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2.
Sci Rep ; 10(1): 16290, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004927

RESUMO

Celiac disease (CeD) is a gastrointestinal autoimmune disorder, whose specific molecular basis is not yet fully interpreted. Therefore, in this study, we compared the global gene expression profile of duodenum tissues from CeD patients, both at the time of disease diagnosis and after two years of the gluten-free diet. A series of advanced systems biology approaches like differential gene expression, protein-protein interactions, gene network-cluster analysis were deployed to annotate the candidate pathways relevant to CeD pathogenesis. The duodenum tissues from CeD patients revealed the differential expression of 106 up- and 193 down-regulated genes. The pathway enrichment of differentially expressed genes (DEGs) highlights the involvement of biological pathways related to loss of cell division regulation (cell cycle, p53 signalling pathway), immune system processes (NOD-like receptor signalling pathway, Th1, and Th2 cell differentiation, IL-17 signalling pathway) and impaired metabolism and absorption (mineral and vitamin absorptions and drug metabolism) in celiac disease. The molecular dysfunctions of these 3 biological events tend to increase the number of intraepithelial lymphocytes (IELs) and villous atrophy of the duodenal mucosa promoting the development of CeD. For the first time, this study highlights the involvement of aberrant cell division, immune system, absorption, and metabolism pathways in CeD pathophysiology and presents potential novel therapeutic opportunities.


Assuntos
Doença Celíaca/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/genética , Redes e Vias Metabólicas/genética , Doença Celíaca/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Mapas de Interação de Proteínas/genética
3.
Environ Res ; 186: 109439, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32409013

RESUMO

Celiac disease affects approximately 1% of the population worldwide. Little is known about environmental factors that may modulate risk in genetically susceptible populations. Persistent organic pollutants (POPs) are known endocrine disruptors and, given the interplay between the endocrine and immune systems, are plausible contributors to celiac disease. The current study aims to elucidate the association between POPs and celiac disease. We conducted a single-site pilot study of 88 patients recruited from NYU Langone's Hassenfeld Children's Hospital outpatient clinic, 30 of which were subsequently diagnosed with celiac disease using standard serology and duodenal biopsy examination. Polybrominated diphenyl ether (PBDEs), perfluoroalkyl substances (PFASs), and p,p'-dichlorodiphenyldichloroethylene (DDE) and HLA-DQ genotype category were measured in blood serum and whole blood, respectively. Multivariable logistic regressions were used to obtain odds ratios for celiac disease associated with serum POP concentrations. Controlling for sex, race, age, BMI, and genetic susceptibility score, patients with higher serum DDE concentrations had 2-fold higher odds of celiac disease (95% CI: 1.08, 3.84). After stratifying by sex, we found higher odds of celiac disease in females with serum concentrations of DDE (OR = 13.0, 95% CI = 1.54, 110), PFOS (OR = 12.8, 95% CI = 1.17, 141), perfluorooctanoic acid (OR = 20.6, 95% CI = 1.13, 375) and in males with serum BDE153, a PBDE congener (OR = 2.28, 95% CI = 1.01, 5.18). This is the first study to report on celiac disease with POP exposure in children. These findings raise further questions of how environmental chemicals may affect autoimmunity in genetically susceptible individuals.


Assuntos
Doença Celíaca , Poluentes Ambientais , Bifenilos Policlorados , Doença Celíaca/induzido quimicamente , Doença Celíaca/epidemiologia , Doença Celíaca/genética , Criança , Diclorodifenil Dicloroetileno , Poluentes Ambientais/toxicidade , Feminino , Éteres Difenil Halogenados/análise , Éteres Difenil Halogenados/toxicidade , Humanos , Masculino , Projetos Piloto
4.
Clin Sci (Lond) ; 134(10): 1151-1166, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32420596

RESUMO

A percentage of celiac disease (CD) patients develop refractory type-2 disease (RCD2), a condition associated with increased risk of enteropathy-associated T-cell-lymphoma (EATL) and without therapeutic option. Therefore, we profiled the miRNome in series of peripheral T-cell lymphomas (PTCLs), CD, RCD1 or 2 and in the murine interleukin-15 (IL15)-transgenic (TG) model of RCD. The transcriptome was analyzed in 18 intestinal T-cell lymphomas (ITLs). Bioinformatics pipelines provided significant microRNA (miRNA) lists and predicted targets that were confirmed in a second set of patients. Our data show that ITLs have a unique miRNA profile with respect to other PTCLs. The c-MYC regulated miR-17/92 cluster distinguishes monomorphic epitheliotropic ITL (MEITL) from EATL and prognosticates EATL outcome. These miRNAs are decreased in IL15-TG mice upon Janus kinase (JAK) inhibition. The random forest algorithm identified a signature of 38 classifier miRNAs, among which, the miR-200 and miR-192/215 families were progressively lost in RCD2 and ITL-CD, whereas miR-17/92 and C19MC miRNAs were up-regulated. Accordingly, SMAD3, MDM2, c-Myc and activated-STAT3 were increased in RCD2 and EATL tissues while JAK inhibition in IL15-TG mice restored their levels to baseline. Our data suggest that miRNAs circuit supports activation of STAT3 and c-Myc oncogenic signaling in RCD2, thus contributing to lymphomagenesis. This novel understanding might pave the way to personalized medicine approaches for RCD and EATL.


Assuntos
Carcinogênese/genética , Doença Celíaca/genética , Regulação Neoplásica da Expressão Gênica , Linfoma/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Algoritmos , Animais , Biomarcadores Tumorais/metabolismo , Feminino , Intestinos/patologia , Linfoma/patologia , Masculino , Camundongos Transgênicos , MicroRNAs/metabolismo , Modelos Biológicos , Prognóstico , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Smad3/metabolismo , Regulação para Cima/genética
6.
Eur J Endocrinol ; 182(5): 473-480, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32229696

RESUMO

Objective: Co-aggregation of autoimmune diseases is common, suggesting partly shared etiologies. Genetic factors are believed to be important, but objective measures of environmental vs heritable influences on co-aggregation are absent. With a novel approach to twin studies, we aimed at estimating heritability and genetic overlap in seven organ-specific autoimmune diseases. Design: Prospective twin cohort study. Methods: We used a cohort of 110 814 twins to examine co-aggregation and heritability of Hashimoto's thyroiditis, atrophic gastritis, celiac disease, Graves' disease, type 1 diabetes, vitiligo and Addison's disease. Hazard ratios (HR) were calculated for twins developing the same or different disease as compared to their co-twin. The differences between monozygotic and dizygotic twin pairs were used to estimate the genetic influence on co-aggregation. Heritability for individual disorders was calculated using structural equational modeling adjusting for censoring and truncation of data. Results: Co-aggregation was more pronounced in monozygotic twins (median HR: 3.2, range: 2.2-9.2) than in dizygotic twins (median HR: 2.4, range: 1.1-10.0). Heritability was moderate for atrophic gastritis (0.38, 95% CI: 0.23-0.53) but high for all other diseases, ranging from 0.60 (95% CI: 0.49-0.71) for Graves' disease to 0.97 (95% CI: 0.91-1.00) for Addison's disease. Conclusions: Overall, co-aggregation was more pronounced in monozygotic than in dizygotic twins, suggesting that disease overlap is largely attributable to genetic factors. Co-aggregation was common, and twins faced up to a ten-fold risk of developing diseases not present in their co-twin. Our results validate and refine previous heritability estimates based on smaller twin cohorts.


Assuntos
Autoimunidade/fisiologia , Doença de Addison/genética , Autoimunidade/genética , Doença Celíaca/genética , Estudos de Coortes , Feminino , Gastrite Atrófica/genética , Predisposição Genética para Doença/genética , Doença de Graves/genética , Humanos , Masculino , Modelos de Riscos Proporcionais , Estudos Prospectivos , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética
7.
J Diabetes Res ; 2020: 7869350, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32149153

RESUMO

Aim: The aim of the study was to determine the usefulness of HLA DQ2/DQ8 genotyping in children with T1D in various clinical situations: as a screening test at the diabetes onset, as a verification of the diagnosis in doubtful situations, and as a test estimating the risk of CD in the future. Materials and methods. Three groups of patients with T1D were included: newly diagnosed (n = 92), with CD and villous atrophy (n = 92), with CD and villous atrophy (n = 92), with CD and villous atrophy (n = 30), and with potential CD (n = 23). Genetic tests were performed (commercial test, PCR, and REX), and clinical data were collected. Results: The results of genetic tests confirmed the presence of DQ2/DQ8 in 94% of children with diabetes (group I) and in 100% of children with diabetes and CD (groups II and III, respectively). Comparative analysis of the HLA DQ2/DQ8 distribution did not show any differences. Allele DRB1∗04 (linked with HLA DQ8) was significantly less common in children with diabetes and CD (group I versus groups II and III, 56.5% vs. 24.5%; p = 0.001). The probability of developing CD in DRB1∗04-positive patients was 4 times lower (OR 0.25; 95% CI 0.118-0.529; p = 0.001). The probability of developing CD in DRB1∗04-positive patients was 4 times lower (OR 0.25; 95% CI 0.118-0.529; p = 0.001). The probability of developing CD in DRB1∗04-positive patients was 4 times lower (OR 0.25; 95% CI 0.118-0.529. Conclusions: Genotyping HLA DQ2/DQ8 as a negative screening has limited use in assessing the risk of CD at the diabetes onset and does not allow to verify the diagnosis of CD in doubtful situations. The presence of the DRB1∗04 allele modulates the risk of CD and significantly reduces it and can predict a potential form.


Assuntos
Doença Celíaca/genética , Diabetes Mellitus Tipo 1/genética , Antígenos HLA-DQ/genética , Adolescente , Alelos , Criança , Pré-Escolar , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino
8.
J Agric Food Chem ; 68(15): 4485-4492, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32195585

RESUMO

Celiac disease (CD) is a chronic illness characterized by an inflammatory process triggered by gluten protein intake. Recent evidence has suggested that the lower relative abundance of bifidobacteria in the intestinal lumen may be associated with CD. Herein, we assessed the effect of the Bifidobacterium species Bifidobacterium bifidum, Bifidobacterium longum, Bembidion breve, Bifidobacterium animalis alone, and also a Bifidobacterium consortium on the digestion of intact gluten proteins (gliadins and glutenins) and the associated immunomodulatory responses elicited by the resulting peptides. The cytotoxicity and proinflammatory responses were evaluated through the activation of NF-kB p65 and the expression of cytokines TNF-α and IL-1ß in Caco-2 cell cultures exposed to gluten-derived peptides. The peptides induced a clear reduction in cytotoxic responses and proinflammatory marker levels compared to the gluten fragments generated during noninoculated gastrointestinal digestion. These results highlight the possible use of probiotics based on bifidobacteria as a prospective treatment for CD.


Assuntos
Bifidobacterium/metabolismo , Gliadina/metabolismo , Glutens/metabolismo , Biotransformação , Células CACO-2 , Doença Celíaca/tratamento farmacológico , Doença Celíaca/genética , Doença Celíaca/imunologia , Gliadina/química , Gliadina/imunologia , Glutens/imunologia , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Probióticos/administração & dosagem , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
9.
Hematol Oncol ; 38(3): 399-405, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32010998

RESUMO

Refractory celiac disease (RCD) is a rare condition associated with high morbidity that develops in individuals with celiac disease. It is known to be biologically heterogeneous, and currently two types are recognized based on immunophenotypic and molecular features, type I (RCD I) and type II (RCD II). Differentiating between RCD I and RCD II is critical, as patients with RCD II have substantially worse outcomes and a high risk of developing enteropathy-associated T-cell lymphoma. However, the current RCD classification is limited in scope, and atypical presentations and immunophenotypes are not recognized at present. Herein, we describe a unique case of RCD II with atypical clinical (primarily neurologic manifestations and lack of significant gastrointestinal symptoms), histopathologic (no villous atrophy), immunophenotypic (virtual absence of cytoplasmic CD3 expression), and molecular features (absence of clonal TR rearrangement and identification of pathogenic STAT3 and KMT2D mutations). This case highlights limitations of the current RCD classification system and the utility of next generation sequencing (NGS) studies in the diagnostic workup of RCD. Future algorithms need to recognize extraintestinal manifestations and incorporate atypical histopathologic and immunophenotypic features, as well as results of NGS analysis for RCD II classification.


Assuntos
Biomarcadores/análise , Doença Celíaca/classificação , Doença Celíaca/patologia , Rearranjo Gênico , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T/genética , Imunofenotipagem/normas , Idoso , Doença Celíaca/genética , Doença Celíaca/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino
10.
Int J Mol Sci ; 21(3)2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32046248

RESUMO

Microbial transglutaminase (mTG) is a survival factor for microbes, but yeasts, fungi, and plants also produce transglutaminase. mTG is a cross-linker that is heavily consumed as a protein glue in multiple processed food industries. According to the manufacturers' claims, microbial transglutaminase and its cross-linked products are safe, i.e., nonallergenic, nonimmunogenic, and nonpathogenic. The regulatory authorities declare it as "generally recognized as safe" for public users. However, scientific observations are accumulating concerning its undesirable effects on human health. Functionally, mTG imitates its family member, tissue transglutaminase, which is the autoantigen of celiac disease. Both these transglutaminases mediate cross-linked complexes, which are immunogenic in celiac patients. The enzyme enhances intestinal permeability, suppresses mechanical (mucus) and immunological (anti phagocytic) enteric protective barriers, stimulates luminal bacterial growth, and augments the uptake of gliadin peptide. mTG and gliadin molecules are cotranscytosed through the enterocytes and deposited subepithelially. Moreover, mucosal dendritic cell surface transglutaminase induces gliadin endocytosis, and the enzyme-treated wheat products are immunoreactive in CD patients. The present review summarizes and updates the potentially detrimental effects of mTG, aiming to stimulate scientific and regulatory debates on its safety, to protect the public from the enzyme's unwanted effects.


Assuntos
Doença Celíaca/metabolismo , Aditivos Alimentares/química , Transglutaminases/metabolismo , Animais , Doença Celíaca/genética , Células Dendríticas/metabolismo , Humanos , Saúde Pública , Transglutaminases/genética
11.
Hum Immunol ; 81(2-3): 59-64, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32005535

RESUMO

BACKGROUNDS: Patients with celiac disease (CeD) carry the major histocompatibility complex class II, HLA-DQ2 or DQ8 haplotype; the absence of these haplotypes excludes a diagnosis of CeD. While the most common and highest risk HLA haplotypes in CeD have been established, the risk profiles of the less common and equivocal HLA haplotypes need further refinement. The aim of this study was to use a large national patient cohort to further stratify the risk gradient of HLA-DQ haplotypes. METHODS: The study cohort included 24,339 adult patients with suspected CeD and immunoglobulin (Ig)A sufficiency (total IgA ≥ 70 mg/dL) whose samples were assessed at Mayo Clinic Laboratories for HLA-DQ genotyping, total IgA, and tissue transglutaminase (tTG)-IgA. Data from a subset of the patients who had duodenal biopsies were analyzed to determine the risk gradient of CeD. Logistic regression models were used to evaluate the risk gradient and to calculate odds ratios (ORs) for being positive to CeD serology according to different HLA-DQ2 and DQ8 heterodimers. RESULTS: Of the 24,339 patients, 55% (n = 13,456) expressed HLA-DQ2 or DQ8 heterodimers. Compared with patients who had non-permissive HLA-DQ heterodimers, patients who had HLA-DQ2 homozygosity (HLA-DQ2.5/DQ2.5, HLA-DQ2.5/DQ2.2, or HLA-DQ2.2/DQ2.2) showed increased odds for tTG-IgA positivity (OR = 96.9; 95% CI, 58.3-147.9). Interestingly, the odds for patients who were compound heterozygous for HLA-DQ2.5 and HLA-DQ8 were similar to those for HLA-DQ2.5 heterozygotes. However, a single HLA-DQ2.2 haplotype (without HLA-DQ8, DQ2.2 heterozygous) was not associated with tTG-IgA positivity. These findings were confirmed in a subset of patients (n = 738) who had duodenal biopsies performed in addition to CeD serologic testing. DISCUSSION: This large national reference laboratory cohort study demonstrated that HLA-DQ2.2 heterozygous is not associated with positive tTG-IgA serology, suggesting the reclassification of this haplotype as non-permissive for CeD.


Assuntos
Doença Celíaca/genética , Predisposição Genética para Doença/genética , Antígenos HLA-DQ/genética , Adulto , Estudos de Coortes , Feminino , Haplótipos , Heterozigoto , Humanos , Masculino , Medição de Risco
12.
BMC Med Genomics ; 13(1): 16, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32014011

RESUMO

BACKGROUND: Coeliac disease (CD) is a autoimmune disease characterised by mucosal inflammation in the small intestine in response to dietary gluten. Genetic factors play a key role with CD individuals carrying either the HLA-DQ2 or HLA-DQ8 haplotype, however these haplotypes are present in half the general population making them necessary but insufficient to cause CD. Epigenetic modifications, including DNA methylation that can change in response to environmental exposure could help to explain how interactions between genes and environmental factors combine to trigger disease development. Identifying changes in DNA methylation profiles in individuals with CD could help discover novel genomic regions involved in the onset and development of CD. METHODS: The Illumina InfiniumMethylation450 Beadchip array (HM450) was used to compare DNA methylation profiles in saliva, in CD and non-CD affected individuals. CD individuals who had been diagnosed at least 2 years previously; were on a GFD; and who were currently asymptomatic; were compared to age and sex-matched non-CD affected healthy controls. Bisulphite pyrosequencing was used to validate regions found to be differentially methylated. These regions were also validated in a second larger cohort of CD and non-CD affected individuals. RESULTS: Methylation differences within the HLA region at HLA-DQB1 were identified on HM450 but could not be confirmed with pyrosequencing. Significant methylation differences near the SLC17A3 gene were confirmed on pyrosequencing in the initial pilot cohort. Interestingly pyrosequencing sequencing of these same sites within a second cohort of CD and non-CD affected controls produced significant methylation differences in the opposite direction. CONCLUSION: Altered DNA methylation profiles appear to be present in saliva in CD individuals. Further work to confirm whether these differences are truly associated with CD is needed.


Assuntos
Doença Celíaca/genética , Metilação de DNA , Cadeias beta de HLA-DQ/genética , Haplótipos , Proteínas Cotransportadoras de Sódio-Fosfato Tipo I/genética , Adulto , Feminino , Antígenos HLA-DQ/genética , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto
13.
An Pediatr (Barc) ; 92(2): 110.e1-110.e9, 2020 Feb.
Artigo em Espanhol | MEDLINE | ID: mdl-31956054

RESUMO

Coeliac disease is a systemic immune-mediated disorder triggered by the ingestion of gluten, which is given in genetically predisposed subjects. It manifests with a wide variety of clinical symptoms, specific serological markers, HLA-DQ2/DQ8 haplotype and enteropathy. The criteria followed for this have usually been those established by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) since 1969. These criteria have advanced from the need of several intestinal biopsies to, thanks to the development of serological tests of high sensitivity and specificity, considering the enteropathy as one more element in this diagnosis and makes it possible to perform a diagnosis without the need of an intestinal biopsy in certain circumstances. The updated review of the 2012 criteria in 2019 provides new evidence on some aspects, such as the role of HLA, the diagnosis of asymptomatic patients, and the effectiveness of the serological markers. These aspects are reviewed in detail, with the aim of facilitating the rational application of the new 2020 criteria at all care levels. In this sense, Paediatric Primary Care is fundamental in the search for active cases and to perform a first serological study, being recommended that the diagnosis is always established by a Paediatric Gastroenterologist.


Assuntos
Doença Celíaca/diagnóstico , Antígenos HLA-DQ/genética , Doença Celíaca/genética , Criança , Gastroenterologia , Glutens/efeitos adversos , Humanos , Sensibilidade e Especificidade
14.
Proc Natl Acad Sci U S A ; 117(6): 3063-3073, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31974305

RESUMO

The highly homologous human leukocyte antigen (HLA)-DQ2 molecules, HLA-DQ2.5 and HLA-DQ2.2, are implicated in the pathogenesis of celiac disease (CeD) by presenting gluten peptides to CD4+ T cells. However, while HLA-DQ2.5 is strongly associated with disease, HLA-DQ2.2 is not, and the molecular basis underpinning this differential disease association is unresolved. We here provide structural evidence for how the single polymorphic residue (HLA-DQ2.5-Tyr22α and HLA-DQ2.2-Phe22α) accounts for HLA-DQ2.2 additionally requiring gluten epitopes possessing a serine at the P3 position of the peptide. In marked contrast to the biased T cell receptor (TCR) usage associated with HLA-DQ2.5-mediated CeD, we demonstrate with extensive single-cell sequencing that a diverse TCR repertoire enables recognition of the immunodominant HLA-DQ2.2-glut-L1 epitope. The crystal structure of two CeD patient-derived TCR in complex with HLA-DQ2.2 and DQ2.2-glut-L1 (PFSEQEQPV) revealed a docking strategy, and associated interatomic contacts, which was notably distinct from the structures of the TCR:HLA-DQ2.5:gliadin epitope complexes. Accordingly, while the molecular surfaces of the antigen-binding clefts of HLA-DQ2.5 and HLA-DQ2.2 are very similar, differences in the nature of the peptides presented translates to differences in responding T cell repertoires and the nature of engagement of the respective antigen-presenting molecules, which ultimately is associated with differing disease penetrance.


Assuntos
Doença Celíaca , Antígenos HLA-DQ , Receptores de Antígenos de Linfócitos T , Linfócitos T CD4-Positivos/química , Linfócitos T CD4-Positivos/metabolismo , Doença Celíaca/genética , Doença Celíaca/imunologia , Doença Celíaca/metabolismo , Linhagem Celular , Cristalografia por Raios X , Epitopos de Linfócito T/química , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/metabolismo , Glutens/química , Glutens/imunologia , Glutens/metabolismo , Antígenos HLA-DQ/química , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/metabolismo , Humanos , Modelos Moleculares , Ligação Proteica , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo
16.
PLoS One ; 15(1): e0226546, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31895924

RESUMO

BACKGROUND: Celiac disease (CD) is a systemic immune-mediated disorder developing in HLA genetically predisposed individuals carrying HLA-DQ2 and/or HLA-DQ8 molecules. Recent evidences supported a predominant importance of HLA-DQB1 locus and, in particular, HLA-DQB1*02 alleles. This diagnosis is poorly considered in Kazakhstan, because of the assumption that CD is not prevalent in this population. OBJECTIVE: To demonstrate that the genetic predisposition to CD in Kazakhstan is not negligible and is actually comparable to Western populations. METHODS: Through the analysis of HLA-DQ genotypes of healthy bone marrow donors from Kazakhstan's national registry, we estimated the HLA-related genetic predisposition to CD in the country. RESULTS: We demonstrated that the frequency of CD-related HLA-DQB1 alleles and, as a consequence, of predisposed individuals to CD in Kazakhstan is significant and comparable to countries with the highest disease prevalence. CONCLUSION: Considering the dietary style in Kazakhstan, including wheat as a staple food, these results provided a preliminary background of knowledge to expect a significant CD prevalence in Kazakhstan and Central Asia by implementing appropriate and cost-effective diagnostic strategies.


Assuntos
Doença Celíaca/epidemiologia , Predisposição Genética para Doença , Cadeias beta de HLA-DQ/genética , Polimorfismo Genético , Padrões de Prática Médica/estatística & dados numéricos , Adolescente , Adulto , Alelos , Estudos de Casos e Controles , Doença Celíaca/genética , Feminino , Genótipo , Humanos , Cazaquistão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto Jovem
17.
Virchows Arch ; 476(5): 711-723, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31696360

RESUMO

Celiac disease (CD) is a risk factor for developing small-bowel carcinoma with a 14-fold higher risk compared with general population. As small-bowel carcinomas associated with CD (CD-SBCs) are extremely rare, very few molecular data are available about their pathogenesis, and information about their transcriptomic profiling is lacking. We generated RNA-seq data on 13 CD-SBCs, taken from the largest well-characterized series published so far, collected by the Small Bowel Cancer Italian Consortium, and compared the tumor transcriptional signatures with the four Consensus Molecular Subtypes (CMS) of colorectal carcinoma by applying the "CMS classifier." CpG Island Methylator Phenotype (CIMP) was evaluated using methylation-sensitive multiple ligation-dependent probe amplification. Up to 12 of 13 cancers fell within the two main subtypes exhibiting high immune and inflammatory signatures, i.e., subtypes 1 and 4. The first and predominant subset was commonly microsatellite unstable, and exhibited CIMP and high CD3+ and CD8+ T cell infiltration. Moreover, it showed increased expression of genes associated with T helper 1 and natural killer cell infiltration, as well as upregulation of apoptosis, cell cycle progression, and proteasome pathways. By contrast, cancers falling in subtype 4 showed prominent transforming growth factor-ß activation and were characterized by complement-associated inflammation, matrix remodeling, cancer-associated stroma production, and angiogenesis. Parallel histologic and histochemical analysis confirmed such tumor subtyping. In conclusion, two molecular subtypes have been consistently identified in our series of CD-SBCs, a microsatellite instability-immune and a mesenchymal subtype, the former likely associated with an indolent and the latter with a worse tumor behavior.


Assuntos
Doença Celíaca/genética , Neoplasias Intestinais/genética , Instabilidade de Microssatélites , Transcriptoma , Adulto , Idoso , Doença Celíaca/classificação , Doença Celíaca/complicações , Doença Celíaca/patologia , Estudos de Coortes , Biologia Computacional , Ilhas de CpG/genética , Metilação de DNA , Feminino , Perfilação da Expressão Gênica , Humanos , Mucosa Intestinal/patologia , Neoplasias Intestinais/classificação , Neoplasias Intestinais/etiologia , Neoplasias Intestinais/patologia , Intestino Delgado/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Fatores de Risco , Análise de Sequência de RNA
18.
Gene ; 726: 144165, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31726085

RESUMO

GWAS studies have identified variant rs 17810546 in a non-coding region on chromosome 3 as a risk factor for several auto-immune diseases, including Celiac Disease. In silico analysis reveals that this variant is located in a transcription regulatory site. By means of reporter constructs we show that this region can override the expression rate of a gene as determined by its native promoter and that this modulation is influenced by the genetic composition of the haplotype which rs17810546 forms with a nearby other variant, rs761008. Secondly, we present data that this genetically imprinted modulation could be involved in Celiac Disease through the IL12A gene which is located 40 Kb downstream of this regulatory region. Based on our findings it is most likely that the IL12A gene does so as part of the cytokine IL-35.


Assuntos
Doença Celíaca/genética , Inativação Gênica/fisiologia , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Linhagem Celular , Estudo de Associação Genômica Ampla/métodos , Células HEK293 , Haplótipos/genética , Humanos , Interleucinas/genética , Regiões Promotoras Genéticas/genética , Transcrição Genética/genética
19.
PLoS One ; 14(12): e0226478, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31834915

RESUMO

Non-celiac wheat sensitivity (NCWS), also referred to as non-celiac gluten sensitivity, is a recently described disorder triggered by wheat/gluten ingestion. NCWS elicits a wide range of symptoms including diarrhoea, intestinal discomfort, and fatigue in analogy with other wheat/gluten-related disorders and celiac disease in particular. From the pathological standpoint, NCWS patients only have a slight increase of intraepithelial lymphocytes, while antibodies to tissue transglutaminase (tTG) and villous atrophy, otherwise diagnostic features of celiac disease, are absent. To date, the diagnosis of NCWS relies on symptoms and exclusion of confounding diseases, since biomarkers are not yet available. Here, the expression levels of selected miRNAs were examined in duodenal biopsies and peripheral blood leukocytes collected from newly diagnosed patients with NCWS and, as controls, from patients with celiac disease and gluten-independent gastrointestinal problems. We identified a few miRNAs whose expression is higher in the intestinal mucosa of patients affected by NCWS in comparison to control patients affect by gluten-independent dyspeptic symptoms (Helicobacter pylori-negative) and celiac disease. The present study provided the first evidence that NCWS patients have a characteristic miRNA expression patterns, such peculiarity could be exploited as a biomarker to the diagnosis of this disease.


Assuntos
Biomarcadores/análise , Doença Celíaca/diagnóstico , Glutens/imunologia , MicroRNAs/genética , Triticum/imunologia , Hipersensibilidade a Trigo/diagnóstico , Adulto , Estudos de Casos e Controles , Doença Celíaca/genética , Doença Celíaca/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hipersensibilidade a Trigo/genética , Hipersensibilidade a Trigo/imunologia
20.
BMC Gastroenterol ; 19(1): 189, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730447

RESUMO

BACKGROUND: There is an unmet need for novel treatments, such as drugs or vaccines, adjunctive to or replacing a burdensome life-long gluten-free diet for coeliac disease. The gold standard for successful treatment is a healed small intestinal mucosa, and therefore, the outcome measures in proof-of-concept studies should be based on evaluation of small intestine biopsies. We here evaluated morphometric, immunohistochemical and messenger RNA (mRNA) expression changes in coeliac disease patients challenged with gluten using PAXgene fixed paraffin-embedded biopsies. METHODS: Fifteen coeliac disease patients were challenged with 4 g of gluten per day for 10 weeks and 24 non-coeliac patients served as disease controls. A wide array of histological and immunohistochemical staining and mRNA-based gene expression tests (RT-qPCR and RNAseq) were carried out. RESULTS: Digital quantitative villous height: crypt depth ratio (VH: CrD) measurements revealed significant duodenal mucosal deterioration in all coeliac disease patients on gluten challenge. In contrast, the Marsh-Oberhuber class worsened in only 80% of coeliac patients. Measuring the intraepithelial CD3+ T-lymphocyte and lamina propria CD138+ plasma cell densities simultaneously proved to be a meaningful new measure of inflammation. Stainings for γδ T cells and IgA deposits, where previously frozen samples have been needed, were successful in PAXgene fixed paraffin-embedded samples. Messenger RNA extraction from the same paraffin-embedded biopsy block was successful and allowed large-scale qRT-PCR and RNAseq analyses for gene expression. Molecular morphometry, using the mRNA expression ratio of villous epithelium-specific gene APOA4 to crypt proliferation gene Ki67, showed a similar significant distinction between paired baseline and post-gluten challenge biopsies as quantitative histomorphometry. CONCLUSION: Rigorous digitally measured histologic and molecular markers suitable for gluten challenge studies can be obtained from a single paraffin-embedded biopsy specimen. Molecular morphometry seems to be a promising new tool that can be used in situations where assessing duodenal mucosal health is of paramount importance. In addition, the diagnostically valuable IgA deposits were now stained in paraffin-embedded specimens making them more accessible in routine clinics.


Assuntos
Biópsia/métodos , Doença Celíaca/genética , Doença Celíaca/patologia , Duodeno/patologia , Expressão Gênica , Mucosa Intestinal/patologia , RNA Mensageiro/genética , Adulto , Doença Celíaca/dietoterapia , Doença Celíaca/imunologia , Duodeno/imunologia , Fixadores , Imunofluorescência , Formaldeído , Glutens/imunologia , Humanos , Mucosa Intestinal/imunologia , Inclusão em Parafina , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA , Linfócitos T/patologia
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