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1.
Clin Gastroenterol Hepatol ; 14(5): 713-9, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26656297

RESUMEN

BACKGROUND & AIMS: Patients with colitis have an increased risk of colorectal cancer, compared with persons without colitis. Many studies have shown chromoendoscopy (CE) to be superior to standard methods of detecting dysplasia in patients with colitis at index examination. We performed a prospective, longitudinal study to compare standard colonoscopy vs CE in detecting dysplasia in patients with inflammatory bowel diseases in a surveillance program. METHODS: We analyzed data from 68 patients (44 men, 24 women) diagnosed with ulcerative colitis (n = 55) or Crohn's disease (n = 13) at Mount Sinai Medical Center from September 2005 through October 2011. The patients were followed from June 2006 through October 2011 (median, 27.8 months); each patient was analyzed by random biopsy, targeted white light examination (WLE), and CE. Specimens were reviewed by a single blinded pathologist. The 3 methods were compared by using the generalized estimating equations method, and the odds ratios (ORs) for detection of dysplasia were calculated (primary outcome). Time to colectomy was analyzed by using the Cox model. RESULTS: In the 208 examinations conducted, 44 dysplastic lesions were identified in 24 patients; 6 were detected by random biopsy, 11 by WLE, and 27 by CE. Ten patients were referred for colectomy, and no carcinomas were found. At any time during the study period, CE (OR, 5.4; 95% confidence interval [CI], 2.9-9.9) and targeted WLE (OR, 2.3; 95% CI, 1.0-5.3) were more likely than random biopsy analysis to detect dysplasia. CE was superior to WLE (OR, 2.4; 95% CI, 1.4-4.0). Patients identified as positive for dysplasia were more likely to need colectomy (hazard ratio, 12.1; 95% CI, 3.2-46.2). CONCLUSIONS: In a prospective study of 68 patients with inflammatory bowel diseases, CE was superior to random biopsy or WLE analyses in detecting dysplasia in patients with colitis during an almost 28-month period. A negative result from CE examination was the best indicator of a dysplasia-free outcome, whereas a positive result was associated with earlier referral for colectomy.


Asunto(s)
Colitis/complicaciones , Neoplasias Colorrectales/diagnóstico , Endoscopía/métodos , Enfermedades Inflamatorias del Intestino/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto Joven
2.
Mol Med ; 20: 707-19, 2015 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-25826676

RESUMEN

A single nucleotide polymorphism of PRDM1, the gene encoding Blimp-1, is strongly associated with inflammatory bowel disease. Here, we demonstrate that Blimp-1 in CD103(+) dendritic cells (DCs) critically contributes to the regulation of macrophage homeostasis in the colon. Dextran sodium sulfate (DSS)-exposed Blimp-1(cko) mice with a deletion of Blimp-1 in CD103(+) DCs and CD11c(hi) macrophages exhibited severe inflammatory symptoms, pronounced weight loss, high mortality, robust infiltration of neutrophils in epithelial regions of the colon, an increased expression of proinflammatory cytokines and a significant decrease in CD103(+) DCs in the colon compared with DSS exposed wild-type (WT) mice. Purified colonic macrophages from Blimp-1(cko) mice expressed increased levels of matrix metalloproteinase 8, 9 and 12 mRNA. WT macrophages cocultured with colonic DCs but not bone marrow-derived DCs from Blimp-1(cko) produced increased matrix metalloproteinases in an interleukin (IL)-1ß- and IL-6-dependent manner. Treatment of Blimp-1(cko) mice with anti-IL-1ß and anti-IL-6 abrogated the exaggerated clinical response. Overall, these data demonstrate that Blimp-1 expression in DCs can alter an innate inflammatory response by modulating the activation of myeloid cells. This is a novel mechanism of contribution of Blimp-1 for the pathogenesis of inflammatory bowel diseases, implicating another therapeutic target for the development of inflammatory bowel disease.


Asunto(s)
Colitis/inmunología , Células Dendríticas/inmunología , Proteínas Represoras/inmunología , Factores de Transcripción/inmunología , Animales , Colitis/inducido químicamente , Citocinas/genética , Citocinas/metabolismo , Sulfato de Dextran , Humanos , Macrófagos/inmunología , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Ratones Endogámicos BALB C , Ratones Noqueados , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Factores de Transcripción/genética
3.
Blood ; 121(9): 1595-603, 2013 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-23223361

RESUMEN

Regulatory T cells (Tregs) play an essential role in preventing autoimmunity. Mutations in the forkhead box protein 3 (FOXP3) gene, which encodes a transcription factor critical for Treg function, result in a severe autoimmune disorder and the production of various autoantibodies in mice and in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) patients. However, it is unknown whether Tregs normally suppress autoreactive B cells. To investigate a role for Tregs in maintaining human B-cell tolerance, we tested the reactivity of recombinant antibodies isolated from single B cells isolated from IPEX patients. Characteristics and reactivity of antibodies expressed by new emigrant/transitional B cells from IPEX patients were similar to those from healthy donors, demonstrating that defective Treg function does not impact central B-cell tolerance. In contrast, mature naive B cells from IPEX patients often expressed autoreactive antibodies, suggesting an important role for Tregs in maintaining peripheral B-cell tolerance. T cells displayed an activated phenotype in IPEX patients, including their Treg-like cells, and showed up-regulation of CD40L, PD-1, and inducibl T-cell costimulator (ICOS), which may favor the accumulation of autoreactive mature naive B cells in these patients. Hence, our data demonstrate an essential role for Tregs in the establishment and the maintenance of peripheral B-cell tolerance in humans.


Asunto(s)
Autoinmunidad , Linfocitos B/citología , Linfocitos B/inmunología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/fisiología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Autoinmunidad/inmunología , Linfocitos B/patología , Estudios de Casos y Controles , Células Cultivadas , Preescolar , Humanos , Lactante , Recién Nacido , Recuento de Linfocitos , Tolerancia Periférica/inmunología , Síndrome , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/inmunología , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/patología
4.
PLoS Genet ; 8(3): e1002559, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22412388

RESUMEN

Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10⁻6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10⁻8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10⁻9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10⁻8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10⁻8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10⁻9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.


Asunto(s)
Enfermedad de Crohn/genética , Estudio de Asociación del Genoma Completo , Judíos/genética , Cromosomas Humanos Par 5/genética , Estudios de Cohortes , Predisposición Genética a la Enfermedad , Humanos , Desequilibrio de Ligamiento , Población Blanca
5.
J Allergy Clin Immunol ; 133(2): 492-9, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24636473

RESUMEN

BACKGROUND: There are few studies on the natural history of egg allergy, and most are single-site and nonlongitudinal and have not identified early predictors of outcomes. OBJECTIVE: We sought to describe the natural course of egg allergy and to identify early prognostic markers. METHODS: Children age 3 to 15 months were enrolled in a multicenter observational study with either (1) a convincing history of an immediate allergic reaction to egg, milk, or both with a positive skin prick test (SPT) response to the trigger food and/or (2) moderate-to-severe atopic dermatitis and a positive SPT response to egg or milk. Children enrolled with a clinical history of egg allergy were followed longitudinally, and resolution was established based on successful ingestion. RESULTS: The cohort with egg allergy consists of 213 children followed to a median age of 74 months. Egg allergy resolved in 105 (49.3%) children at a median age of 72 months. Factors that were most predictive of resolution included the following: initial reaction characteristics (isolated urticaria/angioedema vs other presentations), baseline egg-specific IgE level, egg SPT wheal size, atopic dermatitis severity, IgG4 level, and IL-4 response (all P < .05). Numerous additional baseline clinical and demographic factors and laboratory assessments were not associated with resolution. Multivariate analysis identified baseline egg-specific IgE levels and initial reaction characteristics as strongly associated with resolution; a calculator to estimate resolution probabilities using these variables was established. CONCLUSIONS: In this cohort of infants with egg allergy, approximately one half had resolved over 74 months of follow-up. Baseline egg-specific IgE levels and initial reaction characteristics were important predictors of the likelihood of resolution.


Asunto(s)
Hipersensibilidad al Huevo/epidemiología , Tolerancia Inmunológica , Niño , Preescolar , Estudios de Cohortes , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/epidemiología , Dermatitis Atópica/inmunología , Hipersensibilidad al Huevo/diagnóstico , Hipersensibilidad al Huevo/inmunología , Femenino , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Lactante , Masculino , Pruebas Cutáneas
6.
Gut ; 63(3): 442-50, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23461895

RESUMEN

OBJECTIVE: Interferon-γ-inducible protein-10 (IP-10 or CXCL10) plays a role in inflammatory cell migration and epithelial cell survival and migration. It is expressed in higher levels in the colonic tissue and plasma of patients with ulcerative colitis (UC). This phase II study assessed the efficacy and safety of BMS-936557, a fully human, monoclonal antibody to IP-10, in the treatment of moderately-to-severely active UC. DESIGN: In this 8-week, phase II, double-blind, multicentre, randomised study, patients with active UC received placebo or BMS-936557 (10 mg/kg) intravenously every other week. The primary endpoint was the rate of clinical response at Day 57; clinical remission and mucosal healing rates were secondary endpoints. Post hoc analyses evaluated the drug exposure-response relationship and histological improvement. RESULTS: 109 patients were included (BMS-936557: n=55; placebo: n=54). Prespecified primary and secondary endpoints were not met; clinical response rate at Day 57 was 52.7% versus 35.2% for BMS-936557 versus placebo (p=0.083), and clinical remission and mucosal healing rates were 18.2% versus 16.7% (p=1.00) and 41.8% versus 35.2% (p=0.556), respectively. However, higher BMS-936557 steady-state trough concentration (Cminss) was associated with increased clinical response (87.5% vs 37.0% (p<0.001) for patients with Cminss 108-235 µg/ml vs placebo) and histological improvements (73.0% vs 41.0%; p=0.004). Infections occurred in 7 (12.7%) BMS-936557-treated patients and 3 (5.8%) placebo-treated patients. 2 (3.6%) BMS-936557 patients discontinued due to adverse events. CONCLUSIONS: Anti-IP-10 antibody, BMS-936557, is a potentially effective therapy for moderately-to-severely active UC. Higher drug exposure correlated with increasing clinical response and histological improvement. Further dose-response studies are warranted. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00656890.


Asunto(s)
Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Quimiocina CXCL10/antagonistas & inhibidores , Colitis Ulcerosa/tratamiento farmacológico , Quimioterapia de Inducción , Administración Intravenosa , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Colitis Ulcerosa/patología , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Análisis de Intención de Tratar , Modelos Logísticos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto Joven
7.
Gastroenterology ; 144(3): 601-612.e1, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23232296

RESUMEN

BACKGROUND & AIMS: In healthy individuals, interactions between intestinal epithelial cells and lamina propria lymphocytes give rise to a population of CD8(+) T cells with suppressor functions (Ts cells). Disruption of Ts cell activities can lead to mucosal inflammation. We investigated what factors were required for expansion of the Ts cell population or loss of their activity in patients with Crohn's disease (CD). METHODS: We developed a method to generate Ts cell lines from freshly isolated lamina propria lymphocytes from patients with ulcerative colitis (UC), patients with CD, or healthy individuals (controls). Cells were stimulated with a monoclonal antibody against CD3, interleukin (IL)-7, and IL-15. After 14 days in culture, CD8(+)T cells were purified and cultured with IL-7 and IL-15. The resulting Ts cells were analyzed for suppressor activity, expression of surface markers, and cytokine secretion profiles. RNA was isolated from the 3 groups of Ts cells and used in microarray analyses. RESULTS: Ts cells from patients with UC and controls suppressed proliferation of CD4(+) T cells; the suppression required cell contact. In contrast, Ts cells from patients with CD had a reduced capacity to suppress CD4(+) T-cell proliferation. The difference in suppressive ability was not associated with surface or intracytoplasmic markers or secretion of cytokines. Microarray analysis identified changes in expression of genes regulated by transforming growth factor (TGF)-ß that were associated with the suppressive abilities of Ts cells. We found that TGF-ß or supernatants from Ts cells of patients with CD reduced the suppressor activity of control Ts cells. CONCLUSIONS: Ts cells isolated from patients with CD have a reduced ability to suppress proliferation of CD4(+)T cells compared with control Ts cells. TGF-ß signaling reduces the suppressor activity of Ts cells.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Tolerancia Inmunológica/inmunología , Mucosa Intestinal/inmunología , Factor de Crecimiento Transformador beta/inmunología , Antígenos CD28/inmunología , Complejo CD3/inmunología , Línea Celular , Separación Celular , Perfilación de la Expresión Génica , Humanos , Tolerancia Inmunológica/genética , Interferón gamma/inmunología , Intestinos/inmunología , Transducción de Señal , Factor de Necrosis Tumoral alfa/inmunología
8.
Pediatr Allergy Immunol ; 25(3): 243-9, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24576111

RESUMEN

BACKGROUND: Recently, a study from the Consortium of Food Allergy Research (CoFAR) showed that allergen-induced IL-4 expression in CD25(+) mononuclear cells was increased in allergic patients. However, they did not find the expected increase in GATA-3 expression, suggesting that allergen-induced IL-4 might not be of T-cell origin. We sought to determine whether other cell types were responsible for the increased IL-4 expression in the CD25(+) cell population. METHODS: Comparing six allergic patients and six healthy controls, we analyzed the CD25(+) isolated population from PBMC for the presence of potential IL-4-expressing non-T cells. We also compared spontaneous expression levels of surface markers (CD203c, CD63, CD25, and HLA-DR) on basophils from whole blood of 42 peanut-allergic patients and from 12 non-atopic controls. Expression of these markers was also evaluated following basophil activation in eight peanut-allergic patients selected from the previous cohort. RESULTS: In addition to CD4(+) T cells, a substantial proportion of non-T cells were found in the CD25(+) -isolated cell population: basophils, NK, and NK-T cells with a mean percentage ± s.e.m. of 5.24 ± 0.63%, 6.65 ± 1.01%, and 6.01 ± 1.04%, respectively. The majority of these cells exhibited positive intracytoplasmic staining for IL-4. Expression of CD63 and CD25 was significantly higher in allergic patients compared with controls (p < 0.05). Interestingly, we found a significantly higher proportion of activated basophils expressing HLA-DR, compared with non-activated basophils (p < 0.05). CONCLUSIONS: Our results support the suggested key role of non-T cells secreting IL-4 in food allergy, particularly basophils, which may also play a central role in antigen presentation.


Asunto(s)
Hipersensibilidad a los Alimentos/inmunología , Interleucina-4/biosíntesis , Adolescente , Adulto , Presentación de Antígeno , Basófilos/inmunología , Niño , Preescolar , Femenino , Humanos , Lactante , Subunidad alfa del Receptor de Interleucina-2/análisis , Masculino , Tetraspanina 30/análisis
9.
J Allergy Clin Immunol ; 131(1): 14-22, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23265693

RESUMEN

Immune tolerance is defined as nonresponsiveness of the adaptive immune system to antigens. Immune mechanisms preventing inappropriate immune reactivity to innocuous antigens include deletion of reactive lymphocytes and generation of regulatory T (Treg) cells. The normal response to food antigens is the generation of antigen-specific Treg cells. In patients with food allergy, the dominant immune response is a T(H)2-skewed T-cell response and the generation of food-specific IgE antibodies from B cells. It is not known whether a failure of the Treg cell response is behind this inappropriate immune response, but interventions that boost the Treg cell response, such as mucosal immunotherapy, might lead to a restoration of immune tolerance to foods. Tolerance has been notoriously difficult to restore in animal disease models, but limited data from human trials suggest that tolerance (sustained nonresponsiveness) can be re-established in a subset of patients. Furthermore, studies on the natural history of food allergy indicate that spontaneous development of tolerance to foods over time is not uncommon. The current challenge is to understand the mechanisms responsible for restoration of natural or induced tolerance so that interventions can be developed to more successfully induce tolerance in the majority of patients with food allergy.


Asunto(s)
Hipersensibilidad a los Alimentos/inmunología , Tolerancia Inmunológica , Hipersensibilidad a los Alimentos/terapia , Mucosa Gástrica/inmunología , Humanos , Inmunidad Mucosa , Inmunoterapia/tendencias , Mucosa Intestinal/inmunología , Linfocitos T Reguladores/inmunología
10.
J Allergy Clin Immunol ; 131(1): 119-27.e1-7, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23265698

RESUMEN

BACKGROUND: There are presently no available therapeutic options for patients with peanut allergy. OBJECTIVE: We sought to investigate the safety, efficacy, and immunologic effects of peanut sublingual immunotherapy (SLIT). METHODS: After a baseline oral food challenge (OFC) of up to 2 g of peanut powder (approximately 50% protein; median successfully consumed dose [SCD], 46 mg), 40 subjects, aged 12 to 37 years (median, 15 years), were randomized 1:1 across 5 sites to daily peanut or placebo SLIT. A 5-g OFC was performed after 44 weeks, followed by unblinding; placebo-treated subjects then crossed over to higher dose peanut SLIT, followed by a subsequent crossover Week 44 5-g OFC. Week 44 OFCs from both groups were compared with baseline OFCs; subjects successfully consuming 5 g or at least 10-fold more peanut powder than the baseline OFC threshold were considered responders. RESULTS: After 44 weeks of SLIT, 14 (70%) of 20 subjects receiving peanut SLIT were responders compared with 3 (15%) of 20 subjects receiving placebo (P < .001). In peanut SLIT responders, median SCD increased from 3.5 to 496 mg. After 68 weeks of SLIT, median SCD significantly increased to 996 mg (compared with Week 44, P = .05). The median SCD at the Week 44 Crossover OFC was significantly higher than baseline (603 vs 71 mg, P = .02). Seven (44%) of 16 crossover subjects were responders; median SCD increased from 21 to 496 mg among responders. Of 10,855 peanut doses through the Week 44 OFCs, 63.1% were symptom free; excluding oral-pharyngeal symptoms, 95.2% were symptom free. CONCLUSIONS: Peanut SLIT safely induced a modest level of desensitization in a majority of subjects compared with placebo. Longer duration of therapy showed statistically significant increases in the SCD.


Asunto(s)
Alérgenos/inmunología , Arachis/inmunología , Desensibilización Inmunológica , Hipersensibilidad al Cacahuete/terapia , Administración Sublingual , Adolescente , Adulto , Alérgenos/administración & dosificación , Arachis/efectos adversos , Basófilos/inmunología , Niño , Desensibilización Inmunológica/efectos adversos , Femenino , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Masculino , Hipersensibilidad al Cacahuete/inmunología , Resultado del Tratamiento , Adulto Joven
11.
J Allergy Clin Immunol ; 131(3): 805-12, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23273958

RESUMEN

OBJECTIVE: There are few studies on the natural history of milk allergy. Most are single-site and not longitudinal, and these have not identified a means for early prediction of outcomes. METHODS: Children aged 3 to 15 months were enrolled in an observational study with either (1) a convincing history of egg allergy, milk allergy, or both with a positive skin prick test (SPT) response to the trigger food and/or (2) moderate-to-severe atopic dermatitis (AD) and a positive SPT response to milk or egg. Children enrolled with a clinical history of milk allergy were followed longitudinally, and resolution was established by means of successful ingestion. RESULTS: The cohort consists of 293 children, of whom 244 were given a diagnosis of milk allergy at baseline. Milk allergy has resolved in 154 (52.6%) subjects at a median age of 63 months and a median age at last follow-up of 66 months. Baseline characteristics that were most predictive of resolution included milk-specific IgE level, milk SPT wheal size, and AD severity (all P < .001). Baseline milk-specific IgG4 level and milk IgE/IgG4 ratio were not predictive of resolution and neither was expression of cytokine-inducible SH2-containing protein, forkhead box protein 3, GATA3, IL-10, IL-4, IFN-γ, or T-bet by using real-time PCR in CD25-selected, casein-stimulated mononuclear cells. A calculator to estimate resolution probabilities using baseline milk IgE level, SPT response, and AD severity was devised for use in the clinical setting. CONCLUSIONS: In this cohort of infants with milk allergy, approximately one half had resolved over 66 months of follow-up. Baseline milk-specific IgE level, SPT wheal size, and AD severity were all important predictors of the likelihood of resolution.


Asunto(s)
Dermatitis Atópica/epidemiología , Tolerancia Inmunológica , Hipersensibilidad a la Leche/epidemiología , Animales , Preescolar , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/inmunología , Femenino , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Lactante , Leucocitos Mononucleares/inmunología , Estudios Longitudinales , Masculino , Leche/efectos adversos , Leche/inmunología , Hipersensibilidad a la Leche/diagnóstico , Hipersensibilidad a la Leche/inmunología , Pruebas Cutáneas
12.
Clin Gastroenterol Hepatol ; 11(9): 1050-63, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23501398

RESUMEN

Gastrointestinal disorders such as chronic or acute diarrhea, malabsorption, abdominal pain, and inflammatory bowel diseases can indicate immune deficiency. The gastrointestinal tract is the largest lymphoid organ in the body, so it is not surprising that intestinal diseases are common among immunodeficient patients. Gastroenterologists therefore must be able to diagnose and treat patients with primary immunodeficiency. Immune-related gastrointestinal diseases can be classified as those that develop primarily via autoimmunity, infection, an inflammatory response, or malignancy. Immunodeficient and immunocompetent patients with gastrointestinal diseases present with similar symptoms. However, intestinal biopsy specimens from immunodeficient patients often have distinct histologic features, and these patients often fail to respond to conventional therapies. Therefore, early recognition of symptoms and referral to an immunologist for a basic immune evaluation is required to select appropriate treatments. Therapies for primary immunodeficiency comprise immunoglobulin replacement, antibiotics, and, in severe cases, bone marrow transplantation. Treatment of immunodeficient patients with concomitant gastrointestinal disease can be challenging, and therapy with immunomodulators often is required for severe disease. This review aims to guide gastroenterologists in the diagnosis and treatment of patients with primary immunodeficiency.


Asunto(s)
Enfermedades Gastrointestinales/diagnóstico , Enfermedades Gastrointestinales/terapia , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/diagnóstico , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/inmunología , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/patología , Humanos
13.
Gastroenterology ; 143(3): 730-740, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22643351

RESUMEN

BACKGROUND & AIMS: Epithelial cancers can be initiated by activating mutations in components of the mitogen-activated protein kinase signaling pathway such as v-raf murine sarcoma viral oncogene homolog B1 (BRAF), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), or epidermal growth factor receptor (EGFR). Human intestinal serrated polyps are a heterogeneous group of benign lesions, but some progress to colorectal cancer. Tumors that arise from these polyps frequently contain activating mutations in BRAF or KRAS, but little is known about the role of EGFR activation in their development. METHODS: Polyp samples were obtained from adults during screening colonoscopies at Mount Sinai Hospital in New York. We measured levels of EGFR protein and phosphorylation in human serrated polyps by immunohistochemical and immunoblot analyses. We generated transgenic mice that express the ligand for EGFR, Heparin-binding EGF-like growth factor (HB-EGF), in the intestine. RESULTS: EGFR and the extracellular-regulated kinases (ERK)1/2 were phosphorylated in serrated areas of human hyperplastic polyps (HPPs), sessile serrated adenomas, and traditional serrated adenomas. EGFR and ERK1/2 were phosphorylated in the absence of KRAS or BRAF activating mutations in a subset of HPP. Transgenic expression of the EGFR ligand HB-EGF in the intestines of mice promoted development of small cecal serrated polyps. Mice that expressed a combination of HB-EGF and US28 (a constitutively active, G-protein-coupled receptor that increases processing of HB-EGF from the membrane) rapidly developed large cecal serrated polyps. These polyps were similar to HPPs and had increased phosphorylation of EGFR and ERK1/2 within the serrated epithelium. Administration of pharmacologic inhibitors of EGFR or MAPK to these transgenic mice significantly reduced polyp development. CONCLUSIONS: Activation of EGFR signaling in the intestine of mice promotes development of serrated polyps. EGFR signaling also is activated in human HPPs, sessile serrated adenomas, and traditional serrated adenomas.


Asunto(s)
Adenoma/metabolismo , Receptores ErbB/metabolismo , Mucosa Intestinal/metabolismo , Neoplasias Intestinales/metabolismo , Pólipos Intestinales/metabolismo , Transducción de Señal , Adenoma/genética , Adenoma/patología , Adenoma/prevención & control , Animales , Western Blotting , Células CACO-2 , Colonoscopía , Activación Enzimática , Receptores ErbB/antagonistas & inhibidores , Factor de Crecimiento Similar a EGF de Unión a Heparina , Humanos , Hiperplasia , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Neoplasias Intestinales/genética , Neoplasias Intestinales/patología , Neoplasias Intestinales/prevención & control , Pólipos Intestinales/genética , Pólipos Intestinales/patología , Pólipos Intestinales/prevención & control , Ligandos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Mutación , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras) , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Transducción de Señal/efectos de los fármacos , Transfección , Proteínas ras/genética
14.
Gastroenterology ; 140(3): 957-65, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21147109

RESUMEN

BACKGROUND & AIMS: Interleukin (IL)-17-producing CD4(+) helper T cells (Th17) mediate mucosal immunity and are involved in the pathogenesis of inflammatory bowel disease (IBD). They are believed to arise from the same precursor population as regulatory T (Treg) cells, but little is known about how these T-cell subsets interact under chronic inflammatory conditions. We studied Th17 and Treg cells isolated from intestinal lamina propria of patients with IBD to investigate their role in pathogenesis. METHODS: FoxP3 expression (a marker of Treg cells) and IL-17 production were assessed in CD4(+) lamina propria lymphocytes isolated from IBD patients and healthy subjects. IL-17(+)FoxP3(+) and IL-17(+) CD4(+) T-cell clones were generated by limiting dilution. An in vitro suppression assay was performed to assess the functional capacity of derived T-cell clones. RESULTS: IL-17(+)FoxP3(+) T cells were identified in inflamed intestinal mucosa of patients with Crohn disease (CD), but not in patients with ulcerative colitis (UC) or healthy controls. These cells shared phenotypic characteristics of Th17 and Treg cells, and showed potent suppressor activity in vitro. Transforming growth factor-ß was necessary and sufficient to induce development of an IL-17(+) FoxP3(+) cell population in CD4(+) lamina propria lymphocytes derived from patients with UC. CONCLUSIONS: The inflammatory environment in the intestinal mucosa of patients with CD contributes to the generation of a distinct population of Treg cells that are FoxP3(+) and produce IL-17. These cells are likely to arise during differentiation of Th17 and Treg cells. Specific microenvironmental cues from tissues are likely to determine their commitment to either lineage and affect the balance between regulation and inflammation in the intestine.


Asunto(s)
Colitis Ulcerosa/inmunología , Enfermedad de Crohn/inmunología , Inmunidad Mucosa , Interleucina-17/metabolismo , Mucosa Intestinal/inmunología , Células Th17/inmunología , Estudios de Casos y Controles , Células Cultivadas , Factores de Transcripción Forkhead/metabolismo , Humanos , Inmunofenotipificación , Mediadores de Inflamación/metabolismo , Ciudad de Nueva York , Fenotipo , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Linfocitos T Reguladores/inmunología , Factores de Tiempo , Factor de Crecimiento Transformador beta1/metabolismo
15.
Gastroenterology ; 140(2): 550-9, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21056041

RESUMEN

BACKGROUND & AIMS: Interactions between lymphocytes and intestinal epithelial cells occur in the subepithelial space of the gastrointestinal tract. Normal human lamina propria lymphocytes (LPLs) induce differentiation of intestinal epithelial cells. The absence of LPLs in mice, such as in RAG1(-/-) mice, results in defects in epithelial cell differentiation. We investigated the role of lymphoepithelial interactions in epithelial differentiation and barrier function. METHODS: We used adoptive transfer to determine if CD4(+) T cells (CD4(+)CD62L(+)CD45Rb(Hi) and/or CD4(+)CD62L(+)CD45Rb(Lo)) could overcome permeability defect (quantified in Ussing chambers). Immunofluorescence staining was performed to determine expression of cleaved Notch-1, villin, and claudin 5 in colon samples from mice and humans. Caco-2 cells were infected with a lentivirus containing a specific Notch-1 or scrambled short hairpin RNA sequence. Tight junction assembly was analyzed by immunoblot and immunofluorescence analyses, and transepithelial resistance was monitored. RESULTS: Expression of cleaved Notch-1, villin, or claudin 5 was not detected in RAG1(-/-) colonocytes; their loss correlated with increased intestinal permeability. Transfer of CD45Rb(Hi) and/or CD45Rb(Lo) cells into RAG1(-/-) mice induced expression of cleaved Notch, villin, and claudin 5 in colonocytes and significantly reduced the permeability of the distal colon. Loss of Notch-1 expression in Caco-2 cells correlated with decreased transepithelial resistance and dysregulated expression and localization of tight junction proteins. Levels of cleaved Notch-1 were increased in colonic epithelium of patients with Crohn's disease. CONCLUSIONS: LPLs promote mucosal barrier function, which is associated with activation of the Notch-1 signaling pathway. LPLs maintain intestinal homeostasis by inducing intestinal epithelial cell differentiation, polarization, and barrier function.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Mucosa Intestinal/fisiología , Receptor Notch1/fisiología , Traslado Adoptivo , Animales , Linfocitos T CD4-Positivos/inmunología , Células CACO-2 , Claudina-5 , Enfermedad de Crohn/patología , Enfermedad de Crohn/fisiopatología , Humanos , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Selectina L/análisis , Selectina L/inmunología , Antígenos Comunes de Leucocito/análisis , Antígenos Comunes de Leucocito/inmunología , Proteínas de la Membrana/análisis , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/metabolismo , Receptor Notch1/análisis , Transducción de Señal/fisiología , Uniones Estrechas/inmunología , Uniones Estrechas/fisiología
16.
J Allergy Clin Immunol ; 128(6): 1251-1258.e2, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21762973

RESUMEN

BACKGROUND: Oral exposure to food allergens may be limited in infancy, and the initial site of antigen exposure likely plays an important role in food allergy induction. OBJECTIVE: To examine the impact of different routes of exposure by using milk allergens, with and without adjuvant, on sensitization. METHODS: C3H/HeJ mice were repeatedly exposed to the milk allergen α-lactalbumin (ALA), with or without cholera toxin (CT). Sensitization routes used were intragastric, cutaneous, intranasal, and sublingual. Anaphylaxis severity was assessed by symptoms and body temperature in response to oral challenge. Antigen-specific serum antibodies were measured by ELISA. The mechanism of adjuvant activity of cutaneous CT was also determined. RESULTS: Sensitization to ALA as measured by allergen-specific IgE occurred by all routes of sensitization and was maximal in response to cutaneous exposure. Sensitization was dependent on CT and did not occur to antigen alone by any route. Mucosal, but not cutaneous, exposure resulted in a robust allergen-specific IgA response. Anaphylaxis occurred in all sensitized groups when orally challenged with ALA. Topical CT induced migration of langerin(neg) dermal dendritic cells to the lymph node, resulting in enhanced proliferation and T(H)2 cytokine production from responder T cells. CONCLUSIONS: Sensitization can occur via all physiologic routes when adjuvant is present. The skin is a potent and likely important physiologic route of sensitization whereby adjuvant induces an efflux of antigen-bearing dermal dendritic cells to the lymph node that generate a proallergic T(H)2 response.


Asunto(s)
Adyuvantes Inmunológicos , Alérgenos/administración & dosificación , Hipersensibilidad/inmunología , Animales , Ensayo de Inmunoadsorción Enzimática , Femenino , Inmunoglobulina E/análisis , Inmunoglobulina E/biosíntesis , Inmunoglobulina E/inmunología , Lactalbúmina/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Linfocitos T/inmunología
17.
J Biol Chem ; 285(2): 1479-89, 2010 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-19892711

RESUMEN

The transmembrane glycoprotein CD98 regulates multiple cellular functions, including extracellular signaling, epithelial cell adhesion/polarity, amino acid transport, and cell-cell interactions. MicroRNAs post-transcriptionally regulate gene expression, thereby functioning as modulators of numerous cellular processes, such as cell differentiation, proliferation, and apoptosis. Here, we investigated if microRNAs regulate CD98 expression during intestinal epithelial cell differentiation and inflammation. We found that microRNA-7 repressed CD98 expression in Caco2-BBE cells by directly targeting the 3'-untranslated region of human CD98 mRNA. Expression of CD98 was decreased, whereas that of microRNA-7 was increased in well-differentiated Caco2-BBE cells compared with undifferentiated cells. Undifferentiated crypt cells isolated from mouse jejunum showed higher CD98 levels and lower levels of mmu-microRNA-706, a murine original microRNA candidate for CD98, than well-differentiated villus cells. Importantly, microRNA-7 decreased Caco2-BBE cell attachment on laminin-1, and CD98 overexpression recovered this inhibition, suggesting that microRNA-7 modulates epithelial cell adhesion to extracellular matrix, which in turn could affect proliferation and differentiation during the migration of enterocytes across the crypt-villus axis, by regulating CD98 expression. In a pathological context, the pro-inflammatory cytokine interleukin 1-beta increased CD98 expression in Caco2-BBE cells by decreasing microRNA-7 levels. Consistent with the in vitro findings, microRNA-7 levels were decreased in actively inflamed Crohn disease colonic tissues, where CD98 expression was up-regulated, compared with normal tissues. Together, these results reveal a novel mechanism underlying regulation of CD98 expression during patho-physiological states. This study raises microRNAs as a promising target for therapeutic modulations of CD98 expression in intestinal inflammatory disorders.


Asunto(s)
Diferenciación Celular , Proteína-1 Reguladora de Fusión/biosíntesis , Regulación de la Expresión Génica , Mucosa Intestinal/metabolismo , MicroARNs/metabolismo , Regiones no Traducidas 3'/genética , Animales , Células CACO-2 , Adhesión Celular/genética , Comunicación Celular/genética , Polaridad Celular/genética , Enfermedad de Crohn/genética , Enfermedad de Crohn/metabolismo , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Proteína-1 Reguladora de Fusión/genética , Humanos , Inflamación/genética , Inflamación/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Yeyuno/metabolismo , Laminina/genética , Laminina/metabolismo , Masculino , Ratones , MicroARNs/genética
18.
Clin Immunol ; 138(1): 14-22, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20956091

RESUMEN

Chronic granulomatous disease (CGD) and inflammatory bowel disease (IBD) have overlapping gastrointestinal manifestations. Serum antibodies to intestinal microbial antigens in IBD are thought to reflect a loss of tolerance in the setting of genetically encoded innate immune defects. CGD subjects studied here, with or without colitis, had considerably higher levels of ASCA IgA, ASCA IgG, anti-OmpC, anti-I2, and anti-CBir1, but absent to low pANCA, compared to IBD-predictive cutoffs. Higher antibody levels were not associated with a history of colitis. Except for higher ASCA IgG in subjects <18 years, antibody levels were not age-dependent. In comparison, 7 HIES subjects expressed negative to low antibody levels to all of these antigens; none had colitis. Our results suggest that markedly elevated levels of antimicrobial antibodies in CGD do not correlate with a history of colitis but may reflect a specific defect in innate immunity in the face of chronic antigenic stimulation.


Asunto(s)
Anticuerpos Antibacterianos/sangre , Anticuerpos Antifúngicos/sangre , Colitis/etiología , Enfermedad de Crohn/inmunología , Enfermedad Granulomatosa Crónica/complicaciones , Enfermedad Granulomatosa Crónica/inmunología , Adolescente , Adulto , Envejecimiento/sangre , Envejecimiento/inmunología , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Anticuerpos Antibacterianos/inmunología , Anticuerpos Antifúngicos/inmunología , Niño , Preescolar , Colitis/patología , Femenino , Flagelina/inmunología , Enfermedad Granulomatosa Crónica/sangre , Enfermedad Granulomatosa Crónica/diagnóstico , Enfermedad Granulomatosa Crónica/genética , Humanos , Inmunidad Innata/inmunología , Síndrome de Job/sangre , Síndrome de Job/inmunología , Masculino , Persona de Mediana Edad , Porinas/inmunología , Pseudomonas fluorescens/inmunología , Saccharomyces cerevisiae/inmunología , Adulto Joven
19.
Gastroenterology ; 139(4): 1301-9, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20600023

RESUMEN

BACKGROUND & AIMS: Thymic stromal lymphopoietin (TSLP) is a cytokine produced by epithelial cells that acts on dendritic cells, mast cells, T cells, and B cells. TSLP is involved in the pathogenesis of allergic inflammation in the lung and skin, but data indicate a regulatory role in the gastrointestinal tract. We tested the functional role of TSLP in mouse models of gastrointestinal allergy and tolerance. METHODS: TSLP Receptor (TSLPR)(+/+) and TSLPR(-/-) mice were sensitized and challenged with ovalbumin; models of allergic diarrhea or systemic anaphylaxis were studied. To induce oral tolerance, mice were fed with low-dose ovalbumin before they were immunized with it. Tolerance was measured from inhibition of ear swelling in a delayed-type hypersensitivity reaction. RESULTS: TSLPR(-/-) mice were protected from the onset of allergic diarrhea; they did not develop mastocytosis in the jejunum and had reduced ovalbumin-immunoglobulin E in their serum, compared with TSLPR(+/+) mice. TSLPR(-/-) mice also lost T helper cell (Th) 2-mediated inflammation in the jejunum. In contrast, sensitization and oral tolerance were not impaired in TSLPR(-/-) mice. Transfer of wild-type, Th2-primed cells to TSLPR(-/-) mice completely restored the development of allergic diarrhea. Antigen presentation assays showed that TSLPR on T cells, but not dendritic cells, was required to mediate the Th2 response. CONCLUSIONS: TSLP is required for allergic inflammation but not primary sensitization or tolerance to food proteins in the gastrointestinal tract; it amplifies Th2 responses directly from CD4(+) T cells.


Asunto(s)
Citocinas/fisiología , Hipersensibilidad a los Alimentos/etiología , Tracto Gastrointestinal/inmunología , Tolerancia Inmunológica , Anafilaxia/etiología , Animales , Citocinas/biosíntesis , Células Dendríticas/fisiología , Diarrea/etiología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/inmunología , Células Th2/inmunología , Linfopoyetina del Estroma Tímico
20.
Gastroenterology ; 138(1): 275-84.e1-4, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19782082

RESUMEN

BACKGROUND & AIMS: CCL20 is a chemokine that regulates the homeostatic and inflammatory trafficking of leukocytes to the small intestine and regulates the development of the gastrointestinal lymphoid architecture. T cells expressing T helper cell (Th) 2 cytokines are critical for experimental food allergy, and we hypothesized that CCL20 is involved in the localization of these cells to the gut. METHODS: We evaluated the role of CCR6 in allergic diarrhea induced by sensitization and oral challenge with ovalbumin (OVA) using CCR6(+/+) and CCR6(-/-) mice. RESULTS: CCR6(-/-) mice were protected from OVA-induced diarrhea but surprisingly were not impaired in mastocytosis or allergen-specific immunoglobulin E. CCR6(-/-) mice were also protected from T cell-mediated diarrhea induced by anti-CD3 antibody. Allergic diarrhea was associated with an increased expression of Th2 cytokines within the intestinal mucosa that was significantly reduced in CCR6(-/-) mice. Inhibition of lymphocyte homing by treatment with FTY720 did not impair allergic diarrhea, indicating that reactivation of T cells could occur locally within the small intestine. Finally, T-cell transfer studies demonstrated that CCR6 was required both on the transferred T cells and in the recipient mouse to manifest allergic disease in the gastrointestinal tract. CONCLUSIONS: These studies highlight a mast cell- and immunoglobulin E-independent role for CCR6-bearing T cells in the pathogenesis of gastrointestinal allergic disease.


Asunto(s)
Diarrea/inmunología , Hipersensibilidad a los Alimentos/inmunología , Yeyuno/inmunología , Receptores CCR6/inmunología , Células Th2/inmunología , Traslado Adoptivo , Animales , Anticuerpos/farmacología , Complejo CD3/inmunología , Células Cultivadas , Quimiocina CCL20/inmunología , Toxina del Cólera/toxicidad , Diarrea/inducido químicamente , Femenino , Clorhidrato de Fingolimod , Inmunoglobulina E/inmunología , Inmunosupresores/farmacología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Mastocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Mutantes , Ovalbúmina/inmunología , Ovalbúmina/farmacología , Glicoles de Propileno/farmacología , Receptores CCR6/genética , Esfingosina/análogos & derivados , Esfingosina/farmacología
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