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78 GENETICALLY DETOXIFIED GRAINS of chromosome 1 at three homologous loci, named Gli-1. However, some w-gliadin peptides have been found to be encoded by additional dispersed genes located on the same arm of the same set of chromosomes. Genes controlling LMW glutenin subunits are clustered at Glu-A3, B3, and D3 loci and only the genes coding for HMW glutenin subunits occur on the long arm of the group 1 chromosomes, at a major locus named Glu-1. So, the multigene family nature of the wheat genes and the spread of these genes over six different chromosomes entail a very high degree of genetic polymorphism. By applying a Southern analysis to the common cultivar Cheyenne, Anderson et al. found that up to 150 genes code for a-gliadin, although only half of them are expressed 12-13 . An Italian study showed that there is a high degree of variability in the genomic DNA between different cultivars. A genetic polymorphism at the Gli-2 locus encoding 14 for a-gliadin was evident among different subspecies of Triticum aestivum . Naturally occurring detoxified grains This huge genetic variability let people hope to individuate a “naturally occurring” GDG. This was the case of the nullisomic 6A-tetrasomic 6D variety of Chinese Spring wheat, in which chromosome 6A is missing but compensated for by two extradoses of chromosome 6D. Preliminary results were encouraging. The administration for two weeks of 65 grams of bread made with this wheat variety did not deteriorate absorptive 15 function . However, it was later proven that these variants do contain a-gliadin, coded by B and D chromosomes, and that they are toxic, on both histological and clinical 16 ground, for patients affected by CD . More recently, the toxicity of two lines of cultivar Raeder, one lacking the Gli-A2 encoded gliadin components and the other lacking both Gli-A2 and Gli-D1 gliadin components was tested with an organ culture system based on coeliac duodenal biopsy 17 specimens . Although the Gli-A2 components were not compensated for by extradoses of chromosomes B and D, those lines were deficient but not devoid of gliadins. Although the toxicity of these two mutant lines was reduced compared to the original cultivar Raeder, yet it was still present. In conclusion, all these studies show that a naturally-occurring non-toxic line has not been found so far. Technologies to develop genetically detoxified grains Technologies allowing genetic plant transformation do exist. For example, a fragment of foreign DNA cut with a restriction enzyme, and plasmid, cut open with the same enzyme, are mixed together. DNA ligase is added to stitch the complementary base sequences so that the recombinant plasmid contains foreign DNA that, under appropriate conditions, is taken up by the Agrobacterium, a naturally occurring plant pathogen. When host plant cells are exposed to Agrobacterium, plasmid DNA is transferred into plant chromosomes. At the end of the process transgenic plants are 18 regenerated from single transformed cells (Fig. 3A) . An alternative method is the biolistic “gene gun technique”. A suspension of thousands of tiny gold or tungsten particles coated with transgenic DNA are fired into the target tissue, using compressed helium as propellant. Particles 19 penetrate the nucleus and incorporate into the host genoma (Fig. 3B) .
• • GENETICALLY DETOXIFIED GRAINS 79 Foreign DNA EcoR1 DNA ligase Plasmid from Agrobacterium EcoR1 Agrobacterium Recombinant plasmid containing foreign DNA • • Gene suspension Sheath fluid • Carbon dioxide 3A Cultured cells from host plant Whole plants regenerated from single cells Plasmid DNA transferred into plant chromosomes A) agrobacterium technique B) gene gun technique Fig. 3. Genetic plant transformation technologies. Additionally, it may be possible to switch off specific plant genes to eliminate or reduce natural toxins or allergens. This can take place both at posttranscriptional and transcriptional level. In the first case, which is the most common, injected doublestranded RNA is cut into small fragments of 20-30 nucleotides, amplified and then dissociated into single strands complementary, but in reverse to the target messenger RNA which is thus inactivated. In other words, silenced genes are still active but 20 messenger RNA is degraded before it can be translated into proteins . It should be kept in mind that these techniques have been applied to wheat only with the aim of improving dough rheological properties by increasing the level of high molecular weight glutenins, resulting in improved functional properties. Moreover, transformed plants show Mendelian segregation of the transgenes and strategies have 21-24 been developed to ensure transgene stability through generations . However, these techniques have not been directed to the treatment of CD so far. Genetically detoxified grains for coeliac disease Petri dish with receiving cells Power source Electric field A project aiming at the production of a genetically detoxified wheat still suitable for mixing and baking should be set up taking into account a few points: (a) a minimal amount of gluten can be toxic to the coeliac small intestine; (b) all the different classes of gliadins have been shown to be harmful for coeliac patients; (c) upwards 150 genes codify for the a-gliadins; (d) identification of all possible toxic sequences is still lacking; (e) bakery properties are mainly due to HMW glutenins. Obviously, the first thing to be checked is whether HMW glutenins are really safe 8 for CD patients. Despite the most recent findings on T cell assays , it should be noted that pure glutenins have not been tested on coeliac small bowel mucosa so far. So, once pure glutenins would be obtained, their safety should be tested first in-vitro and then in- 3B
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Perspectives on Coeliac Disease Vol
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The AIC Meeting was held in the Aul
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Italian Coeliac Society, Via Picott
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Preface Coeliac disease (CD) is a u
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Contents Current understanding of t
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2 THE BASIS OF COELIAC DISEASE hapl
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4 THE BASIS OF COELIAC DISEASE 1 pr
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6 THE BASIS OF COELIAC DISEASE spre
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8 THE BASIS OF COELIAC DISEASE Ackn
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10 THE BASIS OF COELIAC DISEASE glu
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Catassi C, Fasano A, Corazza GR (ed
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T CELL RESPONSES TO GLUTEN PEPTIDES
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18 A DOMINANT EPITOPE IN GLUTEN PEP
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Page 42 and 43: 28 ROLE OF A-GLIADIN 31-49 PEPTIDE
Page 45 and 46: Catassi C, Fasano A, Corazza GR (ed
Page 47 and 48: COELIAC DISEASE IN THE SAHARAWI 33
Page 55: COELIAC DISEASE IN THE SAHARAWI 41
Page 58 and 59: 44 INFANT FEEDING PRACTICES AND COE
Page 66 and 67: Age (years) 52 INFANT FEEDING PRACT
Page 76 and 77: 62 MECHANISMS OF ORAL TOLERANCE the
Page 78 and 79: 64 MECHANISMS OF ORAL TOLERANCE pot
Page 80 and 81: 66 MECHANISMS OF ORAL TOLERANCE Epi
Page 82 and 83: 68 MECHANISMS OF ORAL TOLERANCE typ
Page 84 and 85: 70 MECHANISMS OF ORAL TOLERANCE 51
Page 86 and 87: 72 MECHANISMS OF ORAL TOLERANCE 23.
Page 91: GENETICALLY DETOXIFIED GRAINS 77 to
Page 95 and 96: GENETICALLY DETOXIFIED GRAINS 81 3.
Page 99 and 100: IMMUNOTHERAPY OF COELIAC DISEASE 85
Page 101 and 102: IMMUNOTHERAPY OF COELIAC DISEASE 87
Page 105 and 106: RECENT ADVANCES ON GLUTEN TOXICITY
Page 107 and 108: Index A Antiendomysium antibodies (
Page 109: INDEX 95 W Wheat, 7, 23, 27, 31, 53
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