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2 THE BASIS OF COELIAC DISEASE haplotype (the DR3, DQ2 haplotype) or are DRB1*11/12-DQA1*0505- DQB1*0301/DRB1*07-DQA1*0201-DQB1*0202 heterozygotes (carry the DR5- 7-11 DQ7/DR7-DQ2 haplotypes) . The chains encoded by DQA1*0501 and DQA1*0505 differ by one residue in the leader peptide, and the DQbchains encoded by DQB1*0201 and DQB1*0202 differ by one residue in the membrane proximal domain. These substitutions are highly unlikely to have any functional consequence. CD patients with the above mentioned DR-DQ combinations share the same functional DQ molecule on the cell surface, encoded by genes carried in cis (e.g. DQA1*05 and DQB1*02 carried on the same haplotype) or trans position (e.g. DQA1*05 carried on a different 12 haplotype to DQB1*02) . Accumulating evidence suggests that the DR3-DQ2, the DR7-DQ2 and the DR5-DQ7 haplotypes have a close evolutionary relationship. Fragments of DNA flanking the DQA1 gene of the DR3-DQ2 haplotype have been identified on the DR5-DQ7 haplotype, and fragments of DNA flanking the DQB1 gene 13-14 of the DR3-DQ2 haplotype have been identified on the DR7-DQ2 haplotype . The genetic information in the DQ subregion of the DR3-DQ2 haplotype is thus reestablished in DR5-DQ7/DR7-DQ2 heterozygotes, although the sequence information is split between two chromosomes. Susceptibility to CD therefore likely depends on an interaction between at least two genes on the DR3-DQ2 haplotype that are reunited in DR5-DQ7 / DR7-DQ2 heterozygous individuals. The DQA1 and DQB1 genes are the primordial candidates since their products interact to form an HLA class II heterodimer and since they are situated close to a putative recombination site. Almost all the CD patients who are DQA1*05 and DQB1*02 negative bear the DRB1*04, DQA1*03, DQB1*0302 haplotype (i.e. DR4-DQ8 haplotype) and it is likely that these patients have an HLA association which is different to those who are DQ2 positive. Although it is less clear what the primary disease susceptibility determinant of 15 the DR4-DQ8 haplotype is, most data favour DQ8 . Overall the existing data suggest that the susceptibility to develop CD is primarily associated with two conventional DQ molecules DQ(a1*05,b1*02) (=DQ2) and to a lesser extent DQ(a1*03,b1*0302) (=DQ8). DQ molecules bind peptides and present these to CD4+ T helper cells carrying the abT cell receptor (TCR). The genetic evidence thus points towards a central role of CD4+ T cells in controlling the disease development in CD. Genome wide linkage studies in CD have indicated numerous susceptibility regions with weak genetic effects, and the indications are strongest for susceptibility genes 16-17 located at 5qter and 11qter . However, no disease associations have been established so far for any gene of these regions. The only gene for which there are relatively 18-20 consistent reports on disease association is the CTLA4 gene on chromosome 2q33 . CTLA4 is involved in down regulating T-cell responses, and the A allele of the +49 dimorphism is associated with increased CTLA4 expression and enhanced control of T 21-22 cell proliferation . Thus the +49 dimorphism is a prime suspect for the observed genetic effect, although other polymorphisms in linkage disequilibrium cannot be ruled out. In this respect it is worth noting that the CD28 and ICOS genes whose gene products are central players in T and B cell activation, are located very close to the CTLA4 gene.
THE BASIS OF COELIAC DISEASE 3 Environmental factors Gluten is obviously a critical environmental factor in CD. Whether other environmental factors are also involved is still an open question. Gut infections may well be involved. Adenovirus 12 has been in the forefront among the candidate microorganisms. This virus was originally proposed as a candidate because of partial 23 linear homology over 12 amino acids in a virus protein and a-gliadin . Based on our current understanding of the pathogenesis of coeliac disease, the rationale for the candidacy of this virus is weak, and there is in fact very little epidemiological data 24 supporting a role for this virus . Peptide binding to the CD associated DQ2 and DQ8 molecules Both HLA class I and class II molecules bind peptides in a groove located in their 25 membrane distal part . Stable binding is achieved by multiple hydrogen bonds between amino acids of HLA and peptide main chain atoms. Many polymorphic variants of HLA molecules exist. Amino acid residues which differ between the polymorphic variants are clustered around the peptide binding site where they contribute to the formation of specific binding pockets. Side chains of amino acids of the peptide (so-called anchor residues) fit into these pockets and their interaction with HLA contribute to the binding of the peptide. The binding site of HLA class II molecules, in contrast to HLA class I molecules, is open at both ends allowing the bound peptides to protrude. The class II peptide ligands thus vary in length. The interactions with HLA mainly take place in a core region of nine residues. Within this region side chains of amino acids in positions P1, P4, P6, P7 and P9 dock into pockets of the class II binding site. The chemistry and size of the various pockets vary between the different class II alleles so that some amino acids are preferred and some are not preferred. DQ2 has a unique preference for binding peptides with negatively charged 26-28 side chains at the three middle anchor positions . The binding motif of DQ8 is different from that of DQ2, but DQ8 also displays a preference for binding negatively 29-31 charged residues at several positions (i.e. P1, P4 and P9) . Hence, both the DQ2 and DQ8 molecules share a preference for negatively charged residues at some of their anchor positions. Preferential T cell recognition of gluten peptides presented by DQ2 and Dq8 The observation that gluten reactive CD4+ TCRabT cells can be isolated and propagated from intestinal biopsies of CD patients has been instrumental for recent 32 achievements . Strikingly, such T cells of patients carrying the DR3-DQ2 haplotype were found to recognise gluten fragments presented by the DQ2 molecule rather than 32-33 by other HLA molecules of the patients . Both DR3-DQ2 positive and DR5- DQ7/DR7-DQ2 positive antigen presenting cells (i.e. carrying the DQA1*05 and DQB1*02 genes in cis or in trans configuration) are able to present the gluten antigen to these patient T cells. Likewise, T cells isolated from small intestinal biopsies of DQ2 negative, DR4-DQ8 positive patients predominantly recognise gluten-derived peptides 32-33 when presented by the DQ8 molecule . Taken together, these results allude to
Page 1: Perspectives on Coeliac Disease Vol
Page 4: The AIC Meeting was held in the Aul
Page 8 and 9: Italian Coeliac Society, Via Picott
Page 11 and 12: Preface Coeliac disease (CD) is a u
Page 13: Contents Current understanding of t
Page 18 and 19: 4 THE BASIS OF COELIAC DISEASE 1 pr
Page 20 and 21: 6 THE BASIS OF COELIAC DISEASE spre
Page 22 and 23: 8 THE BASIS OF COELIAC DISEASE Ackn
Page 24 and 25: 10 THE BASIS OF COELIAC DISEASE glu
Page 27 and 28: Catassi C, Fasano A, Corazza GR (ed
Page 29: T CELL RESPONSES TO GLUTEN PEPTIDES
Page 32 and 33: 18 A DOMINANT EPITOPE IN GLUTEN PEP
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
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Age (years) 52 INFANT FEEDING PRACT
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54 INFANT FEEDING PRACTICES AND COE
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62 MECHANISMS OF ORAL TOLERANCE the
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64 MECHANISMS OF ORAL TOLERANCE pot
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66 MECHANISMS OF ORAL TOLERANCE Epi
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68 MECHANISMS OF ORAL TOLERANCE typ
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70 MECHANISMS OF ORAL TOLERANCE 51
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72 MECHANISMS OF ORAL TOLERANCE 23.
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Catassi C, Fasano A, Corazza GR (ed
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GENETICALLY DETOXIFIED GRAINS 77 to
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• • GENETICALLY DETOXIFIED GRAI
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GENETICALLY DETOXIFIED GRAINS 81 3.
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IMMUNOTHERAPY OF COELIAC DISEASE 85
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IMMUNOTHERAPY OF COELIAC DISEASE 87
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RECENT ADVANCES ON GLUTEN TOXICITY
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Index A Antiendomysium antibodies (
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INDEX 95 W Wheat, 7, 23, 27, 31, 53
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