Kickas.org Forums Ankylosing Spondylitis General Discussion #1 AS Web Support Group Diff btwn TNF Responders and Non-Responders

Evelyn, thank you for clarifying that. My eyes are always slightly less crossed when you've explained things than they are when I try to read an abstract or some other medical paper.

So, given the information that Paul initially posted about the genotype and efficacy of biologics, is it necessarily an easy jump to the idea that if the AS/Reactive Arthritis has a genetic ... ah crap, my brain just turned to mush. It's hot and sunny outside and end of month inside and my brain developed a tic. I guess I'm trying to see if there's any corelation between the research that Paul posted and genetic factors to these diseases.

Many hugs,

Oh yes Kat, to my understanding, you and Paul both have interpreted his original postings correctly. My understanding is that the abstract does indeed have to do with gene variations between people, in a region of the TNF alpha gene called the promoter. The promoter, usually found upstream of the coding region of a gene, is a "non-coding" region of the gene, but it serves a very important gate-keeper function. The job of a gene's promoter region is to allow certain proteins called "transcription factors" to bind, and these in turn will influence how actively that gene is "transcribed" (that is, copied into "messenger RNA". Messenger RNA in turn is "translated" into the specific protein that the gene encoded). Variations in a promoter will not influence the sequence of the protein ultimately made through transcription/translation, but variations in the promoter COULD conceivably influence how transcription factors bind, and thereby COULD influence how much of that protein (the gene product) ultimately gets made. This is greatly simplified, but it is the gist.

see also:
http://www.ncbi.nlm.nih.gov/entrez/query...t_uids=16446172
Aguillon JC, Cruzat A, Aravena O, Salazar L, Llanos C, Cuchacovich M.
Could single-nucleotide polymorphisms (SNPs) affecting the tumour necrosis
factor promoter be considered as part of rheumatoid arthritis evolution?
Immunobiology. 2006;211(1-2):75-84. Epub 2005 Dec 27.
PMID: 16446172
"..The -308 TNF SNP is a mutation that affects the promoter region of the TNF gene. It defines the TNF1 and TNF2 alleles, determining low and high levels of TNF expression, respectively. The presence of the TNF2 allele has also been linked to increased susceptibility to and severity in a variety of autoimmune and inflammatory disorders, including RA, systemic lupus erythematosus, and ankylosing spondylitis. Studies on the functional significance of -308 SNP have detected higher levels of TNF production by cells from TNF2-carrying individuals than cells from TNF1 individuals. .."


As for its association with AS/SpA's - there is a mixed literature, with some folks reporting association of variations at this gene promoter position with AS/SpA (like the abstract just above suggests), but others do not find any association. No clear picture emerges.

I don't see how this would distinguish primary AS from reactive arthritis though

Link to Kimball's BIology page on promoters:
"Promoter Region of DNA, usually on the 5' side of a gene, that is needed for the initiation of the transcription of that gene. RNA polymerase and other transcription factors bind to the promoter."
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Promoter.html


Best to enjoy that lovely summer weather!

time to get that sunlight!

What if you don't have the HLAB27 gene? What impact does all this have then? I'm on Enbrel and have been responding wonderfully for a little over a year now. Just curious.

Thanks...That paper you found on the connection to TNF expression really neatens things up!


I hope someone is looking at therapies targeted against the promoter (but maybe the side effects of such a drug would be even worse than those of the anti-TNF drugs).

And as far as Kat's comments go, I remember reading somewhere that TNF is one of the body's main defenses against influenza -- although I suppose that TNF gone crazy might be bad in influenzas that kill via cytokine storm.....

Well, as I understand it, as long as whatever process is causing AS in you has TNF-alpha in the inflammatory cascade, Enbrel and its friends will work :-).

TNF seems to turn up in a lot of places where you wouldn't really expect it...but then I'm not a biologist, just a patient with a web browser--and my day job involves sounding like an expert after reading one to four web pages about any of a variety of esoteric subjects.

Hi Paul, I believe you are on the right track on the question of ability to deal with viruses

Here are a couple of links re:TNF alpha having a role in immunity against viral infection:

http://www.ebmonline.org/cgi/content/full/223/3/241
Herbein G, O'Brien WA.
Tumor necrosis factor (TNF)-alpha and TNF receptors in viral pathogenesis.
Proc Soc Exp Biol Med. 2000 Mar;223(3):241-57. Review.
PMID: 10719836
"...TNF and TNFR usually have been considered as a main component of antiviral activity, often acting synergistically with IFN-gamma[interferon-gamma]..."

http://www.jem.org/cgi/content/full/186/9/1591
Ruby J, Bluethmann H, Peschon JJ.
Antiviral activity of tumor necrosis factor (TNF) is mediated via p55 and p75 TNF receptors.
J Exp Med. 1997 Nov 3;186(9):1591-6.
PMID: 9348317

http://www.pnas.org/cgi/content/full/98/21/12162
Trevejo JM, Marino MW, Philpott N, Josien R, Richards EC, Elkon KB,
Falck-Pedersen E.
TNF-alpha -dependent maturation of local dendritic cells is critical for activating the adaptive immune response to virus infection.
Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12162-7. Epub 2001 Oct 2.
PMID: 11593031

http://jvi.asm.org/cgi/content/full/76/3/1071
Seo SH, Webster RG.
Tumor necrosis factor alpha exerts powerful anti-influenza virus effects in lung epithelial cells.
J Virol. 2002 Feb;76(3):1071-6.
PMID: 11773383



ON a related note, it is known that HLA class one molecules (HLA B27 is one form of this HLA class one ) do participate in host defense against viruses, and HLA B27 provides superior protection against certain viruses.

ON HLA B27 and immunity to viral infection:

https://www.kickas.org/ubbthreads/showthreaded.php?Cat=0&Number=192210&page=&vc=1

https://www.kickas.org/ubbthreads/showthreaded.php?Cat=0&Number=88038&page=&vc=1

my apologies for any broken links in these older posts

Good find Paul, interesting article, though not without a little mistake. I often wonder how critical those peer reviewers are actually. This is however a mistake with no impact just makes things a bit unclear. Somewhere in the article is written that the amount of average responders is 44 (n= 44). However as you can see there are only 54 + 10 + 22 = 86 patients. As there are also 59 good responders (exclusively G/G)and 5 non responders this would make a total of 108 patients. The sum would be correct if there were 22 average responders as further on the article correctly shows when the average responders are divided in A/G type (18/22) and G/G type (4/22).
But let me stop searching for nails at low tide as a Dutch proverb says. What this research shows is that a clear distinction can be made between responders and non responders on a molecular basis. Apparently the promoter region for TNF determines if TNF blockers are likely to work or not. It is however difficult to make further conclusions but it is sure there is no inflammational disease without a role for TNF. There are more cytokines then TNF that have inflammatory activity, some increase inflammation some even decrease inflammation. It is tempting to think that in these cases that the TNF promoter has no role one of the other cytokines takes over the role of inflammation enhancer.
Gerard

Yup. Next time you ask "why me?" remember your genetics worked well for your ancestors.
There is a certain rare group of people who are very resistant to the AIDs virus and I am very curious if they are positive for HLA-B27.

HLAB27 has been reported to be protective re: HIV/AIDS progression
Link to Gerard's (wishing well's) old post:
https://www.kickas.org/ubbthreads/showthreaded.php?Cat=0&Number=181836&page=