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Posted By: DavidP Enthesis Organ Concept in SpA - 01/08/10 12:41 PM
See
http://www.ncbi.nlm.nih.gov/pubmed/19371620

I've transcribed most of the conlusion from this article below.

Concluson
The historical view on the immunopathogenesis of ankylosing spondylitis and the related spondylarthropathies was that an unknown “arthritogenic” peptide derived from somewhere within the joint, most probably the synovium was presented to the T-cells. This culminated in joint inflammation and especially synovitis at sites such as the synovial part of the sacroiliac joint. However, we think that there is evidence for a unifying biomechanical, rather than an autoimmune basis for disease, since inflammation localizes to sites of high mechanical stress as indicated by the presence of fibrocartilage. Therefore, enthesitis, adjacent osteitis, and synovitis and even fibrocartilaginous joint disease can be viewed in a different light – and the enthesitis organ concept is central to a clear understanding of these pathologies.

We would emphasize that the sites to which disease localizes is SpA are also sites of microdamage. This is especially pertinent given the recent claims that the innate immune system is involved in SpA. Of course the innate immune system is involved in all inflammatory reactions. However there is no compelling evidence, thus far, that genetic polymorphisms in innate immune-related receptors play a role in ankylosing spondylitis in particular or SpA in general. It is more likely that innate immune activation occurs in normal and appropriate manner at sites of tissue microdamage that is best exemplified by insertions. Indeed an increasing number of damage associated molecular patterns, that would be anticipated at sites of microdamage (where they can initiate innate immunity) have now been identified. Furthermore, viable microbes may not be necessary to trigger innate immunity and the presence of microbial products at an enthesis could be sufficient to lead to disease initiation via the activation of Toll-like receptors and other pattern recognition receptors. This offers a simple explanation for the failure to incriminate viable microbes in SpA.
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What then has the enthesis organ concept told us about SpA? Perhaps its greatest value is that it rationalises the diffuse nature of entheseal pathology, especially the location of bone oedema and synovitis and makes sense of the seemingly disparate symptoms with which patients may present.
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My notes
Bits of some particular gut bacteria are being presented to the enthesis by T-cells. A NSD must be having a probiotic effect and reducing the amount of that particular microbial bit that is available. IL 23 might help present more or less of the offending bit depending on whether you get the protective allele or a disease associated allele of IL23.

A rather profound paper!!
One point I can relate to is that the load carried by the tendon or ligament at an effected ethesis (damaged joint) may be dissipated over a wide area to another point of attachemnt which then itself becomes effected. Eg Elbow bursitis can be relayed by loading of forearm muscles to cause an enthesitis in the knuckle.
Posted By: DavidP Re: Enthesis Organ Concept in SpA - 01/08/10 07:29 PM
If I can extend my line of thinking a step further.
Lets for a minute accept that Kleb pneumoniae is the causative microbe of AS and the SpA in general.
Are the Klebs causing an infection as we might normally think?
Well NO. Klebs unlike Salmonella Shigella Campylocbacter etc lack receptors that allow them to attach to gut lining cells and initiate infection and a cause response by the body to gut tissue dammage.
Instead the Klebs just sit in the gut waiting for some starch to come along so they can multiply (they are 'normal flora' just like in any normal non-B27 person).
The abberant HLA B27 molecule (bear in mind that some B27 subtypes actually are protective against AS) means that a cascade is initiated that results in short peptide bits of the microbe being presented in enthesial microdamaged joints. The result is SpA instead of the normal repair of the micro tears that happens for non-B27 people.
Posted By: jroc Re: Enthesis Organ Concept in SpA - 01/08/10 11:45 PM
Interesting stuff. Keep it coming. Would you be able to recheck the link? Its taking me to a pubmed article on "Effects of nickel, chromate, and arsenite on histone 3 lysine methylation."
Posted By: Sue22 Re: Enthesis Organ Concept in SpA - 01/08/10 11:49 PM
Originally Posted By: jroc
Interesting stuff. Keep it coming. Would you be able to recheck the link? Its taking me to a pubmed article on "Effects of nickel, chromate, and arsenite on histone 3 lysine methylation."


same here!
Posted By: inkyfingers Re: Enthesis Organ Concept in SpA - 01/09/10 01:00 AM
Try this:

http://www.ncbi.nlm.nih.gov/pubmed/19731...mp;ordinalpos=1

Sorry - dunno how to do tinyurls...
Posted By: Dow Re: Enthesis Organ Concept in SpA - 01/09/10 01:19 AM
"Sorry - dunno how to do tinyurls..."

tiny url dot com
Posted By: DavidP Re: Enthesis Organ Concept in SpA - 01/09/10 01:24 AM
I'll try again, this time using my eyes
http://www.ncbi.nlm.nih.gov/pubmed/19731620

Cheers David
Posted By: DavidP Re: Enthesis Organ Concept in SpA - 01/09/10 01:50 AM
If I can extend the argument one step further.
AS and the SpA's in general are probably preceeded by an episode involving a breach in the integrity of the gut lining, such as a bacterial gastroenteritis, re Salmonella etc in Reactive Arthitis (also a SpA). Interestingly some RE's are triggered by a non-gonococcal urethritis caused by Chlamydia trachomatis and C. trachomatis has been implicated by some researchers as having of 'bit'that could be taken up some of the disease causing subtypes of B27 molecules.

The gut is a wonderful thing. When the gut lining is in tact there should be no immune response directed against the friendly gut flora which should be considered as more than just commensal micro organisms. Rather, there is a symbiotic (mutually beneficial) relationship between the gut flora and the host. Between 300-1000 different species, half of which can't be grown on conventional media and hence haven't been identified live in the gut. They are mostly anaerobes and constitute 60-90 dry weight of faeces - see Wikipedia Gut Flora.
An E coli in the bladder is a pathogen and attacked but in an intact gut it should not be attacked by the immune system. Something in AS causes the gut to remain leaky as many of us know if we stray from the NSD - and this probably drives the progression of the disease.

Cheers again David
Posted By: Sue22 Re: Enthesis Organ Concept in SpA - 01/09/10 01:58 AM
thanks louise and david,

that looks like the right paper now!
Posted By: jroc Re: Enthesis Organ Concept in SpA - 01/09/10 02:14 AM
Perhaps zonulin could be driving the leaky gut cycle in AS like it does in celiac disease - http://www.eurekalert.org/pub_releases/2000-04/UoMM-Rfiz-2804100.php

"Besides CD, increased IP has been reported in other autoimmune diseases, including T1D (11), systemic lupus erythematosus (37), and ankylosing spondylitis (38), further delineating the importance of the paracellular pathway in the pathogenesis of autoimmune diseases. These findings, together with the observation that zonulin is overexpressed during the acute phase of several immune-mediated diseases and its blockage prevents the onset of the autoimmune response, suggest that zonulin contributes to the pathogenesis of these conditions, opening previously undescribed paradigms in the pathobiology and treatment options of immune-mediated diseases."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2744629/
Posted By: DavidP Re: Enthesis Organ Concept in SpA - 01/09/10 06:51 AM
One last idea.
The spine as a whole could be viewed as giant enthesis organ so that in conventional AS, as inflammation slowly crept upwards from the initiating point at the SI joints, attempting to fuse each vertebrae in upwards direction, the longitudinal ligament would be progressively inflamed, altered and shortened such that over time the thoracic spine would be pulled forward into familiar hyper-hyper kyphosis!
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