dq2.5 isoform called dq2.5cis. it is found in almost all coeliacs and the haplotype is frequently called, also, dq2.5 haplotype. 25% of coeliacs are dq2 homozygotes (hla dqb1*02 homozygotes), only a small percent of these do not bear dq2.5cis. this minority are invariably dqa1*0201:dqb1*0202 (dq2.2cis homozygotes). isoform pairings in dq2.5/dq2.2 results in two functionally unique isoform the majority of dq2 homozygotes are homozygotes of the dq2.5 haplotype or dq2.5 and dq2.2 haplotypes. these dq2 homozygotes tend to show increased mucosa damage and degradation and are at greatest risk for severe complications of coeliac disease, refractory disease, and enteritis associated t-cell lymphoma (eatl). further information: dq2.5, dq2.2, dq2 and coeliac disease, and hla dr3-dq2 risk for disease tends to be carried in families because of the dq2.5cis encoding haplotypes. atypically about 3% of coeliacs get dq2.5 isoform as a result of trans-chromosomal encoding. this can occur because one dq haplotype, dqa1*0505:dqb1*0301 (dq7.5) produces an alpha chain in which the variable portion relative to dqa1*0501 is chopped off during processing to dq heterodymer.isoform pairings in dq7.5/dq2.2 result in 4 proteins isoforms, dq2.5trans isoform is one(circled) therefore, it can produce the α5 subunit. the dq2.2 haplotypes provide the β2 subunit, and consequently dq7.5/dq2.2 phenotype creates the dq2.5trans isoform. the dq isoform has a complex genetic involvement in coeliac disease. and these involvements explain the majority of disease. one other haplotype exists that is associated with disease, although not as common in europe, dq8 is found to be involved in coeliac disease in peoples where dq2 is not present. dq8.1 haplotype encodes the dqa1*0301:dqb1*0302 haplotype and represents the overwhelming majority of all dq8. dq2.5 is generally highest in northern, islandic europe, and the basque of northern spain. phenotype frequency exceeds 50% in certain parts of ireland. dq8 is extremely high in native americans of central america and tribes of eastern american origin, fortunately most of these peoples have retained a maize based diet. hla-dq proteins present polypeptide regions of proteins of about 9 amino acids and larger in size (10 to 14 residues in involved in binding is common for gliadin) to t lymphocytes. gliadin proteins can be adsorbed by apc. after digestion in the lysozomes of apcs, gliadin peptides can be recycled to the cell's surface bound to dq, or they can be bound and presented directly from the cell surface. the major source of inflammatory gluten is dietary gluten. optimal reactivity of gliadin occurs when the protein is partially digested by small intestinal lysozyme and trypsin into proteolytic digests. 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. (see: underlying conditions) the apc bearing dq-gliadin peptide on the surface can bind to t-cells that have an antibody-like t-cell receptor the specifically recognized dq2.5 with gliadin. the complex (apc-dq-gliadin) thus stimulates the gliadin specific t-cells to divide. these cells cause b-cells that recognize gliadin to proliferate. the b-cells mature into plasma cells producing anti-gliadin antibodies. this does not cause coeliac disease and is an unknown factor in idiopathic disease. 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. this appears to result in the destruction of the villi. the release of gliadin by transglutaminase does not lessen disease. when ttg-gliadin undergoes hydrolysis, the result is deamidated gliadin. deamidated gliadin peptides are more inflammatory relative to natural peptides. deamidated gliadin is also found in foods that have added gluten, such as wheat bread, food pastes. the major gluten proteins that are involved in coeliac disease are the α-gliadin isoforms. alpha gliadin is composed of repeated motifs that, when digested, can be presented by hla-dq molecules. dq2.5 recognizes several motifs in gluten proteins, and therefore hla-dq can recognize many motifs on each gliadin (see understanding dq haplotypes and dq isoforms on the right) however, numbers of different proteins from the grass tribe triticeae have been found to carry motifs presented by hla dq2.5 and dq8. wheat has a large number of these proteins because its genome contains chromosomes derived from two goat grass species and a primitive wheat species. the positions of these motifs in different species, strains and isoforms may vary because of insertions and deletions in sequence. there are a large number of wheat variants, and a large number of gliadins in each variant, and thus many potential sites. these proteins once identified and sequenced can be surveyed by sequence homology searches. dq α5-β2 -binding cleft with a deamidated gliadin peptide (yellow), modified from pdb: 1s9v​ hla-dq2.5 hla-dq recognition of gliadin is critical to the pathogenesis of gluten-sensitive enteropathy, it also appears to be involved in idiopathic gluten sensitivity (see:understanding dq haplotypes and dq isoforms on the right). hla-dq2 primarily presents gliadins with the hla-dq isoform dq2.5 (dq α5-β2) isoform. 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. dq2.5 and α-gliadin 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. the most important recognition appears to be directed toward the α-/β-gliadins. an example of the repetition of a motif across many proteins, the α-2 gliadin (57-68) and (62-75) are also found on α-4, α-9 gliadin. many gliadins contain the "α-20 motif", which is found in wheat and other triticeae genera.(see also: "α-20" gliadin motifs). 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). a2-gliadin illustration of deamidated α2-gliadin's 33mer, amino acids 56–88 in sequence, showing the overlapping of three varieties of t-cell epitope although t-cell responses to many prolamins can be found in coeliac disease, one particular gliadin, α2-gliadin appears to be the focus of t-cells. these responses were dependent on prior treatment with tissue transglutaminase. α2-gliadin differs from the other α-gliadins, specifically because it contains an insert of 14 amino acids. this particular insertion creates six t-cell sites where, in the most similar gliadins, there are two or fewer sites. the sites belong to three epitope groups "α-i", "α-ii", and "α-iii" the insertion also creates a larger region of α-gliadin that is resistant to gastrointestinal proteases. the smallest digest of trypsin and chymotrypsin for the region is a 33mer. this particular region has three tissue transglutaminase sites, two sites that lie within the 14 amino acid insertion, a region of maximal stimulation are found with more than 80% reduction in response for native, un-deaminated, sequence at the position. because of the density of t-cell sites on the "33mer" the affinity for deamidated gliadin is strongly indicates that it may be best treated as a single t-cell site of much higher affinity. this site alone may fulfill all the t-helper cell adaptive immune requirements with hla-dq2.5 involvement in some coeliac disease. dq2.5 and γ-gliadin while gamma gliadin is not as important to dq2.5 mediated disease as α-2 gliadin there are a number of identified motifs. the gamma epitopes identified are dq2-"γ-i", -"γ-ii" (γ30), -"γ-iii", -"γ-iv", -"γ-vi" and -"γ-vii" some of these epitopes are recognized in children who do not have t-cell reactivities toward α-2 gliadin. a 26 residue proteolytic resistance fragment has been found on γ-5 gliadin, positions 26–51, that has multiple transglutaminase and t-cell epitopes. this site has five overlapping t-cells sites of dq2-"γ-ii", -"γ-iii", -"γ-iv", and "γ-glia 2". 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. dq2 and glutelins triticeae glutelins presented by dq2 is some coeliacs. in wheat, the low molecular weight glutenins often share structural similarity with the prolamins of the similar species of triticeae. two motifs, k1-like (46-60), pgh3-like (41-59) and gf1(33-51) have been identified. high molecular weight glutenin has also been identified as a potentially toxic protein some of the hmw glutenins increase response with transglutaminase treatment, indicating the sites might be similar to alpha-gliadin and gamma gliadin t-cell sites. dq2.2 restricted gliadin sites dq2.2 can present a fewer number of lower affinity sites relative to dq2.5. some of these sites are found on γ-gliadin the gliadin most similar to prolamins of other triticeae genera, a gliadin that appears to similar to ancestral. antigen presenting cells bearing dq2.2 can present alpha gliadin sites, for example alpha-ii region of the "33mer" and therefore the "33mer" may have a role in dq2.2 bearing individuals, but the binding capacity is substantially lower. hla-dq8 hla-dq8 confers susceptibility to coeliac disease but in a fashion somewhat similar to dq2.5. homozygotes of dq8, dq2.5/dq8 and dq8/dq2.2 are higher than expected based on levels in the general population.(see: understanding dq haplotypes and dq isoforms). hla-dq8 is generally not as involved in the most severe complications, and it does not recognize the "33mer" of α-2 gliadin to the same degree as dq2.5. there are a smaller number of gliadin (prolamin) peptides presented by hla-dq8. a few studies have been done on the adaptive immune response for dq8/dq2- individuals. dq8 appears to rely much more on adaptive immunity to the carboxyl half of alpha gliadins. in addition, it appear to react with gamma gliadin to a degree comparable to dq2.5. t-cell responses to the high molecular weight glutenin may be more important with dq8 mediated than dq2.5 mediated coeliac disease. antibody recognition antibody recognition of gluten is complex. direct binding to gluten such as anti-gliadin antibodies has an ambiguous pathogenesis in coeliac disease. the crosslinking of gliadin with tissue transglutaminase leads to the production of anti-transglutaminase antibodies, but this is mediated through t-cell recognition of gliadin. the allergic recognition of gliadin by mast cells, eosinophiles in the presence of ige has notable direct consequences, such as exercise-induced anaphylaxis. anti-gliadin antibodies, like those detected in coeliac disease bind to the α-2 gliadin(57-73). this site is within the t-cell reactive "33mer" presented by dq2.5. there has been some suggestion wheat plays a role in juvenile diabetes as antibodies to the non-glutinous seed storage glb-1 (a globulin) are implicated in crossreactive autoantigenic antibodies that destroy islet cells in the pancreas. anti-gliadin antibodies have been found to synapsin i omega-gliadin and the hmw glutenin subunit antibodies have been found most commonly in individuals with exercise-induced anaphylaxis and baker's allergy, and represent a potent class of gluten allergens. non-glutinous proteins in wheat are also allergens, these include: ltp (albumin/globulin), thioredoxin-hb, and wheat flour peroxidase. a particular 5 residue peptide, gln-gln-gln-pro-pro motif, has been found to be a major wheat allergen. taming triticeae immunochemistry new immunogenic motifs appear in the literature almost monthly and new gliadin and triticeae protein sequences appear that contain these motifs. 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 whereas only a small fraction of triticeae gluten variants have been examined. for this reason the immunochemistry is best discussed at the level of triticeae, because it is clear that the special immunological properties of the proteins appear to have basal affinities to this taxa, appearing concentrated in wheat as a result of its three various genomes. some current studies claim that removing the toxicity of gliadins from wheat as plausible, but, as the above illustrates, the problem is monumental. there are many gluten proteins, three genomes with many genes each for alpha, gamma, and omega gliadins. for each motif many genome-loci are present, and there are many motifs, some still not known. different strains of triticeae exist for different industrial applications; durum for pasta and food pastes, two types of barley for beer, bread wheats used in different areas with different growing conditions. replacing these motifs is not a plausible task since a contamination of 0.02% wheat in a gluten-free diet is considered to be pathogenic and would require replacing the motifs in all known regional varieties—potentially thousands of genetic modifications. class i and antibody responses are downstream of class ii recognition and are of little remedial value in change. the innate response peptide could be a silver bullet, assuming there is only one of these per protein and only a