The immunochemistry of Triticeae glutens is important in several inflammatory diseases. It can be subdivided into innate responses (direct stimulation of immune system), class II mediated presentation (HLA DQ), class I mediated stimulation of killer cells, and antibody recognition. The responses to gluten proteins and polypeptide regions differs according to the type of gluten sensitivity. The response is also dependent on the genetic makeup of the human leukocyte antigen genes. In gluten sensitive enteropathy, there are four types of recognition, innate immunity (a form of cellular immunity priming), HLA-DQ, and antibody recognition of gliadin and transglutaminase. With idiopathic gluten sensitivity only antibody recognition to gliadin has been resolved. In wheat allergy, the response pathways are mediated through IgE against other wheat proteins and other forms of gliadin.
Innate immunity
Innate immunity to gluten refers to an immune response that works independently of T-cell receptor or antibody recognition of the 'innate' peptide. This peptide acts directly on cells, such as monocytes, stimulating their growth and differentiation. Innate immunity to gluten is complicated by an apparent role gluten has in bypassing normal host defense and peptide exclusion mechanisms in the gut. While not truly innate, these activities allow gliadin to enter into areas where many lymphocytes patron. In bypassing these filters gliadin alters the normal behavior of both digestive cells, called enterocytes or epithelial cells, and lymphocytes. This increases the potential of causing sensitivity (see Underlying conditions). 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. Other explanation for some may be that food chemicals or drugs are weakening the defenses. This can be the case with ω5-gliadin allergy with salicylate sensitivity. 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). This produces a number of downstream responses that are pro-inflammatory. The other peptide that may have innate behavior is the "CXCR3" receptor binding peptides, the receptor exists on enterocytes, the brush border membrane cells. The peptide displaces an immune factor and signals the disruption of the membrane seal, the tight junctions, between cells.
Alpha gliadin 31–43 Gluten bears an innate response peptide (IRP) found on α-9 gliadin, at positions 31–43 and on α-3, 4, 5, 8, and 11 gliadins. The IRP lies within a 25 amino-acid long region that is resistant to pancreatic proteases. The 25mer is also resistant to brush border membrane peptidases of the small intestine in coeliacs. IRP induced the rapid expression of interleukin 15 (IL15) and other factors. Thus IRP activates the immune system. Studies show that, while in normal individuals the peptide is trimmed over time to produce inactive peptide, in coeliacs a 19mer may lose a residue from one end or the other, after prolonged incubation that 50% remains intact.
Intraepithileal lymphocytes and IL15 The release of IL15 is a major factor in coeliac disease as IL15 has been found to attract intraepithelial lymphocytes (IEL) that characterize Marsh grade 1 and 2 coeliac disease. Lymphocytes attracted by IL-15 are composed of markers enriched on natural killer cells versus normal helper T-cells. One hypothesis is that IL-15 induces the highly inflammatory Th1 response that activates T-helper cells (DQ2 restricted gliadin specific) that then orchestrate the destructive response, but the reason why inflammatory cells develop prior to gliadin specific helper cells is not known. The IRP response differs from typical responses that stimulate IL15 release, such as viral infection. In addition, other cytokines such as IL12 and IL2, which are typically associated with T-helper cell stimulation, are not involved. In these two ways the innate peptide activation of T-cells in coeliac disease is strange. IL-15 appears to induce increases in MICA and NKG2D that may increase brush-border cell killing. 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. However, unlike the non-coeliacs, the treated coeliac cells produce the disease marker nitrite. 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.
Infiltrating peptides Some alpha gliadin have other direct-acting properties. Other gliadin peptides, one in a glutamine rich region and another peptide, "QVLQQSTYQLLQELCCQHLW", bind a chemoattractant receptor, CXCR3. Gliadin binds to, blocks and displaces a factor, I-TAC, that binds this receptor. In the process it recruits more CXCR3 receptor, increases MyD88 and zonulin expression. The factor it displaces, I-TAC, is a T-cell attractant. This peptide may also be involved in increased risk for type 1 diabetes as zonulin production is also a factor. 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. Other studies show that IgE reactivity to ω-5 gliadin increases greatly when deamidated or crosslinked to transglutaminase.
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