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Altered immune response to exercise in patients with CFS/ME: a systematic literature review

Discussion in 'Latest ME/CFS Research' started by Bob, Jul 1, 2014.

  1. WillowJ

    WillowJ Senior Member

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    Did it say whether the levels were upregulated or downregulated? If I understand correctly, altered complement response can go with autoimmunity (among other things) if it's downregulated (this is a test they use in SLE).
     
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  2. WillowJ

    WillowJ Senior Member

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    Pretty sure this is a complaint about the topic more than the design, although I am not certain the authors understand this.

    Some of these papers did not set out to study exercise therapy: Therefore they would not be studying the effects of exercise therapy on the immune system.

    What some of those papers wanted to know was: in what ways in the immune system different in the subjects than in the controls. Knowing there is a problem with exercise, they used exercise to flush it out.
     
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  3. Simon

    Simon

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    They don't say, but since the level of c4a - the activated form - is normally negligible, I'm guessing it must be increased.

    That SLE is for overall levels of C4, the inactive precursor, which is a different thing: it's looking at overall levels of complement, not activation status.

    Separately, I see that the Sorenson study found:
    which is odd: it's an enzyme cascade, and C4a is supposed to cleave inactive C3 into C3a & b , which cleaves inactive C5 into C5a and C5b. So it's odd that C3a and C5a are not elevated as this suggests that complement system isn't really activated. Also, the p values were marginal in this study and they look to have made a lot of comparisons without correcting for multiple comparisons (more comparisons increase the chance of false positives) ie there may be a degree of data mining going on here and the association between complement C4a and symptoms may to be real.

    edited to clarify some details
     
    Last edited: Jul 19, 2014
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  4. WillowJ

    WillowJ Senior Member

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  5. WillowJ

    WillowJ Senior Member

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    Would that show a downregulation in part of the immune system? I was unable to classify all the cytokines as to being in a particular group. Or are the studies too small?
     
  6. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    Even then, many/most doctors will be unable or unwilling to look at scientific papers as, in the UK at least, it doesn't seem to be part of their job description and/or they don't have time/claim not to have time.
     
  7. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    This paper says

    Personally I don't bother wasting time reading any animal studies if I am trying to learn about humans, as they are generally just as likely to be irrelevant as they are to be relevant (these two possibilities cancelling each other out, so why bother?). But this does appear to be generally relevant to us.
     
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  8. anciendaze

    anciendaze Senior Member

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    Opsonisation is one of the few parts of immune response with a long research history going back to 1907. It even made it into world literature via the works of G.B. Shaw and Sinclair Lewis. At that time the most important diseases were syphilis, typhoid and TB, which were very hard to treat without antibiotics.

    Chemotherapy meant something different at that time than it does today, but one aspect of the ideas has not changed: there are bad cells in there, and it is up to us to destroy them. The principle goal was to find what Ehrlich called "magic bullets" (Zauberkugeln). From the German word it is clear he was thinking about a scatter-shot approach. This was total war, with the patient's body as the unfortunate battlefield.

    The other aspect was that besides homing in on the offending cells, it was necessary for these bullets to have a toxic payload. In the case of Salvarsan, that was arsenic.

    When Protosil was discovered, many years later, the idea was that a dye molecule would bind to bacteria, which would then be poisoned by the rest of the chemical. Scientists at the Pasteur Institute then found that metabolism separated the dye from the sulfanilamide molecule before it reached bacteria. This unpatentable molecule had stronger antibacterial action than Prontosil.

    The final question about toxicity was answered even later. Sulfanilamide has remarkably low toxicity, which allowed it to be sprinkled directly on fresh wounds during WWII. It is an antimetabolite which bacteria will consume without gaining energy. In effect it is diet food for germs. It didn't directly kill them, but it slowed their metabolism enough to limit reproduction so that ordinary immune cells could cope.

    So, in short, the two fundamental features of that theory of chemotherapy were wrong. It was only through a great deal of trial and error that researchers stumbled across an antibacterial that did more harm to bacteria than to patients.

    Even this account leaves a major question unanswered: what did these toxic payloads do to the phagocytes which cleaned up the mess after bacteria died? Damaging patient immune systems or organs like the liver could lead to even worse problems.

    We are just now emerging from that era, with techniques like adoptive immunotherapy, to concentrate on properly directing the patient's own immune cells. These turn out to be quite capable of disposing of pounds of cancer cells without killing patients. Doctors dealing with infectious disease and autoimmune diseases are just beginning to recognize that something is wrong with the predominant paradigms in these fields. Having cleared away a great many microbes which could be killed with crude measures we are now forced to deal with those which have developed sophisticated strategies for misdirecting immune response. Our own ability to direct immune response is severely hampered by not even knowing what we are aiming at in most clinical cases.

    What we can say about current practice is that doctors find it convenient, and most patients survive, most of the time. Such is the state of the art.
     
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  9. Sasha

    Sasha Fine, thank you

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    Mine will look - I hope he's not the only one. He's very sympathetic and keen to do what he can but not very willing to step outside of what there's evidence for. The NHS is very big on evidence-based medicine, as we all know - so when there's some actual evidence, we need a good summary of it.
     
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  10. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    In general, mine will not look properly at printed info I give them, even if I have spent a lot of time summarising things. Even if they look at it, they are not prepared to act on it unless they really understand it and are familiar with the contents (which I suspect they are not).

    You sound lucky with yours. Even a willingness to listen and be supportive is very welcome. I suspect that few people with ME have such a doctor. I really envy those who have.
     
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  11. osisposis

    osisposis

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    J Neuroimmunol. 2010 Jun;223(1-2):124-7. doi: 10.1016/j.jneuroim.2010.03.014. Epub 2010 Apr 20.
    Elevated plasma C4a levels in multiple sclerosis correlate with disease activity.
    Ingram G1, Hakobyan S, Robertson NP, Morgan BP.
    Author information
    Abstract

    http://www.ncbi.nlm.nih.gov/pubmed/20409594
     
  12. osisposis

    osisposis

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    Inhal Toxicol. 2011 Dec;23(14):897-905. doi: 10.3109/08958378.2011.625058.

    Hasegawa G1, Hirano M, Ishihara Y.
    Differential gene expression associated with inflammation and blood pressure regulation induced by concentrated ambient particle exposure.
    Author information
    Abstract

    PMID:
    22122303
    [PubMed - indexed for MEDLINE]

    http://www.ncbi.nlm.nih.gov/pubmed/22122303



    http://informahealthcare.com/doi/abs/10.3109/08958378.2011.625058
     
  13. osisposis

    osisposis

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    C1-Inhibitor protects from focal brain trauma in a cortical cryolesion mice model by reducing thrombo-inflammation

    http://journal.frontiersin.org/journal/10.3389/fncel.2014.00269/full
     
  14. osisposis

    osisposis

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    Immunity. 2011 Feb 25;34(2):258-68. doi: 10.1016/j.immuni.2011.02.008.
    Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo.
    Oschatz C1, Maas C, Lecher B, Jansen T, Björkqvist J, Tradler T, Sedlmeier R, Burfeind P, Cichon S, Hammerschmidt S, Müller-Esterl W, Wuillemin WA, Nilsson G, Renné T.
    Author information
    Abstract

    Activated mast cells trigger edema in allergic and inflammatory disease. We report a paracrine mechanism by which mast cell-released heparin increases vascular permeability in vivo. Heparin activated the protease factor XII, which initiates bradykinin formation in plasma. Targeting factor XII or kinin B2 receptors abolished heparin-triggered leukocyte-endothelium adhesion and interfered with a mast cell-driven drop in blood pressure in rodents. Intravital laser scanning microscopy and tracer measurements showed heparin-driven fluid extravasation in mouse skin microvessels. Ablation of factor XII or kinin B2 receptors abolished heparin-induced skin edema and protected mice from allergen-activated mast cell-driven leakage. In contrast, heparin and activated mast cells induced excessive edema in mice deficient in the major inhibitor of factor XII, C1 esterase inhibitor.
    Allergen exposure triggered edema attacks in hereditary angioedema patients, lacking C1 esterase inhibitor. The data indicate that heparin-initiated bradykinin formation plays a fundamental role in mast cell-mediated diseases.

    http://www.ncbi.nlm.nih.gov/pubmed/21349432

    http://www.cell.com/immunity/abstract/S1074-7613(11)00046-X

    http://ac.els-cdn.com/S107476131100...t=1412734881_6dd4113da27aca6d0735a0f76e94ca12
     
  15. osisposis

    osisposis

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    osisposis, post: 510502, member: 14586"]Immunity. 2011 Feb 25;34(2):258-68. doi: 10.1016/j.immuni.2011.02.008.
    Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo.
    Oschatz C1, Maas C, Lecher B, Jansen T, Björkqvist J, Tradler T, Sedlmeier R, Burfeind P, Cichon S, Hammerschmidt S, Müller-Esterl W, Wuillemin WA, Nilsson G, Renné T.
    Author information
    Abstract

    Activated mast cells trigger edema in allergic and inflammatory disease. We report a paracrine mechanism by which mast cell-released heparin increases vascular permeability in vivo. Heparin activated the protease factor XII, which initiates bradykinin formation in plasma. Targeting factor XII or kinin B2 receptors abolished heparin-triggered leukocyte-endothelium adhesion and interfered with a mast cell-driven drop in blood pressure in rodents. Intravital laser scanning microscopy and tracer measurements showed heparin-driven fluid extravasation in mouse skin microvessels. Ablation of factor XII or kinin B2 receptors abolished heparin-induced skin edema and protected mice from allergen-activated mast cell-driven leakage. In contrast, heparin and activated mast cells induced excessive edema in mice deficient in the major inhibitor of factor XII, C1 esterase inhibitor.
    Allergen exposure triggered edema attacks in hereditary angioedema patients, lacking C1 esterase inhibitor. The data indicate that heparin-initiated bradykinin formation plays a fundamental role in mast cell-mediated diseases.

    http://www.ncbi.nlm.nih.gov/pubmed/21349432

    http://www.cell.com/immunity/abstract/S1074-7613(11)00046-X

    http://ac.els-cdn.com/S107476131100...t=1412734881_6dd4113da27aca6d0735a0f76e94ca12



    Microglia, Alzheimer's Disease, and Complement
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3432348/


    Formation of bradykinin: a major contributor to the innate inflammatory response.
    http://www.ncbi.nlm.nih.gov/pubmed/15705422

    Kinins, Airway Obstruction, and Anaphylaxis
    http://www.karger.com/Article/FullText/315938

    Adv Immunol. 2014;121:41-89. doi: 10.1016/B978-0-12-800100-4.00002-7.
    Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammatory pathway.
    http://www.ncbi.nlm.nih.gov/pubmed/24388213

    http://www.sciencedirect.com/science/article/pii/B9780128001004000027

    The plasma bradykinin-forming pathways and its interrelationships with complement
    http://www.sciencedirect.com/science/article/pii/S0161589010001690


    Chem Immunol Allergy. 2014;100:205-13. doi: 10.1159/000358739. Epub 2014 May 22.
    The bradykinin-forming cascade: a historical perspective.
    http://www.ncbi.nlm.nih.gov/pubmed/24925400

    Chem Immunol Allergy. 2014;100:140-7. doi: 10.1159/000358619. Epub 2014 May 22.
    Bradykinin-mediated diseases.
    http://www.ncbi.nlm.nih.gov/pubmed/24925394
    World Allergy Organ J. 2008 Jun;1(6):103-13. doi: 10.1097/WOX.0b013e31817aecbe.
    Angioedema.
    http://www.ncbi.nlm.nih.gov/pubmed/23282406

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3651192/
     
  16. osisposis

    osisposis

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    Age-related macular degeneration and the complement system

    complement may be activated by oxidative stress

    http://www.sciencedirect.com/science/article/pii/S0171298511001598


    The new face of anaphylatoxins in immune regulation

    http://www.sciencedirect.com/science/article/pii/S0171298511001471



    J Immunol. 1996 Aug 15;157(4):1693-8.
    C3a and C5a are chemotaxins for human mast cells and act through distinct receptors via a pertussis toxin-sensitive signal transduction pathway.
    http://www.ncbi.nlm.nih.gov/pubmed/8759757


    Int Immunopharmacol. 2012 Jan;12(1):158-68. doi: 10.1016/j.intimp.2011.11.006. Epub 2011 Dec 7.
    Inhibitory effects of C4a on chemoattractant and secretagogue functions of the other anaphylatoxins via Gi protein-adenylyl cyclase inhibition pathway in mast cells.

    http://www.ncbi.nlm.nih.gov/pubmed/22155625

    http://www.sciencedirect.com/science/article/pii/S1567576911004462

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

    Elevated plasma C4a levels in multiple sclerosis correlate with disease activity.
    J Neuroimmunol. 2010; 223(1-2):124-7 (ISSN: 1872-8421)

    http://www.medscape.com/medline/abstract/20409594


    Mult Scler. Oct 2012; 18(10): 1401–1411.
    doi: 10.1177/1352458512438238
    PMCID: PMC3697901
    Systemic complement profiling in multiple sclerosis as a biomarker of disease state

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3697901/


    Acta Neuropathol Commun. 2014; 2(1): 53.
    Published online May 9, 2014. doi: 10.1186/2051-5960-2-53
    PMCID: PMC4048455
    Complement activation in multiple sclerosis plaques: an immunohistochemical analysis

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048455/

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


    Immunobiology. 2012 Nov;217(11):1067-79. doi: 10.1016/j.imbio.2012.07.015.
    The immunoglobulin, IgG Fc receptor and complement triangle in autoimmune diseases.


    http://www.ncbi.nlm.nih.gov/pubmed/22964232

    --------------------------------
    J Allergy Clin Immunol. 2013 Feb;131(2):541-8.e1-9. doi: 10.1016/j.jaci.2012.05.009. Epub 2012 Jun 22.
    Mast cell anaphylatoxin receptor expression can enhance IgE-dependent skin inflammation in mice.

    http://www.ncbi.nlm.nih.gov/pubmed/22728083


    Arthritis Res Ther. 2014 Mar 17;16(2):R72. doi: 10.1186/ar4512.
    Roles of mast cells in the pathogenesis of inflammatory myopathy.
    http://www.ncbi.nlm.nih.gov/pubmed/24636001


    Exp Mol Med. 2014 Mar 14;46:e83. doi: 10.1038/emm.2014.7.
    New era for mucosal mast cells: their roles in inflammation, allergic immune responses and adjuvant development.

    http://www.ncbi.nlm.nih.gov/pubmed/24626169


    Immunol Res. 2007;37(3):161-75.
    Anaphylatoxins: their role in bacterial infection and inflammation.

    http://www.ncbi.nlm.nih.gov/pubmed/17873401


    Mast cells and inflammation
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318920/
     
  17. osisposis

    osisposis

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  18. osisposis

    osisposis

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    Brain Res Brain Res Rev. 2005 Apr;48(2):388-99. Epub 2005 Jan 28.
    Closed head injury--an inflammatory disease?
    Schmidt OI1, Heyde CE, Ertel W, Stahel PF.
    Author information
    Abstract

    http://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=15850678
     
  19. osisposis

    osisposis

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    Shock. 2012 Aug;38(2):220-5. doi: 10.1097/SHK.0b013e31825bf40e.
    C1 inhibitor suppresses the endotoxic activity of a wide range of lipopolysaccharides and interacts with live gram-negative bacteria.
    Mejia P1, Davis AE 3rd.
    Author information
    Abstract


    http://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=22576004
     
  20. Sea

    Sea Senior Member

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    NSW Australia
    @osisposis the theme of this thread is altered immunity in CFS after exercise. You will get more discussion on your postings if you start another thread instead of adding off topic research here
     
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