I posted some of my notes on VGV-L on LNE, related to the previous entry on VGV-L which I posted on Monday. While there is a lot I posted about VGV-L based on interviews, press releases, and patents - and while I outlined how the immune system normally should work - I did not give a concise explanation of how the immune system doesn't work relative to polyclonal b cell activation.
I think another entry on this topic is in order. But in the meantime, I have decided to share the notes I posted on LNE about VGV-L here before I write a more concise post on the immune system and polyclonal b cell activation...
I did as much poking around about Viral Genetics' new chronic Lyme disease candidate drug, VGV-L, as I could and it wasn't easy. One CV, several patents, and a few Dr. Karen Newell Roger interviews later, and the best I could get out of it is that it is not just a synthetic thymus peptide that they patented but a method of replacing a peptide, CLIP, on the surface of B cells with this synthetic thymus peptide (which somehow maps to the MHC genetic type (HLA) of the patient) so that it activates Treg cells. The activation of these Treg cells is supposed to lead to reduction of non-specific B cells (polyclonal B cell activation).
In the patent, there is also mention of using bacterial antigens and antibiotics as adjunct treatments which are optional. The impression I'm left with is the bacterial antigens are used to prime new B cells and if there is any existing infection, antibiotics are used.
So the entire method of treating patients may be: a) VGV-L alone, b) VGV-L and antigen exposure, or c) VGV-L, antigen exposure, and antibiotics are used. (antivirals and antiparasitics may also be used, depending on the patient's diagnosis)
[...] I don't get the impression after reading everything I've read thus far that chronic Lyme disease is a pure B-cell disorder. But maybe it's a variant on that? Maybe cell-mediated immunity is somehow affected by B. burgdorferi?
I've made a major edit on my blog entry. I still think I need a revised version of the post to be made in the future, but I am so exhausted at the moment that I think it won't be for a few days at least. Maybe call it the revised executive summary version, because the current post is rambling even relative to rambling for me.
Why do I mention this edit here? Because it is very important to note, relative to how I infer the way VGV-L has been hypothesized to work:
The edit was about Tunev and Barthold's research on lymphadenopathy in Borrelia burgdorferi infection in mice. In their research, they noticed an outsized B-cell response to the presence of spirochetes. However, what they found differed from what has been found in polyclonal B-cell activation in other infections - where it's clear runaway non-specific polyclonal B-cell activation leads to autoimmune disorders. In Tunev and Barthold's research, the outsized immune response had B-cells which were specific for Borrelia burgdorferi yet were of low quality. This is notably different from typical polyclonal B-cell activation.
"From their observations, the authors speculated that B. burgdorferi somehow subverted B cell activation in the lymph node so that the end result was a large number of plasma cells secreting antibodies of poor quality. By poor "quality," I assume that the authors meant that the affinity of the antibody for B. burgdorferi proteins was low and that the "wrong" subclasses of IgG antibodies were expressed. The most abundant IgG subclasses being produced in the draining lymph node at its most swollen state were IgG2b and IgG3. Whether other IgG subclasses would be more effective at clearing B. burgdorferi from the host and whether the affinities of the antibodies for B. burgdorferi proteins were poor still need to be determined experimentally. Perhaps a classic T-cell dependent B cell response involving the formation of germinal centers accompanied by somatic hypermutation, affinity maturation, and appropriate class switching would have led to production of "high" quality antibodies. If the authors are correct, they have revealed yet another means by which B. burgdorferi could persist in the host."
I don't know how this difference in response would work with VGV-L. It isn't clear to me, and I have to read through more research to understand it - at least hypothetically. I also want to know if anyone else has used similar technology to treat pure B-cell disorders and if so, what the pros and cons were. If this is a completely novel invention, then it's harder to evaluate and all one can do is look at the animal trials if one has access to them and examine the underlying hypothesis for its application.
The paper that this technology primarily appears to be based on is this one:
M. K. Newell, R. P. Tobin, J. H. Cabrera, M. B. Sorensen, A. Huckstep, E. M. VillalobosMenuey, M. Burnett, E. McCrea, C. P. Harvey, A. Buddiga, A. Bar-Or, M. S. Freedman, J. Nalbantoglu, N. Arbour, S. S. Zamvil, and J. P. Antel. 2010. TLR-Mediated B Cell Activation Results in Ectopic CLIP Expression that Promotes B Cell-Dependent Inflammation. Journal of Leukocyte Biology.
Online e-Pub. July 14, 2010.
I'll just post the abstract here, and you can read the entire text at the link above:
Abstract
Infectious pathogens produce compounds called Toll ligands that activate TLRs on lymphocytes. Acute activation triggered by certain TLRs appears to "jump start" the innate immune response, characterized by the release of inflammatory cytokines and cellular expansion.
In some individuals, there is a failure to control acute inflammation, resulting in postinfectious, chronic inflammation. Susceptibility to chronic inflammation is strongly associated with an individual's MHC genes. Recent clinical trials for several autoimmune diseases characterized by chronic inflammation suggest that B lymphocyte depletion therapies dampen chronic immune activation. However, currently, there is no known mechanism that accounts for the correlation among TLR activation, MHC genetics, and a pathological role for B-lymphocytes.
Our hypothesis is that TLR-activated B cells (B cells that have been polyclonally activated in the absence of antigen-specific signals) are not controlled properly by T cell-dependent B cell death, thereby causing B cell-dependent chronic inflammation.
Here, we show that treatment with Toll ligands results in polyclonal B cell activation accompanied by ectopic expression of CLIP. Furthermore, by adoptively transferring purified CLIP+ B cells in syngeneic animals, we find that CLIP+ B cells induce production of TNF-α by host T cells. Finally, we demonstrate that CLIP-targeted peptide competition results in the death of polyclonally activated CLIP+ B cells.
I think I know at this point what my missing pieces are now:
- describe the role of Treg cells (regulatory T cells) and how they relate to killing off B cells and generating more targeted immune responses.
- describe the hypothesis that Foxp3+ Treg generation in the thymus is somehow dysfunctional in those with persisting symptoms (I think this has some relationship to the core hypothesis behind VGV-L's use).
- And I have to more clearly state that even if the Foxp3+ Treg generation is what it is happening, there may be some risk involved in proceeding with this kind of treatment. Wikipedia managed to explain some of it, and while Wikipedia is not the most reliable resource on everything, it is relatively easy to follow and this particular entry (so far) jives with what I've seen in other sources:
Plus, of course, there are the papers I link to on the blog.
The more I delve into this, the more questions I have... Tunev and Barthold's paper, in particular, lead me to wonder if the hypothesis underlying VGV-L's design developed with the scenario described in their research being taken into account. Between T & B's research plus other publications, I get the impression that in at least the animal model of immune response to Bb, that there is a mixed state response to it - It is both immune suppressing and immune stimulating. Some research has even indicated a certain amount of tolerizing is involved. (http://en.wikipedia.org/wiki/Peripheral_tolerance - anergy plus inflammation; see also http://users.ox.ac.uk/~path0116/tig/tolg2.html for a more detailed explanation)
Adding a bacterial antigen/adjuvant (and possibly antimicrobial medicine) to the treatment may be a way of working around this combination, in order to produce new B cells which are stimulated and respond specifically to Bb and not be nonspecific - and in order to eliminate any remaining infection if there is one present.
This is complicated - and while more and more is being learned about immunology every day, there are still an enormous number of unknowns...
On Friday I posted about the use of Filgrastim and Ceftriaxone for treating persisting symptoms in a Lyme disease case study as well as the use of Rituximab for treating CFS/ME. I also touched upon Viral Genetics' VGV-L or targeted peptide therapy for treating chronic Lyme disease, and wanted to write an entry about this treatment on its own.
What I can tell you is to some degree limited by the fact that VGV-L's exact design and mechanism is proprietary in nature, so I can only report based on what the researchers and Viral Genetics choose to disclose. But hopefully, what I post here and future publications by Dr. Karen Newell Rogers will shed some light on the matter.
Dr. Karen Newell Rogers from Texas A & M is in the middle of contributing to the following three papers which seem to have a relationship between VGV-L and chronic Lyme disease:
S. Harris, E. W. Newell, R. P. Tobin, C. P. Harvey, N. Kurzman, E. M. Hechinger, P.
Cipriani, and M. K. Newell. 2010. Comparative Analysis of Peptide Binding, MHC alleles,
and B cell activation in patients meeting CDC criterion for Chronic Lyme Disease.
(manuscript in preparation).
E. Connick, R. Schlichtemeier, J. Folkvord, R. Tobin, C. P. Harvey, and M. K. Newell.
2010. TLR activation of human peripheral blood B cells can be reversed by peptide
treatment. 2010. Manuscript in preparation.
Cabrera, J. and M. K. Newell. 2010. Polyclonal TLR-induced B cell activation is
controlled by Peptide-dependent B cell death (manuscript in preparation).
All three in preparation, but I think they are tightly related to the same research and stem from this previous publication:
M. K. Newell, R. P. Tobin, J. H. Cabrera, M. B. Sorensen, A. Huckstep, E. M. VillalobosMenuey, M. Burnett, E. McCrea, C. P. Harvey, A. Buddiga, A. Bar-Or, M. S. Freedman, J. Nalbantoglu, N. Arbour, S. S. Zamvil, and J. P. Antel. 2010. TLR-Mediated B Cell Activation Results in Ectopic CLIP Expression that Promotes B Cell-Dependent Inflammation.Journal of Leukocyte Biology.
Online e-Pub. July 14, 2010.
In this patent, the portion attributed to Lyme disease states:
"[0116] It is believed according to the invention that Borrelia burgdorferi also produces a Toll ligand for TLR2. Replacement of the CLIP on the surface of the B cell by treatment with a thymus derived peptide with high affinity for the MHC fingerprint of a particular individual, would result in activation of the important Tregs that can in turn cause reduction in antigen-non-specific B cells. Thus treatment with thymus derived peptides could reactivate specific Tregs and dampen the pathological inflammation that is required for the chronic inflammatory condition characteristic of Lyme Disease. With the appropriate MHC analysis of the subject, a specific thymus derived peptide can be synthesized to treat that subject. Thus individuals with all different types of MHC fingerprints could effectively be treated for Lyme disease."
However, I just found out that there are additional patents on this technology of which I was previously unaware. These patents contain a great deal of detail about what these targeted peptides can do and their effect on polyclonal B cells:
In addition to the above published paper on CLIP expression, Viral Genetics published the following excerpt in its research newsletter which explains what VGV-L does for HIV in easy-to-understand terms - substitute "Lyme disease" for "HIV" here:
"The conventional approach to HIV vaccines, for example, is to develop therapeutic vaccines to stimulate immune system response. The problem with the conventional approach is that the infected cells are camouflaged and not visible to the body’s immune system. The body’s powerful T-cells are unable to seek out and destroy the infected camouflaged cells because they cannot recognize that the cell is infected.
To understand the issue, think of the Klingon space ship on Star Trek that has its cloaking device activated. The U.S.S. Enterprise has no way of knowing where the enemy is in space. The only hope it has in winning the battle is for the Klingon vessel to be de-cloaked and, once revealed, use their ammunition to destroy it. What’s worse in the case of HIV is that while the infected cell is cloaked, it is also effectively setting off an alarm that triggers the immune system to create inflammation. Why is this important? It turns out that this inflammation is critical for allowing the HIV virus to spread to even more cells.
Many other viruses and bacteria also trigger inflammation but, unlike HIV, the inflammation does not necessarily allow or facilitate the spread of the virus or bacteria itself. * However, in these cases, the inflammation itself is harmful because it creates a hostile and inflamed environment that provides the necessary components for a potential autoimmune reaction that can cause the immune system to attack and damage one’s own body. Viral believes that diseases such as Lyme Disease, Multiple Sclerosis and others involve this inflammatory mechanism.
To use the Star Trek metaphor, what Dr. Newell Rogers has developed with TPT is a de-cloaking device for the body’s immune system to use in its pursuit of invaders. Through the development and use of computational biology programs and databases, Dr. Newell Rogers and her team havecreated a way to remove the camouflage that is cloaking the infected cells, flagging them with custom peptides that allow the body’s immune system to seek out and destroy them.
The key discovery of the TPT platform is that a self-peptide (in other words, one that is naturally produced and a healthy part of one’s normally functioning immune system) called ―CLIP2 that was until now thought only to exist primarily inside certain immune system cells, is sometimes displayed on the outside of cells, thus leading to harmful inflammation. Dr. Newell Rogers discovered that the products of some pathogen invaders such as viruses and bacteria, when picked up on the surface of certain immune system cells, sometimes incorrectly cause those cells to display CLIP externally (i.e. ―ectopically).
Normally, when an invader strikes, this process may promote needed inflammation early in infection, but it is quickly controlled when a more specific, immune response takes over, allowing a highly-targeted immune response to be marshaled against the pathogen. However, when CLIP is improperly displayed, displayed for too long or displayed chronically, the immune system is marshaled to promote a broad and unspecified inflammation without the specific targeting, leaving open the possibility that this inflammation actually turns against one’s own cells. Replacing CLIP is the focus of Viral’s Targeted Peptides because it turns off the harmful alarm."
One thing which I have thought of (and heard a few patients mention in passing) is that this candidate drug is only for treating inflammation and would only address an autoimmune angle relating to chronic Lyme disease.
However, this is not the case:
If you read the full patents, VGV-L's technology works not only to reduce inflammation, it also works to rebalance the immune system so that it is focused on fighting infection in a targeted manner. And in terms of treatment with VGV-L, patients may not just receive VGV-L alone - but also receive a bacterial antigen and antibacterial (possibly also antiparasitic and/or antiviral) therapy concurrently to treat their condition.
Here is the excerpt from the patent concerning the treatment of infections using this technology - including Lyme disease:
[0169] Bacterial diseases that can be treated or prevented by the methods of the present invention are caused by bacteria including, but not limited to, mycobacteria, rickettsia, mycoplasma, neisseria, Borrelia and legionella.
[0170] Although Applicant is not bound by a specific mechanism of action it is believed that the CLIP inhibitors of the invention displace CLIP from MHC class I and cause down regulation of Treg activity and/or activation of effector T cells such as γδT cells.Downregulation of regulatory function of Treg activity prevents suppression of the immune response and enables the subject to mount an effective or enhanced immune response against the bacteria.At the same time the Treg cell may shift to an effector function, producing an antigen specific immune response. Thus, replacement of CLIP with a peptide of the invention results in the promotion of an antigen specific CD8+ response against the bacteria, particularly when the peptide is administered in conjunction with a tumor specific antigen. Activation of effector T cells also enhances the immune response against the bacteria, leading to a more effective treatment.
[0171] One component of the invention involves promoting an enhanced immune response against the bacteria by administering the compounds of the invention. The compounds may be administered in conjunction with an antigen to further promote a bacterial specific immune response. A "bacterial antigen" as used herein is a compound, such as a peptide or carbohydrate, associated with a bacteria surface and which is capable of provoking an immune response when expressed on the surface of an antigen presenting cell in the context of an MHC molecule. Preferably, the antigen is expressed at the cell surface of the bacteria.
[0172] The compounds of the invention may be used in combination with anti-bacterial agents. Examples of such agents to treat bacterial infections include, but are not limited to, folate antagonists (e.g., mafenide, silver sulfadiazine, succinylsulfathiazole, sulfacetamide, sulfadiazine, sulfamethoxazole, sulfasalazine, sulfisoxazole, pyrimethoamine, trimethoprim, co-trimoxazole), inhibitors of cell wall synthesis (e.g., penicillins, cephalosporins, carbapenems, monobactams, vacomycin, bacitracin, clavulanic acid, sulbactam, tazobactam), protein synthesis inhibitors (e.g., tetracyclines, aminoglycosides, macrolides, chloramphenicol, clindamycin), fluoroquinolones (e.g., ciproloxacin, enoxacin, lomefloxacin, norfloxacin, ofloxacin), nalidixic acid, methenamine, nitrofurantoin, aminosalicylic acid, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampin, clofazimine, and dapsone.
I don't know entirely what the researchers intend to use as a bacterial antigen... An Osp? They are suggesting a peptide or carbohydrate, though, and not a highly immunogenic lipoprotein from the cell's outer membrane - even though that's what I think they would have to use if they were to use an antigen. Reading ahead, though, there is the potential that any of a number of Borrelia burgdorferi antigenic products may be used.
Both items #0171 and #0172 have wording which implies that they are optional treatments, as they use the word, "may be administered" or "may be used" rather than "will be administered" or "will be used", respectively. I would assume that whether or not these individual treatments are applied depends entirely on the individual patient and their needs and clinical diagnosis.
So, it seems that whether there is current infection or not, VGV-L may be one way to effectively treat chronic Lyme disease and lower inflammation due to runaway immune dysregulation. And if infection is currently present, then it looks like VGV-L will trigger a more targeted immune response towards bacteria rather than the overload that polyclonally expanded B cells can be.
One of the more fascinating sections of the patent is towards the end. The researchers give a number of examples of how their technology was applied and what the results were. Example 13 of this patent appears relevant to demonstrating how Borrelia burgdorferi activators affect tissue and about eliminating excessive B cells which cause inflammation in tissues. They did an in vitro post-mortem study of these actions in mice:
Example 13 - TLR Activators Promote CLIP-MHC HLA Association and CLIP Inhibitor Peptides Reduce an TLR Activator Promoted CLIP-MHC HLA Association
[0480] Methods
[0481] Preparation of Cells: Mice were Sacrificed by Cervical Dislocation. Spleens and lymph nodes were removed; the tissues were minced through cell strainers to create single cell suspensions; red cells were lysed using buffered ammonium chloride followed by addition of phosphate buffered saline and centrifugation to wash out the ammonium chloride; and the cells were counted using trypan blue exclusion to determine live versus dead cell discrimination and to determine the number of cells per tissue.
[0482] Treatments: The spleen or lymph node cells were treated in vitro with various stimuli (TLR activators: CpG ODN (Alexis), LPS (Sigma), Polyl:C (BD Pharmagen), Pam3Cys (Genway); IL-4 (BD Pharmagen), anti-CD40 monoclonal antibody (BD Pharmagen), both IL-4 and anti-CD40 antibody and OspA and Osp C (Genway) and the cells were cultured for the indicated time periods. The cells were grown in RPMI 1640 medium supplemented with standard supplements, including 10% fetal calf serum, gentamycin, penicillin, streptomycin, sodium pyruvate, HEPES buffer, 1-glutamine, and 2-ME as well as (where indicated) the stimuli listed above. The cells were incubated at 37° C. in an atmosphere containing 5% CO2 and approximately 92% humidity. The cells were incubated for 3, 24, and 48 hours. At each time point, the cells from that experimental time were harvested and stained for flow cytometric analysis of cell surface expression of CLIP (MHC Class II invariant peptide/IAb, Santa Cruz) by using the commercially available anti-mouse CLIP/IAb peptide, anti-mouse B220, anti-mouse CD4, anti-mouse CD8, and anti-mouse FoxP3 (all commercially available from Becton Dickinson/Pharmingen). Harvested cells were stained using standard staining procedure that called for a 1:100 dilution of Fitc-anti-mouse CLIP/IAb or isotype control. Following staining on ice for 25 minutes, cells were washed with PBS/FCS and resuspended in 100 microliters and added to staining tubes containing 400 microliters of PBS. Samples were acquired and analyzed on a Coulter Excel Flow Cytometer. The data were analyzed using FloJo software.
[0483] Results
[0484] B cell death, including total B cell death and % CLIP positive B cell death in cells treated with a TLR activator (CpG ODN) alone or in combination with MKN3 in the presence or absence of CLIP was assessed. The results are shown in FIG. 12. FIG. 12 is a line graph having a double Y axis, on one side depicting % total B cell death (diamonds, representing CpG ODN alone and squares representing CpG ODN+MKN3) and on the other side depicting % CLIP+ B cell death (triangles, representing CpG ODN and CLIP alone and Xs representing CpG ODN+MKN3 and CLIP). The data reveal that CpG ODN cause an initial increase in B cell death which after 72 hours appears to level off. The CpG ODN+MKN3 data demonstrate that MKN3 is capable of preventing the increase in B cell death.
[0485] Changes in CLIP positive B cells in spleen versus lymph nodes were also assessed. FIG. 13 is a line graph having a double Y axis, on one side depicting % CLIP+ B cell numbers in spleen (light gray square with solid lines representing CpG ODN alone and dark gray square with solid lines representing CpG ODN+MKN3) and on the other side depicting % CLIP+ B cell numbers in lymph nodes (diamonds with dashed lines representing CpG ODN alone and light gray square with dashed lines representing CpG ODN+MKN3). In both spleen and lymph nodes the addition of the peptide to the cells with CpG ODN resulted in less CLIP positive B cells.
[0486] CLIP positive B6.129 cultured B cells (H-2b haplotype) and H2M-/- (from C3H HeJ mice) cultured B cells were also examined in the presence or absence of treatment with a number of different TLR activators. The data is shown in FIGS. 14A and 14B. As shown in the Figures, several TLR activators were able to induce levels of CLIP+ B cells.
Just so it's clear, this isn't the treatment a patient would receive - Dr. Newell Rogers and her colleagues won't be breaking your neck and removing your tissues if you sign up for a clinical trial, okay?
This is an example of an experiment they did to show that VGV-L technology is effective in reducing the number of ineffective B cells which cause inflammation. The end result measured this change, and also measured the end of the sordid relationship between TLR-promoted CLIP MHC-HLA association in the immune system.
[Edited Apr. 3, 2012: Removed mention of CLIP positive cells - these cells need to be removed not added. ]
Now time for a brief lesson in immunology, based on what normally happens in immune response:
Terminology: MHC = major histocompatibility complex; key components of T cell immunity. Think of them as immune response genes. HLA = human leukocyte antigen (think of earlier discussions on this blog about HLA-DR4 and HLA-DR11, and different alleles which respond to infection differently)
So the story goes, B cells express MHC class II. Once antigen has been bound on the antigen receptor on the B cell, the antigen and its receptor are sucked into an endosomal compartment inside the B cell. Then the endsomal compartment fuses with another compartment, the lysosome.
Antigens are broken down into smaller pieces inside the lysosome and then loaded onto the MHC class II component, then the MHC is transported to the B cell surface where the B cell displays the antigen to a CD4+ T cell. This T cell is also known as a helper cell, of which there are two types - Th1 and Th2.
Susceptibility or resistance to many diseases appears to be determined by the genes encoding Major Histocompatibilty Complex (MHC) molecules. Often referred to as immune response genes (or IR genes), these molecules are the key players in restricting T cell activation.
T cells, both CD8 and CD4 positive T cells, recognize antigens only when the antigen is presented to the T cell in association with MHC class I (expressed on all nucleated cells) or MHC class II molecules (expressed on cells that present antigens to CD4+ T cells), respectively.
To sum up:
B cells express MHC class II.
Different people produce different levels of allele variation in MHC locus.
Because of this genetic difference, some people are more or less vulnerable to certain diseases.
The B cell's expression of MHC class II is noticed by CD4+ T cells.
These CD4+ T cells are known as helper cells - of which there are two types, Th1 and Th2.
CD4+ T cells are a major player in our immune systems for fighting infection.
These helper cells do not kill - they activate and direct other immune cells. They are essential in B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages.
Look at these handy diagrams as an overview to what happens with B cells, MHC molecules, and T-cells...
Or, if your learning style is better geared towards watching videos, watch this one (warning: might be preceded by an ad, which you can mostly skip):
A simple overview of the immune system [Time: 5:56]
If you've gotten this far, right about now you might be asking yourself, "So what's the big deal? Why is it an issue that there are excess B cells, and how getting rid of them going to make a difference in fighting off Lyme disease if I have a chronic infection?"
Good questions.
Obviously, you can see so far that one reason to not have certain B cells around is that they trigger autoimmune responses. No one wants that. But there are other reasons to avoid an overzealous non-specific B cell response.
Let me unwind the answer, step by step.
Google "polyclonally expanded B cells Borrelia" and tell me what you find. Or, read on and I'll tell you what I found:
Remember that study on Borrelia burgdoferi that Tunev and Barthold did, where it was noted that there was an outsized yet seemingly inadequate immune response to Borrelia burgdorferi found in lymph nodes? One with ill-formed B cells? This one: http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002066 ?
Well, the phenomenon that's happening there is somewhat different from what is happening in polyclonal B cell activation in general. In polyclonal B cell activation, there can be lots of B cells which are produced which are non-specific. In this case, in Tunev and Barthold's research, a notable percentage of the B cells were Borrelia burgdorferi antigen specific - yet the cells were of low quality and inadequate to the task.
That's different than what is generally understood to be the typical polyclonal B cell activation, which is what I think is the hypothesis behind this treatment, VGV-L. In both cases, what one observes is an overwhelming number of B cells being produced.
[Edit Apr. 3. 2012: Updated correction to describe Tunev and Barthold difference in outcome of B cell activation.]
Polyclonal b cell activation has been thought to be a useful immune defense mechanism early in acute infection. What has not been investigated as much is how it might be a damaging process in chronic infection and immune dysregulation.
It's important to settle this argument because dysregulated and mis-targeted B cell antibody responses could result in autoimmunity, whereas impaired antibody responses during an actual infection could result in an immune deficiency.
Either way, over time it has become clearer that the production of these B cells relates to the appearance of an IgM response, and the relevance of the presence of an IgM response - particularly a prolonged IgM response - has also become a subject of heated discussion. See: "IgM in microbial infections: Taken for granted?"
"We have used the murine model for Lyme disease described by Barthold et al. (S. W. Barthold, D. S. Beck, G. M. Hansen, G. A. Terwilliger, and K. D. Moody, J. Infect. Dis. 162:133-138, 1990) to determine whether the B. burgdorferi B-cell mitogen is expressed during active infection.
To correlate arthritic changes with immune events, we have studied two strains of mice injected with B.
burgdorferi; one of them, C3H/HeJ, developed severe disease, and the other, BALB/c, developed only mild
disease.C3H/HeJ mice displayed a persistent 10-fold increase in circulating immunoglobulin G (IgG) levels, a
2-fold increase in IgM levels, and a 15-fold increase in peripheral lymph node B-cell numbers, providing
evidence of mitogenic activity. Infected BALB/c mice also had evidence for mitogen activity, since the IgG level
in serum increased three- to fourfold.
The bulk of the increase in circulating IgG levels was not directed against B. burgdorferi antigens, supporting the occurrence of polyclonal B-cell activation. Analysis of IgG isotpes pointed out a contrast between C3H/HeJ and BALB/c mice in that levels of all isotypes were elevated somewhat
in both strains of infected mice but IgG2a levels were much more dramatically increased in the C3H/HeJ mice
(28-fold) than in the BALB/c mice (4-fold). In this study, interleukin-6 levels were found to be persistently
elevated in the serum of infected C3H/IHeJ mice. Interestingly, interieukin-6 levels in serum were much lower
in the infected BALB/c mice. These findings indicate that the B. burgdorferi mitogen is active in infected
animals and may contribute to the inflammatory and immune response to infection."
Right from the start, you get the idea that this paper is going to tell you that the presence of these polyclonally activated B cells have a relationship to IgM and IgG levels.
This is relevant, very relevant - because it can reflect how antibodies to Borrelia burgdorferi are present and how they are picked up in serological testing like ELISA and Western Blots.
Meaningful excerpts from this paper include:
"Immunological abnormalities, including hyperactive B cells, elevated IgM levels in serum, lymphadenopathy, impaired natural killer function, and delayed development of humoral immunity, have been documented in patients with Lyme disease (11, 16, 29, 30, 32). This has suggested a possible involvement of the specific or innate host responses
in the pathogenesis associated with stage 2 and 3 disease(32)."
"Because of the persistent nature of infection and the ability of the organism to gain access to the joint and other tissues (5, 15, 29), a B-cell mitogen present during infection could play a role in the pathology of Lyme disease. To support this possibility, it was important to determine whether the mitogen functioned in vivo. This paper provides evidence that a B. burgdorferi mitogen is active in vivo in infected animals.
Three lines of
evidence support the conclusion that B-cell activation in vivo is polyclonal or oligoclonal in addition to being antigen specific.
First, the level of IgG in serum in infected mice was elevated about 10- to 15-fold, with the value ranging from 10
to 15 mg/ml (Fig. 1C). In comparison, the amount of IgG specific for B. burgdorferi antigens was approximated at 0.6
mg/ml (Fig. 2).
Second, the number of B lymphocytes in peripheral lymph nodes of infected animals was increased
10- to 15-fold, with a 5-fold rise in the ratio of B to T cells (Fig. 4). The number of B cells also increased about twofold relative to the number of T cells in spleens from C3I/HeJinfected mice.
Third, the IgG titer in the serum of infected animals to an unrelated antigen, ovalbumin, was increased 10- to 15-fold, which resembles the increase in the total IgG level (Fig. 3).
These findings suggest that levels of autoreactive antibodies might be also expanded in infected animals, although anti-collagen antibodies were not identified. Because CD5+ B cells have been shown to produce autoreactive antibodies and are selectively increased in patients with rheumatoid arthritis (7), we determined whether they were expanded in B. burgdorferi-infected animals.No selective increase in the number of B cells of this lineage were found in C3H/HeJ animals at any stage of infection. Further studies are required to determine whether autoreactive antibodies are generated during infection."
So their initial experiment to see if there was an overwhelming B cell response provides us with evidence that yes, there is, and also - while there is a high IgG response, only a small percentage of IgG produced is B. burgdorferi specific. There was at the time no indication that autoreactive antibodies were involved.
(This process can be a precursor to autoimmunity developing - but that's later on.)
A later paper, from 1997, "Why is chronic Lyme Borreliosis chronic?"(full text), also brings up a host of issues related to TLRs, MHC class II, and the relationship between B and T cells in lymph nodes.
Doesn't it seem a little prescient?
"The question remains whether downregulation or even loss of MHC class II molecules on LCs might influence a patient's disease susceptibility. It is MHC class II molecules that bind antigenic peptide fragments, present them to CD4+ Th cells, and induce cytokine secretion and IgG secretion by B cells [55]. In vitro investingations have shown that MHC II class molecules are downregulated on antigen-presenting cells after coculture with Th cell clones in the presence of antigenic peptides of tetanus toxoid or staphylococcal superantigen, which elicit a strong HLA-DR-restricted T cell response.
Several hypotheses were suggested as the cause of this down-regulation.
(1) Downregulation occurs when antigenic peptides catabolized in macrophages are recognized by CD+4 helper T cells, in order to control the size of a T cell clone and provide a homeostatic mechanism [55]. (2) Downregulation occurs for completion of T-B cell collaboration after antigen presentation, limiting excessive T cell help to the triggered B cells, or (3) it occurs for focusing the T cell repines to one or a few immunodominant peptides.
(4) LCs of patients with AIDS express decreased amounts of MHC class II molecules. Polyclonal B-cell activation, as seen in these patients and in patients with ACA, could cause the appearance of autoantibodies or immunocomplexes that interact with LCs and block their surface-staining characteristics [45]. (5) IL-10, originally identified as a product of Th2 cells, has a significant inhibitory influence on the antigen-presenting functions of macrophages and LCs by downregulation of MHC class II molecules. In fact, LCs pretreated with IL-10 were converted from specifically sensitizing to specifically tolerogenic antigen-presenting cells in vitro and in vivo [56]. In other studies treatment of LC cultures with IL-10 inhibited to upregulation of HLA-DR [57].
(6) Downregulation is initiated for establishment of self-tolerance. This downregulation can protect the antigen-presenting cell by inhibiting the presentation of self-antigens [58]. On the other hand, the downregulation of MHC class II antigens on LCs could result in inadequate presentation of antigens in lymph nodes, which in turn may reduce activation and proliferation of both B and T cells and the secretion of relevant cytokines. This may be what happens in CLB."
Dr. Karen Newell Rogers et al recent patent has this to say about TLRs (Toll Like Receptors) and B cells:
"Many bacteria and viruses produce substances, collectively called Toll ligands, that elicit an immediate response from an individual's immune system. These Toll ligands appear to promote inflammation by activating a wide variety of immune cells to bring them rapidly into battle against the invading pathogen.
In most cases, these events correlate with a healthy and productive immune response to the pathogen. However, in some cases the Toll ligand binds to a Toll-like Receptor (TLR) on lymphocytes and non-specifically activates immune cells called B and T lymphocytes that would normally to respond to infectious pathogens with an exquisitely specific response. When Toll ligands activate B cells in a non-specific way, the non-specific activation is a pro-inflammatory event that may result in uncontrolled, or even auto-reactive, production of antibodies. When a B cell is activated non-specifically, we have discovered that the B cell expresses an important, small self-peptide called MHC class II invariant peptide, CLIP. In most individuals, a control cell, known as a T regulatory cell (Treg for short), has been shown, to kill the activated B cell.
During a viral or bacterial infection, non-antigen specific B cells in close proximity to an inflammatory or inciting lesion could manage to become activated in a bystander fashion. In those cases, CLIP would remain in the groove and get transported to the cell surface of the B cell. Its presence on the cell surface can be undesirable because if CLIP gets removed from the groove by a self antigen, the B cell would be in a position to present self antigens to self-reactive T cells, a process that could lead to autoreactivity and autoimmune disease.
For some B cells this may result in death to the B cell by a nearby killer cell, perhaps a natural killer (NK) cell, unless the antigen receptor on the B cell has engaged antigen. Antigen recognition would thereby provide a survival signal for the B cell. However, if a killer cell doesn't remove the potentially autoreactive B cell and it encounters a CD4+ T cell that can recognize that antigen (most likely one that was not in the thymus) the B cell might receive additional help from a T cell specific for the antigen that now occupies the groove (antigen binding location in the MHC molecule). Alternatively, a nearby cell whose job it is to detect damaged self cells, may become activated by the self antigen-presenting B cell. Such a damage detecting cell is, for example, an effector T cell (Teff) such as a gamma delta T cell, also referred to as a γδT cell (γδ refers to the chains of its receptor). The γδT cell can then seek out other sites of inflammation (for example in the brain in MS, in the heart for autoimmune myocarditis, in the pancreas in the case of Type I Diabetes). Alternatively, the γδT cell might attempt to kill the CD4+ T cell that may respond to self antigens."
So based on all this, I think one has to consider that the complex interactions within the immune system related to B. burgdorferi infection have to be paid close attention to - and not just any persisting spirochetes themselves.
I am really interested in seeing what VGV-L - along with supportive and antibacterial treatment together - can do for chronic Lyme disease. It appears it not only prevents autoimmune responses to infection, but redirects the immune response so it can better target infection.
I do wonder, though, how VGV-L would handle a situation where many B cells are being created and a good percentage of them are antigen specific but are of low quality - such as those mentioned in Tunev and Barthold's research.
* It may be that Lyme disease is more like HIV in that inflammation may allow or facilitate the spread of spirochetes as it encourages vlsE recombination. See: http://www.jimmunol.org/content/167/6/3383.long for one example.
The Guardian has written about a new molecular test using nanoparticles which was developed by Alessandra Luchini, of George Mason University, to initially detect cancers. The new test is being used in clinical trials to detect early Lyme disease - even if there is no rash present in the infected patient.
Excerpt that will be of interest to readers:
"Q: In years to come, is this something that could be available in hospitals?
That's the hope we have. The first clinical trial is on the detection of Lyme disease. A fraction of patients get a skin rash but for those without the rash it is very difficult to diagnose. So with the particles we are able to capture the antigens that come from the spirochaete that is the causative agent of Lyme disease. If we see in the urine a piece of the bacteria of the spirochaete, we are sure that the patient has Lyme disease. We are gathering all the evidence and then we will need to go first for FDA approval before it is available in clinics.
Q: How much earlier will you be able to detect Lyme disease?
Lyme disease has a window of two to three weeks before seroconversion [production of antibodies in the host blood, indicating infection]. With our tests, we're able to detect it before seroconversion, because we're not looking for the antibodies, we just look for the spirochaete. I would say here, yes, by weeks, and earlier diagnosis would be beneficial for the prognosis."
Because of this, no one qualifies for Round Two and that round is forfeit. Readers playing along at home will have to compete in the remaining rounds and complete both Part A and Part B. So far, we have one winner of Round One, Rita.
(The answers to Round Two will be posted in a separate upcoming entry.)
Now I'll present those who wish to play along with our basic game instructions and round three of the scavenger hunt:
This is an online scavenger hunt to determine which Lyme disease research being conducted in which universities and colleges involves or has involved members of the 2006 Lyme disease guidelines group.
How to play:
I'm going to list Lyme disease related research either completed or currently being done in Column A, and in Column B, list the educational institution where the research was (or is) being conducted.
Match the research in Column A with the correct educational institution in Column B.
THEN determine if members of the department involved are A) currently doing research with a member of the 2006 Lyme disease guideline authors or B) have worked on any research in a past with said guideline author(s).
Write your matches and mentions of any guideline authors in a comment and submit your comment for posting.
You can use google, Wikipedia, and any on and offline tools for your answers.
Roughly two weeks after I post a round, I'll post the correct answers as well as post the next round of the game. I intend to run the game for several weeks - end date to be announced later.
If anyone wins all rounds, after that win is confirmed, the next post I write will be based on the winner's selected topic of choice and include hand-drawn illustrations by me.
Round Three: Lyme Disease Scavenger Hunt
Research Description
Educational Institution
1) Lyme arthritis is an inflammatory disease with periods of inflammation and resolution. Eicosanoids are powerful lipid mediators of inflammatory responses which may be involved in disease processes. Cyclooxygenase-2 (COX-2) is upregulated during injury or infection and catalyzes the production of prostaglandins from arachidonic acid. Several commercially available drugs block this response (celebrex, vioxx) and act to suppress the symptoms of chronic inflammation (pain and swelling), but their effect on underlying disease processes is currently unknown. Treatment of mice infected with B. burgdorferi with these compounds does not inhibit their ability to develop Lyme arthritis, but it does prevent its natural resolution. Current experiments are exploring the mechanism for this examining: altered prostaglandin production; increased leukotriene production; and decreased lipoxin production.
A) University of Tennessee
2) iNKT cells play an important immunoregulatory role within the immune system. This function is regulated by endogenous and exogenous glycolipid antigen presentation by CD1d molecules. Thus, by using Borellia burgdorferi, the agent of Lyme disease, as the model system, we are working to elucidate the molecules involved with and the mechanism(s) of CD1d-antigen assembly. Additionally, by understanding how antigens load onto CD1d we can determine the molecular and structural features of the iNKT cell receptor-antigen interface. Elucidating glycolipid antigen processing and presentation and its recognition by iNKT cells will allow insights into how different responses are induced and how these immunoregulatory T lymphocytes function. This insight will advance our understanding of the physiological role of the CD1d antigen presentation system and iNKT cells within the context of the immune system.
B) University of Missouri
3) One major project is the development of a Reservoir Target Vaccine for the Control of Lyme Borreliosis. Borrelia burgdorferi causes Lyme disease (LD) and is the most common vector borne infectious disease in the United States. This spirochete is maintained in endemic areas of LD by cycling between wildlife reservoirs (i. e. white-footed mice, shrews, etc) and the Ixodes scapularis tick vector. Human disseminated infection can cause permanent damage to the nervous and musculoskeletal systems and currently, there is no vaccine approved for prevention of this disease. A promising method to reduce human LD incidence is to break the mouse-tick transmission cycle by eliminating the spirochete from the reservoir and from the ticks that feed on them. To accomplish this we have developed a wildlife oral bait vaccine based in OspA and are currently testing its efficacy in a field trial.
C) Vanderbilt University
There is much to learn from playing this game in and of itself that you gain something whether you win or lose. (I also have a point to make in playing it, and I'll reveal it at the end of the series... It might not be the point you suspect I'm going to make.)
Now I'll present those who wish to play along with our basic game instructions and round two of the scavenger hunt:
This is an online scavenger hunt to determine which Lyme disease research being conducted in which universities and colleges involves or has involved members of the 2006 Lyme disease guidelines group.
I'm going to list Lyme disease related research either completed or currently being done in Column A, and in Column B, list the educational institution where the research was (or is) being conducted.
How to play:
Match the research in Column A with the correct educational institution in Column B.
Determine if members of the department involved are A) currently doing research with a member of the 2006 Lyme disease guideline authors or B) have worked on any research in a past with said guideline author(s).
Write your matches and mentions of any guideline authors in a comment and submit your comment for posting.
You can use google, Wikipedia, and any on and offline tools for your answers.
Roughly one week (perhaps we should make this two?) after I post a round, I'll post the correct answers as well as post the next round of the game. I intend to run the game for several weeks - end date to be announced later.
If anyone wins all rounds, after that win is confirmed, the next post I write will be based on the winner's selected topic of choice and include hand-drawn illustrations by me.
Research Description
Educational Institution
1)
Established the rhesus monkey model of Lyme disease.
Discovered an immune evasion mechanism that Borrelia burgdorferi, the spirochete that causes the disease, may use to cause persistent infections.
Discovered that B cells produce the regulatory cytokine IFN-gamma in animals infected with B. burdoferi.
Discovered that spirochetes elicit not only inflammatory but also anti-inflammatory cytokines from monocytes, thus contributing a method to control the inflammation they themselves cause.
A) Medical College of Wisconsin
2) B. burgdorferi binds to members of a family of receptors on the surface of human cells termed "integrins", which are important in many cellular processes, including inflammation and blood vessel growth. Using a phage display library of B. burgdorferi genomic DNA, we identified a B. burgdorferi protein that mediates bacterial binding to β3-chain integrins, and have defined portions of this protein that participate in integrin recognition. Our current work focuses on determining the role of Borrelia-integrin recognition in the course of infection and the development of Lyme disease in the mouse model. We have also studied the mammalian cell response to B. burgdorferi strains that do or do not express the β3-chain integrin ligand, and by microarray analyses, have identified several signaling/regulatory pathways that show integrin-ligand specific changes in expression. Some of these may be important to the ability of this organism to disseminate from the site of the tick bite to other tissues. We also discovered that another B. burgdorferi protein, BBB07, signals through integrin α3β1 to promote a proinflammatory response in human chondrocytes, which may contribute to the pathogenesis of Lyme arthritis. Our phage display library was also used in vivo to identify B. burgdorferi proteins that bind to vessel walls in specific tissues such as the joint and heart, and further characterization of these proteins is underway.
B) Tulane University
3) Critical to this work has been our development of green fluorescent protein (GFP) reporters that enable us to track live spirochetes in ticks and mice. Our live-imaging studies have fundamentally changed our understanding of the transmission process. In order to reach the mouse, spirochetes disseminate through the midgut into the salivary glands in order to access the salivary stream which they “ride” into the vertebrate host. We have found that dissemination of spirochetes in ticks is actually biphasic. In the first phase, which we have termed “adherence-mediated migration, spirochetes replicate in close association with differentiating midgut epithelial cells, “working” their way as aggregates or networks to the base of the epithelium. In the second phase, they transition into typically motile spirochetes, complete the penetration through the midgut, and then move on to the salivary glands en route to the mouse. Most recently, we have found that spirochetes lacking RpoS are deficient in this process and we are developing various strategies to identify the RpoS-dependent genes involved.
C) University of Connecticut
There is much to learn from playing this game in and of itself that you gain something whether you win or lose. (I also have a point to make in playing it, and I'll reveal it at the end of the series... It might not be the point you suspect I'm going to make.)
So, I've decided to start a little game here on Camp Other blog. It is an online scavenger hunt to determine which Lyme disease research being conducted in which universities and colleges involves or has involved members of the 2006 Lyme disease guidelines group.
I'm going to list Lyme disease related research either completed or currently being done in Column A, and in Column B, list the educational institution where the research was (or is) being conducted.
How to play:
Match the research in Column A with the correct educational institution in Column B.
Determine if members of the department involved are A) currently doing research with a member of the 2006 Lyme disease guideline authors or B) have worked on any research in a past with said guideline author(s).
Write your matches and mentions of any guideline authors in a comment and submit your comment for posting.
You can use google, Wikipedia, and any on and offline tools for your answers.
Roughly one week after I post a round, I'll post the correct answers as well as post the next round of the game. I intend to run the game for several weeks - end date to be announced later.
If anyone wins all rounds, after that win is confirmed, the next post I write will be based on the winner's selected topic of choice and include hand-drawn illustrations by me.
Round One: Lyme Disease Scavenger Hunt
Research Description
Educational Institution
1) We ask the question what genes in the B. burgdorferi genome are responsible for the pathogenesis and long-term survival, and how can these genes be identified? Our strategy is to analyze the B. burgdorferi virulence determinants by Signature-Tagged Mutagenesis in combination with Luminex®-based high-throughput screening procedures, and infectivity studies to identify genes and gene products required for infectivity in a mouse model. We are also exploring the etiology of an emerging tick-borne disease, Southern Tick-Associated Rash Illness.
A) Michigan State University
2) Our laboratory studies Borrelia spirochetes and the diseases they cause, Lyme disease and relapsing fever. After transmission of Borrelia through bites of certain tick species, both Lyme disease and relapsing fever are characterized by the spread of bacteria via the bloodstream, which may lead to the infection of multiple organs such as the skin, heart, joints, and brain. While these pathogenic processes are not yet well understood on the molecular level, the involved virulence factors identified so far have been surface lipoproteins.
A first project identifies lipoprotein sequence determinants, membrane protein complexes and chaperones involved in spirochete lipoprotein export.We are currently using fluorescent proteins as markers for protein localization in live Borrelia cells to determine the sorting signals for surface and subsurface lipoproteins. Using biochemical and novel genetic approaches, we are also in the process of characterizing the lipoprotein export machinery in Borrelia burgdorferi, the Lyme disease spirochete. These studies will ultimately help in the design of novel intervention strategies for spirochetal infections.
B) The University of Texas
3) My career goal is to help reduce the burden of human, wild animal, and domestic animal disease through improved understanding of disease systems. I approach this goal by conducting novel research to elucidate the ecology of maintenance and transmission of zoonotic pathogens, so as to identify key targets within disease cycles for interventions that will reduce disease risk.My dual training in wildlife disease ecology and veterinary medicine allows me to combine ecological and epidemiological principles, field techniques, molecular analytical tools, and medicine to address important problems in ecosystem health at the population level.Thus far, I have studied the ecology of two vector-borne disease systems in North America - West Nile virus and Lyme disease.
C) University of Kansas
There is much to learn from playing this game in and of itself that you gain something whether you win or lose. (I also have a point to make in playing it, and I'll reveal it at the end of the series.)
I came across this article earlier today, though so far I haven't seen mention of it in the Lyme disease community. (It was published earlier this month, though, so I might have missed it.)
In this case, the following scenario and outcome was presented:
"The trainee was sequentially presented the details of a fictitious patient: there’s an eye problem; vision is blurred; the family, living in Connecticut, has a history of arthritis. The trainee’s initial response was uveitis. More clues and the diagnosis was changed to Behcet’s disease until finally the trainee settled on Lyme disease. How sure was this seemingly hasty student of medicine? Seventy-three percent sure."
One important point to be made about the database-based doctor:
"Following its resounding victory on Jeopardy!, IBM’s Watson has been working hard to learn as much about medicine as it can with a steady diet of medical textbooks and healthcare journals. The mock case described above was part of a recent demonstration to the Associated Press showing just how much Watson has learned. The robot’s diagnosis was correct and it identified a link between symptom and cause that was “not common,” as one participating physician called it. After being told the patient was pregnant and allergic to penicillin, Watson suggested treating her with cefuroxine. Its human colleagues agreed."
A striking statement was made further on about how the amount of medical knowledge available doubles every 5-7 years and doctors struggle to keep up with it. This would definitely make the case for having a medical database at one's disposal to assist with diagnosis, but to me nothing is going to replace observation and good old hands-on examinations for many conditions.
We aren't quite at the level of Star Trek probes, but perhaps we're headed that way in the future.
So, I'm not sure how familiar my readers are with Wolfram Alpha. If you've ever heard of the Mathematica software package, these are the guys that created it.
Wolfram Alpha is an online tool that uses computational algorithms and data modeling to output objective information on a variety of topics.
In other words: It takes statistics and facts from numerous sources and creates a database on given topics on the fly.
(To learn more about what Wolfram Alpha's online tool does, go here: http://www.wolframalpha.com/tour1.html)
You can go to their homepage and type any term into their search engine and it will build a page based on that term and nothing but that term. Instead of a list of different link results like you see on Google, you get one page with many different kinds of information on that term or topic.
So for fun, I typed "Lyme disease" into their homepage.
Now, as part of the output for that query, I received the following table of data:
This is one of those moments where my head is breaking, and I can see where they are drawing their data from in the notes below the table - so I need to follow up and see if I can look at the original source for this data.
But just based on what I'm looking at right now, the words "Oh my god, where are they getting these numbers?" escaped my lips.
According to the footnote, the data is not CDC based, but is based on actual patient visits to US healthcare providers between 2006-2007. I have to wonder why Wolfram Alpha is mining data from this source and not more recent NAMCS/NHAMCS statistics or another source, but it is interesting to see something that is not CDC for a change.
The data in this table does and does not reflect what I've observed online in the Lyme disease patient community.
For one thing, the chart states far more men than women contract Lyme disease and are diagnosed for it than women. Yet the number of women I see online who discuss Lyme disease outweighs the number of men a great deal.
After reading Polly Murray's book, The Widening Circle, why women are more active online participants and more activist in general has been made more clear to me: the children. If you are sick with Lyme disease, that's bad enough - but if your child is sick, that's worse, and mothers seem to be more likely than fathers to reach out for answers and support online to help not only themselves but their children. (Sorry dads, I don't like the dissing either, and I'm sure a lot of you are active in your child's health - but statistically speaking more women do end up dealing with their kids' health issues for whatever reason.)
This reaching out and forming support groups began with women way before the internet - the internet is just an extension of what happens in real life.
(By 1992 there were over 100 patient support groups for Lyme disease - which kinda chips away at this idea that Lyme disease is a disease spread by reading the internet. What was the internet in 1992? Usenet?*)
But in this table, it's saying far more men get Lyme disease, and I see fewer of them online.
Okay, so another thing about this table, just so the reader is clear on what they're reading, it doesn't take 22 doctors for one woman to achieve a diagnosis for Lyme disease here, even though I've heard so many stories about this phenomenon - no, what the table means is that for every 22 office visits a doctor sees, one of them will be a woman that gets diagnosed with Lyme disease.
That one in six visits for men seems really high to me - too high, if you ask me - but in reading the fine print these are estimates and estimates which are weighted for US demographics (how? in what manner?).
I think what's striking about this one year of data is the extrapolation of just how many patients were diagnosed with Lyme disease over the course of 131,748 doctor visits.
86,700 people in one year... is that closer to reality than the CDC reported 40,000 or so?
I really don't know how much stock to put in this data at all. I feel like writing Wolfram and asking them what gives. How was the estimation made and weighed and why are they drawing their data from NAMCS/NHAMCS - and if so, can they get more recent data or is this it?
I'm thinking it would be more accurate a head count to get diagnosis numbers from doctors rather than the CDC, because not all cases are reported - but I don't know how reliable these numbers are or how the estimation was computed.
Update:
Just to add to this, check out this other table generated from the same data set:
Interesting.
Now look at the ratio for the number of men who are diagnosed with Lyme disease to the number of women. And now look at the total number of estimated cases.
The only factor changed for initial data output was from "primary diagnosis at visit" to "any diagnosis at visit". What exactly does this mean?
Update #2:
Well, isn't this interesting. I googled "NAMCS" and my first result was this:
"The National Ambulatory Medical Care Survey (NAMCS) is a national survey designed to meet the need for objective, reliable information about the provision and use of ambulatory medical care services in the United States. Findings are based on a sample of visits to non-federal employed office-based physicians who are primarily engaged in direct patient care.
The National Hospital Ambulatory Medical Care Survey (NHAMCS) is designed to collect data on the utilization and provision of ambulatory care services in hospital emergency and outpatient departments. Findings are based on a national sample of visits to the emergency departments and outpatient departments of noninstitutional general and short-stay hospitals."
So wait. This IS data from a survey the CDC knows about?
What percentage of these diagnosed cases are included in the CDC Lyme disease reported cases?
Why aren't these diagnosed cases mentioned on the reporting page for Lyme disease as a separate category of cases - even if doctors did not fill out an official report?
Or are they mentioned somewhere on the CDC Lyme disease pages and I've missed it? Anyone want to confirm this for me?
Update #3:
Pointed out by an anonymous commenter on the blog just now - from the same page above:
Wow, let's give the women lots of Ativan and give the guys none?
After reading this, we're all going to need Ativan.
Where they hell are these numbers coming from, though? The footnote here is really not useful.
And I'm sorry, if I am feeling sick with Lyme disease, getting it up is the last thing that would be on my mind... that must refer to a preexisting drug regimen. Even then... ouch.
A. NAMCS and NHAMCS data are used to statistically describe the patients that utilize physician services and hospital outpatient and emergency department services, the conditions most often treated, and the diagnostic and therapeutic services rendered, including medications prescribed. The data are used by public health policy makers, health services researchers, medical schools, physician associations, epidemiologists, and the print and broadcast media to describe and understand the changes that occur in medical care requirements and practices. The data are disseminated in the form of public health reports, journal articles, and microdata files.
Q: Can the ambulatory medical care surveys be used to find out how many people have a certain diagnosis?
A: No. The ambulatory medical care surveys (NAMCS and NHAMCS) are not based on a sample of the population. They are based on a sample of visits rather than a sample of people. The data can be used to find out how many ambulatory care visits were made involving a certain diagnosis. To get an idea of utilization of ambulatory care in the population, the number of visits can be divided by the population of interest to get a rate of visits for a diagnosis of interest.
Okay, partially answered. I still have to wonder how public health policy makers, epidemiologists, etc. use this data, though... and how closely this sample of visits maps to reality.
I really don't think anyone has a true picture of how extensive Lyme disease is and how many people have persisting symptoms of Lyme disease pre- and post-antibiotic treatment, and it would be useful to know how many cases physicians actually diagnose and treat versus report to the CDC as those are different numbers.
Even then, these surveys are only representational of doctor caseloads over a one week period during a given year - they are not solid figures.
While looking around You tube for something interesting and educational to share with my minions readers, I came across this little two minute video (no audio):
It really got my attention, because I suspect that long-term complications that come on the heels of a Lyme disease infection could be because a certain number of people are either misdiagnosed to begin with (and thus treatment is delayed) - or they are under-treated for Lyme disease in the first place when they have neuroborreliosis.
Throwing 10-14 days worth of doxycycline at an infection that is passing or has passed the blood-brain barrier is not going to cut it, and this is why IV Rocephin for 30 days is the baseline treatment for early neuroborreliosis.
There has been some debate over what dose of which antibiotic can be used to treat neuroborreliosis, but putting that debate aside, one big step in treating it properly is being able to diagnose its presence early.
So when I found this little video, I had to know more...
N-acetylaspartate (NAA) concentrations in the brain are decreased if there is damage.
I noticed there was a name on the lower lefthand corner: Dr. Oded Gonen. Tiny, tiny print, but there.
So I looked that name up to see if I could learn more about him. Maybe you're reading this and you already know about him, but I suspect a number of my readers may not.
Dr. Oded Gonen is working for the clinic that Dr. David Younger began - a clinic mentioned in Cure Unknown:
A new program led by neurologist David S. Younger M.D. will open its arms to patients and their treating doctors, wielding science to get a handle on the disease.
And so, the Lyme Neuroborreliosis Program was born in New York City, and Dr. Onen Gonen is one of the researchers on staff who is conducting his own clinical trials on neuroborreliosis.
The clinic has this to say about neuroborreliosis symptoms and treatment:
"The spectrum of neurological and behavioral disorders ascribed to Lyme disease has been the subject of intense debate. Three clinical syndromes are seen in such increased frequency that their presence alone or together should prompt consideration of Lyme neuroborreliosis in a given patient. They include meningitis, painful polyradiculitis, and cranial neuritis (most commonly a facial palsy). It is important to recognize them and potentially other central, peripheral, and autonomic nervous system manifestations, abbreviated CNS, PNS, and ANS, because they occur early in the infectious illness, lead to a vigorous immune response, and their symptoms resolve more quickly with early institution of antibiotics. There is still debate about encephalopathy, cognitive impairment, and neuropsychiatric involvement in Lyme disease, and the frequency of chronic and late Lyme disease in treated individuals. Notwithstanding, the vigorous immunological response triggered by the Borrelia spirochete infection appears to be a potent factor in the perpetuation of symptoms long after effective treatment has been administered and the infection has been presumably eradicated."
Whatever your beliefs about the efficacy of long-term antibiotic treatment, early treatment of neuroborreliosis is particularly important, but one of its stumbling blocks has been accurate diagnosis.
As mentioned in this blog before, only a small percentage of early neuroborreliosis patients are diagnosed using a positive CSF culture or blood tests - often a good clinician has to pay close attention to symptoms and history to pin down the diagnosis.
Even Dr. Younger has suggested a combined testing method for neuroborreliosis and Lyme disease in general, in his 2010 publication, Lyme Neuroborreliosis: Preliminary Results from an Urban Referral Center Employing Strict CDC Criteria for Case Selection.
Dr.Younger stated:
"A two-tier test approach for active disease and previous infection with the demonstration of a significant change in IgM or IgG antibody response to B. burgdorferi in paired acute- and convalescent-phase serum samples, examination of diagnostic levels of IgM and IgG antibodies to the spirochete in CSF, and isolation of B. burgdorferi from CSF are recommended to improve the diagnostic accuracy of serological testing in Lyme disease, including LNB."
This is better than just giving someone with a tick bite and rash an ELISA and then calling it a day when it comes back negative if they are symptomatic. It's not perfect - but it's an improvement.
Dr. Younger further wrote in his summary:
"The management of LNB remains controversial as to the timing and duration of oral and intravenous antibiotics. The occurrence of peripheral neuropathy, dysautonomia, and encephalopathy years later after adequate antibiotic therapy underscores the selective vulnerability of the nervous system to the immunological effects of B. burgdorferi infection, although the exact mechanisms remain uncertain."
Maybe further test development could at least uncover more cases earlier, even as the mechanisms are said to be unknown.
Right now Dr. Gonen is working on a new test for diagnosing neuroborreliosis. He's conducting clinical trials on the use of proton magnetic resonance spectroscopy (1H-MRS), which detects metabolic disturbances in the brain - even without showing an MRI abnormality such as a visible lesion. In the trial, he intends to examine metabolic parameters in neuroborreliosis patients.
The parameters he is examining are demyelination, oxidative, and neuronal damage processes indicated by monitoring their surrogate markers: creatine, chloride, lactate and N-acetyl aspartate (NAA).
Of these markers, N-acetyl aspartate or NAA is specific to the brain, being the second-most-concentrated molecule in the brain after the amino acid glutamate. NAA is a useful indicator for disease, as it gives off the largest signal in magnetic resonance spectroscopy of the human brain - and the levels measured are decreased in numerous neuropathological conditions ranging from brain injury to stroke to Alzheimer's disease.
1H-MRS is also used to measure the impact of HIV on the brain and in Lupus and MS studies. It's good to know that someone is conducting more tests using this technology if it can help diagnose early neuroborreliosis - so far, I've only found the below study in the use of 1H-MRS for neuroborreliosis, and it may yet be another tool in the Lyme toolbox.
