RESUMEN
Stromal cells support epithelial cell and immune cell homeostasis and play an important role in inflammatory bowel disease (IBD) pathogenesis. Here, we quantify the stromal response to inflammation in pediatric IBD and reveal subset-specific inflammatory responses across colon segments and intestinal layers. Using data from a murine dynamic gut injury model and human ex vivo transcriptomic, protein and spatial analyses, we report that PDGFRA+CD142-/low fibroblasts and monocytes/macrophages co-localize in the intestine. In primary human fibroblast-monocyte co-cultures, intestinal PDGFRA+CD142-/low fibroblasts foster monocyte transition to CCR2+CD206+ macrophages through granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocyte-derived CCR2+CD206+ cells from co-cultures have a phenotype similar to intestinal CCR2+CD206+ macrophages from newly diagnosed pediatric IBD patients, with high levels of PD-L1 and low levels of GM-CSF receptor. The study describes subset-specific changes in stromal responses to inflammation and suggests that the intestinal stroma guides intestinal macrophage differentiation.
Asunto(s)
Enfermedades Inflamatorias del Intestino , Monocitos , Humanos , Animales , Ratones , Niño , Monocitos/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Macrófagos/metabolismo , Inflamación/metabolismo , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/metabolismo , Diferenciación CelularRESUMEN
Innate lymphoid cells (ILCs) are considered innate counterparts of adaptive T cells; however, their common and unique transcriptional signatures in pediatric inflammatory bowel disease (pIBD) are largely unknown. Here, we report a dysregulated colonic ILC composition in pIBD colitis that correlates with inflammatory activity, including accumulation of naive-like CD45RA+CD62L- ILCs. Weighted gene co-expression network analysis (WGCNA) reveals modules of genes that are shared or unique across innate and adaptive lymphocytes. Shared modules include genes associated with activation/tissue residency, naivety/quiescence, and antigen presentation. Lastly, nearest-neighbor-based analysis facilitates the identification of "most inflamed" and "least inflamed" lymphocytes in pIBD colon with unique transcriptional signatures. Our study reveals shared and unique transcriptional signatures of colonic ILCs and T cells in pIBD. We also provide insight into the transcriptional regulation of colonic inflammation, deepening our understanding of the potential mechanisms involved in pIBD.
Asunto(s)
Colitis , Enfermedades Inflamatorias del Intestino , Humanos , Niño , Linfocitos , Inmunidad Innata/genética , Colitis/genética , Linfocitos TRESUMEN
BACKGROUND: Orofacial granulomatosis (OFG) is an inflammatory disorder of the perioral region and oral cavity. Crohn's disease (CD) in conjunction with OFG (CD-OFG), has been suggested to constitute a phenotype of CD with distinct features at diagnosis. AIMS: The aim of this project was to investigate whether the distinct phenotypic features of CD-OFG persist in the years following the initial diagnosis of CD. METHODS: Clinical data were extracted from medical records covering the first 5 years post-diagnosis for a cohort of patients with CD-OFG, and were compared to those of references with CD without OFG. RESULTS: The clinical characteristics of our cohort of patients with CD-OFG (N = 25) were evaluated in comparison to references with CD without OFG (ratio 1:2). Five years post-diagnosis, more patients with CD-OFG had a phenotype with perianal disease (cumulative incidence: 16/25, 64% vs 13/50, 26%, P = 0.002) and intestinal granulomas (cumulative incidence: 22/25, 88% vs 24/50, 48%, P = 0.0009) than patients in the CD reference group. The patients with CD-OFG were also more likely to have undergone perianal surgery (12/25, 48% vs 4/50, 8%, P = 0.0002). At the end of the observation period, more of the patients with CD-OFG were receiving combination therapy, i.e., immunomodulators and tumor necrosis factor antagonists, than those in the CD reference group (9/25, 36% vs 5/50, 10%, P = 0.01). CONCLUSION: The results support the notion that CD in conjunction with OFG represents a specific phenotype of CD that is characterized by frequent perianal disease, pronounced intestinal granuloma formation and a need for extensive therapy.
Asunto(s)
Enfermedad de Crohn , Granulomatosis Orofacial , Enfermedades Intestinales , Humanos , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Granulomatosis Orofacial/diagnóstico , Granulomatosis Orofacial/tratamiento farmacológico , Granulomatosis Orofacial/epidemiología , Intestinos/patología , Granuloma/epidemiología , Enfermedades Intestinales/patologíaRESUMEN
AIM: To present the first case series of patients with Langerhans cell histiocytosis (LCH) also affected by Crohn's disease (CD), both of which are granulomatous diseases, and in LCH investigate the role of interleukin (IL)-23, which is a well-described disease mediator in CD. METHODS: A case series of three patients with LCH and CD were described; a cohort of LCH patients (n = 55) as well as controls (n = 55) were analysed for circulating IL-23 levels; and the relation between the percentage of LCH cells in lesions and circulating IL-23 levels was analysed in seven LCH patients. RESULTS: Differential diagnostic challenges for these two granulomatous diseases were highlighted in the case series, and it took up to 3 years to diagnose CD. Elevated IL-23 levels were found in LCH patients. The amount of lesional LCH cells correlated with the levels of circulating IL-23. CONCLUSION: Both CD and LCH should be considered in patients with inflammatory gastrointestinal involvement. The IL-23 pathway is a common immunological trait between these two granulomatous diseases.
Asunto(s)
Enfermedad de Crohn , Histiocitosis de Células de Langerhans , Enfermedad de Crohn/diagnóstico , Histiocitosis de Células de Langerhans/diagnóstico , Humanos , Interleucina-23RESUMEN
OBJECTIVE: In IBD, interleukin-23 (IL-23) and its receptor (IL-23R) are implicated in disease initiation and progression. Novel insight into which cells produce IL-23 at the site of inflammation at an early stage of IBD will promote the development of new tools for diagnosis, treatment and patient monitoring. We examined the cellular source of IL-23 in colon tissue of untreated newly diagnosed paediatric patients with IBD. DESIGN: Colon tissues from IBD and non-IBD patients were analysed by quantitative real-time PCR (qPCR), immunofluorescence confocal microscopy and flow cytometry after appropriate sample preparation. Blood samples from IBD and non-IBD patients and healthy controls were analysed using flow cytometry and qPCR. RESULTS: We discovered that tissue-infiltrating neutrophils were the main source of IL-23 in the colon of paediatric patients with IBD, while IL-23(+) human leucocyte antigen-DR(+) or IL-23(+)CD14(+) cells were scarce or non-detectable, respectively. The colonic IL-23(+) neutrophils expressed C-X-C motif (CXC)R1 and CXCR2, receptors for the CXC ligand 8 (CXCL8) chemokine family, and a corresponding CXCR1(+)CXCR2(+)IL-23(+)subpopulation of neutrophils was also identified in the blood of both patients with IBD and healthy individuals. However, CXCL8-family chemokines were only elevated in colon tissue from patients with IBD. CONCLUSIONS: This study provides the first evidence of CXCR1(+)CXCR2(+)IL-23-producing neutrophils that infiltrate and accumulate in inflamed colon tissue of patients with IBD. Thus, this novel source of IL-23 may play a key role in disease progression and will be important to take into consideration in the development of future strategies to monitor, treat and prevent IBD.
Asunto(s)
Enfermedades Inflamatorias del Intestino , Interleucina-23/metabolismo , Interleucina-8/metabolismo , Infiltración Neutrófila/inmunología , Receptores de Interleucina/metabolismo , Adolescente , Niño , Preescolar , Colon/inmunología , Colon/patología , Progresión de la Enfermedad , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/patología , Masculino , Gravedad del PacienteRESUMEN
BACKGROUND: Some studies have suggested that childhood-onset inflammatory bowel disease (IBD) is characterized by extensive intestinal involvement and rapid progression to complications. Here, we report the presentation and progression of patients diagnosed with IBD during childhood in a population-based cohort from northern Stockholm County. METHODS: Medical records for all 280 patients diagnosed in the period 1990-2007 with childhood-onset IBD in northern Stockholm County were followed until 2011 (median follow-up time, 8.8 yr). Disease phenotypes were classified according to the Paris pediatric IBD classification. RESULTS: Among the 74 patients with ulcerative colitis, 72% presented with pancolitis. Among the 200 patients with Crohn's disease (CD), 75% presented with colitis. Complicated disease behavior was observed in 18% of patients with CD by end of follow-up. Extension of the disease territory was observed in 22% of patients with ulcerative colitis and 15% of patients with CD. The cumulative risk of intra-abdominal surgery after 10 years was 8% (95% confidence interval, 4%-20%) for ulcerative colitis and 22% (95% confidence interval, 15%-28%) for patients with CD. Nonmucosal healing at 1 year was associated with a complicated disease course in patients with CD (hazard ratio = 14.56; 95% confidence interval, 1.79-118.68; P = 0.01). CONCLUSIONS: Patients with childhood-onset IBD were characterized by extensive colitis that was relatively stable over time and associated with a relatively low risk of complications and abdominal surgery. Our findings confirm the more extensive disease location in pediatric IBD but did not identify the proposed dynamic and aggressive nature of the childhood-onset phenotype. The association of nonmucosal healing with a complicated disease course suggests that endoscopy should guide treatment intensity in childhood-onset CD.
Asunto(s)
Enfermedades Inflamatorias del Intestino/diagnóstico , Índice de Severidad de la Enfermedad , Adolescente , Edad de Inicio , Niño , Preescolar , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Enfermedades Inflamatorias del Intestino/epidemiología , Masculino , Registros Médicos , Fenotipo , Pronóstico , Factores de Riesgo , Suecia/epidemiología , Factores de TiempoRESUMEN
OBJECTIVE: Childhood onset Crohn's disease (CD) is considered more aggressive than adult onset disease. Epithelioid cell granulomas in intestinal biopsies are one, non-obligate, criterion of CD. We investigated granulomas as markers of CD severity in children followed to adulthood. MATERIAL AND METHODS: Forty-five individuals with childhood onset CD were studied from diagnosis until attainment of final height, with data on disease location, medical and surgical management and with detailed growth data analyses. A blinded review of diagnostic biopsies was also performed. RESULTS: We found granulomas in 22/45 (49%) children at diagnosis, altogether in 28/45 (62%) patients during the disease course (median overall follow-up - 12.3 years, range 9.3-18). Granulomas were found in 9/11 (82%) with upper gastrointestinal involvement (cumulatively 17/20, 85%) (p = 0.017 and p = 0.006, respectively). The time from diagnosis to initiating immune modulating treatment (median 4.5 months, range 0-75) was shorter in the granuloma-positive group (16/22) compared to the granuloma-negative group (18/23) (median 33 months, range 2-105; p = 0.01). The median standard deviation score height at diagnosis and final adult height (both adjusted for target height) did not correlate to findings of granulomas. CONCLUSIONS: Epithelioid cell granulomas were associated with a shorter time to initiating immune modulating drugs, as a possible sign of more severe disease, but growth was not affected.
Asunto(s)
Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/patología , Granuloma/patología , Inmunosupresores/uso terapéutico , Adolescente , Adulto , Biopsia , Niño , Preescolar , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/mortalidad , Diagnóstico Diferencial , Progresión de la Enfermedad , Diagnóstico Precoz , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Estimación de Kaplan-Meier , Masculino , Pronóstico , Medición de Riesgo , Índice de Severidad de la Enfermedad , SueciaRESUMEN
BACKGROUND: Caeliac disease is a common immune-mediated condition in the proximal small intestine, generated by a permanent intolerance to cereal gluten proteins in genetically predisposed individuals. It has become apparent that abnormal microbiota proliferate in the duodenal lumen of patients with caeliac disease. Recently it was also noticed that an antibody against multiple myeloma oncogene 1/IRF4 (MUM1) stained plasma cells and their precursors. MATERIALS AND METHODS: Eleven consecutive duodenal biopsies were investigated; four had villous atrophy (caeliac patients) and the remaining seven exhibited histologically normal mucosa (non-caeliac patients). Sections were stained with H&E and with anti-MUM1. A graticulated eyepiece (10 mm, divided into 10 × 10 squares) was used for counting of MUM1-expressing cells in the superficial compartment (SC) and in the deep compartment (DC) of the lamina propria mucosa (lpm). RESULTS: In the duodenal mucosa of caeliac patients the mean number of MUM1-labelled cells in 12 areas of the lpm was 67.1 (range 37-88) in the SC and 61.5 (range 42-84) in the DC. In the duodenal mucosa of non-caeliac patients, the mean number of MUM1-labelled cells in 21 areas of the lpm was 7.6 (range 0-24) in the SC, and 29.2 (range 22-40) in the DC (p<0.05). CONCLUSION: These preliminary results showed that a significantly higher number of plasma cells/plasma cell precursors accumulate in the lpm in patients with caeliac disease, particularly in the SC. This abnormal accumulation of MUM1-expressing cells might be a defence mechanism against the alien bacterial flora recently reported in the duodenal microenvironment in caeliac patients. This appears to be the first report in which MUM1 immunostaining is applied to assess the frequency of plasma cell precursors in the duodenal mucosa in caeliac patients.
Asunto(s)
Enfermedad Celíaca/patología , Mucosa Intestinal/patología , Células Plasmáticas/metabolismo , Estudios de Casos y Controles , Enfermedad Celíaca/metabolismo , Recuento de Células/métodos , Duodeno/metabolismo , Duodeno/patología , Humanos , Factores Reguladores del Interferón/metabolismo , Células Plasmáticas/patología , Estadísticas no ParamétricasRESUMEN
BACKGROUND: Several authors demonstrated that normal goblet cells intermingle with dysplastic cells in duodenal adenomas. Goblet cells in the normal duodenum were found to cross-react with the neurotransmitter synaptophysin, a synaptic glycoprotein present in neuroendocrine cells and in virtually all neurons of the central nervous system. In this work, we investigated whether goblet cells in duodenal adenomas express synaptophysin. MATERIALS AND METHODS: Sections from 29 duodenal adenomas were immunostained for synaptophysin. RESULTS: All intercalated normal goblet cells in duodenal adenomas expressed synaptophysin. The mean percentage of synaptophysin-expressing goblet cells in the basal third of the adenomas was 49%, in the middle third 38% and in the superficial third 5% (basal and middle thirds vs. superficial third, p<0.05). Synaptophysin-positive goblet cells were also stained with alcian blue (pH 2.5) and MUC2, that stain sialomucins. In the normal ileum, only occasional goblet cells were stained (faintly) with synaptophysin. On the other hand, all goblet cells in the normal cecum were synaptophysin negative. CONCLUSION: Normal goblet cells found in duodenal adenomas express synaptophysin. Consequently, duodenal adenomas with synaptophysin-expressing goblet cells should also be stained with alcian blue (pH 2.5) or with MUC2 to confirm that these are native normal goblet cells, thereby rejecting the possibility of a composite adenoma-microcarcinoid in the duodenum.
Asunto(s)
Adenoma/patología , Neoplasias Duodenales/patología , Células Caliciformes/patología , Sinaptofisina/metabolismo , Adenoma/metabolismo , Estudios de Cohortes , Neoplasias Duodenales/metabolismo , HumanosRESUMEN
Inflammatory diseases frequently impair linear growth. Crohn's disease inhibits growth in up to one third of affected children. In rats with trinitrobenzenesulphonic acid-induced colitis, 40% of growth impairment is attributable to inflammation, with the rest being due to undernutrition. In transgenic mice without inflammation, raised IL-6 retards growth, suppressing insulin-like growth factor (IGF)-I. We hypothesized that IL-6, induced by intestinal inflammation, suppresses growth and inhibits IGF-I expression. Therefore, an anti-IL-6 Ab was given to rats with trinitrobenzene-sulphonic acid colitis. The Ab did not improve nutrient intake or decrease inflammation compared with untreated disease controls, but it significantly restored linear growth (P = 0.023) and increased IGF-I (P = 0.05). In humans, the IL-6 -174 G/C promoter polymorphism affects IL-6 transcription, with the GG genotype inducing the greatest IL-6 levels. Because IL-6 is increased in Crohn's disease, we further hypothesized that growth failure would vary with the IL-6 -174 genotype. At diagnosis, among 153 children with Crohn's disease, those with the IL-6 GG genotype were more growth-retarded than those with the GC or CC genotypes (height SD score, -0.51 vs. -0.10; P = 0.031). Also, the patients with the IL-6 GG genotype had higher circulating levels of C-reactive protein, an IL-6-induced product (36 vs. 18 mg/dl, P = 0.028). However, their risk of developing Crohn's disease was similar to other genotypes when compared with 351 healthy controls (P = 0.7). Thus, the IL-6 -174 genotype mediates growth failure in children with Crohn's disease.
Asunto(s)
Trastornos del Crecimiento/etiología , Inflamación/fisiopatología , Interleucina-6/fisiología , Enfermedades Intestinales/etiología , Polimorfismo de Nucleótido Simple , Animales , Anticuerpos/administración & dosificación , Anticuerpos/farmacología , Estudios de Casos y Controles , Niño , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Enfermedad de Crohn/genética , Modelos Animales de Enfermedad , Genotipo , Humanos , Inflamación/etiología , Factor I del Crecimiento Similar a la Insulina/genética , Interleucina-6/genética , Interleucina-6/inmunología , Enfermedades Intestinales/tratamiento farmacológico , Enfermedades Intestinales/genética , Regiones Promotoras Genéticas , Ratas , Ratas Wistar , Ácido TrinitrobencenosulfónicoRESUMEN
BACKGROUND: Lymphoid follicles (LFs) have been suggested to play a role at the early stage of Crohn's disease (CD) lesions. In the small bowel, LFs are grouped, forming Peyer's patches, which develop early in fetal life, grow in size and number until puberty, and undergo involution. In contrast, colonic LFs are isolated and undergo little change during life. As a result, if LFs play a role in the occurrence of CD lesions, the distribution of ileal and colonic lesions is expected to be altered in small children. METHODS: Medical records of 2 independent French (n = 136) and Swedish (n = 55) cohorts of consecutive pediatric CD were reviewed. Disease sites and age of onset were recorded, and the age-dependent probability to develop ileal lesions was computed. The CARD15/NOD2 genotype was also analyzed when available (n = 99). RESULTS: The curves of disease occurrence were significantly different in case of CD with or without ileal lesions (P < 0.0001). At the age of 8 years, the probability (95% confidence interval) of small bowel involvement was 0.19 (0.07-0.39). It increased until 16 years of age to 0.61 (0.54-0.68). It was slightly higher in patients carrying 1 or more CARD15/NOD2 mutations [0.75 (0.55-0.89)] than in wild-type patients [0.46 (0.34-0.58)]. CARD15 mutations also influenced the age of onset of ileal disease (P < 0.02). CONCLUSIONS: In children, ileal CD lesions are delayed compared with colonic lesions. This observation is in agreement with the previously proposed hypothesis of a pathophysiological role of Peyer's patches in ileal CD. The rarity of small bowel lesions should be a warning to be cautious when classifying chronic colitis in small children.
Asunto(s)
Enfermedad de Crohn/patología , Ileítis/epidemiología , Íleon/patología , Adolescente , Distribución por Edad , Edad de Inicio , Niño , Preescolar , Enfermedad de Crohn/epidemiología , Enfermedad de Crohn/genética , Femenino , Francia/epidemiología , Humanos , Lactante , Recién Nacido , Péptidos y Proteínas de Señalización Intracelular/genética , Funciones de Verosimilitud , Masculino , Proteína Adaptadora de Señalización NOD2 , Ganglios Linfáticos Agregados , Estudios Retrospectivos , Suecia/epidemiologíaRESUMEN
BACKGROUND: An association between mutations in a gene involved in bacterial recognition by monocytes, CARD15/NOD2 and Crohn disease (CD) has been reported in studies of adults and children. The aim of this study was to investigate the presence of CARD15 mutations in Swedish children with CD and analyze genotype-phenotype correlations. PATIENTS AND METHODS: Fifty-eight children (62% boys) with CD diagnosed between 2.8 and 16.9 years (median 10.9 years), were reviewed. Histopathology, retrospective data collection and mutational analyses for the three main mutations R702W, G908R and 1007fs were independently performed. First-degree relatives were also genotyped. RESULTS: A CARD15 mutation was found in 8.6% (95% confidence interval, 2.9% to 19.0%), all of whom were heterozygotes, giving an overall allele frequency of 4.3% (95% confidence interval, 1.4-9.8). In 12%, all patients without mutations, a first-degree relative had CD. In four of five children, mutations were transferred from their healthy mothers. Granulomas at onset were found in 80% of patients with mutations and in 43% of those without (P = 0.17). No statistical association was found between mutation and phenotype regarding age at onset, anatomic location at onset or follow-up, severity of inflammation at onset, development of stenosis, perianal disease or extra intestinal manifestations. CONCLUSIONS: The frequency of CARD15 mutation in this Swedish pediatric CD population is lower than reported in a mixed adult and pediatric population. The genotype-phenotype correlations were non-significant although a trend was found between the presence of mutations and granuloma formation. Healthy heterozygote mothers conveyed the mutation to their children with CD.