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  1. #1
    Senior Member FunkOdyssey's Avatar
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    I've been researching Lyme Disease for over two years at a fairly hardcore level for a layperson. What follows is what I currently think to be the best way to set your body up to fight this infection. Bear in mind that this relies heavily on incomplete data, conjecture, and extrapolation. In other words, do not rely on it as gospel.

    We'll begin by examining associations between immune responses in Lyme and disease outcomes. I will use primarily human data as I suspect there may be differences in the murine Lyme infection. We'll use this data to form a hypothesis of what an optimal immune response to the infection should look like.

    (PMID: 17177959)
    <blockquote><span style="font-size:10pt;line-height:100%">Lyme borreliosis (LB) can, despite adequate antibiotic treatment, develop into a chronic condition with persisting symptoms such as musculoskeletal pain, subjective alteration of cognition and fatigue. The mechanism behind this is unclear, but it has been postulated that an aberrant immunological response might be the cause. In this study we investigated the expression of the T helper 1 (Th1) marker interleukin (IL)-12Rbeta2, the marker for T regulatory cells, forkhead box P3 (FoxP3) and the cytokine profile in patients with a history of chronic LB, subacute LB, previously Borrelia-exposed asymptomatic individuals and healthy controls.
    ....
    Chronic LB patients displayed a lower expression of Borrelia-specific IL-12Rbeta2 on CD8(+) cells and also a lower number of Borrelia-specific IFN-gamma-secreting cells compared to asymptomatic individuals. Furthermore, chronic LB patients had higher amounts of Borrelia-specific FoxP3 mRNA than healthy controls. We speculate that this may indicate that a strong Th1 response is of importance for a positive outcome of a Borrelia infection. In addition, regulatory T cells might also play a role, by immunosuppression, in the development of chronic LB.
    </span></blockquote>
    We see changes in the chronic patients above that indicate reduced Th1 signaling (IL-12 and IFN-gamma are key Th1 cytokines) compared to asymptomatically infected and healthy controls.


    (PMID: 15958074)
    <blockquote><span style="font-size:10pt;line-height:100%">Innate immunity is important for early defence against borrelia spirochetes and should play a role in the clinical outcome of the infection. In order to study early cytokine responses, in vitro differentiated dendritic cells (DCs) and whole blood cells from 21 patients with different clinical outcomes of Lyme neuroborreliosis were stimulated with live borrelia spirochetes.
    ...
    We found increased numbers of TNF-alpha-secreting DCs (P = 0.018) in asymptomatic seropositive individuals compared to patients with subacute neuroborreliosis and seronegative controls. Asymptomatic individuals were also found to have elevated levels of IL-12p70 (P = 0.031) in whole blood cell supernatants compared to seronegative controls. These results are in line with previous experiments using cells of the adaptive immune response, indicating that strong T helper type 1 (Th1) proinflammatory responses might be associated with a successful resolution of Lyme disease.</span>
    </blockquote>
    If you have Lyme, forget sports heroes, movie stars and the like, because asymptomatic seropositive individuals are your new role model. Whatever their immune system is doing is successfully controlling the infection, and they are living their entirely normal lives in blissful ignorance of the process. We see again that a strong Th1 response is associated with a successful outcome, specifically elevated circulating levels of IL-12 and increased TNF-alpha secreting potential (though not necessarily high circulating TNF-a).


    (PMID: 11159956)
    <blockquote><span style="font-size:10pt;line-height:100%">In lipopolysaccharide-stimulated blood from 71 late-stage borreliosis patients, the ex vivo cytokine release capacity of tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) was reduced to 28% +/- 5% and to 31% +/- 5% (P < or = 0.001), respectively, compared to that of 24 healthy controls. White blood cell counts were normal in both groups. To investigate direct interactions between the pathogen and the immune cells, blood from healthy controls was exposed in vitro to live or heat-killed Borrelia or to Borrelia lysate. Compared to the pattern induced by bacterial endotoxins, a reduced release of TNF-alpha and IFN-gamma and an enhanced secretion of interleukin-10 and granulocyte colony-stimulating factor was found. In blood from 10 borreliosis patients stimulated with Borrelia lysate, TNF-alpha formation was decreased to 31% +/- 14% and IFN-gamma formation was decreased to 8% +/- 3% (P < or = 0.001) compared to the cytokine response of blood from healthy controls (n = 24). We propose to consider anti-inflammatory changes in the blood cytokine response capacity elicited by Borrelia as a condition that might favor the persistence of the spirochete.</span></blockquote>
    We see evidence of a reduced Th1 response and upregulated Th2 response in late stage Lyme. IFN-gamma and TNF-alpha secretion is dramatically reduced compared to healthy controls, while IL-10 is upregulated. The authors believe these anti-inflammatory changes, which are duplicated by MANY dietary supplements generally thoughtful to be healthful and even recommended specifically for Lyme, favor the persistence of the infection.


    (PMID: 10193424)
    <blockquote><span style="font-size:10pt;line-height:100%">Borrelia Lyme disease is a complex disorder that sometimes becomes chronic. There are contradictory reports of experimental Borrelia infections regarding which type of T cell cytokine responses, i.e. Th1 or Th2, are needed to eradicate the Borrelia spirochaetes.
    ...
    Interestingly, the proportion of spontaneously IL-4-secreting cells, reflecting the unstimulated in vivo secretion, was lower in the seropositive asymptomatic individuals compared with patients with chronic Borrelia infections (n = 13, P = 0.02), whereas no such difference was found compared with subacute Borrelia infections (n = 12). These findings indicate that IFN-gamma secretion alone is not sufficient to eliminate Borrelia spirochaetes in humans, although IFN-gamma may still have a beneficial role in borreliosis acting in concert with other mechanisms.
    ...
    In this context, the finding of a tendency to lower proportions of spontaneously IL-4-secreting cells in the seropositive asymptomatic individuals compared with patients with chronic Borrelia infections is interesting, since the effects of IL-4 have been reported to dominate over the effects of IFN-γ [22]. In the murine model of Leishmaniasis, where IFN-γ is needed for cure, the mice are not cured if there are elevated levels of IL-4, despite high levels of IFN-γ [23]. Furthermore, in another study of the same model, administration of anti-IL-4 antibodies cured the mice [24]. The spontaneous secretion of cytokines in blood may reflect a background secretion, which is always present, and these patterns may differ between individuals. Based on this assumption, we speculate that individuals with a higher proportion of spontaneously IL-4-secreting cells (i.e. higher spontaneous IL-4/IFN-γ ratio) may not benefit from an increased pathogen-specific secretion of IFN-γ, since the potential eradicating effects of IFN-γ are blocked by the high background level of IL-4.
    </span></blockquote>
    This one is very important in my opinion: IL-4 emerges as a villain here in a direct comparison between chronic Lyme and asymptomatic infection. It appears that no matter how robust your Th1 response is, excess IL-4 may effectively castrate it. We'll definitely be revisiting this later as we explore various interventions.


    (PMID: 16771857)
    <blockquote><span style="font-size:10pt;line-height:100%">In a 5-year follow-up study in southern Sweden, 31 of 708 individuals initially diagnosed with erythema migrans and treated with antibiotics were found to be reinfected with Borrelia burgdorferi. Although men and women were tick-bitten to the same extent, 27 of the 31 reinfected individuals were women, all of whom were over 44 years of age. The aim of this study was to determine whether this discrepancy in gender distribution could be a result of differences in immunological response.
    ...
    The ratios of IL-4:IFN-gamma and IL-10:TNF-alpha were significantly higher in women. Gender differences in immune reactivity might in part explain the higher incidence of reinfection in women. The higher IL-4:IFN-gamma and IL-10:TNF-alpha ratios seen in women indicate that postmenopausal women have T helper type 2 (Th2)-directed reactivity with impaired inflammatory responses which might inhibit the elimination of spirochetes.
    </span></blockquote>
    First, we have verification of the importance of the IL-4:IFN-gamma ratio that we just discussed. The IL-10:TNF-alpha ratio appears to be relevant as well. But most importantly, we see a massive gender discrepancy in reinfection rates. Might hormonal influences on immune function be the reason? Very likely, as we'll discuss later. Now, lets talk more about IL-10.


    (PMID: 11367577)
    <blockquote><span style="font-size:10pt;line-height:100%">Immunity against the Lyme spirochete B. burgdorferi was studied in a murine model of UV-induced immune suppression.
    ...
    The results demonstrated that UV irradiation, administered at the site of infection or at a distant site, suppressed Borrelia-specific cellular and humoral responses in infected mice. Suppression of delayed-type hypersensitivity and antibody responses to UV was abrogated by administration of anti-interleukin (IL)-10 after UV irradiation.
    ...
    Furthermore, our studies suggest that IL-10 is in part responsible for the suppression of both cellular and humoral responses in addition to playing a role in the development of Lyme arthritis.
    </span></blockquote>
    Excess sun exposure may be contraindicated in Lyme. Significantly, its negative impact seems to be mediated by increased IL-10 production.


    (PMID: 12819085)
    <blockquote><span style="font-size:10pt;line-height:100%">If left untreated, infection with Borrelia burgdorferi sensu lato may lead to chronic Lyme borreliosis. It is still unknown how this pathogen manages to persist in the host in the presence of competent immune cells. It was recently reported that Borrelia suppresses the host's immune response, thus perhaps preventing the elimination of the pathogen (I. Diterich, L. Härter, D. Hassler, A. Wendel, and T. Hartung, Infect. Immun. 69:687-694, 2001). Here, we further characterize Borrelia-induced immunomodulation in order to develop a model of this anergy. We observed that the different Borrelia preparations that we tested, i.e., live, heat-inactivated, and sonicated Borrelia, could desensitize human blood monocytes, as shown by attenuated cytokine release upon restimulation with any of the different preparations. Next, we investigated whether these Borrelia-specific stimuli render monocytes tolerant, i.e. hyporesponsive, towards another Toll-like receptor 2 (TLR2) agonist, such as lipoteichoic acid from gram-positive bacteria, or towards the TLR4 agonist lipopolysaccharide. Cross-tolerance towards all tested stimuli was induced. Furthermore, using primary bone marrow cells from TLR2-deficient mice and from mice with a nonfunctional TLR4 (strain C3H/HeJ), we demonstrated that the TLR2 was required for tolerance induction by Borrelia, and using neutralizing antibodies, we identified interleukin-10 as the key mediator involved. Although peripheral blood mononuclear cells tolerized by Borrelia exhibited reduced TLR2 and TLR4 mRNA levels, the expression of the respective proteins on monocytes was not decreased, ruling out the possibility that tolerance to Borrelia is attributed to a reduced TLR2 expression. In summary, we characterized tolerance induced by B. burgdorferi, describing a model of desensitization which might mirror the immunosuppression recently attributed to the persistence of Borrelia in immunocompetent hosts.</span></blockquote>
    I quoted that entire abstract because its so important. Here we have a solid mechanism contributing to both immunosuppression in chronic infection and induced tolerance toward the pathogen (and others similar to it), mediated by none other than IL-10.


    (PMID: 7836761)
    <blockquote><span style="font-size:10pt;line-height:100%">The possible involvement of specific T cells in resolution of infections with Borrelia burgdorferi (Bb), the causative agent of human Lyme disease, has not been adequately studied. To investigate the potential role of T cell subsets in resistance, we have depleted mice of CD4+ and CD8+ T cell subsets in vivo by the administration of specific mAbs and have examined outcomes after infection with Bb. Our results indicate that CD4+ T cells are required for immunologic control of spirochete levels, because their depletion in both susceptible C3H/HeN and resistant BALB/c mice increased the severity of arthritis and the numbers of spirochetes found in joints and skin, as compared with Bb-infected mice treated with a control mAb. In contrast, the CD8+ T cell compartment, particularly in susceptible C3H/HeN mice, appears to promote the disease process, possibly by interfering with the generation of protective immunity, as abrogation of this subset in vivo led to a reduction in both arthritis and in spirochete levels found in joints and skin when compared with Bb-infected control mice.
    ...
    These findings suggest that the final outcome in Bb-infected hosts may be the net effect of antagonistic influences exerted by CD4+ and CD8+ T cell subsets.
    </span></blockquote>
    Lastly, the CD4:CD8 ratio may be important. CD4 T cells are required for control of the infection, while CD8 cells may promote the disease process.


    Let's summarize what we've learned so far:
    <blockquote>-A strong Th1 response appears to be critical, mediated by IFN-gamma, IL-12, and possibly TNF-alpha
    -Th2 signaling, specifically the cytokines IL-4 and IL-10, may be actively detrimental
    -gender plays a huge role in Lyme (you want to be a man if possible) [img]style_emoticons/<#EMO_DIR#>/tongue.gif[/img]
    -a higher CD4:CD8 ratio should be helpful</blockquote>

    In the next installment, we'll explore various ways to modulate the immune system and replicate this ideal response that we've now identified, beginning with the influence of sex hormones on the immune system.
    "Also, can I rig some sort of enema out of household items?" -Tussman

    "I don't have the stamina for a 3-some, and I am a one-pump chump" -Ubiyca

  2. #2
    Senior Member karoloydi's Avatar
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    So, are you saying that in people with symptomatic Lyme's disease TNF-alpha is lowered and IL-10 is increased?

    I was expecting the opposite. I was expecting the inflammation to be causing the symptoms. But if TNF-alpha is lowered and IL-10 is increased that means the opposite.

    Is this a sign that the immune system is compromised?
    Meditation is Medication's Twin Sister

  3. #3
    Senior Member FunkOdyssey's Avatar
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    <div class='quotetop'>QUOTE (karoloydi @ Aug 13 2010, 02:23 PM) <{POST_SNAPBACK}></div><div class='quotemain'>So, are you saying that in people with symptomatic Lyme's disease TNF-alpha is lowered and IL-10 is increased?

    I was expecting the opposite. I was expecting the inflammation to be causing the symptoms. But if TNF-alpha is lowered and IL-10 is increased that means the opposite.

    Is this a sign that the immune system is compromised?</div>

    IL-10 is certainly increased. I'm not sure whether circulating TNF-alpha is higher or not; the studies I quoted looked at TNF-alpha secreting capacity of immune cells in response to stimulation, not the circulating blood level. It may be higher in symptomatic individuals and mediate inflammatory symptoms.

    It is entirely possible and even likely that the interventions we'll be discussing here will acutely worsen inflammatory symptoms of the disease. Nonetheless, I believe they will ultimately help lead to resolution or at least control of the infection.

    If you care more about reducing pathogen load than making yourself [temporarily] comfortable, this guide is for you.
    "Also, can I rig some sort of enema out of household items?" -Tussman

    "I don't have the stamina for a 3-some, and I am a one-pump chump" -Ubiyca

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    Senior Member karoloydi's Avatar
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    <div class='quotetop'>QUOTE (FunkOdyssey @ Aug 13 2010, 02:39 PM) <{POST_SNAPBACK}></div><div class='quotemain'>IL-10 is certainly increased. I'm not sure whether circulating TNF-alpha is higher or not; the studies I quoted looked at TNF-alpha secreting capacity of immune cells in response to stimulation, not the circulating blood level. It may be higher in symptomatic individuals and mediate inflammatory symptoms.

    It is entirely possible and even likely that the interventions we'll be discussing here will acutely worsen inflammatory symptoms of the disease. Nonetheless, I believe they will ultimately help lead to resolution or at least control of the infection.

    If you care more about reducing pathogen load than making yourself [temporarily] comfortable, this guide is for you.</div>

    Yeah, you are right. Better trade short term pain for long term gain.
    Meditation is Medication's Twin Sister

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    -you'd be surprised at how much this is all known to those with or who have been interested in understanding CFS.

    Yes, the bug suppresses the immune system - in common with all chronic infections it is a necessary part of what they do. What is probably surprising to many people is that infections have evolved so much. Its also the case that deficiencies in Th-1 signalling were known to many sufferers of CFS and correcting it formed the basis of their treatment, for exactly the same reasons you hypothesise. It was then realised that increasing inflammation unilaterally makes you feel much worse.

    This can be acheived with a number of protocols and seems generally to last a few days and then their is sharp but very vulnerable improvement.

    The solution seems to be in the utmost importance of reestablishing good rest and good activity patterns. This way you get 1: anti-inflammatory effects (increased stamina) in the day, 2: increased immune function at night, 3: increased regeneration of immune functions and thereby increased immune efficiency at infection sites, which because thea ction is in the growth of key cells in the body, including stem cells, the effect alo is immunomodulatory and reduces unecessary and systemic inflammation, meaning its smarter. This results in immunity and vitality. If you allow TH-1 or Th-2 dominance to occur, or overall over stimulation of both wings which can also occur, you just end up with something dysfigured and ineffective at certain key tasks. You also end up sick. The overall picture *seems to be* that Th-1 predominance is supposed to be at night, and Th-2 is during the day. What happens if you get a virus infection in the day? Well in the brain, amyloid builds up with activity and that is an anti-viral. Its not improbable that this has evolved as cover. But overactivity of either wing is not normal and will leave you feeling bad, and this is because of the complexity of membrane and skin inflammation and how this talks through various nerves to the brain, where the brain membranes have very complex interactions with both the peripheral immune and central nervous systems. You can have inflammation from over activity of either wing and you can end up with inflammatory events in the CNS from either, you can also end up with overactivity of both wings.

    A very early assumption here on these forums is that some of these infections deliberately try to dysrupt the natural diurnal rhythms of the immune system through the brain, which was concluded partly from observations of the role of brain infections in psychosis and manicdepression which involves a strong diurnal rhythm dysruption which in instances occurs during periods where genetic analysis showed the infection was actively replicating, and that systematic infections and brain infections can replicate these types of psychiatric symptom. We then hypothesise that infection (of the membranes) causes changes that manifest a long lasting fatigue syndrome as the bodies main response. The infection is not normally observed to do well during this as thee relative difficulty of identifying an infection in CFS testafies, although more detailed analysis shows is likely. That in turn supports that the infection would do well dysrupting these messages and pathways, which is why the fatigue changes. TNF-Alpha in the CNS was always mooted as the obvious target and it is targetted by a number of infections. To be fair, what part is the immune system entering into annergy, and what part is the infection is unknown, but basically the immune system isn't good at working under sustained provocation. A persistent low level infection may be providing that, in the CNS itself. This would cause a weird set of symtoms depending on many factors.
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    Senior Member FunkOdyssey's Avatar
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    Certainly normalization of circadian rythym and amplitude are key to recovery from any infection or insult to the body, but that isn't the sort of thing I'm talking about here. I'm focusing on the very tangible, specific, and measurable immune markers that are different between positive and negative outcomes of lyme infection. Every statement will be accompanied by a citation. No macro level philosophical stuff.
    "Also, can I rig some sort of enema out of household items?" -Tussman

    "I don't have the stamina for a 3-some, and I am a one-pump chump" -Ubiyca

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    Funk, I like your hands-on, pragmatic approach to problems. In my view, besides academic interest, theory is only important if it leads to effective, practical treatment strategies.

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    <div class='quotetop'>QUOTE (FunkOdyssey @ Aug 13 2010, 01:11 PM) <{POST_SNAPBACK}></div><div class='quotemain'>Certainly normalization of circadian rythym and amplitude are key to recovery from any infection or insult to the body, but that isn't the sort of thing I'm talking about here. I'm focusing on the very tangible, specific, and measurable immune markers that are different between positive and negative outcomes of lyme infection. Every statement will be accompanied by a citation. No macro level philosophical stuff.</div>

    The problem is we've already tackled this, and you are wrong. There are many treatments that do what you want and they have been tried extensively. I don't think there is one point you make that hasn't already been written about here.

    In the early stages of infection, the boosting of immune functions works. Otherwise there is no long term influence that can work unless it destroys the bug, which it is unlikely to do, and which wont introduce the very side effects you blame on the infection. The most likely explanation is that you have a very low level of infection, or no infection, and that your symptoms come more from the hypersensitised immune system response, which in which case, being the most likely explanation, will mean your strategy - and it isn't your strategy - will make you feel worse.

    To call this irrelevant macro level stuff is very silly. The immune systems capability through the methods I talk about, and is far in advance of many peoples understanding, is capable of keeping control over your disease. Go on, just tell tell us what we already know, along with thousands of people before you. Why dont you just listen and get drugs that directly challenge the bug, which in your case you probably know all about, and go along with the discoveries of people who have been their and done it.

    And stop patronising them. That goes for both of you!

    Me thinks you both have too much fatigue to actually listen or use the search feature.
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    "I quoted this one because its so important"....you're even using my style of writing!
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    You can try your approach - already done a lot of times - but its just like chemo. You'll feel bad and get no where 9 times out of ten. The disease isn't in the periphery, its in your brain. Chances are nothing shows up in the periphery, which means your immune system is probably over effective.

    Is your blood actually showing up an infection? If not, sleep is the number one way to boost the immune system in your brain. Philosophise this, ass hole (to paraphrase big arnie [img]style_emoticons/<#EMO_DIR#>/wink.gif[/img] )
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    What I would say you can do is equivalent to the 'detox' strategy, with a lot of immune boosting, see if that works after two weeks. Again, because some of us have done this many times, with a lot of Th-1 emphasis, with very limited success, I would say it is worth doing, but the effects dont last but if you keep doing it for long enough, and then do what I say, you can seem to control it and get back your stamina. Eventually you find that controlling inflammation is as much part of the successful strategy. It is not really unilaterally doing any one thing.

    I talk about shot gun strategy because you can do more good for your immune system with that. The problems by the time you end up with something chronic, probably is a lot of dysfunction in your immune system and more something in the brain. I happen to side along with those that think an active infection is involved, although it is probably a very low level, and more the immune response that manifests fatigue. However, infections also seem to become more active under the same conditions that damage immune functions - so by doing everything to boost them, you may have your cake and eat it. Some infections may be activated under inflammatory conditions. Our adoption of very contextual 'anti-inflammatory' strategies is partly based on this. If the infection got out of control that is not what we would advocate.

    There is a very grey area between what symptoms are caused by infection, and what is caused by the immune system.

    Just boosting your immune system by itself doesn't do that in very similar, broadly the same conditions. But you are not beating a new path here. its old ground.

    I'm not sure you can say for certain that it is a spirochete that causes your fatigue. What is your evidence you have an active infection? How do you know you dont have HHV1 or 6 in your brain?
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    One of the problems is, are our treatments killing a bug directly, indirectly by boosting the immune system, or by taming over active responses in the immune system? Since we use a shot gun approach that may involve all three, it is hard to actually know.

    http://www.canlyme.com/fibrocfslyme.html

    You may not have seen that, though its probably old news to you. So Lymes involves little inflammation? But in CFS there usually isn't either, at least in the periphery. Our best guess at present, based on the data, is that centrally its different. Infections in the nerve tissue itself also dont show up in inflammation. This occurs in the membranes.

    But once a disease is recognised and infection fighting immune cells have gone into the brain, there will be complex consequences, whether an infection is there or not.

    Lymes prognosis is also worse in women, according to the doctor above. He subscribes to the idea that oestrogen receptors allow infections into brain cells. Maybe, but broadly speaking, almost all inflammatory chronic diseases are worse in women by the same ratio, or higher, and women have stronger immune responses.



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    The IL-4 stuff was cool. I found this, it may be of relevance:

    Flavonoids such as luteolin, fisetin and apigenin are inhibitors of interleukin-4 and interleukin-13 production by activated human basophils.
    Int Arch Allergy Immunol. 2004 Jun;134(2):135-40.

    We have previously shown that fisetin, a flavonol, inhibits IL-4 and IL-13 synthesis by allergen- or anti-IgE-antibody-stimulated basophils. This time, we investigated the inhibition of IL-4 and IL-13 production by basophils by other flavonoids and attempted to determine the fundamental structure of flavonoids related to inhibition. We additionally investigated whether flavonoids suppress leukotriene C4 synthesis by basophils and IL-4 synthesis by T cells in response to anti-CD3 antibody. Highly purified peripheral basophils were stimulated for 12 h with anti-IgE antibody alone or anti-IgE antibody plus IL-3 in the presence of various concentrations of 18 different kinds of flavones and flavonols. IL-4 and IL-13 concentrations in the supernatants were then measured. Leukotriene C4 synthesis was also measured after basophils were stimulated for 1 h in the presence of flavonoids. Regarding the inhibitory activity of flavonoids on IL-4 synthesis by T cells, peripheral blood mononuclear cells were cultured with flavonoids in anti-CD3-antibody-bound plates for 2 days. RESULTS: Luteolin, fisetin and apigenin were found to be the strongest inhibitors of both IL-4 and IL-13 production by basophils but did not affect leukotriene C4 synthesis. At higher concentrations, these flavonoids suppressed IL-4 production by T cells. Based on a hierarchy of inhibitory activity, the basic structure for IL-4 inhibition by basophils was determined. Due to the inhibitory activity of flavonoids on IL-4 and IL-13 synthesis, it can be expected that the intake of flavonoids, depending on the quantity and quality, may ameliorate allergic symptoms or prevent the onset of allergic diseases.

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    Senior Member Necrosis's Avatar
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    ATB you are a weirdo dude, jesus you have some issues with feeling important or some shit. You didn't discover shit and you attack anyone that posts anything academic. In fact i have studied immunology not surfed pubmed and i honestly am having a hard time understanding what the fuck you are talking about. It's flism to be honest, you have outlined no practical approachs, if you have some do so.
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    ATB,

    I am sure many of us appreciate your insights and knowledge but can you please summarise what you say into bullet points in a more pragmatic fashion? What do you recommend to deal with Lyme disease? I am interested in your views because I, for one, support the theory of viruses causing a host of autoimmune issues.
    "I am a man of few words" - Mayor Adam West

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    Senior Member FunkOdyssey's Avatar
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    <div class='quotetop'>QUOTE (adrenoguy @ Aug 14 2010, 02:29 AM) <{POST_SNAPBACK}></div><div class='quotemain'>Funk, I like your hands-on, pragmatic approach to problems. In my view, besides academic interest, theory is only important if it leads to effective, practical treatment strategies.</div>

    Thanks, I agree with you entirely -- I'm not one for mental masturbation. I'll post Part II tomorrow and I assume ATB's nerd rage will have petered out by then.
    "Also, can I rig some sort of enema out of household items?" -Tussman

    "I don't have the stamina for a 3-some, and I am a one-pump chump" -Ubiyca

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    Senior Member FunkOdyssey's Avatar
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    Sex hormones, the immune system, and Lyme. We'll start with a quote from Dr. Sam Donta MD, published Lyme researcher and LLMD:

    <div class='quotetop'>QUOTE (Dr. Sam Donta MD)</div><div class='quotemain'>Gender also influences outcome. Why is that? There is probably a hormonal influence on the disease and I know in the chronic fatigue literature it is like a 2 to 1 ratio of females to males and in chronic Lyme it is about the same too where females seem to have a higher incidence and perhaps more of a severity.
    ....
    Again, idle thoughts, if you will, about what might be happening. However, women do have a harder time, both being cured and having a higher fail rate than men in our studies of both tetracyclines.</div>

    I will attempt to explain this phenomenon by examining the effects of sex hormones on the immune system.

    (PMID: 10870028)
    <blockquote><span style="font-size:10pt;line-height:100%">OBJECTIVE: To evaluate the T helper 1 (T(H)1)/T helper 2 (T(H)2) lymphocyte cytokine profiles in women and men and to study the in vitro effects of sex hormones on lymphocyte secretion of cytokines.
    ...
    RESULTS: Higher levels of INF-gamma and IL-2 and lower levels of IL-4 and IL-10 were detected in the phytohemagglutinin-stimulated lymphocyte culture supernatants of men compared with women; the INF-gamma:IL-4 ratio was significantly higher in men.
    ...
    CONCLUSIONS: Women present a predominant T(H)2 cytokine profile, which could be involved in immune responses characterized principally by the secretion of antibodies. This could be a factor implicated in the higher concentration of immunoglobulins or the increased prevalence of autoimmune diseases detected in females.
    </span></blockquote>
    We see here that the male immune system when stimulated "defaults" toward a response that is optimal to fight Lyme, higher IFN-gamma, lower IL-4 and IL-10 -- exactly what we want. Now, let's examine the effect of sex hormones in isolation.

    (PMID: 16855144)
    <blockquote><span style="font-size:10pt;line-height:100%">Estrogens at physiological concentrations are thought to play an immune-stimulating role, whereas androgens have an anti-inflammatory impact. However, their role on cytokine secretion in the presence or absence of cortisol has not been investigated. Furthermore, the role of hydroxylated estrogens downstream of 17beta-estradiol (E2) on secretion of tumor necrosis factor (TNF) is not known. In this study on peripheral blood leukocytes of healthy male subjects, we scrutinized the influence of prior sex hormones (for 24 h) with and without later addition of cortisol (for another 24 h) on stimulated secretion of TNF, IL-2, IL-4, IL-6, IL-10, and interferon-gamma (IFN-gamma). E2 stabilized or increased immune stimuli-induced secretion of TNF, IL-2, IL-4, IL-6, IL-10, and IFNgamma in relation to testosterone. Testosterone, in contrast, inhibited (IL-2, IL-4, IL-10) or tended to inhibit stimulated secretion of these cytokines (TNF, IFNgamma). This effect of E2 was pronounced at a concentration of 10(-10) M (testosterone: 10(-7) M) in the presence of cortisol. E2 (10(-8) M, 10(-10) M) and testosterone (10(-7) M) did not change glucocorticoid receptor expression. The downstream estrogens 2OH-estradiol(one), 4OH-estradiol(one), and 16OH-estradiol(one) did not stimulate TNF secretion at 10(-10) M, but even inhibited its secretion at 10(-11) M. However, the combination of 16OH-estradiol(one) on one side and 2OH-estradiol(one) or 4OH-estradiol(one) on the other side markedly stimulated TNF secretion that was only observable in the presence of cortisol. In conclusion, at physiological concentrations, E2 and a combination of downstream estrogens stabilized or increased immune stimuli-induced TNF secretion. These effects are dependent on the presence of physiological concentrations of cortisol. This study underlines the proinflammatory role of E2, which is probably dependent on conversion to a proinflammatory cocktail of downstream estrogens and the presence of cortisol.</span></blockquote>
    In addition to absolute concentrations of cytokines, their RATIO is significant in their effects on immunity. Although testosterone is generally immunosuppressive and estradiol immunostimulating, testosterone more strongly inhibits IL-4 and IL-10 than it inhibits IFN-gamma and TNF, producing the superior TH1:TH2 ratio in men that we demonstrated previously. Estradiol, with its across the board stimulation of everything, looks like a recipe for autoimmunity, supporting the huge statistical discrepancy in autoimmune disease rates by gender.

    (PMID: 15494044)
    <blockquote><span style="font-size:10pt;line-height:100%">PROBLEM: Cytokine production of monocytes and lymphocytes differs between males and females. This difference is characterized by a decreased percentage of interleukin (IL)-2-producing lymphocytes and an increased percentage of IL-12, IL-1beta and tumour necrosis factor (TNF)-alpha-producing monocytes in males compared with females. In the present study, we investigated whether testosterone may explain these differences. METHOD OF STUDY: Stimulated whole blood of healthy woman was incubated with different concentrations of testosterone. Intracellular lymphocyte production of IL-2 and interferon (IFN)-gamma, as well as intracellular monocyte production of IL-12, IL-1beta and TNF-alpha were measured using flow cytometry. RESULTS: A significant increased percentage of IL-12- and IL-1beta-producing monocytes was found after incubation with physiological concentrations of testosterone. No effect of testosterone was found on IL-2- and IFN-gamma-producing lymphocytes and TNF-alpha-producing monocytes. CONCLUSIONS: The increased percentage of IL-12- and IL-1beta-producing monocytes in males compared with females in vivo may be induced by testosterone, as the in vitro percentage of IL-12- and IL-1beta-producing monocytes is increased after incubation with physiological concentrations of testosterone.</span></blockquote>
    Testosterone increasing percentages of IL-12 producing monocytes, desirable for Lyme-fighting.

    (PMID: 12699415)<blockquote><span style="font-size:10pt;line-height:100%">
    In the present study, we aimed to investigate the effects of testosterone deficiency and gonadotropin therapy on the in vitro production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) by peripheral blood mononuclear cells (PBMCs) from patients with idiopathic hypogonadotropic hypogonadism (IHH) in order to elucidate the modulatory role of androgen in cytokine production.
    ...
    Females are more immunoreactive than males, exhibiting greater antibody formation, cell-mediated immunity and predisposition for autoimmune disorders such as systemic lupus erythematosus (SLE), Sjogren's syndrome, rheumatoid arthritis (RA), Hashimoto's thyroiditis and multiple sclerosis [4,6,8]. However, it is not fully understood how these gender biases in immune-system function affect the clinical expression of autoimmunity. Classically, androgens exert an inhibitory influence on both humoral and cell-mediated immune responses, whereas oestrogens present a dual role by suppressing cell-mediated, but enhancing humoral, immune responses [9].
    ...
    IL-2 and IL-4 levels in the patients were significantly decreased after gonadotropin treatment.
    ...
    Likewise, as demonstrated in our recent study [2], a negative relationship was found between FT [Free Testosterone] and IL-4, but not IL-2.
    ...
    Additionally, a high level of IL-4 production is reported in androgen resistance [48]. It has also been shown that dihydrotestosterone exerts a depressive effect on the production of IL-4 by activated murine T cells [49].
    </span></blockquote>
    It looks like testosterone and now DHT as well are contributing significantly toward positive Lyme outcomes mainly by inhibiting IL-4.

    (PMID: 19497624)
    <blockquote><span style="font-size:10pt;line-height:100%">To investigate the effect of oral and transdermal estrogen replacement therapy (ERT) on the expression of different estrogen receptor (ER) subtypes and the secretion of immunoregulatory cytokines, we performed a clinical investigation on previously healthy women who had undergone a total hysterectomy and bilateral salpingo-oopherectomy.
    ...
    Levels of type 1 cytokines (IL-2 and IFNgamma), which were secreted by T helper 1 (Th1), after ERT were substantially decreased. The level of type 2 cytokine (IL-4), which were secreted by T helper 2 (Th2), was significantly increased after ERT (P<0.01 for the oral group and P<0.05 for the transdermal group).
    </span></blockquote>
    Estradiol up to more mischief, significantly increasing IL-4 secretion, and even suppressing IFN-gamma (although this effect isn't consistent in all models). Not good.

    Let's look at our first potential intervention:

    (PMID: 19298850)
    <blockquote><span style="font-size:10pt;line-height:100%">Aromatase inhibitors have become the standard of care for the adjuvant treatment of postmenopausal, hormone-sensitive breast cancer. Meanwhile, more and more breast cancer patients who are treated with aromatase inhibitors as adjuvant therapies often experience arthralgias and musculoskeletal aching, in some cases, have necessitated discontinuation of treatment. We therefore use a rat model of human RA to test the hypothesis that anastrozole, an aromatase inhibitor, could enhance arthritis. The parameters used for analyzing the disease severity included paw volume, radiology, histopathological examination, markers for cytokine profile, immunophenotypic assays, and immune response to type II collagen. Administration of anastrozole significantly increased the severity of arthritis. Anastrozole induced the increased levels of proinflammatory cytokines, IFN-gamma, IL-12, and the decreased levels of IL-4, IL-10 secretion. We further found that anastrozole suppressed the differentiation of naive T cells to Treg cells, and it blocked the balance of IgG2a/IgG1 in peripheral blood. Meanwhile, estradiol concentration was the lowest in the anastrozole group. In a well-established model of postmenopausal RA, anastrozole potently promote the progression of arthritis and the associated development of osteoporosis. This potential problem should alert the oncologists and other health professionals.</span></blockquote>
    I warned you this might hurt a little. Anastrozole increases IFN-gamma and IL-12 while simultaneously reducing IL-4 and IL-10 in this model, perfectly replicating the desired immune response. Aromatase inhibition for Lyme Disease? You heard it here first!

    Arimidex is a little extreme, you say. Could a milder aromatase inhibiting supplement be used? Perhaps one with positive immune modulating effects independent of its aromatase inhibition? That is also neuroprotective, enhances endothelial function, and erections?

    (PMID: 16740737)
    <blockquote><span style="font-size:10pt;line-height:100%">Aromatase is the enzyme that converts androgen to estrogen. It is expressed at higher levels in breast cancer tissues than normal breast tissues. Grape seed extract (GSE) contains high levels of procyanidin dimers that have been shown in our laboratory to be potent inhibitors of aromatase. In this study, GSE was found to inhibit aromatase activity in a dose-dependent manner and reduce androgen-dependent tumor growth in an aromatase-transfected MCF-7 (MCF-7aro) breast cancer xenograft model, agreeing with our previous findings. We have also examined the effect of GSE on aromatase expression. Reverse transcription-PCR experiments showed that treatment with 60 mug/mL of GSE suppressed the levels of exon I.3-, exon PII-, and exon I.6-containing aromatase mRNAs in MCF-7 and SK-BR-3 cells. The levels of exon I.1-containing mRNA, however, did not change with GSE treatment. Transient transfection experiments with luciferase-aromatase promoter I.3/II or I.4 reporter vectors showed the suppression of the promoter activity in a dose-dependent manner. The GSE treatment also led to the down-regulation of two transcription factors, cyclic AMP-responsive element binding protein-1 (CREB-1) and glucocorticoid receptor (GR). CREB-1 and GR are known to up-regulate aromatase gene expression through promoters I.3/II and I.4, respectively. We believe that these results are exciting in that they show GSE to be potentially useful in the prevention/treatment of hormone-dependent breast cancer through the inhibition of aromatase activity as well as its expression.</span></blockquote>
    (PMID: 11874895)
    <blockquote><span style="font-size:10pt;line-height:100%">Although flavonoids manifest a diverse range of biological activities, including antitumor and antiviral effects, the molecular mechanisms underlying these activities await elucidation. We hypothesize that the flavonoid constituents of a proprietary grape seed extract (GSE) that contains procyandins exert significant antiviral and antitumor effects, by inducing production of the Th1-derived cytokine gamma interferon (IFN-gamma) by peripheral blood mononuclear cells) from healthy donors. Our results show that GSE significantly induced the transcription of IFN-gamma mRNA as demonstrated by reverse transcription-PCR but had no effect on the Th2-derived cytokine interleukin-6. The enhancing effect of GSE on IFN-gamma expression was further supported by a concomitant increase in the number of cells with intracytoplasmic IFN-gamma as well as the synthesis and secretion of IFN-gamma. Our results demonstrate that the potentially beneficial immunostimulatory effects of GSE may be mediated through the induction of IFN-gamma.</span></blockquote>

    Grape Seed Extract! Not only does it inhibit aromatase, it directly induces production of IFN-gamma. The particular extract I'd recommend, which has been studied in several clinical trials (occasionally unnamed or with a different name) is the MegaNatural-BP extract.

    If one were to attempt an aromatase inhibition intervention, regular monitoring of E2 would be required to ensure E2 is not reduced too low for overall health and well-being.

    Here comes some wild speculation. Its possible that any intervention which improves or exaggerates the typical male hormonal profile in the androgenic direction may further improve lyme outcomes. That could include testosterone-boosting supplements, direct supplementation of testosterone itself, and maybe some anabolic/androgenic steroids.

    Anecdotally, Dr. Burrascano recommends specifically anaerobic weight-training for Lyme and goes so far as to call it necessary for recovery. Could its positive effects be mediated by increased testosterone production?

    With the hormonal perspective under our belt, we'll move on to interventions that directly modulate immunity in a positive direction.
    "Also, can I rig some sort of enema out of household items?" -Tussman

    "I don't have the stamina for a 3-some, and I am a one-pump chump" -Ubiyca

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    Senior Member Cinn's Avatar
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    <div class='quotetop'>QUOTE (Necrosis @ Aug 15 2010, 02:07 AM) <{POST_SNAPBACK}></div><div class='quotemain'>ATB you are a weirdo dude, jesus you have some issues with feeling important or some shit. You didn't discover shit and you attack anyone that posts anything academic. In fact i have studied immunology not surfed pubmed and i honestly am having a hard time understanding what the fuck you are talking about. It's flism to be honest, you have outlined no practical approachs, if you have some do so.</div>

    el oh el

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    Hey Funk,

    Now that you have mentioned the role of sex hormones on autoimmunity, I'd like to sort of siderail with a post regarding my own case. I have thyroid antibodies, albeit a low count (out of the two, one is neligible and the other one is on the very low side, almost neligible too). However, the presence of antibodies denotes autoimmunity. Now, here is the awesome part. Autoimmune thyroiditis is seen 7 times more in women than men. Moreover, the women diagnosed are over 40 and into their menopause. I know of the modulating effects of testosterone (beneficial) in the immune system so I could not find a reason as to why a healthy active guy with testosterone levels in the upper range like I have would have a mild case of thyroiditis. It turns out that once I convinced my doctor to test for estradiol, my levels were borderline low, which is what you'd expect from middle age women entering menopause. Interesting to say the least.

    Autoimmune disorders are generally biased towards women except in the case of, I think, diabetes type I and another one (just got back from a party and my mind is not at its best currently hence some of my facts might be a bit sloppy). I have never gotten ill and if I didn't know I had thyroid antibodies I would have guessed my immune system was pretty solid (like high testosterone levels would result in). Since following my own exogenous thyroid supplementation, my antibodies have decreased substantially and they are negilible to the point of no autoimmunity. I recall you were in a similar situation trying to kill those bastards and get the thyroid back working at its best.

    Lastly, I remember when I was a kid (and used to live in a house in the forest), I displayed a red pseudo-circular mark on my right calf which didn't have a bulleye. It did, however, stay for a very long time (years) and I have read that biting by an infected flea might now always yield a bullseye shape but rather, a red circle. We used to be bitten frequently by the small creatures of the forest which is why I am interested in Lyme disease.

    I am one who supports viruses to be a part in autoimmunity, that, and environmental factors coupled with predisposition.
    "I am a man of few words" - Mayor Adam West

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    Senior Member FunkOdyssey's Avatar
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    <div class='quotetop'>QUOTE (Sonic @ Aug 16 2010, 03:29 PM) <{POST_SNAPBACK}></div><div class='quotemain'>Hey Funk,
    Lastly, I remember when I was a kid (and used to live in a house in the forest), I displayed a red pseudo-circular mark on my right calf which didn't have a bulleye. It did, however, stay for a very long time (years) and I have read that biting by an infected flea might now always yield a bullseye shape but rather, a red circle. We used to be bitten frequently by the small creatures of the forest which is why I am interested in Lyme disease.

    I am one who supports viruses to be a part in autoimmunity, that, and environmental factors coupled with predisposition.</div>

    The fact that the rash persisted for years makes me think it was not Lyme. A Lyme associated rash, while not necessarily a bullseye, would visibly expand and change shape over time, and then fade much more quickly than that.

    I agree that autoimmunity results from a combination of environmental factors and genetic predisposition, and is usually triggered by an infection.

    It's funny because the female immune system is generally said to be "stronger", and presumably more effective, than ours. Some believe it is the primary reason they live longer than us (another theory involves additional DNA redundancy on the X vs Y chromosome).

    I guess Lyme is a notable exception.
    "Also, can I rig some sort of enema out of household items?" -Tussman

    "I don't have the stamina for a 3-some, and I am a one-pump chump" -Ubiyca

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