Kickas.org Forums Treatments, Drugs and Alternatives NSD and diet-related; B27 Misfolding and SpA

HLA-B27 is a MHC Class I molecule. The Major Histocompatibility Complex (MHC) is a large genomic region of 3.6Mb (3.6 million base pairs) situated on the short arm of chromosme 6 and it contains upwards of 140 genes, most having immune or related functions.

MHC Class I genes encode peptide binding proteins that are expressed on all nucleated cells. The molecules consist of an α chain and β2microglobulin (not part of MHC) and present ligands (antigen fragments of 8-10 amino acids long, usually virally derived or ‘self’) to T-cells via CD8 receptors on cytotoxic T-cells and also bind inhibitory receptors on Natural Killers cells. NK cells are cytotoxic lymphocytes, different from B and T lymphocytes and are part of the innate immune system.

The synthesis of HLA B heavy chains, their assembly with β2microglobulin and the loading of the trimmed peptide (ligand) cargo occurs in the endoplasmic reticulum (ER) before being transported to the cell surface. It should be noted here that the gene that encodes for ERAP1 (endoplasmic reticulum aminopeptidase 1, which is a zinc metallopeptidase that is a trans-membrane protein localised to the ER which functions to trim antigenic peptides prior to their binding to MHC Class I molecules, thereby affecting antigen presentation to cytotoxic T lymphocytes) has been implicated in the disease susceptibility to AS.

One of the more unusual properties of the HLA-B27 heavy chain when compared to those of other HLA-B alleles, is its tendency to misfold in the ER with the implication that the spondylarthropathies may belong to a rapidly expanding category of protein misfolding disorders.

Misfolded proteins that accumulate within an effected cell can be toxic and may elicit a cellular response referred to as the Unfolded Protein Response (UPR). Issues regarding the specificity and affinity of the ligand for the peptide binding groove of the B27-β2m complex may be important in relation to the tendency toward UPR.

In the gastrointestinal tract, a low level immune response to bacterial colonization could result in interferon (IFN) and/or natural killer lymphocyte (NK) activation. This would result in up-regulation of MHC Class I expression and, in cells expressing HLA-B27, activation of the UPR. Macrophages would then in response to Toll Like Receptor (TLR) agonists like lipopolysaccharide (LPS, which are endotoxins derived from the outer membranes of Gram Negative bacteria, such as Klebsiella pneumoniae) and other bacterial products, be polarized towards the increased production of interferon and Interleukin 23 (IL-23) and possibly IL-6. IL-23 would then drive IL-17 production form CD4 T-cells that have become committed to the Th17 (T-helper17) cell lineage. And here it should be noted that the polymorphism of the gene encoding IL-23R, the receptor for IL-23 has also been implicated in AS disease susceptibility.

Th17 cells may have evolved as another arm of the adaptive immune response for enhanced protection against extracellular bacteria (eg, Klebsiella pneumonia). What has become very clear is that Th17 cells play a crucial role in chronic inflammation in auto inflammatory diseases such as RA, MS, IBD, psoriasis, uveitis and the SpA’s.

Cells with the capacity to produce IL17 are normally present in the colon. Thus, in the unique mucosal environment of the gut, increased IL23 expression could be sufficient stimulus to establish a chronic gastrointestinal inflammation that is the primary lesion in the group of inflammatory diseases collectively referred to as the spondylarthropathies.

I believe that this paper could be interpreted as providing some sort of scientific basis that would underpin the putative benefits of a No Starch Diet by denying the possibly causative bacteria a substrate and thus limiting their ability to proliferate in the gut, In effect, a NSD could be seen as a probiotic disease modifying anti-rheumatic therapeutic treatment for the SpA’s.

The original article can be viewed in all its complexity, in PDF format, at
http://www.landesbioscience.com/journals/prion/article/8072/

Regards David

Unfortunetaly computer said NO
#945 = alpha
#945 = beta

Tried to be too clever by half and insert different character set for alpha and beta

David

Hey, David:



At least they speculate on how a disease process could happen...but I would not bet my AS on any of this; not only does DIET help reduce symptoms but also the right antibiotics!

Mis-folding has been talked about for years but they cannot answer the questions adequately. Questions like WHY does the average age of onset peak at ages 16-23? If mis-folding were involved wouldn't the disease process begin at birth?

John

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=2701

ERAP 1and IL 23R is where the spondylitis association research is driving now

Here is a crazy read on HLAb27 and the theories on AS

INteresting read that goes along with some of the reads you have been posting

http://www3.interscience.wiley.com/cgi-bin/fulltext/120082121/HTMLSTART

Obviously, the exact cascade of events is a long way off being fully elaborated.
Clearly, antibiotics active against a causative bacteria, or perhaps a group or Family of Bacteria with some characteristic cell wall or cell membrane, would be effective in controlling that given bacteria/bacterias.

Reactive Active arthritis could serve as a template for the SpA's. RE does not commence at birth, it has a disease process that is triggerd by a preceeding infection, often gastrointestinal diarrhoea involving Salmonella / Shigella / Yersinia or Campylobacter or urethtitis due to Chlamydia trachomatis. Chlamydia are known obligate intracellular bacteria and the others are thought to be facultatively intracellular, that is, capable of replicating intracellularly by having by-passed host defences within the phagosome. Here B27 might be contributing to their ability to evade the host immune defenses.

In any event, a triggering event may cause a 'naive' CD4 cell to become a committed T helper cell line that ultimately allows for the line clonal expansion of a B cell lineage, complete with memory, that produces specific antibodies against a similar (cross reacting) bacteria.

The last paragraph that you quoted back to me was not the authors but my interpretation of the implications that could follow from their paper.

I'm sure they are doing their best - the whole field is incredibly complex and it's my feeling that no possibility can be overlooked until a more complete resolution of the disease pathogenesis is made.

Thats some heavy reading. Good article though. Thanks

Here is a good read on ERAP 1 and AS

An interesting quote in the discussion session:
"In addition to 14 known coding polymorphisms, we identified three novel coding variants in ERAP1, two of which were observed only in AS patients. Finally, we found six new associations with SNPs in ERAP1 with AS, and many additional markers by imputation which are possible candidates for the causative variant(s) in this gene."

frankly I think we are getting close to the variants causing AS. But who knows for sure.

Source:
http://hmg.oxfordjournals.org/cgi/content/full/18/21/4204

Hi Drizzit,
I did make reference in my original post to ERAP1 and it's peptide trimming capabilities. Clearly ERAP1 allelic polymorphism might contribute to variable functionality and to AS susceptibility, but I'm not sure that this would invalidate the theory that B27 heavy chain misfolding might play a critical role in the development of AS.
They did state that B27 heavy chain misfolding preceeded association with Beta2microglobulin and ligand binding but their contention seemed to be that it did not prevent assembly of the B27-Beta2m-ligand complex.
"High stability of the tri-molecular complex is critical for efficient transport through the Golgi apparatus, a long half life on the cell surface and ultimately a productive immune response."
Misfolding they contended compromised the stability of the trimolecular complex and therefore may have caused ER stress which might ultimately lead to the Unfolded Protein Response (UPR).

Thanks for replying to my post
Regards David

SUre is a lot of work going on and that is a good thing. The second point is the one that got my attention on presenting the info to HLA

Here is another good read on ERAP1 triggering the whole process

Another link on what ERAP does in our immune system

What is the normal function of the ERAP1 gene?
The ERAP1 gene (also known as ERAAP and ARTS1) provides instructions for making a protein called endoplasmic reticulum aminopeptidase 1. As its name suggests, this protein is active in a cellular structure called the endoplasmic reticulum, which is involved in protein processing and transport. This protein is an aminopeptidase, which is an enzyme that cuts (cleaves) other proteins into smaller fragments called peptides.

Endoplasmic reticulum aminopeptidase 1 has two major functions, both of which are important for normal immune system function. First, endoplasmic reticulum aminopeptidase 1 cleaves several proteins called cytokine receptors on the surface of cells. Cleaving these receptors reduces their ability to transmit chemical signals into the cell, which affects the process of inflammation.

Second, endoplasmic reticulum aminopeptidase 1 cleaves many types of proteins into small peptides that can be recognized by the immune system. These peptides are exported to the cell surface, where they attach to major histocompatibility complex (MHC) class I proteins. MHC class I proteins display the peptides to the immune system. If the immune system recognizes the peptides as foreign (such as viral or bacterial peptides), it responds by triggering the infected cell to self-destruct.

Source
http://ghr.nlm.nih.gov/gene=erap1