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1.
Artigo em Japonês | MEDLINE | ID: mdl-33148926

RESUMO

Immunity, which denotes the protection of multicellular organisms against various bacterial and viral infections, is an essential protective mechanism for living organisms. Allergy is a reaction to a foreign substance existing in the environment that is basically not a component of the self. Additionally, autoimmune diseases are associated with the dysfunction in the recognition of self and non-self, and are pathological conditions caused by immune cells attacking their own tissues and cells. In this paper, we outline the current status of immunity with respect to the environment from the epidemiological perspective with regard to the following: (1) evolution and immunity, (2) allergy, (3) autoantibodies, (4) autoimmune diseases, (5) relationships of immunity with the environment, allergy, autoantibodies, and autoimmune diseases, and (6) celiac disease.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade , Hipersensibilidade/imunologia , Adolescente , Adulto , Idoso , Autoanticorpos , Doenças Autoimunes/epidemiologia , Evolução Biológica , Doença Celíaca/imunologia , Criança , Pré-Escolar , Meio Ambiente , Feminino , Humanos , Hipersensibilidade/epidemiologia , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
2.
PLoS One ; 15(9): e0229841, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32946470

RESUMO

Starch based gluten-free bread (formulations containing mixture of corn and potato starch with hydrocolloids) are deficient in nutrients and do not contain health promoting compounds. Therefore they could be supplemented with raw materials rich in such components, especially antioxidants. Among them pseudo-cereals, seeds, fruits and vegetables are often applied to this purpose. Potato pulp produced by processing red fleshed (Magenta Love) and purple fleshed (Violetta) varieties could become a new innovative substrate for gluten-free bread enrichment, because of high levels of endogenous polyphenols, namely flavonoids, flavonols, phenolic acids and especially anthocyanins with high antioxidant potential, as well as dietary fiber. Study material consisted of gluten-free bread enriched in the pulp. Dietary fiber, acrylamide content and antioxidant and antiradical potential of the bread were determined. Sensory evaluation included crumb elasticity, porosity and other characteristics, taste and smell. Among all analyzed gluten-free breads, the sample containing 7.5% share of freeze-dried red potato pulp Magenta Love was characterized by high content of phenolic compounds and dietary fiber, pronounced antioxidant activity, low levels of potentially dangerous acrylamide and good physical and sensory characteristics. Therefore such an addition (7.5% Magenta Love) could be recommended for industrial production of gluten-free bread.


Assuntos
Pão , Farinha/análise , Ingredientes de Alimentos/análise , Solanum tuberosum/química , Verduras/química , Acrilamida/análise , Antioxidantes/análise , Doença Celíaca/dietoterapia , Doença Celíaca/imunologia , Fibras na Dieta/análise , Liofilização/métodos , Glutens/imunologia , Humanos , Valor Nutritivo , Polifenóis/análise , Porosidade , Olfato , Amido/isolamento & purificação , Paladar
4.
Eur J Gastroenterol Hepatol ; 32(12): 1523-1526, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32956181

RESUMO

OBJECTIVES: Recent guidelines for celiac disease have allowed a biopsy-free approach in endomysial antibodies (EMAs) positive children with high antitransglutaminase (TGA-IgA) titer [>10 time upper limit of normal (ULN)]. Esophagogastroduodenoscopy is still necessary for diagnosis in children with lower title. Because elective pediatric endoscopy has been substantially shouted down during coronavirus disease (COVID-19) pandemic, many children remained undiagnosed - and therefore untreated - for a long time. We aimed to analyze the feasibility and accuracy of a biopsy-free approach in suspected celiac disease children with TGA-IgA values <10 ULN to facilitate the diagnostic process by avoiding endoscopy. METHODS: In this study cohort, we retrospectively analyzed all biopsy-confirmed diagnosis of celiac disease in our center (between 2014 and 2019). The positive predictive value (PPV) of TGA-IgA titers between 5 and 10 ULN and positive EMA in diagnosing celiac disease were determined. Mucosal atrophy and resolution of symptoms after gluten-free diet (GFD) were considered to confirm initial diagnosis. RESULTS: Of 430 celiac disease patients (F: 274; mean age 7.54 years) diagnosed by endoscopy, 84 (F: 46; mean age 8 years) with TGA-IgA between 5 and 10 ULN and positive EMA were identified. The PPV of TGA-IgA between 5 and 10 ULN and positive EMA was 0.93 (95% confidence interval 0.90-0.96). All these children had a symptom resolution and antibodies normalization after GFD. CONCLUSION: During the COVID-19 outbreak, a temporarily reduction of the TGA-IgA threshold for biopsy-sparing approach seems feasible in EMA positive children with TGA-IgA between 5 and 10 ULN.


Assuntos
Autoanticorpos/sangue , Betacoronavirus , Doença Celíaca/diagnóstico , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Guias de Prática Clínica como Assunto , Transglutaminases/imunologia , Autoanticorpos/imunologia , Biópsia , Doença Celíaca/epidemiologia , Doença Celíaca/imunologia , Criança , Comorbidade , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/imunologia , Endoscopia do Sistema Digestório , Feminino , Humanos , Masculino , Pandemias , Pneumonia Viral/enzimologia , Pneumonia Viral/imunologia , Estudos Retrospectivos , Transglutaminases/sangue
5.
Autoimmun Rev ; 19(9): 102621, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32693029

RESUMO

Candida albicans is a commensal fungus with a potential pathogenicity and celiac disease is an autoimmune condition. Both share multiple pathophysiological junctions, including serological markers against cell-wall proteins of Candida, anti-gliadin antibodies are positive in both entities, gluten and a candidal virulence factor share sequence similarity and the autoantigen of celiac disease, the tissue transglutaminase, is pivotal in Candida albicans commensalism and hostile behavior and its covalently cross linked products are stable and resistant to breakdown in the two entities. Those autoimmune/infectious cross roads are the basis for the hypothesis that Candida albicans is an additional environmental factor for celiac disease autoimmunogenesis.


Assuntos
Candida albicans/patogenicidade , Doença Celíaca/microbiologia , Anticorpos/imunologia , Autoantígenos/química , Autoantígenos/imunologia , Autoimunidade , Candida albicans/imunologia , Doença Celíaca/imunologia , Gliadina/imunologia , Humanos , Transglutaminases/química , Transglutaminases/imunologia , Fatores de Virulência/química , Fatores de Virulência/imunologia
8.
Virchows Arch ; 477(4): 507-515, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32405928

RESUMO

Coeliac disease (CD) is an autoimmune enteropathy which can present with patchy mucosal lesions. The aim of the present study is to investigate the significance of duodenal bulb biopsy in the diagnostic work-up of CD in both pediatric and adult patients, and to highlight the key points for pathologists. D1 (duodenal bulb) and D2 (distal duodenum) biopsies of 153 newly diagnosed serology-positive CD patients were evaluated for villous/crypt ratio and intraepithelial lymphocyte (IEL) counts on CD3-stained slides and were classified according to Marsh. Mucosal pathology was patchy in 15% (13% only D1 and 2% only D2) of patients, and 85% of patients had diffuse mucosal pathology involving both D1 and D2 biopsies which showed concordant histology in 60% and discordant in 25% of the cases. Though majority of the patients (75%) with only D1 involvement were pediatric cases, no significant difference was found between pediatric and adult patients when all cases were considered (17 vs 14%). Our results clearly indicate that without D1 sampling, diagnosis of CD would have been missed in a significant number of cases (13%), thereby highlighting the importance of taking duodenal biopsies from multiple sites in the diagnostic work-up of CD. We, therefore, conclude that every biopsy piece from both D1 and D2 should be carefully evaluated for the whole spectrum of mucosal changes caused by gluten ingestion and classified using a scheme based on Marsh to allow recognition of mild lesions.


Assuntos
Doença Celíaca/patologia , Duodeno/patologia , Mucosa Intestinal/patologia , Adolescente , Adulto , Idoso , Biomarcadores/análise , Biópsia , Complexo CD3/análise , Doença Celíaca/imunologia , Criança , Pré-Escolar , Duodeno/imunologia , Feminino , Humanos , Mucosa Intestinal/imunologia , Linfócitos Intraepiteliais/imunologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Adulto Jovem
10.
Food Chem ; 324: 126840, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32344339

RESUMO

Functional foods have created an open environment for the development of new solutions to health-related issues. In celiac disease, there is still no therapeutic alternative other than the observance of a gluten-free diet. In this context, we developed a wheat flour enriched in l-theanine aimed to be a potential alternative to the gluten-free diet. Through microbial transglutaminase-catalysed transamidation of gluten proteins using ethylamine as amine nucleophile, substantial amounts of glutamine residues were converted in theanine residues. Furthermore, using T-cell lines generated from intestinal biopsy specimens of celiac disease patients, this treatment showed the potential to strongly reduce the ability of gluten proteins to stimulate a T-cell-mediated immune response. From a rheological point of view, the functionality of gluten was retained. Considering L-theanine's evidence-based health benefits, a novel functional food is presented here and for celiac disease can be a path towards the development of an alternative to the gluten-free diet.


Assuntos
Doença Celíaca/imunologia , Farinha , Glutamatos/química , Glutens/química , Linfócitos T/imunologia , Doença Celíaca/dietoterapia , Dieta Livre de Glúten , Suplementos Nutricionais , Elasticidade , Etilaminas/metabolismo , Alimento Funcional , Glutens/metabolismo , Humanos , Intestinos/citologia , Intestinos/imunologia , Transglutaminases/metabolismo , Triticum
11.
Mol Immunol ; 121: 1-6, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32135400

RESUMO

The transglutaminase 2 (TG2) is one of the enigmatic enzymes with important functional diversity. It plays an important role in several pathologies such as celiac disease (CD). In patients with active CD, the abnormal retrotranscytosis of IgA/gliadin complexes is mediated by Transferrin Receptor 1 (TfR1). This triad association takes also place in IgA nephropathy (IgA-N). IgA-N is characterized by the formation of nephrotoxic complexes of IgA1 and soluble CD89 (sCD89). These complexes are abnormally deposited in the kidney. Using a humanized mouse model of IgA-N (α1KI-CD89Tg), we showed that IgA1-sCD89 complexes engender mesangial cell activation and proliferation with TfR1 and TG2 up-regulation, associated with IgA-N features. This TG2-TfR1 interaction enhances mesangial IgA1 deposition promoting inflammation. Humanized α1KI-CD89Tg mice deficient for TG2 show a decrease in TfR1 expression in kidney leading to reduced IgA1-sCD89 deposits and an improvement in IgA-N features. Moreover, TG2 is active and overexpressed in the intestine of IgA-N mice and gliadin participates to this renal pathology. In kidney as in intestine, the TG2 has a crucial role in the cooperation between TfR1-IgA and a central role in the pathogenic amplification.


Assuntos
Antígenos CD/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Gliadina/imunologia , Glomerulonefrite por IGA/imunologia , Imunoglobulina A/metabolismo , Receptores da Transferrina/metabolismo , Transglutaminases/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Doença Celíaca/imunologia , Doença Celíaca/patologia , Modelos Animais de Doenças , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/imunologia , Gliadina/metabolismo , Humanos , Imunoglobulina A/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Células Mesangiais/imunologia , Células Mesangiais/patologia , Camundongos , Camundongos Transgênicos , Receptores Fc/genética , Receptores Fc/imunologia , Receptores Fc/metabolismo , Receptores da Transferrina/imunologia , Transglutaminases/genética , Transglutaminases/imunologia , Regulação para Cima/imunologia
12.
Aliment Pharmacol Ther ; 51(7): 699-705, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32048756

RESUMO

BACKGROUND: The causes of seronegative villous atrophy can be grouped as coeliac or noncoeliac related. There is no consensus on how to approach subjects with seronegative coeliac disease. AIM: To evaluate the accuracy of both an increase in CD3+ T-cell receptor gamma delta+ (TCRγδ+ ) intraepithelial lymphocytes and coeliac lymphogram for the diagnosis of coeliac disease in patients with seronegative villous atrophy. METHODS: Sixty-seven consecutive patients with seronegative villous atrophy were included. Duodenal biopsies to assess TCRγδ+ and CD3- by flow cytometry were performed at the index endoscopy. Coeliac lymphogram was defined as an increase in TCRγδ+ plus a decrease in CD3- intraepithelial lymphocytes. Sensitivity, specificity and Fagan's nomogram were calculated. RESULTS: Coeliac disease was diagnosed in 37 patients and noncoeliac villous atrophy in 30. Coeliac patients were younger (39 ± 3 vs 55 ± 3 years; P = 0.001), more often showed HLA-DQ2/8 (97.6% vs 61%; P = 0.002) and had a more severe histology (61% vs 32% Marsh 3b-c; P = 0.055), as compared to noncoeliac ones. Coeliac lymphogram was associated with a sensitivity of 87% (CI, 73.7-95) and specificity of 96.7% (82.7-99.9), whereas evaluating only TCRγδ+ yielded a sensitivity of 91.3% (79.2-97.6) and specificity of 83.3% (65.3-94.3). Among patients with a pre-test coeliac disease probability of 30%, post-test probabilities were 92% and 5% for positive and negative coeliac lymphogram, and 70% and 4% for positive and negative TCRγδ+ . CONCLUSIONS: Coeliac lymphogram was associated with a high level of diagnostic evidence either against or in favour of coeliac disease in patients with seronegative villous atrophy.


Assuntos
Doença Celíaca/diagnóstico , Mucosa Intestinal/patologia , Linfócitos Intraepiteliais/metabolismo , Linfócitos Intraepiteliais/patologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Adulto , Atrofia/complicações , Atrofia/diagnóstico , Atrofia/imunologia , Atrofia/patologia , Biópsia , Estudos de Casos e Controles , Doença Celíaca/sangue , Doença Celíaca/imunologia , Doença Celíaca/patologia , Progressão da Doença , Feminino , Citometria de Fluxo , Humanos , Mucosa Intestinal/imunologia , Intestinos/imunologia , Intestinos/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sintomas Prodrômicos , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Testes Sorológicos
13.
Scand J Rheumatol ; 49(3): 233-238, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32043398

RESUMO

Objective: There has been no previous study comparing the frequency of sicca symptoms and Sjögren's syndrome (SS) in coeliac patients (CPs) and healthy controls (HCs) using a tight screening method. The aim of this study was to compare the frequency of sicca symptoms and SS in HCs and CPs.Method: The study included 80 CPs and 100 HCs. This study was designed as a case-control study with four phases. The frequency of SS in CPs and HCs was defined according to the 2002 American-European Consensus Group (AECG) and 2012 American College of Rheumatology (ACR) classification criteria. The frequency of sicca symptoms and SS was compared between CPs and HCs.Results: Ocular and oral symptoms occurred in 22% and 26% of CPs, respectively, compared to 13% and 10% of HCs, respectively. Proportions with oral symptoms were statistically significantly different between CPs and HCs (p = 0.005), whereas there was no significant difference for ocular symptoms (p = 0.113). According to ACR and AECG criteria, the prevalence of SS was 3.8% and 5.0% in CPs and 3.0% and 2.0% in HCs, respectively.Conclusion: Although oral symptoms were more frequent in CPs than in HCs, the frequency of SS was not different between the groups. The increased frequency of oral symptoms may be related to reasons other than autoimmunity.


Assuntos
Doença Celíaca/epidemiologia , Síndromes do Olho Seco/epidemiologia , Síndrome de Sjogren/epidemiologia , Xerostomia/epidemiologia , Adulto , Anticorpos Antinucleares/imunologia , Estudos de Casos e Controles , Doença Celíaca/imunologia , Síndromes do Olho Seco/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fator Reumatoide/imunologia , Síndrome de Sjogren/imunologia , Xerostomia/imunologia
14.
Nature ; 578(7796): 600-604, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32051586

RESUMO

Coeliac disease is a complex, polygenic inflammatory enteropathy caused by exposure to dietary gluten that occurs in a subset of genetically susceptible individuals who express either the HLA-DQ8 or HLA-DQ2 haplotypes1,2. The need to develop non-dietary treatments is now widely recognized3, but no pathophysiologically relevant gluten- and HLA-dependent preclinical model exists. Furthermore, although studies in humans have led to major advances in our understanding of the pathogenesis of coeliac disease4, the respective roles of disease-predisposing HLA molecules, and of adaptive and innate immunity in the development of tissue damage, have not been directly demonstrated. Here we describe a mouse model that reproduces the overexpression of interleukin-15 (IL-15) in the gut epithelium and lamina propria that is characteristic of active coeliac disease, expresses the predisposing HLA-DQ8 molecule, and develops villous atrophy after ingestion of gluten. Overexpression of IL-15 in both the epithelium and the lamina propria is required for the development of villous atrophy, which demonstrates the location-dependent central role of IL-15 in the pathogenesis of coeliac disease. In addition, CD4+ T cells and HLA-DQ8 have a crucial role in the licensing of cytotoxic T cells to mediate intestinal epithelial cell lysis. We also demonstrate a role for the cytokine interferon-γ (IFNγ) and the enzyme transglutaminase 2 (TG2) in tissue destruction. By reflecting the complex interaction between gluten, genetics and IL-15-driven tissue inflammation, this mouse model provides the opportunity to both increase our understanding of coeliac disease, and develop new therapeutic strategies.


Assuntos
Doença Celíaca/imunologia , Doença Celíaca/patologia , Glutens/imunologia , Antígenos HLA-DQ/imunologia , Interleucina-15/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Feminino , Antígenos HLA-DQ/genética , Humanos , Interferon gama/imunologia , Interleucina-15/genética , Masculino , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo
15.
Int J Mol Sci ; 21(3)2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32033029

RESUMO

The present research reported the effects of structural properties and immunoreactivity of celiac-toxic peptides and wheat storage proteins modified by cold jet atmospheric pressure (CJAP) plasma. It could generate numerous high-energy excited atoms, photons, electrons, and reactive oxygen and nitrogen species, including O3, H2O2, •OH, NO2- and NO3- etc., to modify two model peptides and wheat storage proteins. The Orbitrap HR-LC-MS/MS was utilized to identify and quantify CJAP plasma-modified model peptide products. Backbone cleavage of QQPFP and PQPQLPY at specific proline and glutamine residues, accompanied by hydroxylation at the aromatic ring of phenylalanine and tyrosine residues, contributed to the reduction and modification of celiac-toxic peptides. Apart from fragmentation, oxidation, and agglomeration states were evaluated, including carbonyl formation and the decline of γ-gliadin. The immunoreactivity of gliadin extract declined over time, demonstrating a significant decrease by 51.95% after 60 min of CJAP plasma treatment in vitro. The CJAP plasma could initiate depolymerization of gluten polymer, thereby reducing the amounts of large-sized polymers. In conclusion, CJAP plasma could be employed as a potential technique in the modification and reduction of celiac-toxic peptides and wheat storage proteins.


Assuntos
Gliadina/imunologia , Glutens/química , Proteínas de Plantas/imunologia , Gases em Plasma/química , Triticum/química , Pressão Atmosférica , Doença Celíaca/imunologia , Doença Celíaca/patologia , Humanos , Peróxido de Hidrogênio/química , Hidroxilação , Oxirredução , Proteínas de Plantas/química , Espécies Reativas de Nitrogênio/química
16.
Nutrients ; 12(2)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32069794

RESUMO

Dermatitis herpetiformis (DH), a cutaneous manifestation of coeliac disease, is characterized by transglutaminase (TG) 3-targeted dermal immunoglobulin A (IgA) deposits. The treatment for DH is the same as for coeliac disease, namely a life-long gluten-free diet. DH patients typically have gluten-dependent circulating autoantibodies targeting TG3 and TG2, and plasma cells secreting such autoantibodies have been detected in the small intestinal mucosa. This study investigates the gluten-responsiveness of intestinal TG3 and TG2 antibody-secreting plasma cells in 16 treated DH patients undergoing a gluten challenge. The frequency of both plasma cell populations increased significantly during the challenge, and their frequency correlated with the corresponding serum autoantibody levels at post-challenge. TG3-specific plasma cells were absent in all 18 untreated coeliac disease patients and seven non-coeliac control subjects on gluten-containing diets. These findings indicate that, in DH, both intestinal TG3- and TG2-antibody secreting plasma cells are gluten-dependent, and that TG3-antibody secreting plasma cells are DH-specific.


Assuntos
Autoanticorpos/sangue , Dermatite Herpetiforme/imunologia , Proteínas de Ligação ao GTP/imunologia , Glutens/efeitos adversos , Plasmócitos/imunologia , Transglutaminases/imunologia , Adulto , Idoso , Doença Celíaca/complicações , Doença Celíaca/imunologia , Dieta Livre de Glúten , Feminino , Glutens/imunologia , Humanos , Mucosa Intestinal/imunologia , Intestino Delgado/imunologia , Masculino , Pessoa de Meia-Idade
17.
Gastroenterology ; 158(6): 1667-1681.e12, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32032584

RESUMO

BACKGROUND & AIMS: Celiac disease could be treated, and potentially cured, by restoring T-cell tolerance to gliadin. We investigated the safety and efficacy of negatively charged 500-nm poly(lactide-co-glycolide) nanoparticles encapsulating gliadin protein (TIMP-GLIA) in 3 mouse models of celiac disease. Uptake of these nanoparticles by antigen-presenting cells was shown to induce immune tolerance in other animal models of autoimmune disease. METHODS: We performed studies with C57BL/6; RAG1-/- (C57BL/6); and HLA-DQ8, huCD4 transgenic Ab0 NOD mice. Mice were given 1 or 2 tail-vein injections of TIMP-GLIA or control nanoparticles. Some mice were given intradermal injections of gliadin in complete Freund's adjuvant (immunization) or of soluble gliadin or ovalbumin (ear challenge). RAG-/- mice were given intraperitoneal injections of CD4+CD62L-CD44hi T cells from gliadin-immunized C57BL/6 mice and were fed with an AIN-76A-based diet containing wheat gluten (oral challenge) or without gluten. Spleen or lymph node cells were analyzed in proliferation and cytokine secretion assays or by flow cytometry, RNA sequencing, or real-time quantitative polymerase chain reaction. Serum samples were analyzed by gliadin antibody enzyme-linked immunosorbent assay, and intestinal tissues were analyzed by histology. Human peripheral blood mononuclear cells, or immature dendritic cells derived from human peripheral blood mononuclear cells, were cultured in medium containing TIMP-GLIA, anti-CD3 antibody, or lipopolysaccharide (controls) and analyzed in proliferation and cytokine secretion assays or by flow cytometry. Whole blood or plasma from healthy volunteers was incubated with TIMP-GLIA, and hemolysis, platelet activation and aggregation, and complement activation or coagulation were analyzed. RESULTS: TIMP-GLIA did not increase markers of maturation on cultured human dendritic cells or induce activation of T cells from patients with active or treated celiac disease. In the delayed-type hypersensitivity (model 1), the HLA-DQ8 transgenic (model 2), and the gliadin memory T-cell enteropathy (model 3) models of celiac disease, intravenous injections of TIMP-GLIA significantly decreased gliadin-specific T-cell proliferation (in models 1 and 2), inflammatory cytokine secretion (in models 1, 2, and 3), circulating gliadin-specific IgG/IgG2c (in models 1 and 2), ear swelling (in model 1), gluten-dependent enteropathy (in model 3), and body weight loss (in model 3). In model 1, the effects were shown to be dose dependent. Splenocytes from HLA-DQ8 transgenic mice given TIMP-GLIA nanoparticles, but not control nanoparticles, had increased levels of FOXP3 and gene expression signatures associated with tolerance induction. CONCLUSIONS: In mice with gliadin sensitivity, injection of TIMP-GLIA nanoparticles induced unresponsiveness to gliadin and reduced markers of inflammation and enteropathy. This strategy might be developed for the treatment of celiac disease.


Assuntos
Doença Celíaca/tratamento farmacológico , Gliadina/administração & dosagem , Tolerância Imunológica/efeitos dos fármacos , Nanopartículas/administração & dosagem , Administração Intravenosa , Animais , Linfócitos T CD4-Positivos , Doença Celíaca/sangue , Doença Celíaca/imunologia , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Gliadina/imunologia , Gliadina/toxicidade , Glutens/administração & dosagem , Glutens/imunologia , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Humanos , Mucosa Intestinal , Leucócitos Mononucleares , Camundongos , Camundongos Transgênicos , Nanopartículas/química , Nanopartículas/toxicidade , Poliglactina 910/química , Cultura Primária de Células , Testes de Toxicidade Aguda
18.
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
19.
EBioMedicine ; 51: 102567, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31901853

RESUMO

BACKGROUND: Intestinal coeliac auto-antibodies are the marker of coeliac disease (CD). Since the determination of these antibodies is still not widely available, we used immunoassays to identify the most suitable technology for revealing intestinal auto-antibodies in the wide clinical spectrum of CD. METHODS: Intestinal auto-antibodies have been prospectively investigated in CD suspected children using two immunoassays: intestinal-deposits of IgA anti-tissue transglutaminase antibodies (anti-tTG) and biopsy-culture IgA anti-endomysium (AEA). Intestinal IgM antibodies have been determined in IgA-deficient subjects. FINDINGS: Two-hundred and twenty-one suspected CD patients were enrolled. Intestinal antibodies were tested positive for both assays in classical CD patients (n = 178) with villous atrophy and positive serum-CD antibodies, potential CD patients (n = 16) with normal intestinal mucosa and positive serum-CD antibodies, and pre-potential CD patients (n = 14) with normal intestinal mucosa and negative serum-CD antibodies. In 13/221 with normal intestinal mucosa, negative CD-serum antibodies and negative intestinal antibodies CD has been excluded. All classical, 14/16 potential and 11/14 pre-potential CD patients on gluten-free diet (GFD) improved their symptoms. In 9/11 pre-potential patients intestinal antibodies disappeared on GFD. Both assays were negative in 69/71 control subjects. The two assays showed high diagnostic sensitivity (100%) and specificity (99%). INTERPRETATION: Intestinal CD-antibodies make prompt diagnosis in the wide clinical spectrum of CD reducing the delay in diagnosis and treatment, especially in pre-potential CD patients. The easy handling biopsy culture assay is an effective diagnostic tool which should be carried out by any gastroenterology unit to recognize all CD clinical manifestations. FUNDING: Interreg Central-Europe, IRCCS "Burlo Garofolo".


Assuntos
Autoanticorpos/imunologia , Doença Celíaca/diagnóstico , Doença Celíaca/imunologia , Intestinos/imunologia , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Duodeno/imunologia , Feminino , Seguimentos , Humanos , Imunoglobulina A/imunologia , Lactente , Masculino , Sensibilidade e Especificidade , Transglutaminases/imunologia
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