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Tissue-resident memory T (Trm) cells form a heterogeneous population that provides localized protection against pathogens. Here, we identify CD49a as a marker that differentiates CD8+ Trm cells on a compartmental and functional basis. In human skin epithelia, CD8+CD49a+ Trm cells produced interferon-γ, whereas CD8+CD49a- Trm cells produced interleukin-17 (IL-17). In addition, CD8+CD49a+ Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response. In skin from patients with vitiligo, where melanocytes are eradicated locally, CD8+CD49a+ Trm cells that constitutively expressed perforin and granzyme B accumulated both in the epidermis and dermis. Conversely, CD8+CD49a- Trm cells from psoriasis lesions predominantly generated IL-17 responses that promote local inflammation in this skin disease. Overall, CD49a expression delineates CD8+ Trm cell specialization in human epithelial barriers and correlates with the effector cell balance found in distinct inflammatory skin diseases.
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Linfocitos T CD8-positivos/inmunología , Citotoxicidad Inmunológica/inmunología , Integrina alfa1/inmunología , Piel/inmunología , Subgrupos de Linfocitos T/inmunología , Separación Celular , Citometría de Flujo , Humanos , Memoria Inmunológica/inmunología , Integrina alfa1/biosíntesis , Activación de Linfocitos/inmunología , Microscopía Confocal , Psoriasis/inmunología , Vitíligo/inmunologíaRESUMEN
The Ikaros family of transcription factors (TFs) are important regulators of lymphocyte function. However, their roles in human innate lymphoid cell (ILC) function remain unclear. Here, we found that Ikaros (IKZF1) is expressed by all ILC subsets, including NK cells, in blood, tonsil, and gut, while Helios (IKZF2) is preferentially expressed by ILC3 in tonsil and gut. Aiolos (IKZF3) followed the expression pattern of T-bet and Eomes, being predominantly expressed by ILC1 and NK cells. Differentiation of IFN-γ-producing ILC1 and NK cells from ILC3 by IL-1ß plus IL-12-stimulation was associated with upregulation of T-bet and Aiolos. Selective degradation of Aiolos and Ikaros by lenalidomide suppressed ILC1 and NK cell differentiation and expression of ILC1 and NK cell-related transcripts (LEF1, PRF1, GRZB, CD244, NCR3, and IRF8). In line with reduced ILC1/NK cell differentiation, we observed an increase in the expression of the ILC3-related TF Helios, as well as ILC3 transcripts (TNFSF13B, IL22, NRP1, and RORC) and in the frequency of IL-22 producing ILC3 in cultures with IL-1ß and IL-23. These data suggest that suppression of Aiolos and Ikaros expression inhibits ILC1 and NK cell differentiation while ILC3 function is maintained. Hence, our results open up for new possibilities in targeting Ikaros family TFs for modulation of type 1/3 immunity in inflammation and cancer.
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Diferenciación Celular/inmunología , Transdiferenciación Celular/inmunología , Factor de Transcripción Ikaros/inmunología , Células Asesinas Naturales/inmunología , Lenalidomida/inmunología , Células Cultivadas , Humanos , Inmunidad Innata/inmunología , Factores Reguladores del Interferón/inmunología , Interleucina-12/inmunología , Interleucina-1beta/inmunología , Linfocitos/inmunologíaRESUMEN
BACKGROUND: Infliximab (IFX) is used in active Crohn's disease for induction and maintenance of remission. There are scanty data on weight gain in IBD-patients under anti-TNF treatment. We investigated changes in weight and blood chemistry in anti-TNF-naïve Crohn's disease patients during their first course of IFX. METHODS: Retrospective analysis of 110 patients (77 men, 33 women) aged 34 years (range 14-73), 54 with luminal and 56 with fistulising disease, given at least 3 infusions of IFX (range 3-11). Data regarding body weight, height, C-reactive protein (CRP), haemoglobin and S-albumin at baseline, before the third infusion, at three months and at 12 months were collected. RESULTS: At 6 weeks, 65 (59%) increased in weight, 73% and 76% at three and 12 months, respectively. There was an increase in median weight (1.7 kg, IQR = 3.1 kg) and BMI (0.5 kg/m2, IQR = 1.2 kg/m2) at 6 weeks, which persisted at three and 12 months (all p < .001). There was no difference between men and women. Young patients, patients with underweight or fistulising disease increased most in weight. Disease activity assessed by PGA and SES-CD decreased at all time points (p < .05). Increases in weight and BMI correlated with an increase in serum albumin and a decrease in CRP. CONCLUSION: Approximately 60% of Crohn's disease patients experience weight gain within the first six weeks of infliximab treatment. The weight increment correlates with improvements in inflammatory markers and disease activity. The causes of weight gain may be related to treatment induced metabolic changes and reduced inflammatory burden.
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Enfermedad de Crohn , Enfermedad de Crohn/tratamiento farmacológico , Femenino , Fármacos Gastrointestinales/uso terapéutico , Humanos , Infliximab/uso terapéutico , Masculino , Estudios Retrospectivos , Resultado del Tratamiento , Inhibidores del Factor de Necrosis Tumoral , Aumento de PesoRESUMEN
BACKGROUND: Vitamin D deficiency is a risk factor for inflammatory bowel disease (IBD). The IL-23-driven tissue-resident group 3 innate lymphoid cells (ILC3s) play essential roles in intestinal immunity, and targeting IL-23/12 is a promising approach in IBD therapy. OBJECTIVE: We set out to define the role of 1α,25-dihydroxy vitamin D3 (1,25D) in regulating functional responses of human mucosal ILC3s to IL-23 plus IL-1ß stimulation. METHODS: Transcriptomes of sorted tonsillar ILC3s were assessed by using microarray analysis. ILC3 cytokine production, proliferation, and differentiation were determined by means of flow cytometry, ELISA, and multiplex immunoassay. Intestinal cell suspensions and ILC3s sorted from gut biopsy specimens of patients with IBD were also analyzed along with plasma 25-hydroxy vitamin D3 (25D) detection. RESULTS: ILC3s stimulated with IL-23 plus IL-1ß upregulated the vitamin D receptor and responded to 1,25D with downregulation of the IL-23 receptor pathway. Consequently, 1,25D suppressed IL-22, IL-17F, and GM-CSF production from tonsillar and gut ILC3s. In parallel, 1,25D upregulated genes linked to the IL-1ß signaling pathway, as well as the IL-1ß-inducible cytokines IL-6, IL-8, and macrophage inflammatory protein 1α/ß. The 1,25D-triggered skewing in ILC3 function was not accompanied or caused by changes in viability, proliferation, or phenotype. Finally, we confirmed low 25D plasma levels in patients with IBD with active inflammation. CONCLUSION: In light of the beneficial targeting of IL-23/12 in patients with IBD, 1,25D appears as an interesting therapeutic agent that inhibits the IL-23 receptor pathway, providing a novel mechanism for how ILC3s could be manipulated to regulate intestinal inflammation.
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Linfocitos/inmunología , Linfocitos/metabolismo , Membrana Mucosa/citología , Membrana Mucosa/inmunología , Receptores de Interleucina/metabolismo , Transducción de Señal/inmunología , Vitamina D/farmacología , Biomarcadores , Proliferación Celular , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inmunofenotipificación , Activación de Linfocitos/inmunología , Membrana Mucosa/efectos de los fármacos , Membrana Mucosa/metabolismo , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismoRESUMEN
Vedolizumab, a gut-specific biological treatment for inflammatory bowel disease (IBD), is an antibody that binds to the α4ß7 integrin and blocks T-cell migration into intestinal mucosa. We aimed to investigate chemokine levels in serum of IBD-patients treated with vedolizumab. In this pilot study, we included 11 IBD patients (8 Crohn's disease, 3 ulcerative colitis) previously non-respondent to anti-tumor necrosis factor (TNF)-agents. Patients received vedolizumab at week 0, 2 and 6 and were evaluated for clinical efficacy at week 10. Clinical characteristics and routine laboratory parameters were obtained and patients were classified as responders or non-responders. Expression of 21 chemokines in serum was measured using Proximity Extension Assay and related to clinical outcome. At week 10, 6 out of 11 patients had clinically responded. Overall expression of CCL13 increased after treatment. In non-responders, expression of CCL13 and CXCL8 increased after treatment, and CCL20 and CXCL1 expressions were higher compared to responders. In responders, CCL28 decreased after treatment. C-reactive protein (CRP) correlated negatively with 6 chemokines before therapy, but not after therapy. Systemic CCL13 expression increases in IBD-patients after vedolizumab therapy and several chemokine levels differ between responders and non-responders. An increased CCL13-level when starting vedolizumab treatment, might indicate potential prognostic value of measuring chemokine levels when starting therapy with vedolizumab. This study provides new information on modulation of systemic chemokine levels after vedolizumab treatment.
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Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Quimiocinas/metabolismo , Fármacos Gastrointestinales/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/metabolismo , Biomarcadores , Análisis por Conglomerados , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/diagnóstico , Masculino , Terapia Molecular Dirigida , Proyectos Piloto , Proteoma , Proteómica/métodos , Resultado del TratamientoRESUMEN
OBJECTIVE: Capsule endoscopy (CE) is a sensitive method for detecting inflammatory lesions in the small bowel. Such lesions may be due to Crohn's disease but also to other causes and a histological diagnosis may be difficult to achieve in the small bowel. The aim of the study was to find a possible correlation between capsule endoscopic findings, biochemical parameters, and symptoms in patients with suspected or known small-bowel Crohn´s disease. MATERIALS AND METHODS: Thirty patients with inflammatory lesions in the small bowel diagnosed by CE were included. CE findings of inflammation were graded using the Lewis score. C-reactive protein (CRP) and fecal calprotectin were used as biochemical parameters. Symptoms were graded using the Harvey-Bradshaw index. The patients were followed up after 9 months with a second CE, CRP, fecal calprotectin, and Harvey-Bradshaw index. RESULTS: There was a significant persistent correlation between endoscopic inflammation and fecal calprotectin (p = 0.003 at inclusion and p < 0.001 at follow-up). CRP was correlated to endoscopic inflammation at inclusion (p = 0.006), but not at follow-up. Symptoms were not correlated with endoscopic inflammation. CONCLUSION: Inflammatory lesions in the small bowel diagnosed by CE in patients with suspected Crohn´s disease are correlated to fecal calprotectin and CRP, but not to symptoms.
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Proteína C-Reactiva/metabolismo , Enfermedad de Crohn/patología , Heces/química , Ileítis/patología , Complejo de Antígeno L1 de Leucocito/análisis , Adulto , Anciano , Biomarcadores/análisis , Biomarcadores/sangre , Endoscopía Capsular , Enfermedad de Crohn/sangre , Femenino , Humanos , Ileítis/sangre , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Background: Ustekinumab is used to treat inflammatory bowel disease mainly in patients failing anti-tumour necrosis factor (TNF)-agents. Objectives: To provide real-world data in unselected patients with Crohn's disease (CD), treated with ustekinumab. Design: Longitudinal retrospective study at four hospitals in Stockholm, Sweden. Methods: Disease activity (Harvey-Bradshaw index and physician global assessment), laboratory parameters, endoscopic findings and drug persistence were assessed. Follow-up data were obtained in patients that stopped ustekinumab. Results: In total, 322 patients (median age 38 years, 48% women) were included. All had luminal disease and 22% also fistulizing disease. A total of 271 (84%) had failed ⩾1 and 148 (46%) ⩾2 anti-TNF drugs; 34% failed vedolizumab. At inclusion, 93% had active disease; 28% were on oral corticosteroids and 18% on thiopurines. The median follow-up on treatment was 13.5 months; overall 67% were followed at least 24 months. By intention to treat analysis, response rate at 3 and 12 months was 43% and 42%, respectively. Among patients with ongoing ustekinumab, 19% were in steroid-free remission at 3 months and 64% at 12 months. The median faecal calprotectin level decreased from 460 µg/g at baseline to 156 µg/g at 3 months and was 182 µg/g at 12 months. C-reactive protein remained stable at 4 mg/L whereas serum albumin increased slightly. About 31% of patients were withdrawn during the first 12 months, mainly due to persisting disease activity 21%, adverse events 5%, bowel surgery 0.6% or malignancy 0.3%. The overall persistence on ustekinumab was 88%, 51%, 34% and 20% at 3, 12, 24 and 36 months, respectively. Within 12 months following withdrawal of ustekinumab in 121 patients, 64% had active disease most of the time, 68% needed another biologic and 24% underwent surgery. Conclusion: Among difficult-to-treat patients with CD, ustekinumab was effective in the majority, with high drug persistence at 12 and 24 months in combination with a favourable safety profile.
Study of a new biologic treatment in patients with Crohn's disease that have failed previous medications Why was the study done? New medical treatments become available in routine healthcare after rigorous testing on selected groups of patients in what is called clinical trials. The benefits and possible adverse events then need to be assessed in larger groups of unselected patients to gain a more generalizable knowledge of merits and shortfalls. Therefore studies in real-world settings are vital to complement the experience gained from clinical trials and they can provide robust data and reveal previously undetected safety issues. What did the researchers do? The research team studied the effect of a new injectable biological treatment, ustekinumab, in a large group of Swedish patients with an inflammatory bowel disease, Crohn's disease, since the drug became available in routine health care. All patients had previously over long time periods tried several different treatments without obtaining stable symptom control. Information on the severity of disease, symptoms, laboratory tests, examinations performed, outcome and length of treatment and need for surgical interventions was retrieved from the medical records and further analyzed with statistical methods. What did the researchers find? Of all 322 patients 31% stopped the treatment within the first year, most often due to lack of stable symptom control or side effects. Less than one of 100 patients had to undergo surgery. More than half of all patients continued the treatment for at least one year and one-third for at least two years. Laboratory tests and endoscopic examinations used to assess ongoing inflammation improved. What do the findings mean? This study provides reliable information on the routine use of ustekinumab in patients with Crohn's disease and persisting disease symptoms despite several previous treatments attempts. More than half of these difficult-to-treat patients had long-term benefit of this biologic and the drug was most often well tolerated.
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Attached to proteins, lipids, or forming long, complex chains, glycans represent the most versatile post-translational modification in nature and surround all human cells. Unique glycan structures are monitored by the immune system and differentiate self from non-self and healthy from malignant cells. Aberrant glycosylations, termed tumour-associated carbohydrate antigens (TACAs), are a hallmark of cancer and are correlated with all aspects of cancer biology. Therefore, TACAs represent attractive targets for monoclonal antibodies for cancer diagnosis and therapy. However, due to the thick and dense glycocalyx as well as the tumour micro-environment, conventional antibodies often suffer from restricted access and limited effectiveness in vivo. To overcome this issue, many small antibody fragments have come forth, showing similar affinity with better efficiency than their full-length counterparts. Here we review small antibody fragments against specific glycans on tumour cells and highlight their advantages over conventional antibodies.
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Fragmentos de Inmunoglobulinas , Neoplasias , Humanos , Antígenos de Carbohidratos Asociados a Tumores , Anticuerpos Monoclonales , Neoplasias/terapia , Polisacáridos , Microambiente TumoralRESUMEN
The impact of the microenvironment on innate lymphoid cell (ILC)-mediated immunity in humans remains largely unknown. Here we used full-length Smart-seq2 single-cell RNA-sequencing to unravel tissue-specific transcriptional profiles and heterogeneity of CD127+ ILCs across four human tissues. Correlation analysis identified gene modules characterizing the migratory properties of tonsil and blood ILCs, and signatures of tissue-residency, activation and modified metabolism in colon and lung ILCs. Trajectory analysis revealed potential differentiation pathways from circulating and tissue-resident naïve ILCs to a spectrum of mature ILC subsets. In the lung we identified both CRTH2+ and CRTH2- ILC2 with lung-specific signatures, which could be recapitulated by alarmin-exposure of circulating ILC2. Finally, we describe unique TCR-V(D)J-rearrangement patterns of blood ILC1-like cells, revealing a subset of potentially immature ILCs with TCR-δ rearrangement. Our study provides a useful resource for in-depth understanding of ILC-mediated immunity in humans, with implications for disease.
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Inmunidad Innata , Linfocitos , Diferenciación Celular , Humanos , Inmunidad Innata/genética , ARNRESUMEN
BACKGROUND: Angioectasias in the gastrointestinal tract can be found in up to 3% of the population. They are typically asymptomatic but may sometimes result in severe bleeding. The reasons for why some patients bleed from their angioectasias are not fully understood but it has been reported that it may be explained by an acquired von Willebrand syndrome (AVWS). This condition has similar laboratory findings to congenital von Willebrand disease with selective loss of large von Willebrand multimers. The aim of this study was to find out if AVWS or any other bleeding disorder was more common in patients with bleeding from angioectasias than in a control group. METHODS: We compared bleeding tests and coagulation parameters, including von Willebrand multimers, from a group of 23 patients with anemia caused by bleeding from angioectasias, with the results from a control group lacking angioectasias. RESULTS: No significant differences between the two groups were found in coagulation parameters, bleeding time or von Willebrand multimer levels. CONCLUSION: These results do not support a need for routine bleeding tests in cases of bleeding from angioectasias and do not show an overall increased risk of AVWS among these patients.
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Angiodisplasia/complicaciones , Trastornos de la Coagulación Sanguínea/diagnóstico , Factores de Coagulación Sanguínea/metabolismo , Hemorragia Gastrointestinal/etiología , Tracto Gastrointestinal/irrigación sanguínea , Adulto , Anciano , Anciano de 80 o más Años , Angiodisplasia/sangre , Angiodisplasia/diagnóstico , Tiempo de Sangría , Endoscopía Capsular/métodos , Diagnóstico Diferencial , Femenino , Hemorragia Gastrointestinal/sangre , Hemorragia Gastrointestinal/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Inflammatory bowel disease (IBD) can manifest both macroscopically and microscopically in the oral cavity; however, little is known about salivary changes in IBD. Therefore, this study aimed to assess salivary and circulatory inflammatory profiles in IBD and to compare their potential to reflect the presence and activity of IBD. METHODS: We measured 92 known inflammatory proteins in serum and in unstimulated and stimulated whole saliva samples from patients with IBD with active intestinal inflammation (n = 21) and matched control patients (n = 22) by proximity extension assay. Fifteen of the patients with IBD returned 10 to 12 weeks after treatment escalation for resampling. RESULTS: Sixty-seven of the proteins were detected in all 3 sample fluids but formed distinct clusters in serum and saliva. Twenty-one inflammatory proteins were significantly increased and 4 were significantly decreased in the serum of patients with IBD compared with that of the control patients. Two of the increased serum proteins, IL-6 and MMP-10, were also significantly increased in stimulated saliva of patients with IBD and correlated positively to their expressions in serum. None of the investigated proteins in serum or saliva were significantly altered by IBD treatment at follow-up. Overall, inflammatory proteins in serum correlated to biochemical status, and salivary proteins correlated positively to clinical parameters reflecting disease activity. CONCLUSIONS: Saliva and serum inflammatory profiles in IBD share a similar composition but reflect different aspects of disease activity. The oral cavity reflects IBD through elevated IL-6 and MMP-10 in stimulated saliva.
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Mediadores de Inflamación/metabolismo , Enfermedades Inflamatorias del Intestino/metabolismo , Saliva/química , Suero/química , Índice de Severidad de la Enfermedad , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Interleucina-6/metabolismo , Masculino , Metaloproteinasa 10 de la Matriz/metabolismo , Persona de Mediana EdadRESUMEN
BACKGROUND: The size of colorectal neoplastic polyps is important for their clinical management. MATERIALS AND METHODS: The size of 12 polyp phantoms was assessed in tandem colonoscopies carried out by 7 endoscopists differing in years of clinical endoscopical experience. The endoscopists measured, with (n=5) or without (n=2) the aid of open forceps, the largest diameter of 12 polyp phantoms. Measurements in two independent trials were compared with the gold standard-size assessed at The Department of Production Engineering, The Royal Institute of Technology. RESULTS: In tandem trials, 99.4% (167/168) of the measurements underscored the gold standard size. In the 1st trial, the size in all 84 measurements was underestimated by -40% (range -34% to -45%) and in the 2nd trial the size in 83 of the 84 measurements was underestimated by -34% (range -24% to -42%). Neither the age of the participant, nor the years of experience with clinical endoscopy improved the results obtained. The participants significantly underestimated larger devices (>or=20 mm) whereas the smallest "polyps" were also underestimated, but with a lower degree of inaccuracy. The absolute difference between the golden standard size and the mean of all measurements performed on each polyp in 167 out of 168 measurements followed a regular downward trend. The volume of the devices was one of the confounding factors in size assessment. When compared to the gold standard size, the larger the "polyp" size, the higher the degree of underestimation. This may be crucial considering that the risk for colorectal adenomas to shelter an invasive growth is 46%, for adenomas measuring >or=2 cm, a limit accepted as a guideline worldwide for the management of patients with large colorectal polyps. CONCLUSION: Considering the clinical implications of the results obtained, the possibility of developing a method that would allow the assessment of the true size of polyps in clinical colonoscopy, is being explored.
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Pólipos del Colon/patología , Colonoscopía/métodos , Fantasmas de Imagen , HumanosRESUMEN
The therapeutic value of vascular targeted photodynamic therapy (VTP) for cancer has already been recognized in the clinic: TOOKAD® has been clinically approved in Europe and Israel for treatment of men with low-risk prostate cancer. When light is applied shortly after intravenous administration of the photosensitizer, the damage is primarily done to the vasculature. This results in vessel constriction, blood flow stasis, and thrombus formation. Subsequently, the tumor is killed due to oxygen and nutrient deprivation. To further increase treatment specificity and to reduce undesired side effects such as damaging to the surrounding healthy tissues, efforts have been made to selectively target the PS to the tumor vasculature, an approach named molecular targeted VTP (molVTP). Several receptors have already been explored for this approach, namely CD13, CD276, Extra domains of fibronectin (A, B), Integrin αvß3, Neuropilin-1, Nucleolin, PDGFRß, tissue factor, and VEGFR-2, which are overexpressed on tumor vasculature. Preclinical studies have shown promising results, further encouraging the investigation and future application of molVTP, to improve selectivity and efficacy of cancer treatment. This strategy will hopefully lead to even more selective treatments for many cancer patients.
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BACKGROUND AND AIMS: Innate lymphoid cells [ILC] have been suggested to play a role in inflammatory bowel disease [IBD]. Here, we investigated the ILC compartment in intestinal biopsies and blood from distinct patient groups with Crohn's disease [CD] and ulcerative colitis [UC], either newly diagnosed or with disease established for at least 1 year. This approach allowed us to simultaneously investigate temporal, disease-specific, and tissue-specific changes in ILC composition in IBD. METHODS: ILC subset frequencies, phenotype, and transcription factor profile in blood and intestinal biopsies were investigated by multi-parameter flow cytometry analysis. Endoscopic disease severity was judged using the ulcerative colitis endoscopic index of severity and the simple endoscopic score for Crohn's disease. RESULTS: The frequency of NKp44+ILC3 was decreased in inflamed tissue, both in patients with CD and those with UC, already at the time of diagnosis, and correlated with disease severity. Simultaneously, the frequency of ILC1 was increased in patients with CD, whereas the frequency of ILC2 was increased in patients with UC. However, in patients with established UC or CD, both ILC1 and ILC2 were increased. In contrast to the ILC composition in inflamed tissue, ILC in non-inflamed tissue or blood were unchanged compared with non-IBD controls. Finally, in patients undergoing treatment with an anti-α4ß7 antibody the frequencies of ILC in peripheral blood remained unchanged. CONCLUSIONS: We report both shared and distinct changes in ILC composition depending on diagnosis and disease duration. The alterations in ILC composition in IBD occur selectively at inflamed sites in the gut.
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Colitis Ulcerosa/inmunología , Enfermedad de Crohn/inmunología , Mucosa Intestinal/inmunología , Linfocitos/metabolismo , Factores de Transcripción/sangre , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/sangre , Biopsia , Colitis Ulcerosa/sangre , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/patología , Enfermedad de Crohn/sangre , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/patología , Femenino , Factor de Transcripción GATA3/sangre , Fármacos Gastrointestinales/uso terapéutico , Humanos , Factor de Transcripción Ikaros/sangre , Inmunidad Innata , Mucosa Intestinal/patología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Receptor 2 Gatillante de la Citotoxidad Natural/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/sangre , Fenotipo , Receptores de Hidrocarburo de Aril/sangre , Receptores de Quimiocina/sangre , Índice de Severidad de la Enfermedad , Proteínas de Dominio T Box/sangre , Factores de Tiempo , Adulto JovenRESUMEN
A common helper-like innate lymphoid precursor (CHILP) restricted to the innate lymphoid cells (ILC) lineage has been recently characterized. While specific requirements of transcription factors for CHILPs development has been partially described, their ability to sense cytokines and react to peripheral inflammation remains unaddressed. Here, we found that systemic increase in Flt3L levels correlated with the expansion of Lineage (Lin)negα4ß7+ precursors in the adult murine bone marrow. Expanded Linnegα4ß7+ precursors were bona fide CHILPs as seen by their ability to differentiate into all helper ILCs subsets but cNK in vivo. Interestingly, Flt3L-expanded CHILPs transferred into lymphopenic mice preferentially reconstituted the small intestine. While we did not observe changes in serum Flt3L during DSS-induced colitis in mice or plasma from inflammatory bowel disease (IBD) patients, elevated Flt3L levels were detected in acute malaria patients. Interestingly, while CHILP numbers were stable during the course of DSS-induced colitis, they expanded following increased serum Flt3L levels in malaria-infected mice, hence suggesting a role of the Flt3L-ILC axis in malaria. Collectively, our results indicate that Flt3L expands CHILPs in the bone marrow, which might be associated with specific inflammatory conditions.
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Inmunidad Innata/genética , Subgrupos Linfocitarios/metabolismo , Células Progenitoras Linfoides/metabolismo , Proteínas de la Membrana/genética , Animales , Biomarcadores , Células de la Médula Ósea/metabolismo , Modelos Animales de Enfermedad , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Integrinas/metabolismo , Subgrupos Linfocitarios/inmunología , Células Progenitoras Linfoides/inmunología , Melanoma Experimental , Proteínas de la Membrana/sangre , Proteínas de la Membrana/metabolismo , Ratones , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/metabolismoRESUMEN
BACKGROUND: Capsule endoscopy (CE) is a unique tool to visualize the mucosa of the small intestine. Chronic intestinal dysmotility (CID) is a group of rare disorders of gastrointestinal motility that often are complicated by bacterial overgrowth. The aim of this study was to determine the prevalence of small bowel mucosal abnormalities in patients with CID. We also studied the usefulness of CE in the diagnosis of intestinal dysmotility. METHODS: We conducted a prospective study using CE in 18 patients; six with myopathic, 11 with neuropathic and one with indeterminate CID. A control group was used for comparison of small bowel transit. RESULTS: Mucosal breaks (erosions and ulcerations) were found in 16/18 (89%) patients. The capsule reached the caecum in 11/18 (61%) patients with a median transit time of 346 minutes. In the control group the capsule reached the caecum in 29/36 (81%) cases with a median transit time of 241 minutes. The difference in transit time was not significant (p = 0.061) in this material. The capsule was retained in the stomach in 3/18 patients. None of the patients developed symptoms or signs of mechanical obstruction. CONCLUSION: A high frequency of mucosal breaks and signs of motility disturbances were seen in CID patients. CE is feasible for the examination of small bowel mucosa in patients with CID. The relevance of observed mucosal abnormalities in CID remains uncertain.
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Endoscopía Capsular , Ileus/diagnóstico , Úlcera/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Ileus/epidemiología , Mucosa Intestinal , Intestino Delgado , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , Úlcera/epidemiologíaRESUMEN
Capsule endoscopy is a non-invasive method to investigate the small intestine by means of a swallowable videocapsule that takes pictures during its passage throughout the gut. The method has been proven to have a high diagnostic yield in obscure GI bleeding and suspected small bowel Crohn's disease in cases where traditional methods have failed. In 63 patients consecutively evaluated by capsule endoscopy pathological lesions were found in 39 (62%), of which angiodysplasias were the most common (33%). Inflammatory changes including Crohn's disease constituted 40% of the findings. Malignant tumors were found in two patients (5%). Half of the patients with patological findings were either medically treated or referred to surgery. Capsule endoscopy is a new method for small bowel examination that has a great potential to replace some older methods with lower diagnostic yield.
Asunto(s)
Endoscopía Gastrointestinal/métodos , Intestino Delgado/patología , Grabación en Video/instrumentación , Adolescente , Adulto , Anciano , Cápsulas , Niño , Enfermedad de Crohn/diagnóstico , Femenino , Hemorragia Gastrointestinal/diagnóstico , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Sensibilidad y EspecificidadRESUMEN
UNLABELLED: Aim. To evaluate capsule endoscopy in terms of incomplete examinations and capsule retentions and to find risk factors for these events. Material and Methods. This retrospective and consecutive study includes data from 2300 capsule enteroscopy examinations, performed at four different hospitals in Stockholm, Sweden from 2003 to 2009. Results. The frequency of incomplete examinations was 20%. Older age, male gender, suspected, and known Crohn's disease were risk factors for an incomplete examination. The PillCam capsule had the highest rate of completed examinations. Capsule retention occurred in 1.3% (n = 31). Risk factors for capsule retention were known Crohn's disease and suspected tumor. Complications of capsule retention were acute obstructive symptoms in six patients and one death related to complications after acute surgical capsule retrieval. CONCLUSION: Capsule endoscopy is considered a safe procedure, although obstructive symptoms and serious complications due to capsule retention can be found in a large series of patients.