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Dr Trevor Marshall
Foundation Staff
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Posted: Wed Oct 11th, 2006 12:14 |
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WARNING - This video contains occasional images of dissected mice and pieces of organs. If you think you might not be able to handle this, please do not watch the Video
Those of you who have watched my presentations at FDA and LAX would have noticed me saying that a functioning VDR nuclear receptor is critical to the immune system's bacterial response, and noting that VDR transcribes the genes for the Cathelicidin and beta-Defensin antimicrobial peptides (see video on Crohn's I posted on 9 Oct 2006).
But I also mentioned that VDR transcribes genes for the Toll-Like Receptor 4(TLR4), and TLR2, essential for the innate immune system to fight the intra-cellular bacteria. These are signalling molecules, present in the outer surface of phagocytes, and also believed to exist in the cytoplasm and nuclear membrane.
This presentation from the 2006 Host Defenses conference at UCSD, by Professor Vinetz of UCSD, shows how important TLR4 competence really is - this single gene makes the difference between a dead mouse, and a mouse who survives without overt distress from the disease.
When you ingest exogenous Vitamin D then your VDR's ability to transcribe these TLR genes is reduced, and I am sure you can all 'fill in the blanks' from there
The video is in Real Video 9 format, is 27 megabytes (38 minutes) long, and it can be downloaded by right-clicking here, or it can be viewed in streaming presentation by clicking on this link:
http://autoimmunityresearch.org/tlr4.ram
Enjoy
ps: Mice, like the TLR4 deficient mouse shown here, can now be bred without single, or multiple genes. These are called "knock-out" or gene 'KO' mice. Intact or 'Wild-Type' mice are often termed 'WT' or 'intact.'
Where the animals can be made to suffer from a disease, the ability to knock out precise genes is an incredibly powerful research tool. You can see that the TLR4 -/- mouse who died had grown normally, and was no doubt enjoying a 'normal' life before it was challenged with the pathogen...
pps: "TLR4 plays a crucial role in .. control of leptospiral burden during sublethal chronic infection" see:
http://iai.asm.org/cgi/content/full/74/2/887?view=long&pmid=16428731
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jrfoutin
Research Team
| Joined: | Tue Aug 9th, 2005 |
| Location: | Oregon USA |
| Posts: | 3931 |
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Offline
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Posted: Wed Oct 11th, 2006 16:41 |
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In the introduction of the IAI published paper, a massive well-known but somewhat missed clue (but not by Dr Marshall) is shown in the requirement of immunosuppresive treatment with steroids, which had been used in the past to enhance or enable disease reproduction in animal tests:
Infection of mice and rats to reproduce human disease has been inconsistent, often requiring immunosuppressive treatment with drugs such as cyclophosphamide or corticosteroids (1, 2, 19, 24).
This speaks to TH1 pathogenesis as we know it (D is steroid) and in related yin/yang presentation slide:
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CENTRAL ISSUES IN INFECTIOUS DISEASES
What determines the outcome of an infection?
- Host defense *
- Pathogen virulence
- Infectious dose
What is the role of innate vs acquired immunity
in limiting infectious burden, hence disease
pathogenesis?
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*TLR4 defense to leptospirosis is subject of presentation, but principle applies to Th1 (pathogen diseases).
I also enjoyed the late summer slide for Brazil hospital increase in leptospirosis cases. Also the discussion about animal models, with "humans best models to study human disease" and the highlight showing the role of systems biology/genomics to molecular/cellular mechanisms of pathogens.
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Sarcoidosis 125D61, MP10/05 ModP2 12/05 Ph2 6/06 Ph3 10/06, NoIRs limited outings covered, 2/08 25D6.2, 10/08 25D6.9
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Dr Trevor Marshall
Foundation Staff
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Posted: Wed Oct 11th, 2006 18:10 |
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Janet,
Note also the increased incidence in the urban populations, where mothers get pre-natal vitamins, and the babies' "nutrition" would be more carefully tended than in the rural areas.
There was one more presentation of great interest, but I muffed the recording of that (I'm breaking in a new camcorder that works well in the low light of meeting rooms). This presentation showed quantitative data of pathogenic species being passed from mothers to newborns. I will dig up the cited papers and start a new topic to discuss that, however, it was exactly what I have been looking for...
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