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 184.108.40.206 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.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.
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."
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
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