Dermatitis herpetiformis and celiac disease are both primarily associated with the HLA-DQ (α1*0501, (β1*02) or the HLA-DQ (α1*03, (β1*0302) heterodimers
TL;DR: It is concluded that dermatitis herpetiformis and celiac disease are associated to the very same HLA-DQ alpha beta heterodimers.
Abstract: HLA-DRB1,-DQA1, and -DQB1 genomic typing of 50 patients with dermatitis herpetiformis and of 290 healthy blood donors was performed. Genes encoding the DQ (alpha 1*0501, beta 1*02) heterodimer were carried by 43 (86%) of the patients and 72 (25%) of the controls. Of the remaining seven patients six (12% of all the patients) carried genes encoding the DQ (alpha 1*03, beta 1*0302) heterodimer. These HLA associations are very similar to those observed in patients with celiac disease. We thus conclude that dermatitis herpetiformis and celiac disease are associated to the very same HLA-DQ alpha beta heterodimers.
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TL;DR: Evidence is provided that the spacing between glutamine and proline, the second most abundant amino acid in gluten, plays an essential role in the specificity of deamidation.
Abstract: Celiac disease is caused by a selective lack of T cell tolerance for gluten. It is known that the enzyme tissue transglutaminase (tTG) is involved in the generation of T cell stimulatory gluten peptides through deamidation of glutamine, the most abundant amino acid in gluten. Only particular glutamine residues, however, are modified by tTG. Here we provide evidence that the spacing between glutamine and proline, the second most abundant amino acid in gluten, plays an essential role in the specificity of deamidation. On the basis of this, algorithms were designed and used to successfully predict novel T cell stimulatory peptides in gluten. Strikingly, these algorithms identified many similar peptides in the gluten-like hordeins from barley and secalins from rye but not in the avenins from oats. The avenins contain significantly lower percentages of proline residues, which offers a likely explanation for the lack of toxicity of oats. Thus, the unique amino acid composition of gluten and related proteins in barley and rye favors the generation of toxic T cell stimulatory gluten peptides by tTG. This provides a rationale for the observation that celiac disease patients are intolerant to these cereal proteins but not to other common food proteins.
375 citations
259 citations
TL;DR: Using high‐performance liquid chromatography purification steps of gluten with a T cell bioassay and mass spectral analyses, a glutenin peptide is identified that activates T cells from the small intestine of a coeliac disease patient and results in the secretion of large amounts of IFN‐γ.
Abstract: Gluten ingestion causes coeliac disease in susceptible individuals. Gluten is a heterogeneous mixture of glutenin and gliadin, the latter of which is considered responsible for disease induction. By combining high-performance liquid chromatography purification steps of gluten with a T cell bioassay and mass spectral analyses, we have identified a glutenin peptide (glt04 707 – 742) that activates T cells from the small intestine of a coeliac disease patient and results in the secretion of large amounts of IFN-γ. The minimal T cell stimulatory core of the peptide (residues 724 – 734) is repetitively present in glutenin molecules. Moreover, it was observed that a large number of naturally occurring variants of this peptide are recognized by the T cells. These data suggest that the large heterogeneity of glutenin proteins dramatically increases the number of available T cell epitopes. Together, the results provide new insight into the nature of the gluten antigens that lead to coeliac disease and suggest that glutenin, next to gliadin-derived antigens, may be involved in the disease process.
212 citations
TL;DR: A threshold model is proposed, in which the efficiency of gluten presentation to CD4+ T cells determines the likelihood of developing celiac disease and its complications, and might also help to understand the development of refractory celiac Disease and lymphoma.
Abstract: In the small intestine of celiac disease patients, dietary wheat gluten and similar proteins in barley and rye trigger an inflammatory response. While strict adherence to a gluten-free diet induces full recovery in most patients, a small percentage of patients fail to recover. In a subset of these refractory celiac disease patients, an (aberrant) oligoclonal intraepithelial lymphocyte population develops into overt lymphoma. Celiac disease is strongly associated with HLA-DQ2 and/or HLA-DQ8, as both genotypes predispose for disease development. This association can be explained by the fact that gluten peptides can be presented in HLA-DQ2 and HLA-DQ8 molecules on antigen presenting cells. Gluten-specific CD4+ T cells in the lamina propria respond to these peptides, and this likely enhances cytotoxicity of intraepithelial lymphocytes against the intestinal epithelium. We propose a threshold model for the development of celiac disease, in which the efficiency of gluten presentation to CD4+ T cells determines the likelihood of developing celiac disease and its complications. Key factors that influence the efficiency of gluten presentation include: (1) the level of gluten intake, (2) the enzyme tissue transglutaminase 2 which modifies gluten into high affinity binding peptides for HLA-DQ2 and HLA-DQ8, (3) the HLA-DQ type, as HLA-DQ2 binds a wider range of gluten peptides than HLA-DQ8, (4) the gene dose of HLA-DQ2 and HLA-DQ8, and finally,(5) additional genetic polymorphisms that may influence T cell reactivity. This threshold model might also help to understand the development of refractory celiac disease and lymphoma.
163 citations
Cites background from "Dermatitis herpetiformis and celiac..."
...In addition to this environmental factor, CD development involves genetic predisposition, as the vast majority of the CD patients possess human leukocyte antigen (HLA)-DQ2 and/or HLA-DQ8 (Spurkland et al. 1997)....
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...CD is associated, to a lesser extent, with HLA-DQ8 (DQA*03, DQB*0302) (Spurkland et al. 1997)....
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TL;DR: Modification of gluten peptides by tTG can enhance their binding to HLA-DQ2 or -DQ8 and potentiate T cell stimulation, and tTG-catalyzed cross-linking and consequent haptenization of gluten with extracellular matrix proteins allows for storage and extended availability of gluten in the mucosa.
Abstract: Celiac disease is an inflammatory disorder of the small intestine caused by an immune response to ingested wheat gluten and similar proteins of rye and barley. It affects at least 1 in 200 individuals, corresponding to roughly three million patients in Western Europe and Northern America alone. Data accumulated since the discovery of gluten specific T cells in the intestine of celiac disease patients the early 1990s have allowed the deciphering of the interplay between the triggering environmental factor, gluten, the main genetic risk factor, the HLA-DQ2/8 haplotypes and the autoantigen; the enzyme tissue transglutaminase (tTG). This established a key role of adaptive immunity orchestrated by lamina propria T cells responding to a set of gluten derived peptides. More recent work points to an important contribution of innate immunity triggered by a distinct gluten peptide and driven by the proinflammatory cytokine Interleukine-5 (IL-15). Together, these observations provide a unique explanation for the disease inducing capacity of gluten.
157 citations
References
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TL;DR: Analysis of DNA sequences from diabetics indicates that alleles ofHLA-DQβ determine both disease susceptibility and resistance, and that the structure of the DQ molecule, in particular residue 57 of the β-chain, specifies the autoimmune response against the insulin-producing islet cells.
Abstract: Over half of the inherited predisposition to insulin-dependent diabetes mellitus maps to the region of chromosome 6 that contains the highly polymorphic HLA class II genes which determine immune responsiveness. Analysis of DNA sequences from diabetics indicates that alleles of HLA-DQ beta determine both disease susceptibility and resistance, and that the structure of the DQ molecule, in particular residue 57 of the beta-chain, specifies the autoimmune response against the insulin-producing islet cells.
1,909 citations
TL;DR: Typing of DNA from 94 unrelated children with celiac disease with HLA-DQA1 and -DQB1 allele-specific oligonucleotide probes revealed that all but one (i.e., 98.9%) may share a particular combination of a DQA 1 and a DQB1 gene.
Abstract: Typing of DNA from 94 unrelated children with celiac disease (CD) with HLA-DQA1 and -DQB1 allele-specific oligonucleotide probes revealed that all but one (i.e., 98.9%) may share a particular combination of a DQA1 and a DQB1 gene. These genes are arranged in cis position on the DR3DQw2 haplotype and in trans position in DR5DQw7/DR7DQw2 heterozygous individuals. Thus, most CD patients may share the same cis- or trans-encoded HLA-DQ alpha/beta heterodimer.
911 citations
TL;DR: The evidence behind this concept that a particular HLA-DQ heterodimer, encoded by the DQA1*0501 and DQB1*0201 genes in cis or trans configuration, confers the primary disease susceptibility is reviewed.
576 citations
TL;DR: Analysis of sequence variation in the polymorphic second exon of the major histocompatibility complex genes HLA-DQ alpha and -DQ beta has revealed 8 allelic variants at the alpha locus and 13 variant at the beta locus.
Abstract: Analysis of sequence variation in the polymorphic second exon of the major histocompatibility complex genes HLA-DQ alpha and -DQ beta has revealed 8 allelic variants at the alpha locus and 13 variants at the beta locus. Correlation of sequence variation with serologic typing suggests that the DQw2, DQw3, and DQ(blank) types are determined by the DQ beta subunit, while the DQw1 specificity is determined by DQ alpha. The nature of the amino acid at position 57 in the DQ beta subunit is correlated with susceptibility to insulin-dependent diabetes mellitus. This region of the DQ beta chain contains shared peptides with Epstein-Barr virus and rubella virus.
356 citations
TL;DR: DNA or other material, in particular cell lines, should be made available in a publicly accessible repository or at least in the originating laboratory, and documentation on this will be maintained by the Nomenclature Committee.
Abstract: 1. Several clones should have been sequenced. 2. Sequencing should have been performed in both directions. 3. An accession number in a databank should have been obtained. 4. Full length sequences are preferable though not essential. 5. Where possible a paper should have been submitted for publication. 6. DNA or other material, in particular cell lines, should be made available in a publicly accessible repository or at least in the originating laboratory. Documentation on this will be maintained by the Nomenclature Committee.
227 citations