study include autonomic disfunction? I know most do now.
    ,
    And yes, sorry CFS displays a spectrum of orthostatic intolerance, POTS and NMH, although according to Julian Stewart, POTS is the larger catagory.
     
  12. Glynis Steele

    Glynis Steele Senior Member

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    Sorry to but in here with an OT comment, but I found this in Science Daily today, and found it interesting. It is a study on MS, and a possible link between gut bacteria and b cells. I have started a separate thread on it in the "Other Health News and Research" section.

    ScienceDaily (Oct. 27, 2011) Multiple sclerosis is caused by a combination of genetic and environmental factors. For a long time, pathogens were believed to be such external influences. According to scientists from the Max Planck Institute of Neurobiology in Martinsried, however, it is apparently not harmful bacteria that trigger multiple sclerosis, but beneficial ones -- specifically, the natural intestinal flora, which every human being needs for digestion. The researchers discovered that genetically modified mice develop an inflammation in the brain similar to the human disease if they have normal bacterial intestinal flora. The microorganisms begin by activating the immune system's T cells and, in a further step, the B immune cells.


    --------------------------------------------------------------------------------

    The findings, published in the journal Nature, suggest that in humans with the corresponding genetic predisposition, the essentially beneficial intestinal flora could act as a trigger for the development of multiple sclerosis.

    The human intestine is a paradise for microorganisms: it is home to roughly 100 billion bacteria made up from 2,000 different bacterial species. The microorganisms of the intestine are not only indispensable for digestion, but also for the intestine's development. Altogether, this diverse community comprises between ten and one hundred times more genes than the entire human genome. Scientists therefore frequently refer to it as the "extended self." However, the intestinal bacteria can also play a role in diseases in which the immune system attacks the body itself. Intestinal bacteria can thus promote autoimmune disorders such as Crohn's disease and rheumatoid arthritis.

    On the one hand, the likelihood of developing multiple sclerosis, a disease in which proteins on the surface of the myelin layer in the brain activate the immune system, is influenced by genes. On the other, however, environmental factors have an even greater impact on the disease's development. Scientists have long suspected that it is caused by infectious agents. The Max Planck researchers now assume that multiple sclerosis is triggered by the natural intestinal flora.This astonishing finding was made possible by newly developed genetically modified mice. In the absence of exposure to any external influences, inflammatory reactions arise in the brains of these animals which are similar to those associated with multiple sclerosis in humans -- however, this only occurs when the mice have intact intestinal flora. Mice without microorganisms in their intestines and held in a sterile environment remained healthy. When the scientists "vaccinated" the animals raised in sterile conditions with normal intestinal microorganisms, they also became ill.

    According to the Martinsried-based researchers, the intestinal flora influence immune systems in the digestive tract; mice without intestinal flora have fewer T cells there. Moreover, these animals' spleen produces fewer inflammatory substances, like cytokines. In addition, their B cells produce few or no antibodies against myelin. When the researchers restored the intestinal flora to the mice, their T cells and B cells increased their cytokine and antibody production.

    "It appears that the immune system is activated in two stages: to begin, the T cells in the lymph vessels of the intestinal tract become active and proliferate. Together with the surface proteins of the myelin layer, these then stimulate the B cells to form pathogenic antibodies. Both processes trigger inflammatory reactions in the brain which progressively destroy the myelin layer -- a process that is very similar to the way multiple sclerosis develops in humans," says Gurumoorthy Krishnamoorthy from the Max Planck Institute of Neurobiology. Thus, the disease is caused by changes in the immune system and not by disturbances in the functioning of the nervous system. "Multiple sclerosis research has long been preoccupied with this question of cause and effect. Our findings would suggest that the immune system is the driving force here," says Hartmut Wekerle, Director at the Max Planck Institute in Martinsried.

    The scientists are certain that the intestinal flora can also trigger an overreaction of the immune system against the myelin layer in persons with a genetic predisposition for multiple sclerosis. Therefore, nutrition may play a central role in the disease, as diet largely determines the bacteria that colonise the intestines. "Changing eating habits could explain, for example, why the incidence of multiple sclerosis has increased in Asian countries in recent years," explains Hartmut Wekerle.

    Precisely which bacteria are involved in the emergence of multiple sclerosis remains unclear. Possible candidates are clostridiums, which can have direct contact with the intestinal wall. They are also a natural component of healthy intestinal flora but could possibly activate the T cells in persons with a genetic predisposition. The scientists would now like to analyse the entire microbial genome of patients with multiple sclerosis and thereby identify the differences in the intestinal flora of healthy people and multiple sclerosis patients.

    http://www.sciencedaily.com/releases...1027112520.htm
     
  13. Jenny

    Jenny Senior Member

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    Hi Alex

    On B cells, I have an abnormally low percentage of CD19+ B cells (8, normal range is 12-22) and a low absolute CD19 count, but just within normal range.

    Do you think they might be low because they are dying? And do you know if this is common in ME?

    Jenny
     
  14. redo

    redo Senior Member

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  15. Glynis Steele

    Glynis Steele Senior Member

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    Thanks Redo.

    Damned bugs, lol.
     
  16. alex3619

    alex3619 Senior Member

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    Hi Jenny, I don't think anybody knows, but the question has been raised. There was a comment from the WPI some months ago, at a presentation I think, that while they found B cell numbers were normal, most were immature. That woudl imply a high turnover of B cells, with a high demand for DNA and protein synthesis, including methyl donors. If something were blocking the replenishment of a B cell subset, then its possible that this could explain the low CD19. Its only possible, we need to know more. One other issue that is often the case is high levels of uric. acid. Lots of cells dying could produce uric acid as a byproduct - but again I would expect to see other abnormalities if this were the case, and nothing else comes to my attention. Maybe its just been missed, or maybe this explanation is wrong. Bye, Alex

    PS I was briefly looking at wikipedia on CD19. Low levels of CD19 might, just might, be linked to reduced antibody production. I don't have time to investigate this properly at the moment.
     
  17. Jenny

    Jenny Senior Member

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    Thanks Alex. I'll see what I can find out about CD19 and antibody production.

    Jenny
     
  18. Cort

    Cort Phoenix Rising Founder

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  19. Sallysblooms

    Sallysblooms P.O.T.S. now SO MUCH BETTER!

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    I hope they find that it will not cause those terrible side effects and fatal problems like progressive multifocal leucoencephalopathy. SO scary.
     
  20. kurt

    kurt Senior Member

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    no doubt there will be other methods of treatment. Mella and Fluge have opened a door, by identifying a treatable pathology. But there are many angles to this, for example, what is causing the B cell over-expression in the first place? One new theory is the gut flora, for example. Someone already posted this, but I'll mention it again, the new MS study showing B cell over-activation in MS due to flora:

    http://www.sciencedaily.com/releases/2011/10/111027112520.htm

    That could lead to eventual gut treatments in MS to modulate the B cell expression. Just an example, maybe we will find analogous treatments for ME/CFS.
     

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