User:Pdeitiker/Prolamin sandbox

• Already mentioned- gliadin resistance to extensive proteolysis, refine by mentioning 25mer and 33mer.
• yes-Increased epithelial permeability allows longer peptides into villi (secondary sources)
• I want this - other gliadin peptides appear to cause this permeability (one primary source)
• maybe - deficiencies in the cells of CD patients are also permissive (not a prolamin issue).
• yes - innate peptide stimulates mononuclear cells[(MNCs)]
• maybe - mention innate stimulates gamma-delta lymphocytes (those increase IELs, thats them)
• yes - MNCs make IL15
• no - IL15 does 6 additional listed things-not here, too much.
• no - IL15 behaves like IL2 or IL12-not here, too much.
• yes - that [IL15] prime[s] immune response for destruction of villi.
• yes - that the [conversion to coeliacs] proceeds with DQ-presented gliadin peptide.

Gluten immunochemistry

• 1 Innate immunity
  • 1.1 Alpha gliadin 31-43
    • 1.1.1 Intraepithileal lymphocytes and IL15
• 1.2 Infiltrating peptides
• 2 HLA Class I restrictions to gliadin
• 3 HLA-DQ recognition of gluten
  • 3.1 HLA-DQ2.5
    • 3.1.1 DQ2.5 and alpha gliadin
    • 3.1.2 Alpha-2 gliadin
    • 3.1.3 DQ2.5 and gamma gliadin
    • 3.1.4 DQ2 and glutelins
  • 3.2 DQ2.2 restricted gliadin sites
  • 3.3 HLA-DQ8
• 4 Antibody recognition

Gluten sensitivity

• 1 Causes of gluten sensitivity
  • 1.1 Gluten toxicity
  • 1.2 Immunochemistry of glutens
• 2 Separating forms of Gluten sensitivity
• 3 Gluten-sensitive enteropathy
• 4 Idiopathic gluten sensitivity
  • 4.1 Neuropathies
  • 4.2 Other conditions
• 5 Gluten-allergy related sensitivities
• 6 Comparative pathophysiology

<-------------------------Scratch pad^ -------------Proposed changesV------------------------>

This is a proposal for the change in the prolamin section along with references.

Prolamins

Illustration of the innate peptide and CXCR3 sites on α-9 gliadin

The majority of the proteins in food responsible for the immune reaction in coeliac disease are the prolamins. These are storage proteins rich in proline (prol-) and glutamine (-amin) that dissolve in alcohols and are resistant to

proteases and peptidases of the gut. One region of α-gliadin stimulates membrane cells, enterocytes, of the intestine to allow larger molecules around the sealant between cells. Disruption of tight junctions allow peptides larger than 3 amino acids to enter circulation. Membrane leaking permits peptides of gliadin that stimulate two levels of immune response, the innate response and the adaptive (T-helper cell mediated) response. One protease resistant peptide from α-gliadin contains a region that stimulates lymphocytes and results in the release of interleukin-15. This innate response to gliadin results in immune system signaling that attracts inflammatory cells and increase the release inflammatory chemicals.

Illustration of deamidated α-2 gliadin's 33mer, amino acids 56-88, showing the overlapping of 3 varieties of T-cell epitope.

The strongest and most common adaptive response to gliadin is directed toward a α2-gliadin fragment of 33 amino acids in length. The response to 33mer occurs in most coeliacs who have a DQ2 isoform. This peptide, when deamidated by tissue transglutaminase, has a high density of overlapping T-cell epitopes. This increases the likelihood that the DQ2 will bind and stay bound to peptide when recognized by T-cells. Similarly sized epitopes have been found on γ-gliadin. Gliadin in wheat is the best-understood member of this family, but other prolamins exist and hordein (from barley), and secalin (from rye) may contribute to coeliac disease. However, not all prolamins will cause this immune reaction and there is ongoing controversy on the ability of avenin (the prolamin found in oats) to induce this response in coeliac disease.

Notes: Van Heel and West mention proteases "such as pepsin and chymotrypsin" (p.1041) however the original text of the Prolamin section implies these were the only two, so these were removed because gliadin peptides resistant to proteases, trypsin is a gut protease. This is an instance of trying to use only secondary references while trying to avoid a direct quote gets one in trouble. Van Heel covers to a very minor degree other gliadins, it is useless as a reference, the paper by Shan et al. (freely available manuscript) does a far better job. I recommend replacing VanHeelWest (the last reference above) and leaving Shan et al.. There were previous concerns about the conclusion of leaky gut stuff, this is however a fact, whether or not the peptide mentioned above is the only factor now is the question. I certainly could have added more on gangliosides and other upcoming research. This particular citation has been developing over several papers and it is ripe for inclusion. In order for the adapative and innate responses to occur, large peptides need to get behind the brush border membrane, and this has been observed in celiac disease and wheat allergy. There may, however be better ways of wording this than I have done.

-PB666 ^yap 04:31, 19 July 2008 (UTC)