RESUMEN
A nanohybrid-modified glassy carbon electrode based on conducting polypyrrole doped with carbon quantum dots (QDs) was developed and used for the electrochemical detection of anti-tissue transglutaminase (anti-tTG) antibodies. To improve the polypyrrole conductivity, carrier mobility, and carrier concentration, four types of carbon nanoparticles were tested. Furthermore, a polypyrrole-modified electrode doped with QDs was functionalized with a PAMAM dendrimer and transglutaminase 2 protein by cross-linking with N-hydroxysuccinimide (NHS)/N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC). The steps of electrode surface modification were surveyed via electrochemical measurements (differential pulse voltammetry (DPV), impedance spectroscopy, and X-ray photoelectron spectroscopy (XPS)). The surface characteristics were observed by scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, and contact angle measurements. The obtained modified electrode exhibited good stability and repeatability. DPV between - 0.1 and 0.6 V (vs. Ag/AgCl 3 M KCl reference electrode) was used to evaluate the electrochemical alterations that occur after the antibody interacts with the antigen (transglutaminase 2 protein), for which the limit of detection was 0.79 U/mL. Without the use of a secondary label, (anti-tTG) antibodies may be detected at low concentrations because of these modified electrode features.
Asunto(s)
Dendrímeros , Proteína Glutamina Gamma Glutamiltransferasa 2 , Pirroles , Puntos Cuánticos , Transglutaminasas , Humanos , Anticuerpos/inmunología , Anticuerpos/química , Técnicas Biosensibles/métodos , Carbono/química , Dendrímeros/química , Técnicas Electroquímicas/métodos , Electrodos , Proteínas de Unión al GTP/inmunología , Polímeros/química , Pirroles/química , Puntos Cuánticos/química , Transglutaminasas/inmunología , Transglutaminasas/químicaRESUMEN
In vitro models of autoimmunity are constrained by an inability to culture affected epithelium alongside the complex tissue-resident immune microenvironment. Coeliac disease (CeD) is an autoimmune disease in which dietary gluten-derived peptides bind to the major histocompatibility complex (MHC) class II human leukocyte antigen molecules (HLA)-DQ2 or HLA-DQ8 to initiate immune-mediated duodenal mucosal injury1-4. Here, we generated air-liquid interface (ALI) duodenal organoids from intact fragments of endoscopic biopsies that preserve epithelium alongside native mesenchyme and tissue-resident immune cells as a unit without requiring reconstitution. The immune diversity of ALI organoids spanned T cells, B and plasma cells, natural killer (NK) cells and myeloid cells, with extensive T-cell and B-cell receptor repertoires. HLA-DQ2.5-restricted gluten peptides selectively instigated epithelial destruction in HLA-DQ2.5-expressing organoids derived from CeD patients, and this was antagonized by blocking MHC-II or NKG2C/D. Gluten epitopes stimulated a CeD organoid immune network response in lymphoid and myeloid subsets alongside anti-transglutaminase 2 (TG2) autoantibody production. Functional studies in CeD organoids revealed that interleukin-7 (IL-7) is a gluten-inducible pathogenic modulator that regulates CD8+ T-cell NKG2C/D expression and is necessary and sufficient for epithelial destruction. Furthermore, endogenous IL-7 was markedly upregulated in patient biopsies from active CeD compared with remission disease from gluten-free diets, predominantly in lamina propria mesenchyme. By preserving the epithelium alongside diverse immune populations, this human in vitro CeD model recapitulates gluten-dependent pathology, enables mechanistic investigation and establishes a proof of principle for the organoid modelling of autoimmunity.
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Enfermedad Celíaca , Duodeno , Interleucina-7 , Mucosa Intestinal , Modelos Biológicos , Organoides , Humanos , Autoanticuerpos/inmunología , Autoinmunidad , Linfocitos B/inmunología , Linfocitos B/metabolismo , Biopsia , Enfermedad Celíaca/inmunología , Enfermedad Celíaca/patología , Enfermedad Celíaca/metabolismo , Duodeno/inmunología , Duodeno/patología , Duodeno/metabolismo , Epítopos/inmunología , Glútenes/inmunología , Glútenes/metabolismo , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP/inmunología , Antígenos HLA-DQ/inmunología , Antígenos HLA-DQ/metabolismo , Interleucina-7/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Células Asesinas Naturales/inmunología , Células Mieloides/inmunología , Organoides/inmunología , Organoides/metabolismo , Organoides/patología , Proteína Glutamina Gamma Glutamiltransferasa 2/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos B/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismoAsunto(s)
Enfermedad Celíaca , Proteínas de Unión al GTP , Proteína Glutamina Gamma Glutamiltransferasa 2 , Transglutaminasas , Enfermedad Celíaca/genética , Enfermedad Celíaca/inmunología , Humanos , Proteínas de Unión al GTP/genética , Proteínas de Unión al GTP/inmunología , Transglutaminasas/genética , Transglutaminasas/metabolismo , Transcriptoma , Perfilación de la Expresión Génica , Inhibidores Enzimáticos/uso terapéutico , Inhibidores Enzimáticos/farmacologíaRESUMEN
BACKGROUND: Cancer utilizes immunosuppressive mechanisms to create a tumor microenvironment favorable for its progression. The purpose of this study is to histologically characterize the immunological properties of the tumor microenvironment of oral squamous cell carcinoma (OSCC) and identify key molecules involved in the immunological microenvironment and patient prognosis. METHODS: First, overlapping differentially expressed genes (DEGs) were screened from OSCC transcriptome data in public databases. Correlation analysis of DEGs with known immune-related genes identified genes involved in the immune microenvironment of OSCC. Next, stromal patterns of tumor were classified and immunohistochemical staining was performed for immune cell markers (CD3, CD4, Foxp3, CD8, CD20, CD68, and CD163), programmed death-ligand 1 (PD-L1), and guanylate binding protein 5 (GBP5) in resected specimens obtained from 110 patients with OSCC who underwent resection. Correlations between each factor and their prognostic impact were analyzed. RESULTS: Among the novel OSCC-specific immune-related genes screened (including ADAMDEC1, CXCL9, CXCL13, DPT, GBP5, IDO1, and PLA2G7), GBP5 was selected as the target gene. Histopathologic analysis showed that multiple T-cell subsets and CD20-positive cells were less common in the advanced stages, whereas CD163-positive cells were more common in advanced stages. The immature type in the stromal pattern category was associated with less immune cell infiltration, lower expression of PD-L1 in immune cells, lower expression of GBP5 in the stroma, and shorter overall survival and recurrence-free survival. Expression of GBP5 in the tumor and stroma correlated with immune cell infiltration of tumors and PD-L1 expression in tumor and immune cells. Patients with low tumor GBP5 expression and high stromal expression had significantly longer overall survival and recurrence-free survival. CONCLUSIONS: The stromal pattern category may reflect both invasive and immunomodulatory potentials of cancer-associated fibroblasts in OSCC. GBP5 has been suggested as a potential biomarker to predict the prognosis and therapeutic efficacy of immune checkpoint inhibitors.
Asunto(s)
Biomarcadores de Tumor , Biología Computacional , Neoplasias de la Boca , Microambiente Tumoral , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/metabolismo , Biología Computacional/métodos , Regulación Neoplásica de la Expresión Génica , Proteínas de Unión al GTP/genética , Proteínas de Unión al GTP/inmunología , Proteínas de Unión al GTP/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias de la Boca/inmunología , Neoplasias de la Boca/patología , Neoplasias de la Boca/genética , Neoplasias de la Boca/mortalidad , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/cirugía , Pronóstico , Estudios Retrospectivos , Microambiente Tumoral/inmunologíaRESUMEN
Interferon-alpha (IFN-α) is a first-line drug for treating chronic hepatitis B (CHB). Guanylate-binding protein 1 (GBP1) is one of the interferon-stimulating factors, which participates in the innate immunity of the host and plays an antiviral and antibacterial role. In this study, we explored how GBP1 is involved in IFN-α antiviral activity against HBV. Before being gathered, HepG2-NTCP and HepG2 2.15 cells were transfected with the wild-type hGBP1 plasmid or si-GBP1, respectively, and followed by stimulation with Peg-IFNα-2b. We systematically explored the role of GBP1 in regulating HBV infection in cell models. Additionally, we also examined GBP1 levels in CHB patients. GBP1 activity increased, and its half-life was prolonged after HBV infection. Overexpression of GBP1 inhibited the production of HBsAg and HBeAg, as well as HBs protein and HBV total RNA levels, whereas silencing of GBP1 inhibited its ability to block viral infections. Interestingly, overexpressing GBP1 co-treatment with Peg-IFNα-2b further increased the antiviral effect of IFN-α, while GBP1 silencing co-treatment with Peg-IFNα-2b partly restored its inhibitory effect on HBV. Mechanistically, GBP1 mediates the anti-HBV response of Peg-IFNα-2b by targeting HBs. Analysis of clinical samples revealed that GBP1 was elevated in CHB patients and increased with Peg-IFNα-2b treatment, while GBP1 showed good stability in the interferon response group. Our study demonstrates that GBP1 inhibits HBV replication and promotes HBsAg clearance. It is possible to achieve antiviral effects through the regulation of IFN-α induced immune responses in response to HBV.
Asunto(s)
Antivirales , Proteínas de Unión al GTP , Virus de la Hepatitis B , Hepatitis B Crónica , Interferón-alfa , Humanos , Interferón-alfa/farmacología , Interferón-alfa/inmunología , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/fisiología , Antivirales/farmacología , Proteínas de Unión al GTP/genética , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP/inmunología , Células Hep G2 , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Hepatitis B Crónica/inmunología , Masculino , Antígenos de Superficie de la Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/metabolismo , Femenino , Adulto , Replicación Viral/efectos de los fármacos , Hepatitis B/virología , Hepatitis B/inmunología , Hepatitis B/tratamiento farmacológicoRESUMEN
Potential celiac disease (PCD) is a clinical condition characterised by the presence of a positive CD-specific serology and a normal intestinal architecture. Asymptomatic PCD patients are generally advised to continue on a gluten-containing diet (GCD), but long-term risks of this approach have never been explored. In the present study, we aimed to investigate nutritional and autoimmune complications possibly developing overtime in a cohort of asymptomatic PCD children on a GCD. We compared children's parameters of growth, nutritional status, and autoimmunity between the time of diagnosis and on the occasion of their last medical check, after a long-term gluten-containing diet. Altogether, we collected data from 171 PCD children with a mean follow-up time of 3 years (range 0.35-15.3 years). During follow-up, although patients did not reduce their amount of daily gluten intake, their anti-tissue transglutaminase (anti-TG2) antibodies spontaneously and significantly decreased. Most parameters analysed had not changed during follow-up (height centile, ferritin, albumin, cholesterol, calcium, alkaline phosphatase, parathormone, and vitamin D) or even improved significantly (weight and BMI centile, haemoglobin, blood iron, HDL, glycaemia, and HbA1C, p < 0.05), always remaining within the limit of normality. Equally, autoantibodies for other concomitant autoimmune disorders did not increase overtime. Similar results were obtained excluding from analysis patients who had stopped producing anti-TG2 and those with a follow-up time < 3 years. Our pilot study has provided reassuring results regarding the maintenance of a gluten-containing diet in asymptomatic PCD children, even when long-term follow-up was considered.
Asunto(s)
Autoanticuerpos , Enfermedad Celíaca , Dieta Sin Gluten , Estado Nutricional , Humanos , Enfermedad Celíaca/dietoterapia , Enfermedad Celíaca/inmunología , Niño , Masculino , Femenino , Preescolar , Adolescente , Autoanticuerpos/sangre , Proteína Glutamina Gamma Glutamiltransferasa 2 , Proteínas de Unión al GTP/inmunología , Transglutaminasas/inmunología , Glútenes/efectos adversos , Glútenes/inmunología , Estado de Salud , Lactante , Estudios de Seguimiento , AutoinmunidadRESUMEN
Fibrotic remodeling is the primary driver of functional loss in chronic kidney disease, with no specific anti-fibrotic agent available for clinical use. Transglutaminase 2 (TG2), a wound response enzyme that irreversibly crosslinks extracellular matrix proteins causing dysregulation of extracellular matrix turnover, is a well-characterized anti-fibrotic target in the kidney. We describe the humanization and characterization of two anti-TG2 monoclonal antibodies (zampilimab [hDC1/UCB7858] and BB7) that inhibit crosslinking by TG2 in human in vitro and rabbit/cynomolgus monkey in vivo models of chronic kidney disease. Determination of zampilimab half-maximal inhibitory concentration (IC50) against recombinant human TG2 was undertaken using the KxD assay and determination of dissociation constant (Kd) by surface plasmon resonance. Efficacy in vitro was established using a primary human renal epithelial cell model of tubulointerstitial fibrosis, to assess mature deposited extracellular matrix proteins. Proof of concept in vivo used a cynomolgus monkey unilateral ureteral obstruction model of chronic kidney disease. Zampilimab inhibited TG2 crosslinking transamidation activity with an IC50 of 0.25 nM and Kd of <50 pM. In cell culture, zampilimab inhibited extracellular TG2 activity (IC50 119 nM) and dramatically reduced transforming growth factor-ß1-driven accumulation of multiple extracellular matrix proteins including collagens I, III, IV, V, and fibronectin. Intravenous administration of BB7 in rabbits resulted in a 68% reduction in fibrotic index at Day 25 post-unilateral ureteral obstruction. Weekly intravenous administration of zampilimab in cynomolgus monkeys with unilateral ureteral obstruction reduced fibrosis at 4 weeks by >50%, with no safety signals. Our data support the clinical investigation of zampilimab for the treatment of kidney fibrosis.
Asunto(s)
Fibrosis , Proteínas de Unión al GTP , Proteína Glutamina Gamma Glutamiltransferasa 2 , Insuficiencia Renal Crónica , Animales , Humanos , Masculino , Conejos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacología , Modelos Animales de Enfermedad , Fibrosis/tratamiento farmacológico , Proteínas de Unión al GTP/antagonistas & inhibidores , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP/inmunología , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Macaca fascicularis , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/patología , Transglutaminasas/antagonistas & inhibidores , Transglutaminasas/metabolismoRESUMEN
The combination of inflammatory factors resulting from an influenza A virus infection is one of the main causes of death in host animals. Studies have shown that guinea pig guanosine monophosphate binding protein 1 (guanylate-binding protein 1, gGBP1) can downregulate cytokine production induced by the influenza virus. Therefore, exploring the innate immune defense mechanism of GBP1 in the process of H5N1 influenza virus infection has important implications for understanding the pathogenic mechanism, disease prevention, and the control of influenza A virus infections. We found that, in addition to inhibiting the early replication of influenza virus, gGBP1 also inhibited the production of CCL2 and CXCL10 cytokines induced by the influenza virus as well as the proliferation of mononuclear macrophages induced by these cytokines. These findings further confirmed that gGBP1 inhibited the production of cytokines through its GTPase activity and cell proliferation through its C-terminal α-helix structure. This study revealed the effect of gGBP1 on the production of cellular inflammatory factors during influenza virus infection and determined the key amino acid residues that assist in the inhibitory processes mediated by gGBP1.
Asunto(s)
Proteínas de Unión al GTP , Subtipo H5N1 del Virus de la Influenza A , Animales , Subtipo H5N1 del Virus de la Influenza A/fisiología , Subtipo H5N1 del Virus de la Influenza A/inmunología , Proteínas de Unión al GTP/genética , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP/inmunología , Citocinas/metabolismo , Citocinas/genética , Gripe Aviar/virología , Gripe Aviar/inmunología , GTP Fosfohidrolasas/metabolismo , GTP Fosfohidrolasas/genética , Inmunidad Innata , Enfermedades de las Aves de Corral/virología , Enfermedades de las Aves de Corral/inmunología , PollosRESUMEN
OBJECTIVES: European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines enable the diagnosis of celiac disease (CD) without biopsies in patients with immunoglobulin A (IgA)-antibodies against tissue transglutaminase (TGA-IgA) ≥ 10× the upper limit of normal (ULN) and positivity of endomysial antibodies in a second blood sample. Limited data exist comparing the biopsy versus the nonbiopsy diagnostic approach regarding long-term outcomes in CD patients. Our study aimed to investigate the influence of the diagnostic approach on adherence to gluten-free diet (GFD), serological remission (defined as normalization of TGA-IgA during follow-up (FU)) and clinical remission in CD patients with TGA-IgA ≥ 10× ULN. METHODS: Retrospective multicenter study. Patients with CD and TGA-IgA ≥ 10× ULN at diagnosis were included in the study. Patients with confirmed diagnosis by biopsy were compared to patients diagnosed by nonbiopsy approach using univariate analysis, Kaplan-Meier survival curve, and logistic regression models. RESULTS: A total of 282 CD patients (192 [68.1%] in the biopsy group; 90 [31.9%] in the nonbiopsy group) were analyzed. The median time to normalization of TGA-IgA was 16.5 months [interquartile range, IQR: 13, 28] in the biopsy and 15 months [IQR: 12, 26] in the nonbiopsy group; p = 0.14). Rates of normalized TGA-IgA at first to third-year FU were comparable between both groups. Adherence to GFD did not seem to be influenced by the diagnostic approach. CONCLUSIONS: The nonbiopsy approach is not inferior to the biopsy approach in terms of adherence to GFD and serological remission in patients with CD.
Asunto(s)
Enfermedad Celíaca , Dieta Sin Gluten , Inmunoglobulina A , Transglutaminasas , Humanos , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/dietoterapia , Enfermedad Celíaca/sangre , Enfermedad Celíaca/inmunología , Estudios Retrospectivos , Masculino , Niño , Femenino , Biopsia , Transglutaminasas/inmunología , Preescolar , Adolescente , Inmunoglobulina A/sangre , Autoanticuerpos/sangre , Proteína Glutamina Gamma Glutamiltransferasa 2 , Proteínas de Unión al GTP/inmunología , Resultado del Tratamiento , Estudios de Seguimiento , Lactante , Cooperación del PacienteRESUMEN
Polymeric guanylate-binding proteins (GBPs) physically dismember the vacuole membrane formed by Toxoplasma gondii while nitric oxide (NO) poisons and inhibits parasite replication within interferon (IFN)-γ activated macrophages. Zhao et al. report a novel mechanism for synergy between these classical microbicidal and microbistatic effectors in cell-autonomous immunity to the intracellular parasites.
Asunto(s)
Toxoplasma , Toxoplasma/inmunología , Óxido Nítrico/metabolismo , Animales , Humanos , Proteínas de Unión al GTP/inmunología , Proteínas de Unión al GTP/metabolismo , Macrófagos/inmunología , Macrófagos/parasitologíaRESUMEN
Many antibody responses induced by infection, vaccination or autoimmunity show signs of convergence across individuals with epitope-dependent selection of particular variable region gene segments and complementarity determining region 3 properties. However, not much is known about the relationship between antigen-specific effector cells and antigen-specific precursors present in the naïve B-cell repertoire. Here, we sought to address this relationship in the context of celiac disease, where there is a stereotyped autoantibody response against the enzyme transglutaminase 2 (TG2). By generating TG2-specific monoclonal antibodies from both duodenal plasma cells and circulating naïve B cells, we demonstrate a discord between the naïve TG2-specific repertoire and the cells that are selected for autoantibody production. Hence, the naïve repertoire does not fully reflect the epitope preference and gene usage observed for memory B cells and plasma cells. Instead, distinct naïve B cells that target particular TG2 epitopes appear to be selectively activated at the expense of TG2-binding B cells targeting other epitopes.
Asunto(s)
Autoanticuerpos , Linfocitos B , Enfermedad Celíaca , Epítopos de Linfocito B , Proteínas de Unión al GTP , Activación de Linfocitos , Proteína Glutamina Gamma Glutamiltransferasa 2 , Transglutaminasas , Enfermedad Celíaca/inmunología , Humanos , Autoanticuerpos/inmunología , Transglutaminasas/inmunología , Epítopos de Linfocito B/inmunología , Proteínas de Unión al GTP/inmunología , Activación de Linfocitos/inmunología , Linfocitos B/inmunología , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Femenino , Anticuerpos Monoclonales/inmunología , Epítopos/inmunología , Masculino , Adulto , Duodeno/inmunología , Duodeno/patologíaRESUMEN
Immunotherapy is widely used in cancer treatment; however, only a subset of patients responds well to it. Significant efforts have been made to identify patients who will benefit from immunotherapy. Successful anti-tumor immunity depends on an intact cancer-immunity cycle, especially long-lasting CD8+ T-cell responses. Interferon (IFN)-α/ß/IFN-γ/interleukin (IL)-15 pathways have been reported to be involved in the development of CD8+ T cells. And these pathways may predict responses to immunotherapy. Herein, we aimed to analyze multiple public databases to investigate whether IFN-α/ß/IFN-γ/IL-15 pathways could be used to predict the response to immunotherapy. Results showed that IFN-α/ß/IFN-γ/IL-15 pathways could efficiently predict immunotherapy response, and guanylate-binding protein 1 (GBP1) could represent the IFN-α/ß/IFN-γ/IL-15 pathways. In public and private cohorts, we further demonstrated that GBP1 could efficiently predict the response to immunotherapy. Functionally, GBP1 was mainly expressed in macrophages and strongly correlated with chemokines involved in T-cell migration. Therefore, our study comprehensively investigated the potential role of GBP1 in immunotherapy, which could serve as a novel biomarker for immunotherapy and a target for drug development.
Asunto(s)
Proteínas de Unión al GTP , Inmunoterapia , Neoplasias , Humanos , Linfocitos T CD8-positivos/inmunología , Proteínas de Unión al GTP/genética , Proteínas de Unión al GTP/inmunología , Inmunoterapia/métodos , Interferón-alfa/metabolismo , Interferón beta/metabolismo , Interferón gamma/metabolismo , Interleucina-15/genética , Neoplasias/inmunología , Neoplasias/terapia , Transducción de SeñalRESUMEN
Olmesartan is an angiotensin II receptor blocker licensed for the treatment of hypertension. It can cause a sprue-like enteropathy (SLE), characterised by chronic diarrhoea, weight loss and villous atrophy. Transiently raised anti-tissue transglutaminase (ATTG) antibody has also been rarely reported in the literature.We describe the case of a woman in her mid-50s, who presented with a history of intermittent loose stools over 1 year, associated with significant weight loss. She had two marginally raised serum ATTG antibody tests during her work-up.After extensive investigations, she was diagnosed with olmesartan-induced enteropathy. On subsequent follow-up, her symptoms had resolved with cessation of her olmesartan therapy.This case adds to existing literature, highlighting the importance of considering olmesartan as a possible differential diagnosis for SLE. It also reports the presence of a raised ATTG antibody which is infrequently reported in this context.
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Diarrea , Imidazoles , Tetrazoles , Transglutaminasas , Pérdida de Peso , Humanos , Femenino , Imidazoles/efectos adversos , Diarrea/inducido químicamente , Tetrazoles/efectos adversos , Persona de Mediana Edad , Transglutaminasas/inmunología , Diagnóstico Diferencial , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Autoanticuerpos/sangre , Proteína Glutamina Gamma Glutamiltransferasa 2 , Enfermedad Crónica , Enfermedad Celíaca/diagnóstico , Proteínas de Unión al GTP/inmunología , Proteínas de Unión al GTP/antagonistas & inhibidoresRESUMEN
Autoantibodies against the enzyme transglutaminase 2 (TG2) are characteristic of celiac disease (CeD), and TG2-specific immunoglobulin (Ig) A plasma cells are abundant in gut biopsies of patients. Here, we describe the corresponding population of autoreactive B cells in blood. Circulating TG2-specific IgA cells are present in untreated patients on a gluten-containing diet but not in controls. They are clonally related to TG2-specific small intestinal plasma cells, and they express gut-homing molecules, indicating that they are plasma cell precursors. Unlike other IgA-switched cells, the TG2-specific cells are negative for CD27, placing them in the double-negative (IgD-CD27-) category. They have a plasmablast or activated memory B cell phenotype, and they harbor fewer variable region mutations than other IgA cells. Based on their similarity to naive B cells, we propose that autoreactive IgA cells in CeD are generated mainly through chronic recruitment of naive B cells via an extrafollicular response involving gluten-specific CD4+ T cells.
Asunto(s)
Linfocitos B , Enfermedad Celíaca , Proteínas de Unión al GTP , Inmunoglobulina A , Células Plasmáticas , Proteína Glutamina Gamma Glutamiltransferasa 2 , Transglutaminasas , Enfermedad Celíaca/inmunología , Enfermedad Celíaca/patología , Humanos , Transglutaminasas/inmunología , Transglutaminasas/metabolismo , Inmunoglobulina A/inmunología , Inmunoglobulina A/metabolismo , Inmunoglobulina A/sangre , Linfocitos B/inmunología , Linfocitos B/metabolismo , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Proteínas de Unión al GTP/inmunología , Proteínas de Unión al GTP/metabolismo , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Adulto , Masculino , Femenino , Persona de Mediana Edad , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Glútenes/inmunologíaRESUMEN
BACKGROUND & AIMS: The treatment of celiac disease (CeD) with gluten-free diet (GFD) normalizes gut inflammation and disease-specific antibodies. CeD patients have HLA-restricted, gluten-specific T cells persisting in the blood and gut even after decades of GFD, which are reactivated and disease driving upon gluten exposure. Our aim was to examine the transition of activated gluten-specific T cells into a pool of persisting memory T cells concurrent with normalization of clinically relevant biomarkers during the first year of treatment. METHODS: We followed 17 CeD patients during their initial GFD year, leading to disease remission. We assessed activation and frequency of gluten-specific CD4+ blood and gut T cells with HLA-DQ2.5:gluten tetramers and flow cytometry, disease-specific serology, histology, and symptom scores. We assessed gluten-specific blood T cells within the first 3 weeks of GFD in 6 patients and serology in an additional 9 patients. RESULTS: Gluten-specific CD4+ T cells peaked in blood at day 14 while up-regulating Bcl-2 and down-regulating Ki-67 and then decreased in frequency within 10 weeks of GFD. CD38, ICOS, HLA-DR, and Ki-67 decreased in gluten-specific cells within 3 days. PD-1, CD39, and OX40 expression persisted even after 12 months. IgA-transglutaminase 2 decreased significantly within 4 weeks. CONCLUSIONS: GFD induces rapid changes in the phenotype and number of gluten-specific CD4+ blood T cells, including a peak of nonproliferating, nonapoptotic cells at day 14. Subsequent alterations in T-cell phenotype associate with the quiescent but chronic nature of treated CeD. The rapid changes affecting gluten-specific T cells and disease-specific antibodies offer opportunities for clinical trials aiming at developing nondietary treatments for patients with newly diagnosed CeD.
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Linfocitos T CD4-Positivos , Enfermedad Celíaca , Dieta Sin Gluten , Glútenes , Fenotipo , Proteína Glutamina Gamma Glutamiltransferasa 2 , Humanos , Enfermedad Celíaca/dietoterapia , Enfermedad Celíaca/inmunología , Glútenes/inmunología , Glútenes/administración & dosificación , Masculino , Femenino , Adulto , Persona de Mediana Edad , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Antígenos HLA-DQ/inmunología , Proteínas de Unión al GTP/inmunología , Proteínas de Unión al GTP/metabolismo , Activación de Linfocitos , Transglutaminasas/inmunología , Biomarcadores/sangre , Biomarcadores/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , Factores de Tiempo , Adulto Joven , Resultado del Tratamiento , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismoRESUMEN
INTRODUCTION: Circulating tissue transglutaminase immunoglobulin A concentration is a sensitive and specific indicator of celiac disease, but discrepancies between serologic and histologic findings occur. We hypothesized that fecal markers of inflammation and protein loss would be greater in patients with untreated celiac disease than in healthy controls. Our study aims to evaluate multiple fecal and plasma markers in celiac disease and correlate these findings with serologic and histologic findings as noninvasive means of evaluating disease activity. METHODS: Participants with positive celiac serologies and controls with negative celiac serologies were prospectively enrolled before upper endoscopy. Blood, stool, and duodenal biopsies were collected. Concentrations of fecal lipocalin-2, calprotectin, and alpha-1-antitrypsin and plasma lipocalin-2 were determined. Biopsies underwent modified Marsh scoring. Significance was tested between cases and controls, modified Marsh score and tissue transglutaminase immunoglobulin A concentration. RESULTS: Lipocalin-2 was significantly elevated in the stool ( P = 0.006) but not the plasma of participants with positive celiac serologies. There was no significant difference in fecal calprotectin or alpha-1 antitrypsin between participants with positive celiac serologies and controls. Fecal alpha-1 antitrypsin >100 mg/dL was specific, but not sensitive for biopsy-proven celiac disease. DISCUSSION: Lipocalin-2 is elevated in the stool but not the plasma of patients with celiac disease suggesting a role of local inflammatory response. Calprotectin was not a useful marker in the diagnosis of celiac disease. While random fecal alpha-1 antitrypsin was not significantly elevated in cases compared with controls, an elevation of greater than 100 mg/dL was 90% specific for biopsy-proven celiac disease.
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Biomarcadores , Enfermedad Celíaca , Duodeno , Heces , Proteínas de Unión al GTP , Inmunoglobulina A , Complejo de Antígeno L1 de Leucocito , Lipocalina 2 , Proteína Glutamina Gamma Glutamiltransferasa 2 , Transglutaminasas , alfa 1-Antitripsina , Humanos , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/sangre , Enfermedad Celíaca/patología , Femenino , Biomarcadores/sangre , Biomarcadores/análisis , Masculino , Niño , alfa 1-Antitripsina/sangre , Complejo de Antígeno L1 de Leucocito/análisis , Complejo de Antígeno L1 de Leucocito/sangre , Heces/química , Lipocalina 2/sangre , Lipocalina 2/análisis , Transglutaminasas/inmunología , Transglutaminasas/sangre , Estudios Prospectivos , Preescolar , Inmunoglobulina A/sangre , Proteínas de Unión al GTP/inmunología , Proteínas de Unión al GTP/sangre , Adolescente , Duodeno/patología , Biopsia , Estudios de Casos y Controles , Lipocalinas/sangre , Proteínas de Fase Aguda/análisis , Proteínas de Fase Aguda/metabolismo , Inflamación/diagnóstico , Inflamación/sangreRESUMEN
OBJECTIVES: Autoantibodies against tissue transglutaminase (tTG) are serological markers of celiac disease. The aim was to study the applicability of human leukocyte antigen (HLA)-genotyping and tTG autoantibodies in the screening of celiac disease in a longitudinal birth cohort followed to age 15 years. METHODS: Included were 13,860 HLA-DQ-genotyped children at birth and previously invited to a screening at age 3 and 9 years, respectively. HLA-DQB1*02 and/or DQB1*03:02 (HLA-risk) children were compared with non-HLA-DQB1*02 and non-DQB1*03:02 (HLA-nonrisk) children. The present study reinvited 12,948/13,860 (93.4%) children at age 15 years of whom 1056/2374 (44.5%) participated in screening at both age 3 and 9 years. Both immunoglobulin A (IgA) and G (IgG) autoantibodies against tTG were analyzed separately in radiobinding assays. Persistently tTG autoantibody-positive children were examined with intestinal biopsy to confirm the diagnosis of celiac disease. RESULTS: At age 3 years, celiac disease was diagnosed in 56/1635 (3.4%) HLA-risk children compared with 0/1824 HLA-nonrisk children (p < 0.001). By age 9 years, celiac disease was diagnosed in 72/1910 (3.8%) HLA-risk children compared with 0/2167 HLA-nonrisk children (p < 0.001). Screening at age 15 years detected 14/1071 (1.3%) HLA-risk children positive for IgA-tTG and/or IgG-tTG of whom 12/1071 (1.1%) remained persistently positive. Among those, 10/1071 (0.9%, 95% confidence interval: 0.4%-1.7%) HLA-risk children were diagnosed with celiac disease compared with 0/1303 HLA-nonrisk children (p < 0.001) and 5/491 (1.0%) were negative in screenings at both 3 and 9 years of age. CONCLUSIONS: Screening for celiac disease needs to be performed at multiple timepoints to detect all cases but can be restricted to children at HLA-risk.
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Autoanticuerpos , Enfermedad Celíaca , Proteínas de Unión al GTP , Inmunoglobulina A , Transglutaminasas , Humanos , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/inmunología , Enfermedad Celíaca/genética , Niño , Preescolar , Transglutaminasas/inmunología , Estudios Longitudinales , Autoanticuerpos/sangre , Adolescente , Femenino , Masculino , Inmunoglobulina A/sangre , Proteínas de Unión al GTP/inmunología , Inmunoglobulina G/sangre , Proteína Glutamina Gamma Glutamiltransferasa 2 , Antígenos HLA-DQ/genética , Tamizaje Masivo/métodos , Genotipo , Cadenas beta de HLA-DQ/genética , Factores de Riesgo , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND: Ultra-short coeliac disease (USCD) is defined as villous atrophy only present in the duodenal bulb (D1) with concurrent positive coeliac serology. We present the first, multicentre, international study of patients with USCD. METHODS: Patients with USCD were identified from 10 tertiary hospitals (6 from Europe, 2 from Asia, 1 from North America and 1 from Australasia) and compared with age-matched and sex-matched patients with conventional coeliac disease. FINDINGS: Patients with USCD (n=137, median age 27 years, IQR 21-43 years; 73% female) were younger than those with conventional coeliac disease (27 vs 38 years, respectively, p<0.001). Immunoglobulin A-tissue transglutaminase (IgA-tTG) titres at index gastroscopy were lower in patients with USCD versus conventional coeliac disease (1.8×upper limit of normal (ULN) (IQR 1.1-5.9) vs 12.6×ULN (IQR 3.3-18.3), p<0.001).Patients with USCD had the same number of symptoms overall (median 3 (IQR 2-4) vs 3 (IQR 1-4), p=0.875). Patients with USCD experienced less iron deficiency (41.8% vs 22.4%, p=0.006).Both USCD and conventional coeliac disease had the same intraepithelial lymphocytes immunophenotype staining pattern; positive for CD3 and CD8, but not CD4.At follow-up having commenced a gluten-free diet (GFD) (median of 1181 days IQR: 440-2160 days) both USCD and the age-matched and sex-matched controls experienced a similar reduction in IgA-tTG titres (0.5 ULN (IQR 0.2-1.4) vs 0.7 ULN (IQR 0.2-2.6), p=0.312). 95.7% of patients with USCD reported a clinical improvement in their symptoms. INTERPRETATION: Patients with USCD are younger, have a similar symptomatic burden and benefit from a GFD. This study endorses the recommendation of D1 sampling as part of the endoscopic coeliac disease diagnostic workup.
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Enfermedad Celíaca , Duodeno , Transglutaminasas , Humanos , Enfermedad Celíaca/patología , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/dietoterapia , Femenino , Masculino , Adulto , Estudios de Casos y Controles , Duodeno/patología , Adulto Joven , Transglutaminasas/inmunología , Inmunoglobulina A/sangre , Proteínas de Unión al GTP/inmunología , Atrofia , Dieta Sin Gluten , Mucosa Intestinal/patología , Proteína Glutamina Gamma Glutamiltransferasa 2 , Gastroscopía , Persona de Mediana EdadRESUMEN
BACKGROUND: A prior small-scale single center study suggested an association between celiac disease (CD)-type immunity and refractory temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS). The present study addresses this putative association in a large, well-characterized group of drug-resistant epilepsy (DRE) patients. These patients were grouped based on the spectrum of CD and gluten sensitivity-associated antibodies. METHODS: In this cross-sectional study, 253 consecutive adult epilepsy patients (135 females, 118 males; age 16-76 years) were categorized into three groups: (i) CD-positive group with either prior diagnosis of CD or CD-specific TG2/EmA antibodies, (ii) AGA-positive group with antigliadin antibodies (AGA) but without CD, and (iii) CD/AGA-negative group without any gluten sensitivity-associated antibodies or CD. Clinical and immunological findings were then compared among the groups. RESULTS: TLE with HS was more common in the CD-positive group compared to CD/AGA-negative group (31.8% versus 11.9%, P = 0.019). Autoimmune disorders were more common in the AGA-positive group than in the CD/AGA-negative group (P = 0.025). Considering HS lateralization; left lateralization was more common in CD-positive group compared to CD/AGA-negative group (71.4% versus 25%, P = 0.030). TG6 seropositivity did not differ among the groups (P > 0.05). CONCLUSIONS: This study provides further evidence linking TLE with HS and CD-type autoimmunity suggesting that CD-type immune response to gluten can be one potential mechanism as a disease modifier leading to DRE and HS. Understanding these immunological factors is imperative for developing immunomodulatory or dietary treatments for DRE potentially preventing HS progression.
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Enfermedad Celíaca , Epilepsia Refractaria , Epilepsia del Lóbulo Temporal , Esclerosis del Hipocampo , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Autoanticuerpos/sangre , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/inmunología , Estudios Transversales , Epilepsia Refractaria/inmunología , Epilepsia Refractaria/etiología , Epilepsia del Lóbulo Temporal/inmunología , Epilepsia del Lóbulo Temporal/complicaciones , Gliadina/inmunología , Proteínas de Unión al GTP/inmunología , Esclerosis del Hipocampo/inmunología , Proteína Glutamina Gamma Glutamiltransferasa 2 , Transglutaminasas/inmunologíaRESUMEN
In its conventional form, celiac disease (CeD) is characterized by both positive serology and flat villi in the duodenum, and is well known by gastroenterologists and general practitioners. The aim of this review was to shed light on 2 neglected and not yet well-defined celiac phenotypes, that is, seronegative and ultrashort CeD. Seronegative CeD can be suspected in the presence of flat villi, positive HLA-DQ2 and/or HLA-DQ8, and the absence of CeD antibodies. After ruling out other seronegative enteropathies, the diagnosis can be confirmed by both clinical and histologic improvements after 1 year of a gluten-free diet. Ultrashort CeD is characterized by the finding of flat villi in the duodenal bulb in the absence of mucosal damage in the distal duodenum and with serologic positivity. Data on the prevalence, clinical manifestations, histologic lesions, genetic features, and outcome of seronegative and ultrashort CeD are inconclusive due to the few studies available and the small number of patients diagnosed. Some additional diagnostic tools have been developed recently, such as assessing intestinal transglutaminase 2 deposits, flow cytometry technique, microRNA detection, or proteomic analysis, and they seem to be useful in the identification of complex cases. Further cooperative studies are highly desirable to improve the knowledge of these 2 still-obscure variants of CeD.