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1.
Autoimmun Rev ; 19(5): 102513, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32173515

RESUMO

BACKGROUND: The clinical presentation of celiac disease (CD) varies between children. The objective of this study was to document the pre-test probability for CD based on symptoms and routine laboratory test and to evaluate the performance of two IgA anti-tissue transglutaminase (tTG) assays. We critically reviewed the concept of using multiples of the manufacturer's upper limit of normal (ULN), as proposed in the ESPGHAN guidelines (if IgA tTG is >10 times ULN, no biopsy is needed). METHODS: The retrospective study included 91 children with newly diagnosed CD and 605 controls (<16 years). All underwent upper endoscopy with small bowel biopsies. Four laboratory parameters and 16 symptoms were registered. All patients were tested for IgA anti-tTG antibodies with assays from Inova Diagnostics and Thermo Fisher Scientific. RESULTS: Some combinations of clinical symptoms and laboratory parameters had a high pre-test probability for CD, such as (combinations of) anorexia, failure to thrive, low ferritin level and elevated AST. The diagnostic performance of both IgA anti-tTG assays was excellent and comparable (no difference in ROC curve area under the curve). At a threshold that corresponds to a specificity of 100% (5 times ULN for Inova Diagnostics and 2 times ULN for Thermo Fisher), the sensitivity was 82% for both assays. At the 10 times ULN threshold, the sensitivity differed between the assays (77% vs. 57%), indicating that such threshold does not completely align interpretation across companies. CONCLUSIONS: Our study showed that some combinations of symptoms and aberrant laboratory parameters had a high pre-test probability. The use of the ESPGHAN non-biopsy approach could reduce small bowel biopsies, but thresholds for IgA-tTG levels are not aligned across assays and should be based on predefined likelihood ratios or specificity.


Assuntos
Doença Celíaca/sangue , Doença Celíaca/diagnóstico , Adolescente , Autoanticorpos/sangue , Autoanticorpos/imunologia , Biópsia , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Sensibilidade e Especificidade , Transglutaminases/imunologia
3.
Gastroenterology ; 158(1): 151-159.e3, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31560892

RESUMO

BACKGROUND & AIMS: Celiac disease can develop at any age, but outcomes of adults with positive results from serologic tests for tissue transglutaminase antibodies (tTGA) without endoscopic determination of celiac disease (called celiac autoimmunity) have not been thoroughly evaluated. We investigated the proportion of adults with celiac autoimmunity at a community medical center and their progression to celiac disease. METHODS: We analyzed waste blood samples from a community clinic from 15,551 adults for tTGA and, if titer results were above 2 U/mL, for endomysial antibody. The blood samples had been collected at 2 time points (median interval, 8.8 years) from 2006 through 2017. We collected data from the clinic on diagnoses of celiac disease based on duodenal biopsy analysis. RESULTS: Of the serum samples collected at the first time point, 15,398 had negative results for tTGA, and 153 had positive results for tTGA (>4 U/mL). Based on medical records, 6 individuals received a diagnosis of celiac disease, for a cumulative incidence of celiac disease diagnosis of 0.06% (95% confidence interval, 0.01-0.11). Forty-nine (0.32%) individuals with a negative result from the first serologic test for tTGA had a positive result from the second test. Among the 153 adults who were tTGA positive at the first time point, 31 (20%) had a subsequent diagnosis of celiac disease, 81 (53%) remained positive for tTGA without a clinical diagnosis of celiac disease, and 41 (27%) had negative test results for tTGA at the second time point. Higher initial tTGA titers, female sex, and a history of hypothyroidism and autoimmune disease were associated with increased risks of subsequent diagnosis of celiac disease. Interestingly, adults whose first blood sample had a positive test result but second blood sample had a negative result for tTGA were older, had lower-than-average initial tTGA titer results, and had a higher mean body mass index than adults whose blood samples were positive for tTGA at both time points and adults later diagnosed with celiac disease. CONCLUSIONS: In an analysis of serum samples collected from a community clinic an average of 8.8 years apart, we found that fewer than 1% of adults with negative results from an initial test for tTGA have a positive result on a second test. Of adults with positive results from the test for tTGA, only 20% are later diagnosed with celiac disease; the remaining individuals maintain persistent increases in tTGA without diagnoses of celiac disease or have negative results from second tests.


Assuntos
Autoanticorpos/sangue , Autoimunidade , Doença Celíaca/epidemiologia , Centros Comunitários de Saúde/estatística & dados numéricos , Proteínas de Ligação ao GTP/imunologia , Transglutaminases/imunologia , Adulto , Autoanticorpos/imunologia , Biópsia , Doença Celíaca/diagnóstico , Doença Celíaca/imunologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Estudos Prospectivos , Estudos Soroepidemiológicos
4.
Chem Commun (Camb) ; 55(76): 11342-11345, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31479092

RESUMO

Site-selective labelling of antibodies (Abs) can circumvent problems from heterogeneity of conventional conjugation. Here, we evaluate the industrially-applied chemoenzymatic 'Q-tag' strategy based on transglutaminase-mediated (TGase) amide-bond formation in the generation of 89Zr-radiolabelled antibody conjugates. We show that, despite previously suggested high regioselectivity of TGases, in the anti-Her2 Ab Herceptin™ more precise native MS indicates only 70-80% functionalization at the target site (Q298H), in competition with modification at other sites, such as Q3H critically close to the CDR1 region.


Assuntos
Anticorpos/química , Imunoconjugados/química , Radioisótopos/química , Zircônio/química , Amidas/química , Amidas/imunologia , Amidas/metabolismo , Anticorpos/imunologia , Imunoconjugados/imunologia , Estrutura Molecular , Transglutaminases/química , Transglutaminases/imunologia , Transglutaminases/metabolismo , Zircônio/imunologia
5.
Molecules ; 24(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509944

RESUMO

Nucleic Acid Therapeutics (NATs), including siRNAs and AntiSense Oligonucleotides (ASOs), have great potential to drug the undruggable genome. Targeting siRNAs and ASOs to specific cell types of interest has driven dramatic improvement in efficacy and reduction in toxicity. Indeed, conjugation of tris-GalNAc to siRNAs and ASOs has shown clinical efficacy in targeting diseases driven by liver hepatocytes. However, targeting non-hepatic diseases with oligonucleotide therapeutics has remained problematic for several reasons, including targeting specific cell types and endosomal escape. Monoclonal antibody (mAb) targeting of siRNAs and ASOs has the potential to deliver these drugs to a variety of specific cell and tissue types. However, most conjugation strategies rely on random chemical conjugation through lysine or cysteine residues resulting in conjugate heterogeneity and a distribution of Drug:Antibody Ratios (DAR). To produce homogeneous DAR-2 conjugates with two siRNAs per mAb, we developed a novel two-step conjugation procedure involving microbial transglutaminase (MTGase) tagging of the antibody C-terminus with an azide-functionalized linker peptide that can be subsequently conjugated to dibenzylcyclooctyne (DBCO) bearing oligonucleotides through azide-alkyne cycloaddition. Antibody-siRNA (and ASO) conjugates (ARCs) produced using this strategy are soluble, chemically defined targeted oligonucleotide therapeutics that have the potential to greatly increase the number of targetable cell types.


Assuntos
Anticorpos/farmacologia , Imunoconjugados/química , Oligonucleotídeos Antissenso/imunologia , RNA Interferente Pequeno/imunologia , Anticorpos/química , Anticorpos/imunologia , Azidas/química , Linhagem da Célula/efeitos dos fármacos , Reação de Cicloadição , Ciclo-Octanos/química , Sistemas de Liberação de Medicamentos , Endossomos/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/imunologia , Humanos , Imunoconjugados/imunologia , Imunoconjugados/farmacologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Oligonucleotídeos Antissenso/antagonistas & inibidores , Oligonucleotídeos Antissenso/química , Peptídeos/química , Peptídeos/farmacologia , RNA Interferente Pequeno/antagonistas & inibidores , RNA Interferente Pequeno/química , Transglutaminases/química , Transglutaminases/imunologia , Transglutaminases/farmacologia
6.
Pediatrics ; 144(4)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31492765

RESUMO

BACKGROUND AND OBJECTIVES: Celiac disease (CeD) is associated with psychopathology in children. It is unknown whether this association is present in children with celiac disease autoimmunity (CDA) identified by screening. We examined the associations between subclinical CDA and emotional and behavioral problems in children without previous CeD diagnosis. METHODS: In a population-based cohort study of 3715 children (median age: 6 years), blood titers of tissue transglutaminase autoantibodies were analyzed. CDA was defined as a measurement of tissue transglutaminase autoantibodies ≥7 U/mL (n = 51). Children with previous CeD diagnosis or children on a gluten-free diet, were excluded. The Child Behavior Checklist (CBCL) was filled in by parents and was used to assess behavioral and emotional problems of children at a median age of 5.9 years. Multiple linear regression models were applied to evaluate the cross-sectional associations between CDA and CBCL scores. Sensitivity analyses were done in a subgroup of children who were seropositive carrying the HLA antigen risk alleles for CeD. RESULTS: In basic models, CDA was not associated with emotional and behavioral problems on the CBCL scales. After adjustment for confounders, CDA was significantly associated with anxiety problems (ß = .29; 95% confidence interval 0.02 to 0.55; P = .02). After exclusion of children who did not carry the HLA-DQ2 and/or HLA-DQ8 risk alleles (n = 4), CDA was additionally associated with oppositional defiant problems (ß = .35; 95% confidence interval 0.02 to 0.69). Associations were not explained by gastrointestinal complaints. CONCLUSIONS: Our results reveal that CDA, especially combined with the HLA-DQ2 and HLA-DQ8 risk alleles, is associated with anxiety problems and oppositional defiant problems. Further research should be used to establish whether behavioral problems are a reflection of subclinical CeD.


Assuntos
Ansiedade/imunologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/imunologia , Doenças Autoimunes/psicologia , Doença Celíaca/imunologia , Doença Celíaca/psicologia , Autoanticorpos/sangue , Doenças Autoimunes/sangue , Doenças Autoimunes/genética , Doença Celíaca/sangue , Doença Celíaca/diagnóstico , Lista de Checagem , Criança , Pré-Escolar , Intervalos de Confiança , Feminino , Proteínas de Ligação ao GTP/imunologia , Antígenos HLA-DQ/sangue , Antígenos HLA-DQ/genética , Humanos , Lactente , Modelos Lineares , Masculino , Comportamento Problema/psicologia , Estudos Prospectivos , Sensibilidade e Especificidade , Fatores Sexuais , Transglutaminases/imunologia
7.
Nutrients ; 11(8)2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426299

RESUMO

Two Lactobacillus strains have proven anti-inflammatory properties by reducing pro-inflammatory responses to antigens. This randomized double-blind placebo-controlled trial tested the hypothesis that L. plantarum HEAL9 and L. paracasei 8700:2 suppress ongoing celiac disease autoimmunity in genetically at risk children on a gluten-containing diet in a longitudinally screening study for celiac disease. Seventy-eight children with celiac disease autoimmunity participated of whom 40 received 1010 CFU/day of L. plantarum HEAL9 and L. paracasei 8700:2 (probiotic group) and 38 children maltodextrin (placebo group) for six months. Blood samples were drawn at zero, three and six months and phenotyping of peripheral blood lymphocytes and IgA and IgG autoantibodies against tissue transglutaminase (tTG) were measured. In the placebo group, naïve CD45RA+ Th cells decreased (p = 0.002) whereas effector and memory CD45RO+ Th cells increased (p = 0.003). In contrast, populations of cells expressing CD4+CD25highCD45RO+CCR4+ increased in the placebo group (p = 0.001). Changes between the groups were observed for NK cells (p = 0.038) and NKT cells (p = 0.008). Median levels of IgA-tTG decreased more significantly over time in the probiotic (p = 0.013) than in the placebo (p = 0.043) group whereas the opposite was true for IgG-tTG (p = 0.062 respective p = 0.008). In conclusion, daily oral administration of L. plantarum HEAL9 and L. paracasei 8700:2 modulate the peripheral immune response in children with celiac disease autoimmunity.


Assuntos
Autoanticorpos/metabolismo , Doença Celíaca/imunologia , Proteínas de Ligação ao GTP/imunologia , Lactobacillus paracasei , Lactobacillus plantarum , Probióticos/farmacologia , Transglutaminases/imunologia , Autoanticorpos/imunologia , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Masculino
8.
Nutrients ; 11(8)2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434238

RESUMO

We aimed to estimate the seroprevalence and the prevalence of coeliac disease (CD) in women with reproductive problems. A systematic review of English published articles until June 2019 was performed in PubMed and Scopus using the terms: (infertility and (coeliac disease OR gluten) OR (miscarriage and (coeliac disease OR gluten) OR (abortion and (coeliac disease OR gluten). All articles showing numerical data of anti-transglutaminase type 2 or anti-endomisium antibodies, or intestinal biopsy information were included. The study group comprised women with overall infertility, unexplained infertility, or recurrent spontaneous abortions. Two authors independently performed data extraction using a predefined data sheet. The initial search yielded 310 articles, and 23 were selected for data extraction. After meta-analysis, the pooled seroprevalence was very similar for overall and unexplained infertility, with a pooled proportion of around 1.3%-1.6%. This implies three times higher odds of having CD in infertility when compared to controls. The pooled prevalence could not be accurately calculated due to the small sample sizes. Further studies with increased sample sizes are necessary before giving specific recommendations for CD screening in women with reproductive problems, but current data seem to support a higher risk of CD in these women.


Assuntos
Doença Celíaca/epidemiologia , Infertilidade Feminina/epidemiologia , Aborto Habitual/epidemiologia , Autoanticorpos/sangue , Biópsia , Doença Celíaca/diagnóstico , Doença Celíaca/imunologia , Duodeno/patologia , Grupos Étnicos , Feminino , Proteínas de Ligação ao GTP/imunologia , Humanos , Imunoglobulina A/sangue , Gravidez , Transglutaminases/imunologia
9.
JAMA ; 322(6): 514-523, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31408136

RESUMO

Importance: High gluten intake during childhood may confer risk of celiac disease. Objectives: To investigate if the amount of gluten intake is associated with celiac disease autoimmunity and celiac disease in genetically at-risk children. Design, Setting, and Participants: The participants in The Environmental Determinants of Diabetes in the Young (TEDDY), a prospective observational birth cohort study designed to identify environmental triggers of type 1 diabetes and celiac disease, were followed up at 6 clinical centers in Finland, Germany, Sweden, and the United States. Between 2004 and 2010, 8676 newborns carrying HLA antigen genotypes associated with type 1 diabetes and celiac disease were enrolled. Screening for celiac disease with tissue transglutaminase autoantibodies was performed annually in 6757 children from the age of 2 years. Data on gluten intake were available in 6605 children (98%) by September 30, 2017. Exposures: Gluten intake was estimated from 3-day food records collected at ages 6, 9, and 12 months and biannually thereafter until the age of 5 years. Main Outcomes and Measures: The primary outcome was celiac disease autoimmunity, defined as positive tissue transglutaminase autoantibodies found in 2 consecutive serum samples. The secondary outcome was celiac disease confirmed by intestinal biopsy or persistently high tissue transglutaminase autoantibody levels. Results: Of the 6605 children (49% females; median follow-up: 9.0 years [interquartile range, 8.0-10.0 years]), 1216 (18%) developed celiac disease autoimmunity and 447 (7%) developed celiac disease. The incidence for both outcomes peaked at the age of 2 to 3 years. Daily gluten intake was associated with higher risk of celiac disease autoimmunity for every 1-g/d increase in gluten consumption (hazard ratio [HR], 1.30 [95% CI, 1.22-1.38]; absolute risk by the age of 3 years if the reference amount of gluten was consumed, 28.1%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 34.2%; absolute risk difference, 6.1% [95% CI, 4.5%-7.7%]). Daily gluten intake was associated with higher risk of celiac disease for every 1-g/d increase in gluten consumption (HR, 1.50 [95% CI, 1.35-1.66]; absolute risk by age of 3 years if the reference amount of gluten was consumed, 20.7%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 27.9%; absolute risk difference, 7.2% [95% CI, 6.1%-8.3%]). Conclusions and Relevance: Higher gluten intake during the first 5 years of life was associated with increased risk of celiac disease autoimmunity and celiac disease among genetically predisposed children.


Assuntos
Autoanticorpos/sangue , Doença Celíaca/etiologia , Proteínas na Dieta/efeitos adversos , Predisposição Genética para Doença , Glutens/efeitos adversos , Transglutaminases/imunologia , Autoimunidade , Doença Celíaca/epidemiologia , Doença Celíaca/genética , Doença Celíaca/imunologia , Pré-Escolar , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/genética , Registros de Dieta , Feminino , Glutens/administração & dosagem , Humanos , Incidência , Lactente , Masculino , Estudos Prospectivos , Risco
10.
Postgrad Med ; 131(7): 496-500, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31359810

RESUMO

Objectives: The commonest types of peripheral neuropathy in the context of Coeliac Disease (CD) and gluten sensitivity (GS) are length-dependent symmetrical sensorimotor neuropathies and sensory ganglionopathies. In patients with such neuropathy, (gluten neuropathy), peripheral neuropathic pain is prevalent suggesting involvement of small fibers. The purpose of this report was to describe the clinical characteristics of patients with CD or GS and pure small fiber neuropathy (SFN). Methods: We reviewed the records of all patients that had been referred to the Gluten-Related Neurological Disorders clinic who had clinical and neurophysiological evidence of SFN. All patients had serological evidence of gluten sensitivity (GS) prior to commencing GFD. All patients were offered a duodenum biopsy. Patients with comorbidities that could cause SFN were excluded. Results: We identified 13 patients (9 males) with SFN and gluten sensitivity. Of 11 patients who underwent duodenal biopsy 10 had evidence of enteropathy (CD). Mean age at onset of pain was 53.5 ± 11.4 years (range 34-72) and mean age of CD/GS diagnosis was 50.8 ± 10.4 years (range 34-68). In 8 patients (61.5%) pain was the presenting feature. Neurophysiological assessment suggested a length-dependent small fiber neuropathy in 11 patients, whereas in 2, a non-length dependent pattern was identifying suggesting that the predominant pathology lies in the dorsal root ganglia. Conclusion: SFN can be a presenting feature of CD and GS and, therefore, screening for CD and GS should be included in the diagnostic workup of patients with idiopathic SFN.


Assuntos
Doença Celíaca/fisiopatologia , Condução Nervosa , Neuralgia/fisiopatologia , Neuropatia de Pequenas Fibras/fisiopatologia , Adulto , Idoso , Anticorpos/imunologia , Autoanticorpos/imunologia , Doença Celíaca/complicações , Doença Celíaca/dietoterapia , Doença Celíaca/imunologia , Dieta Livre de Glúten , Feminino , Proteínas de Ligação ao GTP/imunologia , Gliadina/imunologia , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Neuralgia/etiologia , Estudos Retrospectivos , Neuropatia de Pequenas Fibras/etiologia , Transglutaminases/imunologia
11.
Parasit Vectors ; 12(1): 302, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31200771

RESUMO

BACKGROUND: Tissue transglutaminase (tTG)-regulating IL-13 plays an important role in the pathogenesis of liver fibrosis resulting from Schistosoma japonicum (Sj) infection. IL-33 and its receptor ST2 are involved in Th2-biased immune responses through the release of IL-5 and IL-13 and subsequent hepatic granuloma pathology induced by Sj infection. However, the relationship between tTG, IL-33/ST2, and liver fibrosis during Schistosoma infection has not been established. RESULTS: This study investigated the link between tTG and IL-33/ST2 in the induction of liver fibrogenesis during Sj infection in mice. The extent of liver fibrosis coincided with an increase in tTG and IL-33/ST2 expression in the liver of infected mice between five to eight weeks, with a peak of correlation at six weeks after Sj infection. The inhibition of tTG activity through cystamine administration or gene knockout alleviated the level of TLR4, NF-κB pathway molecules, IL-33/ST2, and the severity of liver fibrosis resulting from Sj infection. CONCLUSIONS: These results indicate that during Sj infection tTG may control liver fibrosis at least partially through TLR4, NF-κB pathway activation and then IL-33/ST2. tTG, IL-33 or ST2 might be promising drug targets against liver fibrosis induced by Sj infection.


Assuntos
Proteínas de Ligação ao GTP/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Cirrose Hepática/enzimologia , Esquistossomose Japônica/imunologia , Transglutaminases/genética , Animais , Cistamina/administração & dosagem , Sistemas de Liberação de Medicamentos , Feminino , Proteínas de Ligação ao GTP/imunologia , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Fígado/parasitologia , Fígado/patologia , Cirrose Hepática/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Schistosoma japonicum , Esquistossomose Japônica/patologia , Transglutaminases/imunologia
12.
Arab J Gastroenterol ; 20(2): 95-98, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31182344

RESUMO

BACKGROUND AND STUDY AIMS: Juvenile idiopathic arthritis (JIA) is characterized by autoimmune aetiology. A gene locus 4q27 related to rheumatoid arthritis, psoriatic arthritis, and coeliac disease is associated with susceptibility to JIA. There are reports indicating several patients with JIA had been diagnosed with CD. We aimed to assess the frequency of coeliac disease (CD) in patients with juvenile idiopathic arthritis (JIA). PATIENTS AND METHODS: This prospective study was carried out from October 2015 to August 2016 and included 96 patients with JIA. All patients were evaluated in terms of clinical and laboratory findings of CD. Levels of total IgA and tissue transglutaminase antibody (tTG) IgA were measured in all patients. Those with increased level of tTG IgA were further tested for anti-endomysium IgA antibodies (EMA). Gastroduodenoscopy were planned for a definite diagnosis of CD in patients with positive EMA. RESULTS: Of the 96 patients in our study, 34 (35.4%) had oligoarticular form of JIA, 29 (30.2%) had polyarticular form, 12 (12.5%) had ERA form, 11 (11.5%) had systemic form, and 10 (10.4%) had psoriatic form. Sixteen of our patients (16.6%) were not using any drugs during the study. Neither EMA IgA antibodies were analysed nor gastro-duodenoscopy was performed because no patients were positive for tTG IgA. There was no difference in terms of tTG levels between the patients using NSAIDs or other drugs. CONCLUSION: We did not find CD in children with JIA. Long term studies with more JIA patients are needed to provide more precise interpretation.


Assuntos
Artrite Juvenil/epidemiologia , Doença Celíaca/diagnóstico , Doença Celíaca/epidemiologia , Adolescente , Artrite Juvenil/sangue , Artrite Juvenil/tratamento farmacológico , Doença Celíaca/sangue , Criança , Comorbidade , Feminino , Proteínas de Ligação ao GTP/imunologia , Humanos , Imunoglobulina A/sangue , Incidência , Masculino , Estudos Prospectivos , Transglutaminases/imunologia , Turquia/epidemiologia
13.
Indian J Gastroenterol ; 38(3): 203-210, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31183842

RESUMO

BACKGROUND: Celiac disease (CD) is a lifelong condition with significant morbidity and requires an accurate diagnosis. Guidelines for pediatric CD were revised by the European and British Societies of Paediatric Gastroenterology Hepatology and Nutrition in 2012 and 2013, respectively. New recommendations introduced non-biopsy pathway (NBP) of diagnosis for a selective group of symptomatic children whose anti-tissue transglutaminase (anti-tTG) antibody titer is greater than ten times upper limit of normal. A clear understanding of the guidelines amongst consultant pediatricians will ensure all children with suspected CD receive a prompt and secure diagnosis. The aim of this study was to establish the interpretation and implementation of the revised guideline for CD amongst consultant general pediatricians in Southwest England (SWE) during the study period. METHODS: Telephone/email survey was conducted amongst consultant general pediatricians (n ≈ 140) working in 12 secondary care hospitals across SWE. The survey included eight questions incorporating three main themes: understanding of diagnostic pathway particularly for non-biopsy diagnosis, awareness of laboratory tests involved, and variations in practice in relation to the revised guidelines. RESULTS: Responses were available from 101/140 (72%). One hundred respondents were aware of the revised guidelines for diagnosing CD. However, only 17 respondents stated all the criteria of the guideline required for diagnosis by NBP, with further 17 seeking immediate advice from a specialist. Forty-four listed both the criteria for HLA-DQ2/DQ8 testing applicable to pediatricians. Forty-nine out of 100 pediatricians would commence gluten-free diet only after all the results were available. Thirty-three pediatricians also considered asymptomatic children with high anti-tTG titer eligible for diagnosis of CD by NBP. CONCLUSIONS: There is a need for improved understanding of revised CD guidelines amongst consultant general pediatricians especially while using the NBP and requesting HLA-DQ2/DQ8 testing.


Assuntos
Doença Celíaca/diagnóstico , Gastroenterologia , Conhecimentos, Atitudes e Prática em Saúde , Pediatria , Padrões de Prática Médica , Autoanticorpos/sangue , Doença Celíaca/dietoterapia , Dieta Livre de Glúten , Inglaterra , Proteínas de Ligação ao GTP/imunologia , Testes Genéticos , Antígenos HLA-DQ/genética , Haplótipos , Humanos , Guias de Prática Clínica como Assunto , Inquéritos e Questionários , Transglutaminases/imunologia
14.
BMC Gastroenterol ; 19(1): 91, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196071

RESUMO

BACKGROUND: Celiac disease (CD) is triggered by gluten and related prolamines in genetically susceptible individuals. We aimed to investigate the influence of HLA-DQ genotypes in clinical, serological and histological features related to CD. METHODS: A retrospective observational study was performed including 463 Spanish patients with biopsy-proven CD. Clinical, serological, histological and HLA-DQ genetic data were collected from each participant. The presence of a family history of CD was also considered. Bivariate (chi-square tests or the Fisher's exact test) and multivariate (logistic regression after adjusting for age and sex) analyses were performed to assess the association between clinical and laboratory parameters with HLA-DQ. RESULTS: A predominance of females (62%), classical clinical presentation (86%) and positive anti-transglutaminase 2/endomysium antibodies (99%) was observed in our sample, with a mean age at onset of 2.6 ± 0.1 years. Five percent of our patients were first-degree relatives of subjects with CD, with HLA-DQ genetics showing increased homozygosity of HLA-DQ2.5 (p = 0.03) and HLA-DQ8 (p = 0.09). In the non-CD family history group, an association between delayed disease onset and HLA-DQ8 carriage was observed (p < 0.001), besides an influence of HLA-DQB1*02 gene dosage on clinical presentation and severity of histological damage (after adjusting for age and sex, p = 0.05 and p = 0.02, respectively) and a trend towards presence of specific antibodies (p = 0.09). These associations could not be evaluated properly in the group of patients with affected first-degree relatives due to the small sample size. CONCLUSIONS: HLA-DQ genotypic frequencies differ slightly between CD patients depending on their family history of CD. In patients lacking CD first-degree relatives, carriage of HLA-DQ2.5 with double dose of HLA-DQB1*02 seems to be associated with classical clinical presentation and more severe histological damage.


Assuntos
Doença Celíaca/sangue , Doença Celíaca/genética , Antígenos HLA-DQ/sangue , Índice de Gravidade de Doença , Autoanticorpos/sangue , Autoanticorpos/imunologia , Doença Celíaca/imunologia , Pré-Escolar , Feminino , Proteínas de Ligação ao GTP/imunologia , Predisposição Genética para Doença , Genótipo , Antígenos HLA-DQ/imunologia , Homozigoto , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Estudos Retrospectivos , Transglutaminases/imunologia
15.
Gastroenterol Clin North Am ; 48(2): 307-317, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31046977

RESUMO

Most patients affected by celiac disease (CD) are asymptomatic or hyposymptomatic and undiagnosed, and are at risk of preventable complications. Therefore, early diagnosis is highly recommended. Multiple diagnostic antibodies are available; the most frequently used is IgA to tissue transglutaminase (IgA-tTg). It may yield false results and, alone, does not address IgA deficiency. Recently, a new generation of anti-neo-epitope tTg check (IgG + IgA) has become available. It is highly sensitive and specific, covers IgA-deficient patients with CD, reflects intestinal damage, and has predictive potential in the diagnosis of CD.


Assuntos
Biomarcadores/sangue , Doença Celíaca/diagnóstico , Testes Sorológicos/métodos , Diagnóstico Precoce , Proteínas de Ligação ao GTP/imunologia , Gliadina/imunologia , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Transglutaminases/imunologia
16.
Indian J Med Res ; 149(1): 18-25, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31115370

RESUMO

Background & objectives: : Celiac disease (CD) can exist in various forms in type 1 diabetes (T1D) patients and can remain undetected, leading to severe complications. This study was aimed to evaluate five commercially available anti-tissue transglutaminase (tTG) ELISA kits with distinct formats for the detection of CD and potential CD in T1D patients. Clinical and demographic profiles of the patients with different disease subsets were also studied. Methods: : Fifty T1D patients with classical and non-classical symptoms of CD and 100 T1D patients without any symptoms of CD were included in this study. Anti-tTG autoantibody levels were estimated by five ELISA kits followed by histological examination of duodenal biopsy. HLA DQ2-DQ8 and DRB1-DQB1 typing was done, and serum levels for transforming growth factor (TGF)-ß1 were also estimated. Results: : Assay format detecting anti-tTG IgA antibodies against recombinant antigens along with neopeptides of gliadin was most efficient in the detection of CD in symptomatic patients, and assay format detecting IgA+IgG helped in the detection of potential CD in asymptomatic T1D patients. These findings were supported by histological examination and human leucocyte antigen analysis. Patients with potential CD were found to have markedly deranged glycaemic control parameters and also had significantly raised serum levels of TGF-ß1, (P <0.05) compared to T1D patients. Interpretation & conclusions: : Potential CD can be frequently seen in T1D patients. This can be attributed to the dietary patterns prevalent in the subcontinent and the genetic basis of the disease. Anti-tTG IgA+IgG antibodies can be useful in the detection of these potential CD cases in T1D patients. Early intervention with gluten-free diet can be considered in these patients for better disease management.


Assuntos
Doença Celíaca/sangue , Diabetes Mellitus Tipo 1/sangue , Transglutaminases/isolamento & purificação , Adolescente , Adulto , Anticorpos Anti-Idiotípicos/imunologia , Autoanticorpos/imunologia , Doença Celíaca/complicações , Doença Celíaca/dietoterapia , Doença Celíaca/imunologia , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/dietoterapia , Diabetes Mellitus Tipo 1/imunologia , Dieta Livre de Glúten , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Pessoa de Meia-Idade , Fator de Crescimento Transformador beta1/sangue , Transglutaminases/imunologia , Adulto Jovem
17.
Turk J Gastroenterol ; 30(4): 321-325, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30945642

RESUMO

BACKGROUND/AIMS: Celiac disease is an autoimmune, familial disease that results in susceptibility to gluten in cereal and cereal products in genetically susceptible individuals. The aim of the present study was to investigate the presence of HLA-DQ2/DQ8 in patients with celiac disease, their first-degree relatives, and healthy community. MATERIALS AND METHODS: HLA-DQ2/DQ8 analysis was performed in adult patients with celiac disease >18 years old (94 patients), their first-degree relatives (89 people), and healthy group (102 individuals). Anemia, osteoporosis, and diarrhea were interrogated in the celiac patient group and also anti-tissue transglutaminase, anti-endomysium, and anti-gliadin antibodies were recorded. RESULTS: There was a significant relationship between HLA-DQ2/DQ8 presence in all groups, and the distribution of HLA-DQ2/DQ8 in all groups was different (p=0.000). No statistically significant correlation was found between the HLA tissue groups and diarrhea (p=0.087), osteoporosis (p=0.215), anemia (p=1.000), tissue transglutaminase antibodies (p=0.295), anti-gliadin antibodies (p=0.104), and anti-endomysium antibodies (p=0.243) in the celiac patient group. CONCLUSION: HLA-DQ2/DQ8 can be used to diagnose celiac disease particularly when the tests are useless and to screen first-degree relatives.


Assuntos
Autoanticorpos/sangue , Doença Celíaca/sangue , Antígenos HLA-DQ/sangue , Adulto , Autoanticorpos/imunologia , Doença Celíaca/imunologia , Feminino , Gliadina/imunologia , Antígenos HLA-DQ/imunologia , Humanos , Masculino , Linhagem , Transglutaminases/imunologia , Turquia
18.
Gastroenterology ; 157(2): 413-420.e3, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30978358

RESUMO

BACKGROUND & AIMS: Potential celiac disease is characterized by positive results from serologic tests for tissue transglutaminase antibodies (anti-TG2) but normal duodenal architecture (Marsh stages 0-1). There is controversy over the best way to manage these patients. We investigated risk factors associated with the development of villous atrophy in children with potential celiac disease. METHODS: We performed a prospective study of 280 children (ages 2-18 years) in Italy with suspected celiac disease, followed for up to 12 years (range, 18-150 months; median 60 months). The subjects had 2 consecutive positive results from tests for anti-TG2, tested positive for the endomysial antibody (anti-EMA), had total serum levels of immunoglobulin A in the normal range, normal duodenal architecture (Marsh stages 0-1) in 5 biopsies, and HLA DQ2- or DQ8-positive haplotypes. The children underwent serologic tests and clinical analyses every 6 months and a small bowel biopsy was taken every 2 years. A total of 210 patients of the original cohort were assessed at the 9-year follow-up evaluation. We performed multivariate analyses of clinical, genetic, and histologic data to identify factors associated with progression to villous atrophy. RESULTS: During the follow-up period, 42 (15%) of 280 children developed villous atrophy, whereas 89 (32%) children no longer tested positive for anti-TG2 or anti-EMA. The cumulative incidence of progression to villous atrophy was 43% at 12 years. In multivariate analysis, the baseline factors most strongly associated with development of villous atrophy were numbers of γδ intraepithelial lymphocyte cells followed by age and homozygosity for the HLA DQB1*02. In discriminant analysis, these baseline factors identified 80% of the children who developed baseline atrophy. CONCLUSIONS: In a long-term study of 280 children with suspected celiac disease (based on anti-TG2 and anti-EMA) on gluten-containing diets, the cumulative incidence of progression to villous atrophy was 43% over a 12-year period. We identified factors that can be used to identify children at highest risk for villous atrophy. This approach might be used to determine whether children with suspected celiac disease should immediately start a gluten-free diet or be monitored on their regular diet.


Assuntos
Atrofia/patologia , Autoanticorpos/sangue , Doença Celíaca/patologia , Proteínas de Ligação ao GTP/imunologia , Mucosa Intestinal/patologia , Transglutaminases/imunologia , Adolescente , Atrofia/sangue , Atrofia/epidemiologia , Atrofia/imunologia , Autoanticorpos/imunologia , Biópsia , Doença Celíaca/sangue , Doença Celíaca/dietoterapia , Doença Celíaca/imunologia , Criança , Pré-Escolar , Dieta Livre de Glúten , Progressão da Doença , Duodeno , Feminino , Seguimentos , Humanos , Incidência , Itália , Masculino , Estudos Prospectivos
19.
Fish Shellfish Immunol ; 89: 326-336, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30974215

RESUMO

Transglutaminase (TGase) is important in blood coagulation, a conserved immunological defense mechanism among invertebrates. This study is the first report of the TGase in mud crab (Scylla paramamosain) (SpTGase) with a 2304 bp ORF encoding 767 amino acids (molecular weight 85.88 kDa). SpTGase is acidic, hydrophilic, stable and thermostable, containing three transglutaminase domains, one TGase/protease-like homolog domain (TGc), one integrin-binding motif (Arg270, Gly271, Asp272) and three catalytic sites (Cys333, His401, Asp424) within the TGc. Neither a signal peptide nor a transmembrane domain was found, and the random coil is dominant in the secondary structure of SpTGase. Phylogenetic analysis revealed a close relation between SpTGase to its homolog EsTGase 1 from Chinese mitten crab (Eriocheir sinensis). Expression of SpTGase was investigated using qRT-PCR (1) in eight tissues from healthy mud crabs, with the highest expression in hemocytes, and (2) in response to various immune challenges (Vibrio parahaemolyticus, lipopolysaccharide (LPS) or Poly I:C infection), revealing a major up-regulation in hemocytes, skin, and hepatopancreas during the 96-h post injection. The recombinant SpTGase showed a capacity of agglutination activities on both Gram-negative bacteria and yeast. SpTGase was found to directly interact with another important blood coagulation component clip domain serine protease (SpcSP). Moreover, knockdown of SpTGase resulted in a decreased expression of both clotting protein precursor (SppreCP) and SpcSP and an increase of duration time in the blood coagulation. Taken together, the findings of this study suggest SpTGase play an important role in the hemolymph clotting in mud crab S. paramamosain.


Assuntos
Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Penaeidae/genética , Penaeidae/imunologia , Transglutaminases/genética , Transglutaminases/imunologia , Sequência de Aminoácidos , Animais , Proteínas de Artrópodes/química , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/imunologia , Sequência de Bases , Braquiúros , Perfilação da Expressão Gênica , Lipopolissacarídeos/farmacologia , Filogenia , Poli I-C/farmacologia , Alinhamento de Sequência , Transglutaminases/química , Vibrio parahaemolyticus/fisiologia
20.
Hautarzt ; 70(4): 260-264, 2019 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-30868254

RESUMO

Dermatitis herpetiformis (DH) is a genetically determined, gluten sensitive autoimmune bullous dermatosis related to celiac disease in which granular, insoluble aggregates in the papillary dermis of epidermal transglutaminase (TG3), immunoglobulin A (IgA), and fibrinogen are present. Detection of the dermal IgA-TG3 immune complex is the gold standard of diagnosis. DH develops in a subpopulation of patients with gluten sensitive enteropathy, characterized by itching, erythematous, excoriated papules showing characteristic distribution over the knees, elbows and buttocks; vesicles are rarely seen. The primary therapy of DH is a strict, lifelong gluten-free diet, and it may be necessary to temporarily give dapsone in case of severe symptoms.


Assuntos
Doença Celíaca/imunologia , Dermatite Herpetiforme/imunologia , Transglutaminases/imunologia , Doença Celíaca/dietoterapia , Doença Celíaca/patologia , Dermatite Herpetiforme/dietoterapia , Dermatite Herpetiforme/patologia , Dieta Livre de Glúten , Glutens , Humanos
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