Evidence that celiac disease is primarily associated with a DC locus allelic specificity

doi:10.1016/0090-1229(83)90106-X

Clinical Immunology and Immunopathology

Volume 28, Issue 3, September 1983, Pages 395-404

Clinical Immunology ...

https://doi.org/10.1016/0090-1229(83)90106-X Get rights and content

Abstract

Sixty patients with celiac disease were typed by radioimmunoassay for the specificities HLA-DR3, HLA-DR7, and for an allelic specificity, DC3, of the HLA-associated DC locus. We found that celiac disease is primarily associated with the DC determinant. The previously described associations with DR3, DR7, B8, B13, and A1 can be explained by decreasing degrees of linkage disequilibrium with DC3.

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Citation Excerpt :
Here we revisit the Genomics of CeD from GWAS to the Microbiome regulation exerted by the Genetic landscape of the host. The first genetic studies describing the association between CeD and HLA genes were carried out in the early 70’s (Falchuk et al., 1972; Stokes et al., 1972), and one decade later the alleles-encoding HLA-DQ2 were identified (Sollid et al., 1989; Tosi et al., 1983). For a long time, neither the candidate gene approaches in case-control cohorts nor the linkage studies in families were able to identify additional genetic factors outside the well-known HLA-DQ genes.
Celiac Disease (CeD) is an immune-mediated complex disease that is triggered by the ingestion of gluten and develops in genetically susceptible individuals. It has been known for a long time that the Human Leucocyte Antigen (HLA) molecules DQ2 and DQ8 are necessary, although not sufficient, for the disease development, and therefore other susceptibility genes and (epi)genetic events must participate in CeD pathogenesis. The advances in Genomics during the last 15 years have made CeD one of the immune-related disorders with the best-characterized genetic component. In the present work, we will first review the main Genome-Wide Association Studies (GWAS) carried out in the disorder, and emphasize post-GWAS discoveries, including diverse integrative strategies, SNP prioritization approaches, and insights into the Microbiome through the host Genomics. Second, we will explore CeD-related Epigenetics and Epigenomics, mostly focusing on the emerging knowledge of the celiac methylome, and the vast but yet under-explored non-coding RNA (ncRNA) landscape. We conclude that much has been done in the field although there are still completely unvisited areas in the post-Genomics of CeD. Chromatin conformation and accessibility, and Epitranscriptomics are promising domains that need to be unveiled to complete the big picture of the celiac Genome.
T cell receptor repertoire as a potential diagnostic marker for celiac disease
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Citation Excerpt :
Celiac disease (CD) is a chronic HLA-associated inflammatory disorder that primarily affects the small intestine. The disease shows strong genetic association with HLA class II alleles encoding HLA-DQ2.5 (HLA-DQA1*05/HLA-DQB1*02, expressed by 90% of patients), HLA-DQ8 (HLA-DQA1*03/HLA-DQB1*03:02), and HLA-DQ2.2 (HLA-DQA1*02:01/HLA-DQB1*02) [9–11]. The epitopes of the causative antigen gluten are well defined and gluten-specific CD4 T cells that are only found in the small intestine of celiac disease patients, but not in healthy controls, have been isolated and extensively studied.
An individual's T cell repertoire is skewed towards some specificities as a result of past antigen exposure and subsequent clonal expansion. Identifying T cell receptor signatures associated with a disease is challenging due to the overall complexity of antigens and polymorphic HLA allotypes. In celiac disease, the antigen epitopes are well characterised and the specific HLA-DQ2-restricted T-cell repertoire associated with the disease has been explored in depth. By investigating T cell receptor repertoires of unsorted lamina propria T cells from 15 individuals, we provide the first proof-of-concept study showing that it could be possible to infer disease state by matching against a priori known disease-associated T cell receptor sequences.
The genetics of celiac disease: A comprehensive review of clinical implications
2015, Journal of Autoimmunity
Celiac disease (CD) is a complex immune-related disease with a very strong genetic component. Multiple genetic findings over the last decade have added to the already known MHC influence numerous genetic variants associated to CD susceptibility. Currently, it is well-established that 6 MHC and 39 non-MHC loci, including a higher number of independent genetic variants, are associated to disease risk. Moreover, additional regions have been recently implicated in the disease, which would increase the number of involved loci. Together, the firmly described genetic variants account for roughly 31% of CD heritability, being 25% explained by the MHC influence. These new variants represent markers of disease risk and turn the identification of the causal genes and the causal variants inside the associated loci, as well as their precise biological role on the disease, into a major challenge in CD research. Numerous studies have been developed with this aim showing the high impact of risk variants on gene expression. These studies also indicate a central role of CD4⁺ T cells in CD pathogenesis and point to B cells as important players, which is in accordance with the key steps highlighted by the immunological models of pathogenesis. We comprehensively summarize the current knowledge about the genetic architecture of CD, characterized by multiple low-risk variants located within diverse loci which are most likely affecting genes with immune-related functions. These findings are leading to a better understanding of CD pathogenesis and helping in the design of new treatments. The repertoire of potential drug targets for CD has largely broadened last years, bringing us closer to get alternative or complementary treatments to the life-long gluten-free diet, the only effective treatment so far. Epigenetics and microbiota are emerging as potent factors modulating disease risk and putatively affecting disease manifestation, which are also being explored as therapeutic targets.
Historical Aspects of Mucosal Immunology
2015, Mucosal Immunology: Fourth Edition
Immunogenetics of celiac disease
2013, Pathologie Biologie
La maladie cœliaque est une entéropathie auto-immune à prédisposition génétique. Elle est associée chez presque tous les patients atteints à l’expression d’allèles spécifiques de susceptibilité, qui sont certains variants des gènes d’histocompatibilité (gènes human leucocyte antigen [HLA]) de classe II codant la molécule HLA-DQ2, et ceux codant la molécule HLA-DQ8. Sa prévalence est estimée à 1 % dans les populations européenne et nord-américaine, mais si ces allèles constituent le principal facteur de risque génétique connu à ce jour, ces marqueurs ne sont pas pour autant suffisants pour indiquer la maladie car ils sont retrouvés chez environ 30 % des individus dans la population générale. La compréhension des mécanismes immunologiques intimes de cette maladie a bénéficié de la mise en évidence des principaux épitopes immunogènes de l’agent causal, le gluten, du rôle de la transglutaminase tissulaire dans la transformation de ces épitopes, et de l’analyse à la résolution atomique de la présentation de ces antigènes par la molécule HLA-DQ. Malgré ces avancées déterminantes, le génotype HLA ne représente que 40 % du risque génétique, et le défi de demain consiste donc à identifier les gènes responsables des 60 % restants. Les nouvelles technologies de l’ADN (biopuces) ont permis d’entrer dans l’ère des études de liaison génétique pangénomiques qui utilisent les polymorphismes ponctuels de nucléotides pour identifier les loci d’intérêt. Des associations significatives avec plusieurs gènes, pour la plupart impliqués dans la réponse immunitaire, se dessinent, mais laissent entrevoir une situation complexe et variable selon les personnes.
Celiac disease is an auto-immune enteropathy involving genetic factors. It is associated in almost all the patients, to specific susceptibility alleles encoding histocompatibility antigens (HLA for human leucocyte antigen), specifically certain variants of the HLA-DQ2, and the HLA-DQ8 HLA class II molecules. Its estimated prevalence is 1% in the european and north-american populations. However, although these alleles represent the main genetic factor for this disease, they do not explain it on their own, as they are expressed by up to 30% of the population. Recent immunological advances allowed identifying the immunodominant epitopes of gluten, to establish the role of tissue transglutaminase in the disease and to define at the atomic level the presentation of these antigens by the HLA-DQ molecule. It is noteworthy that the HLA susceptibility alleles only account for 40% of the whole genetic risk, and the challenge is now to explain the remaining 60%. Genome-wide association studies using the DNA arrays technology to screen single nucleotide polymorphisms to pinpoint candidate regions and genes, have started to provide answers, but contradictory results sometimes still persist. Most of the genes emerging as statistically significantly associated with celiac disease are involved in the immune response, and suggest that the situation is complex.
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Coeliac disease is a common complex disease caused by a dietary intolerance to wheat gluten. Susceptibility is determined by both environmental and genetic factors. Coeliac disease results from complex interactions between the innate immune system, an adaptive T and B cell response and the mucosal barrier where inflammation is ultimately manifested. Genetic variants within the HLA region are well established, while variants outside of the HLA region have recently been identified. These variants are beginning to enhance our understanding of the immunology of the condition. This review focuses on the immunological pathogenesis of coeliac disease with special reference to the influence of genetic susceptibility on disease development.

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Evidence that celiac disease is primarily associated with a DC locus allelic specificity

Abstract

Lancet

Lancet

Gastroenterology

Brit. Med. Bull.

J. Clin. Invest.

Tissue Antigens

Perspectives in Coeliac Disease

Tissue Antigens

Tissue Antigens

Tissue Antigens

Immunol. Rev.

Acta Paediatr. Scand.

Tissue Antigens