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Joined: Sep 2007
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DavidP Offline OP
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Th17 cells serve a very important function in anti-microbial immunity at epithelial / mucosal barriers.

http://www.pharmalive.com/News/Index.cfm?articleid=737763

Recently it has been shown that the differentiation of a subtype of Th17 cells, here called Th17(23) cells, can occur in the absence of TGF-Beta1 signalling by the combination of IL-6 and IL-1Beta with IL-23. These Th17(23) cells are more active in promoting autoimmunity compared with the other subtype of Th17 cells, called Th17(Beta) cells that are generated with IL-6, IL-1Beta and TGF 1Beta. The two subtypes are thought to be functionally different since Th17(23) cells provoked significantly more severe disease in the mouse model autoimmune condition Experimental Autoimmune Encephalomyelitis (EAE) than Th17(Beta) cells.

Since there are genetic associations between AS and the receptors IL-1R2 and IL-23R, this article supports the hypothesis that Th17 / IL-17 axis is crucial to AS.


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
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More evidence pointing to IL 23 and IL 17. Starting to look very solid to me anyway that IL 23 and IL 17 drugs would be very effective in treating AS.

Have you thought about Stelara?


No families take so little medicine as those of doctors, except those of apothecaries.

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Hi David
I went to the AS annual seminar at the Austin Hospital last week. They mentioned that Dr Matt Brown's research was currently exploring
IL-1A (to the power of 3)
CYP2D6 and
HLA-B60 (to the power of 2)
You and Drizz seem to understand the genetic side of things better than anyone else here. So just though I'd mention it to you as another link to look out for...
Regards
Felicity

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DavidP Offline OP
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Hi Drizzit,

Just when we thought that Th17 cells were important in AS this paper sugests that Th1 cells (derived from precursor Th17 cells) are the pro-inflammatory cell type in human autoinflammatroy disease.

http://bloodjournal.hematologylibrary.org/cgi/content/full/114/11/2213

Studies in mice initially suggested Th17 cells are pathogenic cells in autoimmune disorders, whereas Th1 cells may behave rather as protective. Subsequent studies in humans demonstrated the plasticity of Th17 cells and their possibility to shift to Th1. The plasticity of Th17 to Th1 cells have recently been confirmed in mice, where it was found that Th17 cells seem to be pathogenic only when they shift to Th1 cells. Studies in humans also showed that Th17 cells are different than in mice because all of them express CD161 and exclusively originate from CD161+ precursors present in umbilical cord blood and newborn thymus. While murine Th17 cells develop in response to IL-6, IL-1 and TGF-Beta, human Th17 cells originate from these CD161+ precursors in response to IL-1Beta and IL-23, the need for TGF-β being controversial.

This is interesting because Th1 cells produce large quantities of IFN-γ (and TNF) and are essential for the clearing of intracellular pathogens by mediating cellular immunity (=innate immunity); maximising the killing potential of macrophages and causing the proliferation of cytotoxic CD8+ T cells.

Regard David

In relation to Stelara, no I can't consider it, I'm not bad enough and Celebrex can control my symptoms. I would have to fund Stelara myself if I wanted to go down that path.


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
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DavidP Offline OP
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Hi Felicity,

Thanks for that info.

CYP2D6 (Cytochrome P450 2D6) - I've never heard of it.
Maybe they are interested because they have hits on the Genome wide studies. CYP2D6 is on Chromosome 22q13.1 but as far as I know this isn't listed as a significant loci in AS.

B60 might be of interest because it might be operating like B27 for B27- AS sufferers.

Cheers David


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
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DavidP Offline OP
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CYP2D6 is apparently involved in the metabolism of drugs.
I imagine they are interested in it as a predictor or whether or not people will respond or not to the biologics, that is whether the body will metabolise and break down the drugs quickly or slowly - thus defining drug efficacy in a given patient?


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
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Very_Addicted_to_AS_Kickin
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here, this may help:

http://hmg.oxfordjournals.org/content/9/11/1563.full

other papers too, if one googles "CYP2D6 spondyloarthropathy" but most require subscription to access.

apparently there is a link to CYP2D6 polymorphisms and spondyloarthropathy.

i am HLAB27 negative, appear to have undiff spondy rather than AS, and have suspected that i was a "poor metabolizer" when it comes to this P450 based on my inability to process codeine (when given codeine, it knocked me out, but had absolutely no analgesic affect what so ever. years later when reading about CYP2D6 polymorphisms, i felt like i was reading about myself.)

interesting, i wonder if this is my link: CYP2D6 mutations and undiff spondy. wonder what exactly the connection is?

as for which P450(s) metabolize the biologics? just some quick googling, appears to be other P450s. that's good news for me!

also it was interesting to see that tramadol also processed by CYP2D6. doctor handed me a script for it, same day as handed the script for LDN, so never took the tramadol. good thing, sounds like it wouldn't have done me much good based on my lack of response to codeine. doctors never inquired about this. so in future if i am ever not on LDN and need a pain reliever, though things like codeine or tramadol may be safer than some of the stronger narcotics out there, wouldn't do me much good. good that the question of CYP2D6 has come up again; i had no idea about its action upon tramadol. so that in itself is useful information for me.



sue

Spondyloarthropathy, HLAB27 negative
Humira (still methylprednisone for flares, just not as often. Aleve if needed, rarely.)
LDN/zanaflex/flector patches over SI/ice
vits C, D. probiotics. hyaluronic acid. CoQ, Mg, Ca, K.
chiro
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no dairy (casein sensitivity), limited eggs, limited yeast (bread)
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Very_Addicted_to_AS_Kickin
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in this link as well, see table 4:

http://emedicine.medscape.com/article/332945-overview

wonder though how a defect in a P450 could be associated with spondyloarthropathy?



sue

Spondyloarthropathy, HLAB27 negative
Humira (still methylprednisone for flares, just not as often. Aleve if needed, rarely.)
LDN/zanaflex/flector patches over SI/ice
vits C, D. probiotics. hyaluronic acid. CoQ, Mg, Ca, K.
chiro
walk, bike
no dairy (casein sensitivity), limited eggs, limited yeast (bread)
Joined: Jan 2008
Posts: 21,346
Likes: 2
Very_Addicted_to_AS_Kickin
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another interesting link:

http://www.ncbi.nlm.nih.gov/omim/124030

paragraph pertinent to AS:

Other Disease Associations

Brown et al. (2000) performed a linkage study of chromosome 22 in 200 families with ankylosing spondylitis (AS; 106300)-affected sib pairs. While homozygosity for PM alleles was found to be associated with AS, heterozygosity for the most frequent PM allele (CYP2D6*4) was not associated with increased susceptibility to AS. Significant within-family association of CYP2D6*4 alleles and AS was demonstrated. Weak linkage was also demonstrated between CYP2D6 and AS. The authors hypothesized that altered metabolism of a natural toxin or antigen by the CYP2D6 gene may increase susceptibility to AS.

the last line suggests the possible link between CYP2D6 and AS. though i still wonder the exact mechanism of action?

Last edited by Sue22; 10/26/10 10:13 AM.


sue

Spondyloarthropathy, HLAB27 negative
Humira (still methylprednisone for flares, just not as often. Aleve if needed, rarely.)
LDN/zanaflex/flector patches over SI/ice
vits C, D. probiotics. hyaluronic acid. CoQ, Mg, Ca, K.
chiro
walk, bike
no dairy (casein sensitivity), limited eggs, limited yeast (bread)

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