Friday, August 19, 2011

13 More on Genetic Haplotypes and Lyme Arthritis

So, the more I read, the more unanswered questions there are. Staying on top of all the latest research becomes a job in itself.

Earlier this week, I posted a variety of papers which showed a potential (according to the authors, statistically significant) relationship between haplotype and the development of chronic Lyme arthritis.

Then my attention was drawn to this 2008 paper, and I realized I shouldn't have stopped at papers in 2007 before writing my post about genetic haplotypes...

Human Homologues of a Borrelia T cell Epitope Associated with Antibiotic-Refractory Lyme Arthritis

Source:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2075570

Abstract

Antibiotic-refractory Lyme arthritis, which may result from infection-induced autoimmunity, is associated with HLA-DR molecules that bind an epitope of Borrelia burgdorferi (Bb) outer-surface protein A (OspA165−173) and with T cell reactivity with this epitope. One potential mechanism to explain these associations is molecular mimicry between OspA165−173 and a self-peptide.

Here, we searched the published human genome for peptides with sequence homology with OspA165−173. The two peptides identified with the greatest sequence homology with the OspA epitope were MAWD-BP276−288, which had identity at eight of the nine core amino acid residues, and T-span758−70, which had identity at six residues. MAWD-BP mRNA was expressed by synoviocytes, while T-span7 mRNA was not. However, neither peptide bound all of the HLA-DR molecules associated with antibiotic-refractory Lyme arthritis. Among 11 patients, nine had T cell reactivity with OspA161−170, six had responses to MAWD-BP276−288, and three had reactivity with T-span758−70, but reactivity with the self-peptides was lower than that induced by the spirochetal epitope.

Thus, there remains an association between OspA165−173 and antibiotic-refractory Lyme arthritis, and infection-induced autoimmunity is an attractive hypothesis to explain this outcome. However, molecular mimicry due to sequence homology between OspA165−173 and a human peptide seems unlikely to be the critical mechanism.



I suppose I have to keep reading more research?

What's the present model for the cause of chronic Lyme arthritis these researchers are supporting again?

13 comments:

  1. The conclusion from the above paper states the following two points:

    One:

    "Approximately 60% of HLA-DRB1*0401-positive patients with either antibiotic-responsive or antibiotic-refractory arthritis initially had increased frequencies of OspA165−173–reactive T cells (Kannian et al., 2006). These responses tended to be higher in antibiotic-refractory patients than in antibiotic-responsive patients. However, the frequencies of OspA165−173–reactive T cells declined to baseline levels in both refractory and responsive patients within weeks after the initiation of antibiotic therapy, months before the resolution of arthritis in the refractory group. Thus, since some antibiotic-refractory patients did not develop a response to OspA and since this response declined after antibiotic therapy, these results argue against molecular mimicry with OspA165−173 as a critical mechanism in antibiotic-refractory Lyme arthritis."

    and

    Two:

    "[...] in refractory patients, these inflammatory responses remained high or even increased in the post-antibiotic period, though reactivity with borrelial proteins declined (Shin et al., 2007). The idea that an autoantigen may continue to drive this highly inflammatory immune response after spirochetal killing remains an attractive hypothesis. Thus, similar to the situation with IDDM and coxsackie virus, our current model is that OspA165−173 (or other currently unidentified borrelial epitopes) may cause exceptionally high inflammatory responses in genetically susceptible individuals, and this response might serve as a bridge to activate autoreactive T cells that recognize a non-OspA related self-epitope."

    So, as far as the authors of this paper are concerned, the current model for chronic Lyme arthritis is still based on this hypothesis that OspA causes very high inflammation levels in some people and somehow that triggers T cells which (mistakenly) recognize some part of people's cells as being OspA-like.

    Well, here we are again. Another autoimmune model.

    ReplyDelete
  2. I'm not currently seeing the argument to support this model at the moment, by the way.

    If "the frequencies of OspA165−173–reactive T cells declined to baseline levels in both refractory and responsive patients within weeks after the initiation of antibiotic therapy, months before the resolution of arthritis in the refractory group" then what is driving the arthritis in the refractory group?

    ReplyDelete
  3. Forgive me if this has already been mentioned, but I think it's relevant. There seems to be shift toward (re)considering the pathogenicity of Bb strains when it comes to a couple of factors:

    http://onlinelibrary.wiley.com/doi/10.1002/art.24812/abstract

    Analysis of Borrelia burgdorferi genotypes in patients with lyme arthritis: High frequency of ribosomal RNA intergenic spacer type 1 strains in antibiotic-refractory arthritis

    Kathryn L. Jones, Gail A. McHugh, Lisa J. Glickstein, Allen C. SteereArticle first published online: 29 JUN 2009

    DOI: 10.1002/art.24812

    Abstract
    Objective
    Most of the Borrelia burgdorferi genotypes have been isolated from erythema migrans (EM) skin lesions in patients with Lyme disease. OspC type K strains, which are 16S–23S ribosomal RNA intergenic spacer type 2 (RST2) strains, are most commonly recovered, but a higher percentage of OspC type A strains (RST1), the next most commonly recovered type, is detectable in blood. The goal of this study was to determine the B burgdorferi genotypes in the joints of patients with Lyme arthritis.

    Methods
    Joint fluid samples from 124 patients seen over a 30-year period were analyzed for OspC types by semi-nested polymerase chain reaction (PCR) and sequencing, and for RSTs by nested PCR and restriction fragment length polymorphism analysis. These results were correlated with clinical outcome.

    Results
    OspC and RST genotypes were identified in 49 of the 124 joint fluid samples (40%). In these 49 samples, OspC type K strains (RST2) were identified in 21 samples (43%), OspC type A strains (RST1) were identified in 11 samples (22%), and 8 other OspC types and all 3 RSTs were identified among the remaining 17 samples (35%). However, among the 17 patients who had been treated with antibiotics according to current guidelines, all 7 patients who were infected with RST1 strains had antibiotic-refractory arthritis, compared with 4 of 6 patients infected with RST2 strains and only 1 of 4 infected with RST3 strains (P = 0.03).

    Conclusion
    Most of the B burgdorferi genotypes, particularly OspC type K (RST2), were identified in the joint fluid of patients with Lyme arthritis, and the genotype frequencies found in joints reflected those in EM skin lesions. However, RST1 strains were most frequent in patients with antibiotic-refractory arthritis. Our results help to further the understanding of the differential pathogenicity of strains of B burgdorferi.

    From the (free) full article:

    http://onlinelibrary.wiley.com/doi/10.1002/art.24812/pdf

    "Thus, a marked inflammatory response, such as that induced by RST1 strains, may set the stage for joint inflammation that persists after spirochetal killing, particularly in patients with the HLA–DRB1*0401 or *0101 alleles (26) and immunoreactivity with OspA (39–42). In summary, our results add to the emerging literature concerning the differential pathogenicity of strains of B burgdorferi (5,7,16–18). In the current study, most of the B burgdorferi genotypes infected the joints of patients with Lyme arthritis, and genotype frequencies in joints reflected those in EM skin lesions. However, RST1 strains, which appear to be more virulent, were most common in patients with antibiotic-refractory arthritis".

    CO, it looks like Dr. Steere still believes (at least as of 2009) that a combination of factors may contribute to treatment-resistant Lyme arthritis.

    There's something more I want to post that supports my theory that there has been a shift to considering the virulence of the Bb strain in a couple of ways.

    (to be continued ....)

    ReplyDelete
  4. (...continued)

    http://www.ncbi.nlm.nih.gov/pubmed/21829670

    PLoS One. 2011;6(8):e22926. Epub 2011 Aug 4.

    Biodiversity of Borrelia burgdorferi Strains in Tissues of Lyme Disease Patients.

    Brisson D, Baxamusa N, Schwartz I, Wormser GP.

    Biology Department, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

    Abstract

    Plant and animal biodiversity are essential to ecosystem health and can provide benefits to humans ranging from aesthetics to maintaining air quality. Although the importance of biodiversity to ecology and conservation biology is obvious, such measures have not been applied to strains of an invasive bacterium found in human tissues during infection. In this study, we compared the strain biodiversity of Borrelia burgdorferi found in tick populations with that found in skin, blood, synovial fluid or cerebrospinal fluid of Lyme disease patients. The biodiversity of B. burgdorferi strains is significantly greater in tick populations than in the skin of patients with erythema migrans. In turn, strains from skin are significantly more diverse than strains at any of the disseminated sites. The cerebrospinal fluid of patients with neurologic Lyme disease harbored the least pathogen biodiversity. These results suggest that human tissues act as niches that can allow entry to or maintain only a subset of the total pathogen population. These data help to explain prior clinical observations on the natural history of B. burgdorferi infection and raise several questions that may help to direct future research to better understand the pathogenesis of this infection.

    PMID: 21829670 [PubMed - in process] PMCID: PMC3150399 Free PMC Article

    CO, I haven't looked at the full article, but doesn't this seem to imply that Bb is now viewed as being more complex than originally thought? If so, could this mark the beginning of a fresh look at things? One can only hope.

    ReplyDelete
  5. Rita,

    It's been a long day here, and I need to get some sleep.

    Check out my comment on the previous post I made on Tuesday - see the last paragraph.

    I've read a number of studies about different strains of Bb ss, Bb sl, and Borrelia in general. Absolutely, strain makes a difference in disease progression and symptoms. I wish the research would talk more about the difference in neurotropic behavior between the strains and not only hematogenous spread. But it's clear from research done to date that some strains disseminate more quickly than others - and I'd like to know which of those are more likely to enter immune-privileged locations.

    Bb is more complex than originally thought and new things are being learned about it all the time. Within the microbiology world it's already known as somewhat of an oddball bacteria. It does a number of the same things other bacteria does - but it does those things differently. And in a number of ways, it is unique.

    Sometimes I think that Burgdorfer's "30 years of nothing" quote is about the fact that some research went on full steam ahead without looking at more general pathogenesis questions being answered earlier on - that once certain technologies were made available that could dissect Bb in a way that it could be profitable, answers were selectively honed in on from that angle. Putting the cart before the horse may be an apt phrase here? But I don't know - I wish Burgdorfer had been more specific about the statements he made during his interview rather than be International Man of Mystery.

    ReplyDelete
  6. " These results suggest that human tissues act as niches that can allow entry to or maintain only a subset of the total pathogen population."

    This isn't new information, by the way. It's been known for years.

    ReplyDelete
  7. CO,

    I agree that none of this information is especially new given all the research that supports the persistence of infection theory, however that knowledge doesn't seem to be reflected in the current IDSA guidelines for treating Lyme disease. Unless I'm mistaken, there seems to be a recent and subtle shift by some researchers (Steere and Wormser in this case) away from the theory that persistent signs and symptoms can only be autoimmune in nature. Despite all the research efforts to prove the autoimmune theory (which may even apply in a subset of LD patients), that hasn't been very fruitful in terms of improving treatment methods.

    It certainly seems that at least some of the research has been influenced by the need to test out new technologies. While new "toys" may be fun to acquire -- and no doubt necessary for the advancement of science -- basic building blocks (like believing patients and treating them with respect) should never go out of style.

    The existing IDSA guidelines don't seem to fully take into account the diversity among strains of Bb or that the location of spirochetes matter as far as diagnosis and treatment is concerned. The information about the biodiversity of Bb may not be new, but it is the first time it is being publicly acknowledged according to Wormser and his co-authors. This, and other statements just like it, are getting a bit old: "These data help to explain prior clinical observations on the natural history of B. burgdorferi infection and raise several questions that may help to direct future research to better understand the pathogenesis of this infection".

    I believe Burgdorfer could have, and should have, clarified his statement about the lack of progress in Lyme disease research. If he had useful knowledge, he should have shared it with people who could have made a difference instead of making vague statements in an interview. No one person has all the answers, but everyone with any relevant information about Lyme disease holds one or more pieces of the puzzle. Withholding information of any kind seems inexcusable to me, but then again there are patents and professional pride at stake. This is a reality that applies to much more than Lyme disease.

    Back in the 1960's, my father designed and made a small medical device that was first tested in dogs at McGill University before being refined for use in humans. This device was not patented (at least not by my father), and although he could have used the money, he refused any remuneration because he was so honoured at being able to use his technical knowledge to create something that might help others. Some people these days might find that laughable, but I'm proud that my father taught me at least some of what really matters in life.

    It was the acknowledgement by Steere and Wormser -- rather than the information about strain virulence and the biodiversity of Bb -- that seemed relatively new to me.

    ReplyDelete
  8. CO,

    Sorry -- I forgot to mention that I did in fact read the last part of your post in part 1 before including the link to the 2009 published article co-authored by Steere. My best guess was that the RST quotes you provided near the end of part 1 came from this 2005 article, and you did mention something about the need to continue looking at subsequent research.

    Association between Human Leukocyte Antigen Class II Alleles and Genotype of Borrelia burgdorferi in Patients with Early Lyme Disease

    Gary P. Wormser,1 Richard Kaslow,3 Jianming Tang,3 Karen Wade,4 Dionysios Liveris,2 Ira Schwartz,2 and Mark Klempner5

    The 2009 article co-authored by Steere seemed to confirm at least some of the findings by Wormser, Klempner and others in 2005. Even though it's good to have confirmatory research by replicating previous results, in this case it also implies that nothing much had changed in four years.

    In light of your comments, I'm now wondering how Wormser and others could even imply that biodiversity of Bb (at least from a strain virulence point of view) was a revolutionary way of looking at Lyme disease in 2011.

    ReplyDelete
  9. Rita,

    You said,

    "The existing IDSA guidelines don't seem to fully take into account the diversity among strains of Bb or that the location of spirochetes matter as far as diagnosis and treatment is concerned."

    This is true, but I don't think that the research which demonstrates that different Bb genotypes lead to faster dissemination via the blood and their differences in symptom presentation were something the guidelines were intended to present.

    One thing they'd be looking to do is try to find common ground between what all the strains/genotypes do so that the guidelines could be standardized and testing could be standardized. That's what guidelines are supposed to do: Set up some consistent set of standards.

    The guidelines were originally intended to be treatment guidelines that catered to some most common denominators for the majority of patients. As in, in this one document, what is going to be the most likely case for the average patient who walks in the door who obviously has Lyme disease?

    I think that is where breaks down, though... Because the average treatment for the majority of early cases may not be adequate for all patients - and clearly isn't even for early cases because even the guidelines authors themselves state that up to 10% of early cases lead to treatment failure.

    In other words, I don't think it's supposed to be a comprehensive document about all aspects of Lyme disease presentation in patients. As long as it is, it's still only intended to be more like Cliff's Notes - the rest of the data used would be obtained by reading ongoing studies until the guidelines are updated again.

    "The information about the biodiversity of Bb may not be new, but it is the first time it is being publicly acknowledged according to Wormser and his co-authors."

    What do you mean by "publicly acknowledged"? That it's part of an abstract to make such a statement?

    "This, and other statements just like it, are getting a bit old: "These data help to explain prior clinical observations on the natural history of B. burgdorferi infection and raise several questions that may help to direct future research to better understand the pathogenesis of this infection". "

    I agree they are getting old. I'm wondering how much this statement (and ones which are similar) are just meant to state that they have been collecting clinical observations and have speculated about them but don't have enough evidence to support their speculations as being more solid hypotheses - or if they have some fairly solid hypotheses, but developing a way to address them remains to be seen.

    (more)

    ReplyDelete
  10. (For Rita - continued - more)

    "Withholding information of any kind seems inexcusable to me, but then again there are patents and professional pride at stake. This is a reality that applies to much more than Lyme disease."

    I think it isn't just about patents which are already in the pipeline. It's also about patents that are in early development. I also think that some parties do not want to report their findings and they remain unpublished until they have determined a method for addressing certain problems. It can be a matter of "we found this issue first, and it's important to solve, and we have an inkling of how to solve the issue - but in describing the issue, we leave the door open to other institutions to get a head start on developing a treatment/solution for it and to be highly competitive, we can't share the issue yet."

    "Back in the 1960's, my father designed and made a small medical device that was first tested in dogs at McGill University before being refined for use in humans."

    Your father sounds like an interesting guy and an honest guy.

    "It was the acknowledgement by Steere and Wormser -- rather than the information about strain virulence and the biodiversity of Bb -- that seemed relatively new to me."

    If you read more of their research, they acknowledge it there. It has been there for a while - I think that they've been trying to figure out what elements are common to all the genotypes, though, to make testing by volume more efficient and also to be able to develop vaccines which target a common denominator across strains.

    This was part of the thinking behind developing the C6 test. It's supposed to test for the major Bb strains from the US and Europe. It focuses on detection of antibodies which are supposed to show up very early in infection and catch more cases earlier.

    This doesn't address those with late stage Lyme disease so much, though - or I don't see the direct benefit to them, except where earlier detection and treatment prevents more untreated late stage cases.

    Somewhat of a side note here...

    Earlier in my fight with Lyme disease I found out there were people within my support network who would refuse to look at anything these guys had written just because of who they were and what they had said about chronic Lyme disease and patients.

    While I was not happy with what they said, I thought that not looking at their work was a problem - it's important to know what all the sides have published and said, what they know, and what evidence they were likely to bring to the table to support their perspective.

    This particularly became more important as we edged closer to the 2009 guidelines review panel, but I noticed some people were still not looking at the counterarguments or how those arguments would or could be framed/presented.

    The interesting thing about the controversy is in a number of cases, both sides refer to the Same Exact Research Publications but interpret the content within them differently. And it's within those interpretations, I think, that one has to look for what's really going on... Where is that difference coming from, and is there anything new which has been said which stands out from the rest of the argument?

    ReplyDelete
  11. Rita said,

    "In light of your comments, I'm now wondering how Wormser and others could even imply that biodiversity of Bb (at least from a strain virulence point of view) was a revolutionary way of looking at Lyme disease in 2011."

    Yes. Exactly.

    ReplyDelete
  12. CO,

    Your question (in italics):

    What do you mean by "publicly acknowledged"? That it's part of an abstract to make such a statement?

    I'm not sure if I completely understand your question, but I do think researchers communicate to a large extent through their published work. I was referring to what was written in the both the abstract and the full text of the article.

    The C6 peptide test was certainly a welcome improvement as it has provided some patients in Canada with a diagnosis, but it's still not foolproof by any means (as you suggested) according to an article I came across recently:

    http://www.ncbi.nlm.nih.gov/pubmed/17234451

    Int J Med Microbiol. 2007 Feb;297(1):45-52. Epub 2007 Jan 17.

    Immune responses to borrelial VlsE IR6 peptide variants.

    Sillanpää H, Lahdenne P, Sarvas H, Arnez M, Steere A, Peltomaa M, Seppälä I.

    Department of Bacteriology and Immunology, Haartman Institute, FI-00014 Helsinki, Finland.

    "Thus, antibody specificity to IR(6) peptides may vary according to the infecting Borrelia species. In some manifestations of the disease, C6 ELISA may not cover all LB cases".

    I agree that guidelines are intended to be recommendations based on the majority of cases as opposed to covering every possible clinical scenario. On the other hand, most mainstream doctors don't have the time or interest to learn enough about Lyme disease to stray from guidelines, and especially not when it might jeopardize their ability to practice medicine (according to a few doctors I've spoken to).

    Although I don't think the IDSA guidelines should be expected to address Bb strain diversity in great detail (as in a different treatment for each strain), I do think a clear statement that treatment response may vary for reasons that are not yet clearly understood is more than justified.

    Yes, I know. Dream on.

    ReplyDelete
  13. CO,

    I have also come across people who now reject out of hand anything said or written by certain individuals -- and especially if they had anything at all to do with establishing the IDSA treatment guidelines. That is an unfortunate situation -- not least because it doesn't allow that person to consider more than one point of view.

    Even if I may not agree with what any given individual or group believes, I do my best to understand why they think what they do. It may not change my opinion, but I will often develop respect for someone who takes the time to fully explain their position. My respect grows if that individual then asks me why I believe what I do. This happens so rarely that it always surprises me when it does because people generally can't get past the disagreeing part. I'm guessing that's how most wars get started.

    ReplyDelete

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