RESUMO
Up to 30% of patients with celiac disease (CD) suffer from concurrent autoimmune disease, compared to 3% of the general population. The association between CD and the current clinical phenotypes of inflammatory myopathies (IIM) patients has not been thoroughly addressed. Assess the CD features among patients with IIM and their relationship with the clinical phenotype and the myositis specific (MSA) and associated antibodies (MAA). For this cross-sectional study, we recruited 99 adult patients classified as IIM from a tertiary center in Mexico. We assessed serum MSA, MAA, and CD-associated autoantibodies (IgA anti-tissue transglutaminase (tTG) and both IgA and IgG anti-deaminated gliadin peptide (DGP)). Patients with highly suggestive serology for CD were then tested for IgG anti-endomysium antibodies, and a duodenal biopsy was performed. 70.7% of patients were positive for at least one antibody. Nine duodenal biopsies were taken, revealing findings compatible with celiac disease in two cases. Subjects with anti-MDA5 antibodies were more likely to have positive anti-tTG IgA antibodies (OR 6.76, 95% CI 1.85-24.62, P = 0.013) and suggestive CD serology (OR 6.41, 95% CI 1.62-25.29, P = 0.009). Patients with anti-Mi2 antibodies were more likely to have positive anti-DGP IgG antibodies (OR 3.35, 95% CI 1.12-9.96, P = 0.039), while positivity for these autoantibodies was less frequent in patients with anti-NXP2 antibodies (OR 0.22, 95% CI 0.06-0.80, P = 0.035). There is a higher prevalence of serologic and definite CD in patients with IIM compared to the general population. Identifying this subgroup of patients may have prognostic and therapeutic implications. Key points ⢠The study estimated a serological celiac disease (CD) prevalence of 70.7% in patients with idiopathic inflammatory myopathies (IIM) and a biopsy-confirmed prevalence of 2%, suggesting that IIM patients should be considered a high-risk population for CD. ⢠We identified a significant association between serological CD and the presence of anti-MDA5 and anti-Mi2 antibodies, suggesting a potential justification for celiac disease screening in this specific subgroup of patients. ⢠The impact of gluten-free diets on IIM patients with serological markers of CD remains untested and warrants further investigation through prospective, randomized studies.
Assuntos
Autoanticorpos , Doença Celíaca , Miosite , Humanos , Doença Celíaca/epidemiologia , Doença Celíaca/imunologia , Doença Celíaca/sangue , Doença Celíaca/diagnóstico , Doença Celíaca/complicações , Estudos Transversais , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Prevalência , Autoanticorpos/sangue , Miosite/imunologia , Miosite/epidemiologia , Miosite/sangue , México/epidemiologia , Transglutaminases/imunologia , Idoso , Imunoglobulina A/sangue , Gliadina/imunologia , Imunoglobulina G/sangue , Proteína 2 Glutamina gama-GlutamiltransferaseRESUMO
Gluten-related disorders (GRDs) are a group of diseases that involve the activation of the immune system triggered by the ingestion of gluten, with a worldwide prevalence of 5%. Among them, Celiac disease (CeD) is a T-cell-mediated autoimmune disease causing a plethora of symptoms from diarrhea and malabsorption to lymphoma. Even though GRDs have been intensively studied, the environmental triggers promoting the diverse reactions to gluten proteins in susceptible individuals remain elusive. It has been proposed that pathogens could act as disease-causing environmental triggers of CeD by molecular mimicry mechanisms. Additionally, it could also be possible that unrecognized molecular, structural, and physical parallels between gluten and pathogens have a relevant role. Herein, we report sequence, structural and physical similarities of the two most relevant gluten peptides, the 33-mer and p31-43 gliadin peptides, with bacterial pathogens using bioinformatics going beyond the molecular mimicry hypothesis. First, a stringent BLASTp search using the two gliadin peptides identified high sequence similarity regions within pathogen-derived proteins, e.g., extracellular proteins from Streptococcus pneumoniae and Granulicatella sp. Second, molecular dynamics calculations of an updated α-2-gliadin model revealed close spatial localization and solvent-exposure of the 33-mer and p31-43 peptide, which was compared with the pathogen-related proteins by homology models and localization predictors. We found putative functions of the identified pathogen-derived sequence by identifying T-cell epitopes and SH3/WW-binding domains. Finally, shape and size parallels between the pathogens and the superstructures of gliadin peptides gave rise to novel hypotheses about activation of innate immunity and dysbiosis. Based on our structural findings and the similarities with the bacterial pathogens, evidence emerges that these pathologically relevant gluten-derived peptides could behave as non-replicating pathogens opening new research questions in the interface of innate immunity, microbiome, and food research.
Assuntos
Doença Celíaca/imunologia , Epitopos de Linfócito T , Gliadina/metabolismo , Glutens/metabolismo , Mimetismo Molecular , Fragmentos de Peptídeos/metabolismo , Carnobacteriaceae/metabolismo , Biologia Computacional , Gliadina/química , Gliadina/imunologia , Glutens/química , Glutens/imunologia , Humanos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Streptococcus pneumoniae/metabolismoRESUMO
BACKGROUND: The protective effect of breastfeeding on celiac disease (CD) onset is controversial. We studied a wide range of milk components in milk produced by celiac mothers following long-term gluten-free diet (GFD) in comparison to milk produced by healthy mothers. METHODS: Breast-milk samples from celiac (n = 33) and healthy (n = 41) mothers were obtained during the first year of lactation. A panel of bioactive components was analyzed by enzyme-linked immunosorbent assay in the aqueous fraction. We studied molecules involved in defenses, immunoregulation, and strengthening of the gut-epithelial barrier. RESULTS: During late lactation (from 6 to 12 months after delivery), the content of total immunoglobulin A (IgA) and IgM was significantly lower in the milk produced by celiac patients. Nevertheless, gliadin (GFD)-specific IgA relative contribution was higher in this group, in contrast to tetanus toxoid-specific antibodies. The balance between pro-inflammatory and anti-inflammatory molecules was different. While interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 were most frequently found in samples from celiac mothers, soluble Toll-like receptor-2 prevalence was lower. CONCLUSIONS: We describe differences between the innate and adaptive immune profile of milk produced by celiac and healthy mothers. These results might explain previous controversial reports about breastfeeding and CD protection. IMPACT: In spite of a long-term adherence to GFD, the milk produced by mothers with CD exhibit a different immune profile, in relation with some immunoregulatory factors and antibody content. This work shows a more comprehensive characterization of milk from celiac mothers, including macronutrients, lysozymes, growth factors, and immunoregulatory components that had not been studied before. The present study widens the available data regarding the characteristics of human milk of celiac mothers following GFD. Further follow-up studies of the health of children who were breastfed by celiac mothers will be necessary in order to also estimate the impact of the present results therein.
Assuntos
Doença Celíaca/imunologia , Leite Humano/imunologia , Adulto , Anticorpos Antibacterianos/análise , Autoanticorpos , Aleitamento Materno , Doença Celíaca/dietoterapia , Doença Celíaca/metabolismo , Citocinas/análise , Dieta Livre de Glúten , Feminino , Gliadina/imunologia , Humanos , Imunoglobulina A/análise , Imunoglobulina M/análise , Leite Humano/química , Muramidase/análise , Toxoide Tetânico/imunologia , Receptor 2 Toll-Like/análiseRESUMO
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/imunologiaRESUMO
Celiac disease (CeD) is a highly prevalent chronic immune-mediated enteropathy developed in genetically predisposed individuals after ingestion of a group of wheat proteins (called gliadins and glutenins). The 13mer α-gliadin peptide, p31-43, induces proinflammatory responses, observed by in vitro assays and animal models, that may contribute to innate immune mechanisms of CeD pathogenesis. Since a cellular receptor for p31-43 has not been identified, this raises the question of whether this peptide could mediate different biological effects. In this work, we aimed to characterize the p31-43 secondary structure by different biophysical and in silico techniques. By dynamic light scattering and using an oligomer/fibril-sensitive fluorescent probe, we showed the presence of oligomers of this peptide in solution. Furthermore, atomic force microscopy analysis showed p31-43 oligomers with different height distribution. Also, peptide concentration had a very strong influence on peptide self-organization process. Oligomers gradually increased their size at lower concentration. Whereas, at higher ones, oligomers increased their complexity, forming branched structures. By CD, we observed that p31-43 self-organized in a polyproline II conformation in equilibrium with ß-sheets-like structures, whose pH remained stable in the range of 3-8. In addition, these findings were supported by molecular dynamics simulation. The formation of p31-43 nanostructures with increased ß-sheet structure may help to explain the molecular etiopathogenesis in the induction of proinflammatory effects and subsequent damage at the intestinal mucosa in CeD.
Assuntos
Doença Celíaca/tratamento farmacológico , Gliadina/farmacologia , Imunidade Inata/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Células CACO-2 , Doença Celíaca/genética , Doença Celíaca/imunologia , Doença Celíaca/patologia , Gliadina/genética , Gliadina/imunologia , Gliadina/ultraestrutura , Humanos , Imunidade Inata/imunologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Microscopia de Força Atômica , Conformação Molecular/efeitos dos fármacos , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/ultraestrutura , Peptídeos/química , Peptídeos/imunologia , Peptídeos/farmacologia , Conformação Proteica em Folha beta , Soluções/química , Água/químicaRESUMO
OBJECTIVE: To compare the performance of IgA anti-tissue transglutaminase antibodies (IgA anti-tTG), IgA anti-endomysial antibodies (IgA EMA), and IgA/IgG antibodies against deamidated gliadin peptides (IgA/IgG anti-DGP) for the diagnosis of celiac disease. METHODS: Descriptive study in patients with celiac disease. Anti-DGP (IgA/IgG), IgA EMA, IgA anti-tTG antibodies were measured and an intestinal biopsy was done. Sex: female (61 %). Median age: 78.4 months old. RESULTS: A total of 136 children were included; 108 had high IgA anti-DGP titers; 124, increased IgG anti-DGP titers; 128, positive IgA EMA titers; and 130, increased IgA anti-tTG titers. High IgG anti-DGP titers were observed in 4/6 patients with negative IgA anti-tTG antibodies. The combination of IgG anti-DGP + IgA anti-tTG antibodies showed a positive correlation in 134 patients and the IgG anti-DGP + EMA combination was positive in 133 children. CONCLUSION: IgA EMA, IgA anti-tTG, and IgG anti-DGP antibodies exhibited an adequate specificity and sensitivity. The IgG anti-DGP/anti-tTG combination showed a 98-99 % sensitivity and a 100 % specificity. The anti-tTG and IgG anti-DGP option yields excellent results, with a low cost and independence from the observer.
Objetivo. Comparar el rendimiento de anticuerpos antitransglutaminasa IgA (anti-TG2 IgA), antiendomisio IgA (EMA IgA) y antigliadina desaminada IgA/IgG (AGADGP IgA/IgG) para el diagnóstico de enfermedad celiaca. Métodos. Estudio descriptivo en pacientes con enfermedad celíaca. Se dosaron anticuerpos: AGADGP (IgA/IgG), EMA IgA, anti-TG2 IgA y biopsia intestinal. Sexo: mujeres (61 %). Mediana de edad: 78,4 meses. Resultados. Se incluyeron 136 niños; 108 presentaron AGADGP IgA elevado; 124, AGADGP IgG aumentado; 128, EMA IgA positivo; 130, anti-TG2 IgA aumentado. Cuatro de 6 pacientes con anti-TG2 IgA negativos tenían AGADGP IgG elevado. La combinación de los anticuerpos AGADGP IgG + anti-TG2 IgA tuvo una correlación positiva en 134 pacientes y la combinación AGADGP IgG + EMA fue positiva en 133 niños. Conclusión. Se demostró la buena especificidad y sensibilidad de EMA IgA, anti-TG2 IgA y AGADGP IgG. La combinación AGADGP IgG/anti-TG2 mostró sensibilidad del 98-99 % y especificidad del 100 %. La elección de anti-TG2 y AGADGP IgG da excelentes resultados, con bajo costo y no depende del operador.
Assuntos
Autoanticorpos/sangue , Doença Celíaca/diagnóstico , Doença Celíaca/imunologia , Proteínas de Ligação ao GTP/imunologia , Gliadina/imunologia , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Transglutaminases/imunologia , Criança , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Proteína 2 Glutamina gama-GlutamiltransferaseRESUMO
Celiac disease (CD) is an inflammatory syndrome that affects mainly the intestine, but also other organs. This ailment is also affected by the physicochemical behavior of gluten as such. From the medical standpoint, this pathology results from a combination of genetic and environmental factors. At the same time, gliadin (the alcohol-soluble fraction of gluten) along with other related oligomers, such as 33-gliadin, present high immunogenicity and are responsible for triggering of this disease. Within CD characterization, there are mainly two different approaches to carry out this study; one focuses on its chronic phase, while the other deals with its initial stages. Although the chronic phase of CD has been well characterized, the initiation of the inflammatory process is still unclear. As this process is apparently related to the aggregation of the oligomers involved in CD, the initiation of the disease could be explained by means of clarifying their self-assembly behavior. Thus, this work addresses the clinical explanation, within the chronic approach, attempting to combine it with the physicochemical techniques used for characterization of proteins aggregates as well.
Assuntos
Doença Celíaca/metabolismo , Doença Celíaca/terapia , Doença Celíaca/diagnóstico , Doença Celíaca/imunologia , Doença Crônica , Gliadina/química , Gliadina/imunologia , Gliadina/metabolismo , Glutens/química , Glutens/metabolismo , Humanos , Inflamação/metabolismo , Agregados Proteicos , Dobramento de Proteína , Multimerização ProteicaRESUMO
OBJECTIVE: To determine the impact of the Text Message Educational Automated Compliance Help (TEACH) text message intervention as a pragmatic approach for patient engagement among adolescents with celiac disease (CD) as measured by gluten-free diet (GFD) adherence, patient activation, and quality of life (QOL). STUDY DESIGN: Randomized controlled trial with patient recruitment at a pediatric, university-based hospital and through social media; 61 participants ages 12-24 years with CD diagnosed at least 1 year were enrolled. The TEACH intervention cohort received 45 unique text messages over a 3-month study period while the control group received standard of care treatment. Primary outcome measures included objective markers of GFD adherence included serum tissue transglutaminase IgA and deamidated gliadin peptide IgA levels. Secondary patient-reported outcomes collected via online survey included the Celiac Dietary Adherence Test, National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS) Global Short Form measure of QOL, Celiac Symptom Index, and Patient Activation Measure. All measures were assessed at enrollment and after the 3-month study period. Statistical analysis performed using the 2-tailed paired Student t test. RESULTS: Among the TEACH intervention group, there was significant improvement comparing enrollment scores with 3-month follow-up scores in patient activation (Patient Activation Measure score 63.1 vs 72.5, P?=?.01) and QOL (NIH PROMIS Global Mental Health 50.8 vs 53.3, P?=?.01 and NIH PROMIS Global Physical Health 50.8 vs 57.7, P?=?.03). There was no statistically significant difference in patient-reported or objectively measured GFD adherence. CONCLUSIONS: TEACH is an effective intervention among patients with CD to improve patient activation and QOL, even among a cohort with GFD adherence at baseline. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02458898.