Gluten immunochemistry
There is a growing body of evidence that the gluten-sensitive intestine differs from the normal gut, several gluten peptides can enter behind the brush border membrane cells.
One potential explanation of why certain people become sensitive is that these individuals may not produce adequate peptidases in some areas of the gut, allowing these peptides to survive.
There is no clear reasoning, either from genetics or from long-term studies of susceptible individuals why these gut peptide restrictions would change.
Once inside, α-9 gliadin 31–55 shows the ability to activate undifferentiated immune cells that then proliferate and also produce inflammatory cytokines, notably interleukin 15 (IL-15).
The peptide displaces an immune factor and signals the disruption of the membrane seal, the tight junctions, between cells.
[6] Lymphocytes attracted by IL-15 are composed of markers enriched on natural killer cells versus normal helper T-cells.
[1] In addition, innate immunity to IRP peptide is involved in coeliac disease, dermatitis herpetiformis and possibly juvenile diabetes.
IRP targets monocytes and increases the production of IL-15 by an HLA-DQ independent pathway, a subsequent study showed that both this region and the "33mer" could create the same response, in cells from both treated coeliacs and non-coeliacs.
[8] This indicates that another abnormality in people with coeliac disease that allows stimulation to proceed past the normal healthy state.
After extensive study, there is no known genetic association for this that appears to stand out at present, and implicates other environmental factors in the defect.
[10] This triggering of zonulin ultimately results in the degradation of tight junctions allowing large solutes, such as proteolytic resistant gliadin fragments to enter behind the brush border membrane cells.
One study examined the effect of ω-5 gliadin, the primary cause of WD-EIA, and found increased permeability of intestinal cells.
[11] Other studies show that IgE reactivity to ω-5 gliadin increases greatly when deamidated or crosslinked to transglutaminase.
Discovered by sequence homology analysis these proteins are found on the surface of enterocytes of the small intestine, are believed to play a role in disease.
These are more common isoforms encoded by haplotypes, almost all of the time, one passed without change from a person's mother and father from conception.
These polypeptides of gluten can then make their way behind the epithelial layer of cells (membrane), where APCs and T-cells reside in the lamina propria.
Enteropathy is believed to occur when tissue transglutaminase (tTG) covelantly links itself to gliadin peptides that enter the lamina propria of the intestinal villus.
The resulting structure can be presented by APC (with the same gliadin recognizing DQ isoforms) to T-cells, and B-cells can produce anti-transglutaminase antibodies.
[19][20] The positions of these motifs in different species, strains and isoforms may vary because of insertions and deletions in sequence.
DQA1*0202:DQB1*0201 homozygotes (DQ α2-β2) also appear to be able to present pathogenic gliadin peptides, but a smaller set with lower binding affinity.
Many of these gliadin motifs are substrates for tissue transglutaminase and therefore can be modified by deamidation in the gut to create more inflammatory peptides.
Alpha-2 secalin, the glutinous protein in rye, is composed of two amino-terminal overlapping T-cell sites at positions (8–19) and (13–23).
The sites belong to three epitope groups "α-I", "α-II", and "α-III"[25] The insertion also creates a larger region of α-gliadin that is resistant to gastrointestinal proteases.
[1] This site alone may fulfill all the T-helper cell adaptive immune requirements with HLA-DQ2.5 involvement in some coeliac disease.
[29] A 26 residue proteolytic resistance fragment has been found on γ-5 gliadin, positions 26–51, that has multiple transglutaminase and T-cell epitopes.
[30] Computer analysis of 156 prolamins and glutelins revealed many more resistant fragments; one, a γ-gliadin, containing 4 epitopes was 68 amino acids in length.
The allergic recognition of gliadin by mast cells, eosinophiles in the presence of IgE has notable direct consequences, such as exercise-induced anaphylaxis.
The HLA DQ2.5 restricted peptide "IIQPQQPAQ" produced approximately 50 hits of identical sequences in NCBI-Blast search is one of several dozen known motifs[22] whereas only a small fraction of Triticeae gluten variants have been examined.
Some current studies claim that removing the toxicity of gliadins from wheat as plausible,[44] but, as the above illustrates, the problem is monumental.
Another way to make wheat less immunogenic is to insert proteolytic sites in the longer motifs (25-mer and 33-mer), facilitating more complete digestion.
