Tuesday, August 16, 2011

24 Do Different Genetic Haplotypes Matter?

It seems people are still holding on to the HLA-DR2 and HLA-DR4 concept of subgroup autoimmunity (subgroups of Lyme disease patients who do not respond to additional antibiotic treatment) in the Lyme disease community.

I get the impression that hypothesis has been dropped by a number of researchers in favor of a new one - except in the case of patients with Lyme arthritis. (I don't think HLA-DR2 is associated with Lyme disease, either, and HLA-DR4 is associated with Lyme arthritis.)

I came across this recently:

National Institute of Allergy and Infectious Diseases, NIH: Impact on Global Health (2009) by Vassil St. Georgiev, PhD

Chapter 22.1 Lyme Disease (Lyme Borreliosis, Lyme Arthritis)
Section The Role of Autoimmune Reactivity in Lyme Disease

"In NIAID-supported clinical studies, case subject patients with PTCLD* were compared with control subjects without such symptoms for the presence of several human leukocyte antigen (HLA) class II (DRB1 and DQB1) genetic markers, some of which are known to be associated with the expression of autoimmune reactivity. The results obtained did not support the involvement of an autoimmune mechanism in PTCLD (24). However, because not all autoimmune diseases are associated with specific HLA haplotypes, these findings do not necessarily exclude that possibility. Definitive proof would clearly involve demonstrating the presence of significant levels of relevant autoimmune antibodies and/or autoreactive T cells in patients with PTCLD but not in treated control subjects without such symptoms. A greater frequency of DRB1*0401, which has been reported to be associated with antibiotic-treatment-resistant arthritis, was noted in the case subject patients; although this finding appeared to be nominally significant (p < 0.05), its biological significance is ambiguous because none of the case subjects considered had symptoms of inflammatory arthritis. (http://www3.niaid.nih.gov/research/topics/lyme/research/autoimmune/)"
* In this NIAID-NIH document, PTCLD stands for Post Treatment Chronic Lyme Disease.

24) Klempner MS, Wormser GH, Wade K, Trevino RP, Tang K, Kaslow R, and Schmid C. (2005) A case-control study to examine HLA haplotype associations in patients with posttreatment chronic Lyme disease. J. Jinfect. Dis. 192(6), 1010-1013.

Now this is an interesting piece of information.

This book from the NIAID-NIH is stating following about patients with PTCLD in NIAID-supported studies:

1) Patients with chronic Lyme disease were compared against control subjects with the same genetic markers and the results did not support an autoimmune mechanism for chronic Lyme disease.

2) Not all autoimmune diseases are associated with specific haplotypes.

3) Those patients with chronic Lyme arthritis have had their condition strongly associated with DRB1*0401.

4) None of the case subjects in trials had inflammatory arthritis. None.

I find this particularly interesting since the one statement many patients have made is that some researchers have pegged chronic Lyme disease patients as having an autoimmune disorder, when the research in this regard is fuzzy. What indicates to some researchers today that post-treatment chronic Lyme disease is an autoimmune disorder, if it isn't specific haplotypes which are at risk of developing persisting symptoms?  A different molecular mimicry model than that which leads to Lyme arthritis? A different model of persisting symptoms entirely?

I also find it interesting that none of the case subjects had inflammatory arthritis. I don't know how clinicians defined the criteria for inflammatory arthritis and if they did any serology for inflammation, but I can say that I have had joint swelling, muscle pain, and shooting nerve pain during the course of my illness. That none of the case subjects in trials had inflammatory arthritis comes as a surprise to me.

According to research there is a relationship between a specific haplotype and Lyme arthritis. This is just one such example:

From Persistent arthritis in Borrelia burgdorferi-infected HLA-DR4-positive CD28-negative mice post-antibiotic treatment. Iliopoulou BP, Alroy J, Huber BT. Arthritis Rheum. 2008 Dec; 58(12):3892-901.:
"METHODS:We have previously shown that CD28(-/-) mice develop intermittent monarticular Lyme arthritis that is responsive to antibiotics. Since there seems to be a link in humans between persistent arthritic manifestations post-antibiotic treatment and the HLA-DR4 allele, we generated DR4+/+CD28(-/-)MHCII(-/-) mice, infected them with Borrelia burgdorferi, and subsequently treated them with antibiotics.

RESULTS: Thirty-eight percent of the B burgdorferi-infected DR4+/+CD28(-/-)MHCII(-/-) mice, but none of the B burgdorferi-infected CD28(-/-)MHCII(-/-) mice, remained arthritic post-antibiotic treatment. A significant fraction (36%) of these mice, but none of the mice in which arthritis resolved, had serum antibodies to outer surface protein A of B burgdorferi. After abrogation of active B burgdorferi infection, the inflammatory reaction in mice with persistent joint inflammation was restricted to the joints, since their draining lymph nodes were no longer enlarged. Increased CD20 and interferon-gamma messenger RNA expression in the inflamed joints of these mice suggested a possible role of B cells and inflammatory cytokines in the pathogenesis of persistent arthritis post-antibiotic treatment.

Conclusion: The establishment of this murine model allows, for the first time, the elucidation of the immunologic events that lead to persistent Lyme arthritis post-antibiotic therapy in genetically susceptible individuals."
So according to this, little over a third of the mice with a specific allele remained arthritic after antibiotic treatment, and of this third, about a third of them developed antibodies to OspA.

My questions are: How is it that the remaining roughly two thirds of the mice did not remain arthritic? How is it that two thirds of them did not develop antibodies to OspA?

There are many papers written about the association between specific alleles and development of chronic Lyme arthritis:

1993 - Association of treatment-resistant chronic Lyme arthritis with HLA-DR4 and antibody reactivity to OspA and OspB of Borrelia burgdorferi.

2001 - Autoimmune mechanisms in antibiotic treatment-resistant lyme arthritis. (This is where molecular mimicry as a cause of Lyme arthritis is mentioned.The abstract states: "...only one human protein was identified, lymphocyte function associated antigen-1 (hLFA-1), that had sequence homology with OspA (165-173) and predicted binding in the DRB1*0401 molecule.")

2004 - Molecular characterization of the OspA(161-175) T cell epitope associated with treatment-resistant Lyme arthritis: differences among the three pathogenic species of Borrelia burgdorferi sensu lato. (Borrelia that causes Lyme disease in Europe does not usually lead to chronic Lyme arthritis.)

2006 - Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Borrelia burgdorferi peptide (Concluded that binding of a single spirochetal peptide to certain DRB molecules is a marker for antibiotic-refractory Lyme arthritis and might play a role in the pathogenesis of the disease.)

2007 - Clonal Diversification in OspA-specific Antibodies from Peripheral Circulation of a Chronic Lyme Arthritis Patient

A number of these are Steere's papers - not surprising since he has written so much about the rheumatological aspect of Lyme disease. And some of it is not his research, and I could find a few more by others.

I'm looking for more research on chronic Lyme disease's connection to haplotypes and alleles outside of the Lyme arthritis model. The NIAID-NIH book, written in 2009, states there is no connection.

So to sum up:

1) Particular alleles or haplotypes are not associated with chronic Lyme disease as a whole.

2) Particular alleles or haplotypes are associated strongly with chronic Lyme arthritis.



allele: is one of two or more forms of a gene.Sometimes, different alleles can result in different traits, such as color. Other times, different alleles will have the same result in the expression of a gene. See more info. at: http://en.wikipedia.org/wiki/Allele

haplotype: a combination of alleles (DNA sequences) at different places (loci) on the chromosome that are transmitted together. A haplotype may be one locus, several loci, or an entire chromosome depending on the number of recombination events that have occurred between a given set of loci.See more info. at: http://en.wikipedia.org/wiki/Haplotype

Additional information: http://en.wikipedia.org/wiki/Category:HLA-DR_haplotypes


  1. CO,

    I have seen this in various forms, and cannot personally vouch for the validity of the information. It was apparently refuted in a subsequent study. Everything that follows is a cut-and-paste (up to the last paragraph).

    The Klempner discovery was caught on tape by a Lyme patient at a lecture he gave regarding his study. I hvae heard the tape recording.

    From Kathleen Dickson: Mark Klempner found that a large number of Chronic Lyme patients, seronegatives, have the HLA-DQB1*0602 haplotype that is correlated with narcolepsy. He talks about it during talks to physicians. Here's what he says-

    Mark Klempner:

    "Um, some people will view this as bad news, some will view it as good news, and some people will say, well, where do we go from here?? I think that really is the question, really is to coalesce and say, ?where do we go from here?

    Um, There, these patients obviously, are very, very much interested in that question, as we are, and I just want to highlight a preliminary
    piece of data of where we think we?re going from here, unpublished*, and not for large, uh, dissemination, but here is the preliminary data.

    And, that is, that when you look for the possibility of an autoimmune disease, the best way to look is to see if there is any genetic
    clustering in HLA haplotypes. The reason for that is the way antigens get presented in the context of who you are, that is, your HLA
    haplotype. And we can talk in some detail about that. Those diseases that I think everybody would agree are so called Autoimmune :lupus, rheumatoid arthritis, type 1 diabetes, and perhaps MS, have some clear genetic clustering that leads us to believe that these are indeed autoimmune diseases, although we do not satisfy so-called co-postulates of autoimmune disease that we?ve written about. And the odds ratio for your having that particular HLA type, in the case of R.A, a DR4, or a DQB0602 to protect you from type 1 diabetes, are on the order of 3 to 6. One of the ones that is probably highest, of course, is B27, in patients with alkyloiding spondolytis and the like. It turns out that if you look at the first 51 patients with post-treatment chronic Lyme disease, the patient population that participated in our study, there was a very high incidence of DQB0602 with an odds ratio of 770%. So it may well be that exposure to THAT organism with THAT background of HLA haplotype may lead you to develop chronic symptoms. That is a hypothesis that needs to be tested. It would obviously lead to an entirely new form and approach to therapy."

    CO, there IS a high association between HLA DQB1*0602 and MS which has been documented in many research articles.

  2. CO,

    Regarding the autoimmune angle, I found this article somewhat interesting:


    Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry?

    Nat Immunol. 2001 Sep;2(9):797-801.

    Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry?

    Benoist C, Mathis D.


    Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, One Joslin Place, Boston, MA, USA. cbdm@joslin.harvard.edu


    Autoimmune diseases remain one of the mysteries that perplex immunologists. What makes the immune system, which has evolved to protect an organism from foreign invaders, turn on the organism itself? A popular answer to this question involves the lymphoid network's primordial function: autoimmunity is a by-product of the immune response to microbial infection. For decades there have been tantalizing associations between infectious agents and autoimmunity: beta-hemolytic streptococci and rheumatic fever; B3 Coxsackieviruses and myocarditis; Trypanosoma cruzi and Chagas' disease; diverse viruses and multiple sclerosis; Borrelia burgdorfii and Lyme arthritis; and B4 Coxsackievirus, cytomegalovirus or rubella and type 1 diabetes, to name the most frequently cited examples. In addition, animal models have provided direct evidence that infection with a particular microbe can incite a particular autoimmune disease. Nonetheless, many of the associations appear less than convincing and, even for those that seem to be on solid footing, there is no real understanding of the underlying mechanism(s).

    PMID: 11526389 [PubMed - indexed for MEDLINE]

    From the longer version:


    Support for the theory that autoimmunity underlies Lyme arthritis has come from observations of an MHC association and an anti-borrelia immune response associated in time and severity with the arthritis symptoms. The majority of individuals with the treatment-resistant disease have the HLA-DRB1*0401 or HLA-DRB1*0101 alleles which, interestingly, are also more frequent in rheumatoid arthritis patients (15, 16). Also characteristic of many individuals, and appearing coincidentally with the onset of a prolonged arthritis episode, is a high titer of immunoglobulin G (IgG) antibodies that recognize the outer surface protein A (OspA) of B. burgdorferi (16, 17). T helper 1 (TH1) cells reactive to OspA are often found as well (18-20). Finally, immunization with recombinant OspA has been effective in preventing Lyme disease in two clinical trials (21, 22) and is now available as a vaccine. These findings suggest that an HLA-DRB1*0401- or HLA-DRB1*0101-restricted immune response that is OspA-specific somehow precipitates joint-specific autoimmunity.

    (to be continued)

  3. (continued - from the longer article)

    A breakthrough came when the immunodominant HLA-DRB1*0401-restricted peptide of OspA was identified (23). With the use of a computer alogarithm (24), the nine-residue peptide OspA(165–173) was predicted to be the peptide most effectively bound by HLA-DRB1*0401; this was confirmed experimentally in competitive binding assays. In addition, when injected with OspA protein, mice that were transgenic for HLA-DRB1*0401 responded primarily to the OspA(165–173) peptide, as did T cells from an HLA-DRB1*0401+ antibiotic-resistant patient with Lyme arthritis, which were challenged in vitro. A search of the Genbank Database identified one human protein, leukocyte function–associated antigen 1a (hLFA-1a), which contains the peptide hLFA-1a(L332–340). hLFA-1a(L332–340) has homology to the dominant epitope of OspA and was predicted to bind strongly to HLA-DRB1*0401 (which was eventually confirmed experimentally) (23). Most importantly, synovial fluid T cells from patients with antibiotic-resistant arthritis, but not antibiotic-sensitive or other inflammatory arthritides, could respond to both OspA(165–173) and hLFA-1a (25). Tetramer technology has now been applied to this field and has permitted direct enumeration of HLA-DRB1*0401-restricted T cells that are OspA(164–175)-specific. It has identified increased numbers of these cells in the synovial fluid compared to in the blood of treatment-resistant arthritis patients (26). It has also allowed the demonstration of OspA(165–184) and hLFA-1a(L326–345) cross-reactivity at the single cell level, although for only 10% of OspA(165–184)-reactive clones and with a markedly lower hLFA-1a(L326–345) response (27).

    (to be continued)

  4. (continued)

    These observations suggested the following epitope mimicry scenario. B. burgdorferi sensu stricto infects the host and disseminates to multiple tissues, including the joints. Some time later, often after several months, an inflammatory immune reaction begins in the joints; it is characterized in HLA-DR4B1*0401 individuals by an anti-OspA IgG response and TH1 cell reactivity to the OspA(165–173) peptide. Interferon-g (IFN-g) produced by the TH1 cells up-regulates expression of LFA-1aon synoviocytes and invading leukocytes and HLA-DR4 molecules on APCs. As a result, there is enhanced presentation of self-peptides derived from LFA-1, which are either endogenously synthesized or phagocytozed, that augments and propagates the inflammatory response, even after borrelial antigens have been cleared. Support for this scenario comes from the finding that LFA-1 is, indeed, highly expressed on cells infiltrating the synovia of treatment-resistant Lyme arthritis patients, but not those with other arthritides (28).

    Thus, the case for OspA–LFA-1a epitope mimicry being responsible for the initiation of antibiotic-resistant Lyme arthritis fulfills two, perhaps three, of the criteria we have proposed. First, the association between infection by B. burgdorferi sensu stricto and the eventual development of chronic, treatment-insensitive arthritis is well documented. Inflammation occurs once the microbe has been cleared, but the immune response to the OspA protein and the time of onset and severity of joint inflammation correlate well. Second, the culprit epitopes were defined as OspA(165–173) and hLFA-1a(L332–340); in addition, T cells that were capable of responding to both were elicited in HLA-DRB1*0401-transgenic mice immunized with OspA. Third, dual-responsive T cells were found specifically in patients with antibiotic-resistant Lyme arthritis, especially in the inflammatory lesions.

  5. (continued)

    However interesting and suggestive this putative example of epitope mimicry appears to be, it cannot yet be considered definitive. A major problem has been the lack of an adequate rodent model. Thus, it has not been feasible to evaluate the effect of engineered mutations of the OspA and LFA-1a epitopes on arthritis development; nor has it been possible to provoke arthritis in normal recipients by transferring dual OspA–LFA-1a–reactive T cells. HLA-DRB1*0401-transgenic mice injected with OspA responded primarily to the relevant OspA(165–173), but developed no signs of arthritis (or any other autoimmune disease (23) ). This was probably because the corresponding region of LFA-1a differs between mice and humans (29). Another problem is the extensive cross-reactivity that has been shown for T cells reactive to the OspA(164–173) epitope: "supertopes" have been identified via amino acid substitution analysis and used to screen protein databases. Many (475) supertope-matching peptides were found in human or murine proteins and 16 of these could stimulate at least one of seven OspA(164–175)-reactive T cell hybridomas (8). Thus, one must consider the chance of finding some self-peptide epitope that cross-stimulates with OspA purely due to "multiple sampling". A similar point has been made concerning candidate T cell epitopes and epitope mimics in a chronic borrelial disease of the central nervous system (9). A final problem worth mentioning is that certain features of the proposed epitope mimicry scenario remain unsatisfying: for example, there are no clues as to what precipitates an inflammatory response several months after the borrelial infection and no evidence for whether LFA-1a peptides are actually being presented in the joints or, if so, by which APCs.

    A simplistic (almost certainly oversimplistic) alternative scenario that needs to be ruled out is as follows. An OspA(165–173)-directed immune response is made systemically (perhaps, but not necessarily, including the joint). This leads to the production of anti-OspA and overproduction of inflammatory cytokines, in particular TNF-a and IL-1. Antibodies, cytokine effectors or both provoke a self-propagating arthritis that is similar to those reported for different mouse models (30, 31). This could explain the inflammatory joint response in the absence of any evidence of the inciting microbe. In this scenario, dual reactivity of synovial T cells for OspA and LFA-1a is a chance event that merely reflects the impressive degeneracy of TCR recognition of MHC-peptide comp

    (end of this multi-part comment/message)

  6. CO,

    Then there's this:


    Molecular tracking of antigen‐specific T cell clones in neurological immune‐mediated disorders

    Paolo A. Muraro*,1, Klaus‐Peter Wandinger*,1, Bibiana Bielekova1, Bruno Gran1, Adriana Marques3, Ursula Utz2, Henry F. McFarland1, Steve Jacobson1 and Roland Martin1

    which I found very interesting, but I have to leave for a few hours.


  7. Rita,

    You've been busy.

    I have posted your most recent comments and have left the others out for now so readers can see what you've found - I have more to say about your additional comments, but later.

    I may not be able to respond as much as I'd like today as I will be away from the keyboard and have to attend to something else.

  8. Rita,

    Regarding this paper, Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry? - it's from 2001, and the information is a decade old and now outdated.

    In terms of the link to more of the fulltext, the paper I mentioned from 2008, Persistent arthritis in Borrelia burgdorferi-infected HLA-DR4-positive CD28-negative mice post-antibiotic treatment, responded to the need for a better rodent model for how an autoimmune-based arthritis could develop with infecting DR4+/+CD28(-/-)MHCII(-/-) mice with Bb and seeing the outcome.

    I still wonder about the remaining two thirds of those mice with this specific genetic background though: Why didn't they develop arthritis? 38% develop post-antibiotic treatment arthritis, but 62% of the mice do not. Yes, 38% is notable, but the 62% is notable and I want to know why they ended up without arthritis - what sets them apart when they have the same profile?

    I'll have to do some rereading to catch up on the other points mentioned above - I think some of the research that is out there covers them, though I'm not sure if they cover them entirely. Unfortunately I won't be getting around to responding to them tonight as I'm dead tired - but I wanted to let you know I'd taken the time to read through them.

    On another note...

    Here's my thoughts about the sources you cited outside of this thread:

    The positive side of those sources: Good access to old research that is hard or impossible to find online (including copies of original manuscripts and journals), some background notes on the history of various researchers and their patents, and some educational points about certain aspects of microbiology which are interesting.

    The negative side of those sources: Conspiracy theories abound (and not just about Lyme disease), slurs and insults towards various groups of people, overemphasis on specific aspects of Lyme disease (while ignoring others which are important), outdated information (a general problem on a number of Lyme sites - e.g. has Grier written anything new since the 1990s? Please let me know, I've been looking), and a general incoherent style to the writing.

    While there is merit in the positives, I find it hard to link to such sites as resources for others due to the negatives. And while I have no qualms about linking to some sites which may contain material I do not fully agree with in content (I may at some point even write about that which I disagree with and why) - I must put a limit on sources which have this many negatives against them.

    I would be glad to link to such sources in the future if they became more comprehensive, coherently written sites and left the off-color remarks and conspiracy theories on all kinds of topics to someone else - like Jessie Ventura.

    If those who create the sites are serious about the science and providing supporting evidence for it, mentioning personal axes to grind and conspiracy theories is only going to undermine their credibility.

  9. Rita,

    Is there any chance you can repost that comment that you sent from neurotalk at psychcentral? I wanted to post what you'd found that Klempner said which was posted at that link - unfortunately, I cannot find it in my moderation queue now so I need another copy from you. Thank you.

  10. CO,

    Sorry if I forgot to preface the links I sent with an intended comment that they were/are for your personal information as opposed to posting here (for some of the reasons you stated). That also applies to at least one of the links I sent to support my guesses for part 1 of the scavenger hunt (I seem to recall putting it at the very end so it could easily be deleted).

    As far as the questionable links are concerned, some of the scanned pages of articles and books contain interesting information. Although I did my best to find a respectable source for the Klempner quote, the psych central link probably came the closest. I do believe it's the first comment you posted.

    The material contained in the links I sent is most definitely not up to date. I consider it to be of historical value only -- but still interesting because some opinions seemed to change rather suddenly -- and I still haven't figured out why.

  11. Rita,

    One of your links did include a comment that it was for my personal information, but not the other - and they're owned by the same party. So I made the call not to include both.

    In the future if you want to share something with me but hesitate to have it included in a posted comment, please email me at CampOther */at/* gmail.

    In the future, I may end up referring to some of the content posted on such sites without linking to them in order to point out where the content is correct and where it is veering off the path.

    You're right, the Klemnper quote did get posted as the first comment - it wasn't showing up last night, though, and was concerned it went into the giant internet trash can in the sky. I hold Blogger responsible, I guess... it has been a little flaky now and then.

    Re Lyme disease researchers changing their opinion: I've noticed this too. A number of people have. I want to figure out why as well.

    If people have a difference of opinion, I want to know what was persuasive evidence and the milestone moment - or incremental change - which led to their change of opinion. And if it's a scientific opinion which affects the health of many people, I particularly want to know.

  12. Regarding the Klempner quote on the, I am looking for data which shows a relationship between chronic Lyme disease, and tried to find any other research which demonstrates this relationship.

    So far, I've found one Swedish research abstract:Multiple sclerosis immunopathic trait and HLA-DR(2)15 as independent risk factors in multiple sclerosis

    But this is about MS and HLA-DR2, and not Borrelia. And you're right - there is a high correlation between MS and a specific haplotype, specifically HLA-DRB1*1501-DQB*0602. There are a number of papers on this relationship available.

    The implication of this from those speculating is that Borrelia infection is MS or at least leads to MS - but more evidence is needed to establish this. There is also evidence that viral infection may lead to MS. Is this beginning to look like the Alzheimer's disease progression puzzle? Yes, there is similarity.

    There are a number of papers in Medical Hypotheses on the potential connection between Lyme disease and MS, but it's important to note the journal is called Medical Hypotheses. It's a bunch of researchers kicking around at ideas when so far there is no statistically significant data yet. It's a place to do "what ifs". Other journals indicate a movement from the "what if" stage to demonstrating stronger relationships and clearer findings. So I take what I find in Medical Hypotheses for what they are: Interesting ideas, but not developed or researched thoroughly enough yet to bet the house on them.

    There has been discussion in the past several years on the relationship between MS and Lyme disease in part due to a measured upregulation of CXCL13 in the CSF of patients with neuroborreliosis as well as those with MS.

    But there can be an increase in CXCL13 in other conditions (viral, bacteria) as well, and while one can often separate MS CXCL13 levels from those of infection, one has to be cautious not to misdiagnose people based on this marker. In other words, the elevation of CXCL13 in CSF might be a good general indicator for certain infections - but it's not specific enough to point at and say that Bb is the source. Additional clinical information (history, symptoms, other testing) would be needed, which is the same thing needed now to determine if Lyme disease is the cause.

    And unfortunately, from what I can see so far, looking for CXCL13 to determine if someone has Lyme neuroborreliosis is something being studied in early neuroborreliosis - there is very little research for those whose infections may have been undertreated or untreated for a much longer period of time.

  13. I meant to say, "Klempner quote on the above site" at the start of my last comment. Don't know how I left that out - still tired, I guess.

    I want to hear what Klempner himself said, and make sure of what he said regarding odds ratios and p values. There's a possibility that something he said was missed in transcription and it may be important.

    Has anyone who attended his presentation or read about it approached him directly to ask him more about it? Given it's been a number of years since it occurred, he may have other ideas by now about what he said back then, if what he said then was true.

  14. CO,

    Thanks for your e-mail address. I'm glad to have an alternative to cluttering your moderator bin.

    The voice recording of Klempner's statement is somewhere on those dubious links (or another equally dubious site) where I can only visit briefly because of all the "clutter". If I am able to locate it, I'll send you an e-mail. The recording is not the best quality, and without a voice recognition expert or a credible witness who remembers attending the meeting, it's impossible to know if the recording is legitimate or not. Klempner's "alleged" tape-recorded message is actually played during a video-recorded presentation made by that individual -- explaining exactly what I don't remember -- but a flipchart was the centre of attention. Sorry this all sounds so convoluted but it gets a bit awkward when not using names.

    My lack of rest and additional pain from another possible unexplained fracture (it would be my third) is catching up with me, but I did want to mention that I spent considerable time fairly recently in an attempt to find anything new from Tom Grier -- without success. I was able to determine where he last worked (and possibly still does), but I didn't feel it was appropriate to e-mail him to ask if he had written more about Lyme disease. I'm still considering that possibility, however, because a lot of what he has written makes a lot of sense to me. That doesn't mean that he or anyone else is always right (or wrong) as science continues to evolve. It's possible that Tom Grier doesn't even want to think about Lyme disease, never mind write about it given all the controversy -- hence my hesitation.

    There was something I wanted to mention, but I've already forgotten. Time for a brain break, methinks. Oh yes ... it can be extraordinarily difficult to post comments here at times, but I usually persist.

  15. Almost forgot. I've been on the lookout for common pathways between various neurological disorders well before knowing that Lyme disease was an issue for me. MS and neuroborreliosis do seem to have lots of overlap, and since I'm genetically predisposed to (but not necessarily destined to have) MS, this topic is of particular interest to me. I need to take a closer look at the following two articles one day:


    Original Article
    Genes and Immunity (2011) 12, 335–340; doi:10.1038/gene.2011.3; published online 24 February 2011

    A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility

    W S Bush1, J L McCauley2, P L DeJager3, S M Dudek1, D A Hafler3, R A Gibson4, P M Matthews4, L Kappos5, Y Naegelin5, C H Polman6, S L Hauser7, J Oksenberg7, J L Haines1 and M D Ritchie1 the International Multiple Sclerosis Genetics Consortium

    1Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA
    2Miami Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
    3Division of Molecular Immunology, Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA
    4GlaxoSmithKline, Research & Development, Middlesex, UK
    5Department of Neurology, University Hospital Basel, Basel, Switzerland
    6Department of Neurology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands
    7Department of Neurology, School of Medicine, University of California, San Francisco, CA, USA

    "Epistasis or gene–gene interaction has been promoted as an important part of complex disease etiology because of the monumental complexity of biological systems. In addition, when explicitly modeled, it can increase power to detect the independent effects of susceptibility loci.3, 4 However, key challenges of interaction analysis are the biological interpretation of statistical results and the task of resolving functional relationships between variants from multiple loci across the genome. With these challenges in mind, we assessed gene–gene interactions within established biological contexts based on multiple knowledge sources, such as pathway and ontology databases. This analysis implicates several new functionally related MS risk loci, including three interaction effects centered on calcium signaling, representing a neurodegenerative genetic component to MS etiology."


    Genes and Immunity (2004) 5, 197–202. doi:10.1038/sj.gene.6364058 Published online 11 March 2004

    HLA-DQ6 and ingestion of contaminated water: possible gene–environment interaction in an outbreak of Leptospirosis

    J Lingappa1, T Kuffner2, J Tappero1, W Whitworth2, A Mize2, R Kaiser1 and J McNicholl2

    1Division of Bacterial and Mycotic Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
    2Division of AIDS, STD and TB-Laboratory Research, Centers for Disease Control and Prevention, Atlanta, GA, USA

    "Assuming HLA or TNF- play a role in the host response to leptospirosis, population variants (polymorphisms) in these genes may result in significant differences in that response. Genetic studies suggest that HLA and TNF- polymorphisms alter susceptibility to or outcomes from other infectious diseases.13,14 Furthermore, HLA alleles have been associated with chronic complications from Lyme disease,15 another spirochete-associated illness. However, until now the relationship of host genetic polymorphisms to leptospirosis, had not been examined."

    I think there are lessons to be learned even from research that may not apply directly to Lyme disease.

  16. Rita,

    Thanks for further details about the audio tape and transcription, it's good to know. Whether it can be validated or not, I wonder what Klempner says today and why? I really wonder how this 2009 NIAID-NIH book could state what it did about PTCLD without further discussion about what causes PTCLD and its cognitive and neurological symptoms including fatigue.

    Thank you for your efforts in posting comments here. It helps me focus on different issues and lines of inquiry, and I think it adds to the knowledge base of those reading along. Take a brain break though by all means - I can't look at all of this or take it in all the time and I know breaks are needed; the learning curve is steep even in the best of times.

    I'm sorry to hear you might have another fracture. Ouch. What sort of investigation have you done concerning these and what have doctors said? I recommend no parkour and trampoline jumping for you and to rest up. Hope you feel better.

  17. Something to consider from the Columbia University Lyme and Tick-borne Diseases Research Center:

    "MS and Lyme Disease may cause brain and spinal MRI hyperintense lesions. Lyme Disease however more often causes a CSF pleocytosis and elevated protein. In Lyme Disease, evoked potential studies are generally but not always normal. MS patients do not have extra-neural features, as one may often find in patients with neurologic Lyme Disease (arthralgias, arthritis, myalgias, erythema migrans, carditis). Generally with MS, the laboratory studies reveal "abnormal evoked potentials (50%), CSF oligoclonal bands (90-95%), intrathecal IgG production (70-90%), and CSF myelin basic protein." (Coyle, 1992, Seminars in Neurology). If one finds intrathecal production of antibodies against Borrelia burgdorferi in the CSF, then the diagnosis of Lyme encephalomyelitis is confirmed. If one finds elevated myelin basic protein and oligoclonal bands and no signs of intrathecal Lyme antibody production, then the diagnosis of MS is much more likey. A case of a man with an MS-like illness that ultimately proved to be Lyme Disease responsive to antibiotics is described in the following citation: Psychiatric Clinics of North America, v21: 693-703, 1998)"

    Source: FAQ question: How does one distinguish between Multiple Sclerosis and neurologic Lyme Disease?

  18. CO,

    I lost what I keyed in here when Google rudely interrupted to inquire if I wanted to register my phone number with them (no, I do not), so this message might seem a bit scrambled. I will attempt to explain why I'm not certain whether or not I'm dealing with a fracture (although it certainly feels that way).

    Aug 2007: I went to our local ER for foot pain when my walk (already unsteady at times) turned into a limp while just walking. The x-ray didn't show anything, so I was diagnosed with tendinitis. After doing some internet research and later developing a small round bruise over the painful area, I returned to that ER two weeks later, calmly stating that I needed to be reassessed. The repeat x-ray showed the formation of a bone callus -- which is diagnostic of a fracture -- on M2 of my right foot, so I was prescribed a removable cast that I used for about two months. That was honestly the least of my health challenges at the time, but it did make getting around to ER visits and medical appointments a bit more difficult.

    Spring 2009: I reported the same type of pain in my right foot as I had experienced with my fracture in 2007 to the family physician residents I saw at a downtown hospital (as that clinic now serves as my family doctor). Since I was a bit confused, I did not advocate strongly enough on my own behalf. My husband didn't speak up either because he didn't think anyone would be able to walk (however awkwardly) with a broken foot -- although he should have known better given my 2007 experience.

    Fall 2009: After dismissing my complaints for months, one resident finally broke down and ordered an x-ray -- revealing a healing/healed M3 fracture in my right foot. It was considered too late for me to benefit from a cast even though I believe it might have relieved some of my pain.

    Aug 2011 (this past Monday): I suspect that my walk to see a dentist for an emergency appointment last Friday may have triggered a stress fracture. With arthrodesis (surgical fusing of bones) already required in the 1st MTP joint of my left foot, the additional/different pain prompted me to go my local ER for earlier diagnosis and possible treatment (having learned from 2009). The ER doc instructed me to return to the ER in 2 weeks for a repeat x-ray because he couldn't see a fracture. He suspects I have another fracture and recommended a bone scan, but he doesn't have the authority to order one. Given my past experiences, any family physician resident likely wouldn't order one, so I'm not going to put the additional strain on my foot by going downtown to even ask.

    Aside from that, the surgeon who will eventually be operating on my left foot is the Chief of Orthopedics at our local hospital. Any imaging (x-rays, etc) on my left foot is best done there so he can see the status of bones/joints in that foot -- and maybe even figure out why my bones keep breaking for no good reason(s). Mild Osteonecrosis (bone damage most often resulting from a lack of adequate blood supply to bones) was noted as far back as 2007, but I only found that out about a month ago. I'm not impressed that no one at the time told me about it or bothered to follow up on that finding. As you might be able to tell, I am not a happy camper right now.

    CO, I will follow your advice, and refrain from using a trampoline and doing any other acrobatics/gymnastics until I get the all clear. :)

  19. Rita,

    Man, that sounds like quite the run around. I'm sorry you're going through this. I would think they would have given you a bone scan already - if not at least an MRI of your feet. MRIs can detect chemical changes in the bone marrow and catch problems early - unlike CT scans and X rays (which expose you to radiation).

    I'm guessing your surgeon will want to do an MRI before surgery, so as to get a better idea of what's going on. Did he say if he was going to do a bone graft on it or are you getting an implant? When do you plan to get the surgery done?

    I wouldn't be too impressed that they hadn't told you about the osteonecrosis back in 2007 when they first made a note of it and done something about it then.

    I hope they can do something for you sooner rather than later even on provincial health - I imagine there's a time limit to how long they can make you wait, especially if you are in pain or lose mobility?

  20. Rita,

    I found online what is supposed to be an audio recording of Klempner's presentation which included the statements posted in the transcription. There is no doubt that if it is him, he did say "odds ratio of 770%" for DQB0602.

    Still, I want to know more about this and what he thinks today.

  21. CO,

    I completely agree that an MRI of my feet would be more than justified at this point, and especially after reading this:


    Clin Radiol. 2004 Dec;59(12):1079-93.

    MRI of osteonecrosis.

    Osteonecrosis is a relatively common condition, which may be idiopathic or secondary to a variety of clinical situations. It may involve the subarticular region of a joint, when it is commonly referred to as ischaemic necrosis, or the metaphyseal regions of long bones, when it is referred to as bone infarction. In both situations, early lesions may be radiographically occult. However, magnetic resonance imaging (MRI) is very sensitive in identifying and characterizing osteonecrosis. This review illustrates the varied MRI features of osteonecrosis that enable a confident diagnosis to be made. Complications and differential diagnosis are also considered.

    (end quote)

    My Infectious Diseases specialist made the referral to the orthopedic surgeon this May after reading the results of x-rays he ordered in March. The ID doc considers the ortho doc to be the best in his field when it comes to foot surgery. Being Chief of Orthopedics partially accounts for the year and a half wait even though my ID doc told me an arthrodesis is the only treatment after reviewing the results of the x-rays. My balance (and lots more) had improved considerably with antibiotic treatment, but I still can't stand very long or walk properly partly due to pain in both feet and an inability to bend my big left toe -- which is why the x-ray was ordered. It remains to be seen what the orthopedic surgeon will recommend since some surgeons may steer clear of doing elective surgery on a person with fragile bones given that it could potentially make things even worse. I must admit to being slightly discouraged because I have watched my health deteriorate over much of the past decade -- albeit with a dramatic improvement after being treated by my mainstream ID specialist (from August 2010 to March 2011).

    There has been a concerted effort over the past few years to reduce the wait times for hip and knee replacement surgery, and that campaign has been largely successful. One of the publicly unacknowledged consequences has been longer wait times for other types of elective orthopedic surgery. A person's pain and lack of mobility may be taken into consideration -- but only once they are seen by an orthopedic surgeon. Even if I had an MRI done tomorrow, it wouldn't change anything unless I needed emergency surgery -- which I don't. On a more positive note, I have great faith in the orthopedic surgeon I'll be seeing because of his excellent reputation and having met him very briefly in 2007. He has the blend of technical proficiency and people skills that is harder to find in medical professionals these days, so I consider him to be worth the wait (as long as it may sound).

    With specialists in no fewer than 6 hospitals, I am now regrettably a good example of just how fragmented healthcare has become for some patients. There's certainly lots of room for improvement, and I want to contribute to making things better for everyone, but it's often difficult to know how best to do that.

    p.s. Did you get the e-mail I sent? I would also like to know more, and it's very possible that Klempner's statement was a bit premature since it was apparently based on only 51 patients when he made it. The study that was subsequently published (and probably based on many more people) demonstrated only a slightly increased incidence of people with HLA DQB1*0602.

  22. Rita,

    I just read your email, and I apparently independently found the recordings from the same source listed.

    I've come to the conclusion that his statement was a bit premature given additional research I've read, if I'm to take this one at face value:

    Association between Human Leukocyte Antigen Class II Alleles and Genotype of Borrelia burgdorferi in Patients with Early Lyme Disease
    Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776636

    If you read this (and I've looked at Web of Science and Scopus for citing papers - not much there), then in the end the conclusion is that the data are inconclusive. No one knows if there is a relationship between specific haplotypes and post-treatment persisting symptoms, and there is mention for a need for more research.

    Not seeing further research conducted on this thus far, I can only assume no one is pursuing it and/or another avenue of research is being pursued related to this.

    Excerpts from this research, emphasis in bold mine:

    "The immunologic event that might account for an association between carriage of the DRB1*0101 allele and infection with certain genotypes of B. burgdorferi is unclear. The observation that all but 1 of the patients infected with RST3 strains who carried the DRB1*0101 allele were heterozygous for this allele makes alteration in antigen presentation by this molecule an unlikely explanation. Rather, the association between the DRB1*0101 allele and infection with certain genotypes may be a marker for other genetic factors (e.g., polymorphisms in HLA class III genes) relevant to the host defense against B. burgdorferi. The critical role that complement plays in the innate immune response to B. burgdorferi [17] suggests the potential relevance of variants in major histocompatibility complex–encoded complement genes (complotype) in linkage disequilibrium with DRB1 alleles [18]."

    "Intriguingly, DRB1*0101 is also a principal allele associated with antibiotic treatment–resistant Lyme arthritis [23]. Whether the identical associations in infections with RST3 strains and antibiotic treatment–resistant Lyme arthritis can be linked biologically or are mere coincidences will need to be determined through further research."

  23. Additional excerpt from conclusion area of the last research paper commented on - should have been posted earlier:

    "In the 95 patients with Lyme disease who were recruited from the northeastern United States by Klempner et al. [14], the carriage rate of the DRB1*0101 allele was 12.6%. The genotypes of the infecting strains of B. burgdorferi were unknown in the Klempner et al. study, but, presumably, some of the patients were infected with RST3 strains.

    Nevertheless, the carriage rate of the DRB1*0101 allele was significantly greater in the patients infected with RST3 strains in the present study, compared with that in patients with Lyme disease in the study by Klempner et al. (9/25 vs. 12/95; P = .015) [14]*.

    A statistical adjustment for multiple comparisons is controversial in studies evaluating associations between infectious diseases and HLA haplotypes and alleles [25, 26], and no adjustment was performed in the present study. Because the strength of the observed genetic associations may be relatively modest (OR usually <2) [27], if an adjustment is made, researchers run the risk of overlooking true associations. Consequently, our results should be interpreted cautiously in the absence of confirmation by other investigations."

    * Paper #14 is the Klempner study from 2005 which is mentioned upstream, A case-control study to examine HLA haplotype associations in patients with posttreatment chronic Lyme disease.

    Is there anything about this disease that is not controversial or couldn't be made to be controversial in some way?

    The interesting thing is they're making a connection between RST3 genotypes and this haplotype - over half of the people on the east coast are supposedly infected with RST1 OspC Type A infections, if I recall correctly, and they are virulent and disseminate quickly. Invasive. RST3 is usually a far less invasive strain, but you can get a specific type which is pretty invasive hematogenously speaking (RST3 Type I) that supposedly shows up more frequently in people with a specific haplotype.

  24. Further research is no doubt required to determine whether or not there really is an association between treatment-resistant Lyme arthritis and specific haplotypes/alleles.

    Given all the patients just in the U.S. (because Lyme arthritis seems to occur more frequently in North America), one could reasonably assume that a large volume of data has already been collected from patients with Lyme arthritis. I think it's also more than likely that not every person with Lyme arthritis has has their HLA typing done and recorded in a national database.

    Patients obviously move from time to time, and others get lost to follow-up studies for other reasons (like death), however the good thing about HLA is that it remains constant for any given person. If someone were curious and motivated enough -- and provided with adequate funding -- it wouldn't take much effort to collect some basic genetic information for analysis purposes. Collecting the data would require identifying qualified Lyme disease patients (past or present), assuring them their confidential information would not be shared with insurance companies, and asking them if they would be willing to participate in research that would contribute to a better understanding of Lyme disease. If the person agreed, they could be mailed a test kit including instructions for doing a simple cheek swab which could then be returned in a self-addressed, postage-paid envelope. It wouldn't be a glamorous research project by any means, but it just might provide some useful data and finally answer the question of whether or not treatment-resistant Lyme disease is more closely linked to certain HLA types than others.

    I realize that's a rather simplistic proposal, but it could potentially answer only one of many, many outstanding questions when it comes to Lyme disease.


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