HLA-DR alleles determine responsiveness to Borrelia burgdoferi antigens
Bettina Panagiota Iliopoulou, Mireia Guerau-de-Arellano, and Brigitte T. Huber. Arthritis Rheum. 2009 December; 60(12): 3831–3840.
The authors of this particular paper wrote up their own informative article, Sometimes It's All In Your Genes with descriptions of their project for the layperson. I highly recommend reading it, as it is an educational and easily readable description of their research in greater detail from the perspective of the researchers themselves.
In the above study, researchers experimented with mice who have the genetic profiles of HLA-DR4 (which is related to developing arthritis) and HLA-DR11 (which is predicted to clear spirochetes quickly).They infected both groups of mice with Borrelia burgdorferi and monitored their ability to clear spirochetes and develop signs of arthritis.
According to the researchers, mice with HLA-DR4 alleles produced lots of interferon gamma and very few antibodies to the spirochete - whereas those with HLA-DR11 alleles produced lots of antibodies but no interferon gamma.
Interferon gamma = Produces LOTS of inflammation, which hurts and sucks.
Very few antibodies = Nothing much to fight off the infection.
Lots of antibodies + No Interferon gamma = Fight off infection while having little or no inflammation.
When you look at the paper itself, this is of particular note:
"We found that DR11 tg mice mount a vigorous Ab response, but are defective in IFN-γ production. In addition, Bb-infected DR11 tg mice had decreased spirochete burden compared to DR4 tg mice, measured by qPCR of Bb DNA. This is in contrast to DR4 tg mice, which produce an inflammatory response characterized by high level of IFN-γ production, in accordance with our published results (10). Furthermore, the Ab response to Bb-antigens was significantly lower than that of DR11 tg mice, which is consistent with the higher spirochete burden observed in DR4 tg mice after Bb-infection. Thus, our data provide a possible explanation for the differential regulation of the immune response in DR4+ and DR11+ patients upon Bb-infection; namely, HLA-DR4 would predispose individuals to chronic Lyme arthritis by generating an inflammatory milieu to Bb-infection, while HLA-DR11 would exert a protective role through the production of anti-spirochetal Abs."So, to review, in this study:
HLA-DR4 mice have a significantly lower antibody response to Bb antigens compared to HLA-DR11 mice.
HLA-DR4 mice have a significantly higher inflammatory response (measured as Interferon gamma or IFN-γ ). (It sounds as if HLA-DR11 has no real inflammatory response.)
HLA-DR4 mice have a significantly higher spirochetal load compared to HLA-DR11 mice.
If you look at figure 5b & c (if I'm to read the caption properly based on the full text) the amount of spirochetal DNA present in an ear punch sample was twice as high in the HLA-DR4 mice compared to the HLA-DR11 mice, and the amount of spirochetal DNA present in the joints appears to be about 6 times higher in HLA-DR4 mice compared to the HLA-DR11 mice.
That's a huge difference.
To add to this, the study also immunized two groups of mice with these alleles with rOspA and found out that:
HLA-DR4 mice mount a poor response to rOspA.
HLA-DR11 mice mount a strong antibody response to rOspA. They have a good humoral response.
So upon learning this, of course there are more questions:
- How does this study apply to humans with Lyme arthritis?
- How does this study apply to humans with post-treatment chronic Lyme disease?
- How does this data relate to findings in the recent Alaedini paper about those with post-treatment chronic Lyme disease having had infections for a long time (and Alaedini's speculations about different antibody responses and a possible need for more aggressive treatment)?
- How does this data relate to Steere's study suggesting an additional month of antibiotic treatment is needed for some patients with Lyme arthritis?
(Re:"Patients with Lyme arthritis were treated with oral antibiotics for one or two months, and in those for whom the arthritis did not resolve, IV antibiotics were administered for an additional month. If they had persistent arthritis despite three months of antibiotics, patients were treated with non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs).")
- How does the existence of more virulent and quickly disseminating RST of Bb affect hosts which are HLA-DR4 versus HLA-DR11?
- What kind of mice were studied in this recent study by Barthold et al?
- Is there a reason found here as to why some people experience relief with longer courses of antibiotics? Is it because they just don't have an immune response needed to clear the infection but antibiotics both help keep infection under control plus act as an anti-inflammatory in the presence of interferon gamma?
So much to think about here, tying these studies together.
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