Good Read David
Misfolding is interesting but based on my reading it misses the role of ERAP 1(used to be called ARTS1).
In the model that Dr Brown from Australia is chasing the ERAP 1 is the point where AS begins and there is no misfolding by HLA B27. Dr Brown believes and has unpublished data saying that IL23R influences AS susceptibility, severity, age of onset. This data will answer John's question and the mechanism is sound. He has applied for a patent on a blood test to predict the severity of AS based on variants of IL 23.
Here is his idea on the mechanisms of AS. (gotta love those australians in research)
ARTS1, now ERAP1, alters peptides, may explain link between B27 and AS
The other important new finding is the association between the gene ARTS1 and AS. This gene mediates peptide trimming within the endoplasmic reticulum to the best length for major histocompatibility complex Class I presentation. It also cleaves cell surface receptors for IL-1, IL-6, and TNF.
"The strong association with susceptibility to disease suggests that IL23/IL23R targeted therapies may even be capable of disease prevention, a particularly exciting potential."—Matthew A. Brown, MD.Changes in the first function of ARTS1 would be expected to alter HLA-Class I peptide presentation, and AS is primarily an HLA-Class I mediated autoimmune disease. More than 90% of AS patients have the HLA-B27 allele. Loss-of-function changes in the second function of ARTS1 would be expected to increase the inflammatory effects of the proinflammatory cytokines and of TNF."
Source:
http://www.mskreport.com/articles.cfm?articleID=2701ERAP 1and IL 23R is where the spondylitis association research is driving now
