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.
<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.
<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).
<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.
<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 . 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 . Furthermore, in another study of the same model, administration of anti-IL-4 antibodies cured the mice . 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.
<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.
<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.
<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.
<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.