Abstract The hepatic immune system is constantly exposed to a massive load of harmless dietary and commensal antigens, to which it must remain tolerant. Immune tolerance in the liver is mediated by a ...number of specialized antigen-presenting cells, including dendritic cells, Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells. These cells are capable of presenting antigens to T cells leading to T cell apoptosis, anergy, or differentiation into regulatory T cells. However, the hepatic immune system must also be able to respond to pathogens and tumours and therefore must be equipped with mechanisms to override immune tolerance. The liver is a site of accumulation of a number of innate lymphocyte populations, including natural killer cells, CD56+ T cells, natural killer T cells, γδ T cells, and mucosal-associated invariant T cells. Innate lymphocytes recognize conserved metabolites derived from microorganisms and host cells and respond by killing target cells or promoting the differentiation and/or activation of other cells of the immune system. Innate lymphocytes can promote the maturation of antigen-presenting cells from their precursors and thereby contribute to the generation of immunogenic T cell responses. These cells may be responsible for overriding hepatic immune tolerance to autoantigens, resulting in the induction and maintenance of autoreactive T cells that mediate liver injury causing autoimmune liver disease. Some innate lymphocyte populations can also directly mediate liver injury by killing hepatocytes or bile duct cells in murine models of hepatitis, whilst other populations may protect against liver disease. It is likely that innate lymphocyte populations can promote or protect against autoimmune liver disease in humans and that these cells can be targeted therapeutically. Here I review the cellular mechanisms by which hepatic antigen-presenting cells and innate lymphocytes control the balance between immunity, tolerance and autoimmunity in the liver.
Summary
Background
Lifestyle interventions are the primary treatment for metabolic (dysfunction) associated fatty liver disease (MAFLD). However, the histological and cardiometabolic effects of ...aerobic exercise in MAFLD remain unclear.
Aims
To assess the effects of a 12‐week aerobic exercise intervention on histological and cardiometabolic endpoints in MAFLD.
Methods
Patients with biopsy‐confirmed MAFLD participated in a 12‐week aerobic exercise intervention. Liver histology, cardiorespiratory fitness (estimated V̇O2max), physical activity, anthropometry and biochemical markers were assessed at baseline, intervention completion, and 12 and 52 weeks after intervention completion.
Results
Twenty‐four patients completed the exercise intervention (exercise group n = 16, control group n = 8). In the exercise group, 12 weeks of aerobic exercise reduced fibrosis and hepatocyte ballooning by one stage in 58% (P = 0.034) and 67% (P = 0.020) of patients, with no changes in steatosis (P = 1.000), lobular inflammation (P = 0.739) or NAFLD activity score (P = 0.172). Estimated V̇O2max increased by 17% compared to the control group (P = 0.027) but this level of improvement was not maintained at 12 or 52 weeks after the intervention. Patients with fibrosis and ballooning improvement increased estimated V̇O2max by 25% (P = 0.020) and 26% (P = 0.010), respectively. Anthropometric reductions including body mass (P = 0.038), waist circumference (P = 0.015) and fat mass (P = 0.007) were also observed, but no patient achieved 7%‐10% weight loss.
Conclusion
This study highlights the potential benefits of a 12‐week aerobic exercise intervention in improving histological endpoints of MAFLD. The development of strategies to ensure continued engagement in aerobic exercise in MAFLD are needed.
Immunotherapies, including immune checkpoint inhibitors, have limitations in their effective treatment of malignancies. The immunosuppressive environment associated with the tumor microenvironment ...may prevent the achievement of optimal outcomes for immune checkpoint inhibitors alone, and nanotechnology-based platforms for delivery of immunotherapeutic agents are increasingly being investigated for their potential to improve the efficacy of immune checkpoint blockade therapy. In this manuscript, nanoparticles were designed with appropriate size and surface characteristics to enhance their retention of payload so that they can transmit their loaded drugs to the tumor. We aimed to enhance immune cell stimulation by a small molecule inhibitor of PD-1/PD-L1 (BMS202) using nanodiamonds (ND). Melanoma cells with different disease stages were exposed to bare NDs, BMS202-NDs or BMS202 alone for 6 h. Following this, melanoma cells were co-cultured with freshly isolated human peripheral blood mononuclear cells (hPBMCs). The effects of this treatment combination on melanoma cells were examined on several biological parameters including cell viability, cell membrane damage, lysosomal mass/pH changes and expression of γHA2X, and caspase 3. Exposing melanoma cells to BMS202-NDs led to a stronger than normal interaction between the hPBMCs and the melanoma cells, with significant anti-proliferative effects. We therefore conclude that melanoma therapy has the potential to be enhanced by non-classical T-cell Immune responses via immune checkpoint inhibitors delivered by nanodiamonds-based nanoparticles.
Introduction
Appendicectomy may reduce relapses and need for medication in patients with ulcerative colitis, but long‐term prospective data are lacking. This study aimed to analyse the effect of ...appendicectomy in patients with refractory ulcerative colitis.
Methods
In this prospective multicentre cohort series, all consecutive patients with refractory ulcerative colitis referred for proctocolectomy between November 2012 and June 2015 were counselled to undergo laparoscopic appendicectomy instead. The primary endpoint was clinical response (reduction of at least 3 points in the partial Mayo score) at 12 months and long‐term follow‐up. Secondary endpoints included endoscopic remission (endoscopic Mayo score of 1 or less), failure (colectomy or start of experimental medication), and changes in Inflammatory Bowel Disease Questionnaire (IBDQ) (range 32–224), EQ‐5D™ and EORTC‐QLQ‐C30‐QL scores.
Results
A total of 28 patients (13 women; median age 40·5 years) underwent appendicectomy. The mean baseline IBDQ score was 127·0, the EQ‐5D™ score was 0·65, and the EORTC‐QLQ‐C30‐QL score was 41·1. At 12 months, 13 patients had a clinical response, five were in endoscopic remission, and nine required a colectomy (6 patients) or started new experimental medical therapy (3). IBDQ, EQ‐5D™ and EORTC‐QLQ‐C30‐QL scores improved to 167·1 (P < 0·001), 0·80 (P = 0·003) and 61·0 (P < 0·001) respectively. After a median of 3·7 (range 2·3–5·2) years, a further four patients required a colectomy (2) or new experimental medical therapy (2). Thirteen patients had a clinical response and seven were in endoscopic remission. The improvement in IBDQ, EQ‐5D™ and the EORTC‐QLQ‐C30‐QL scores remained stable over time.
Conclusion
Appendicectomy resulted in a clinical response in nearly half of patients with refractory ulcerative colitis and a substantial proportion were in endoscopic remission. Elective appendicectomy should be considered before proctocolectomy in patients with therapy‐refractory ulcerative colitis.
Antecedentes
La apendicectomía puede reducir las recaídas y la necesidad de medicación en pacientes con colitis ulcerosa (ulcerative colitis, UC), sin embargo, faltan datos a largo plazo obtenidos de forma prospectiva. El objetivo de este estudio fue analizar el efecto de la apendicectomía en pacientes con UC refractarios al tratamiento.
Métodos
En esta serie prospectiva de cohortes multicéntrica, a todos los pacientes consecutivos con UC refractaria remitidos para proctocolectomía entre noviembre de 2012 y junio de 2015 se les recomendó en su lugar someterse a una apendicectomía laparoscópica. El criterio de valoración principal fue la respuesta clínica (disminución de ≥ 3 puntos del sistema de puntuación parcial de Mayo que varía de 0 a 9) a los 12 meses y en el seguimiento a largo plazo. Los criterios de valoración secundarios incluyeron la remisión endoscópica (puntuación endoscópica de Mayo ≤ 1), fracaso (colectomía o inicio de medicación experimental) y cambios en el IBDQ (rango 32‐224), EQ‐5D y EORTC‐QLQ‐C30‐QL.
Resultados
En total, 28 pacientes (13 mujeres, mediana de edad 40,5) se sometieron a una apendicectomía. El IBDQ de referencia promedio fue de 127,0; el EQ‐5D 0,65 y el EORTC‐QLQ‐C30‐QL 41,1. A los 12 meses, 13 pacientes presentaban una respuesta clínica, cinco estaban en remisión endoscópica y nueve precisaron colectomía (n = 6) o un nuevo tratamiento médico experimental (n = 3). El IBDQ, EQ‐5D y EORTC‐QLQ‐C30‐QL mejoraron a 167,1 (P < 0,001); 0,80 (P = 0,003) y 61,0 (P < 0,001) respectivamente. Después de una mediana de 3,7 años (rango 2,3‐5,2), otros cuatro pacientes requirieron una colectomía (n = 2) o un nuevo tratamiento médico experimental (n = 2). Trece pacientes presentaron respuesta clínica y siete se encontraban en remisión endoscópica. La mejora del IBDQ, el EQ‐5D y el EORTC‐QLQ‐C30‐QL se mantuvo estable a lo largo del tiempo.
Conclusión
La apendicectomía consiguió una respuesta clínica en casi la mitad de los pacientes con UC refractaria. La apendicectomía electiva debería ser considerada antes que la proctocolectomía en pacientes con UC refractaria al tratamiento.
Appendicectomy may reduce relapses and need for medication in patients with ulcerative colitis, but long‐term prospective data are lacking. In this study, appendicectomy resulted in a clinical response in 13 of 28 patients with therapy‐refractory ulcerative colitis and a substantial proportion were in endoscopic remission. Elective appendicectomy should therefore be considered before proctocolectomy in these patients.
Has promise
Background
Complete surgical resection is the mainstay of treatment for patients with adrenocortical cancer (ACC). Use of laparoscopy has been questioned in patients with ACC. This study compares the ...outcomes of patients undergoing laparoscopic versus open resection (OR) for ACC.
Methods
A retrospective review (2003–2008) of patients with ACC was performed. Data were collected for demographics, operative and pathologic data, adjuvant therapy, and outcome. Chi-square analysis was performed.
Results
Eighty-eight patients (66% women; median age, 47 (range, 18–81) years) were identified. Seventeen patients underwent laparoscopic adrenalectomy (LA). Median tumor size of those who underwent LA was 7.0 (range, 4–14) cm versus 12.3 (range, 5–27) cm for OR. Recurrent disease in the laparoscopic group occurred in 63% versus 65% in the open group. Mean time to first recurrence for those who underwent LA was 9.6 months (±14) versus 19.2 months (±37.5) in the open group (
p
< 0.005). Fifty percent of patients who underwent LA had positive margins or notation of intraoperative tumor spill versus 18% of those who underwent OR (
p
= 0.01). Local recurrence occurred in 25% of the laparoscopic group versus 20% in the open group (
p
= 0.23). Mean follow-up was 36.5 months (±43.6).
Conclusions
ACC continues to be a deadly disease, and little to no progress has been made from a treatment standpoint in the past 20 years. Careful and complete surgical resection is of the utmost importance. Although feasible in many cases and tempting, laparoscopic resection should not be attempted in patients with tumors suspicious for or known to be adrenocortical carcinoma.
The relevance of spatial composition in the microbial changes associated with UC is unclear. We coupled luminal brush samples, mucosal biopsies and laser capture microdissection with deep sequencing ...of the gut microbiota to develop an integrated spatial assessment of the microbial community in controls and UC.
A total of 98 samples were sequenced to a mean depth of 31,642 reads from nine individuals, four control volunteers undergoing routine colonoscopy and five patients undergoing surgical colectomy for medically-refractory UC. Samples were retrieved at four colorectal locations, incorporating the luminal microbiota, mucus gel layer and whole mucosal biopsies.
Interpersonal variability accounted for approximately half of the total variance. Surprisingly, within individuals, asymmetric Eigenvector map analysis demonstrated differentiation between the luminal and mucus gel microbiota, in both controls and UC, with no differentiation between colorectal regions. At a taxonomic level, differentiation was evident between both cohorts, as well as between the luminal and mucosal compartments, with a small group of taxa uniquely discriminating the luminal and mucosal microbiota in colitis. There was no correlation between regional inflammation and a breakdown in this spatial differentiation or bacterial diversity.
Our study demonstrates a conserved spatial structure to the colonic microbiota, differentiating the luminal and mucosal communities, within the context of marked interpersonal variability. While elements of this structure overlap between UC and control volunteers, there are differences between the two groups, both in terms of the overall taxonomic composition and how spatial structure is ascribable to distinct taxa.
Coeliac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals. The only current therapy is a lifelong ...gluten free diet. While much work has focused on the gliadin-specific adaptive immune response in coeliac disease, little is understood about the involvement of the innate immune system. Here we used multi-colour flow cytometry to determine the number and frequency of γδ T cells (Vδ1, Vδ2 and Vδ3 subsets), natural killer cells, CD56(+) T cells, invariant NKT cells, and mucosal associated invariant T cells, in blood and duodenum from adults and children with coeliac disease and healthy matched controls. All circulating innate lymphocyte populations were significantly decreased in adult, but not paediatric coeliac donors, when compared with healthy controls. Within the normal small intestine, we noted that Vδ3 cells were the most abundant γδ T cell type in the adult epithelium and lamina propria, and in the paediatric lamina propria. In contrast, patients with coeliac disease showed skewing toward a predominant Vδ1 profile, observed for both adult and paediatric coeliac disease cohorts, particularly within the gut epithelium. This was concurrent with decreases in all other gut lymphocyte subsets, suggesting a specific involvement of Vδ1 cells in coeliac disease pathogenesis. Further analysis showed that γδ T cells isolated from the coeliac gut display an activated, effector memory phenotype, and retain the ability to rapidly respond to in vitro stimulation. A profound loss of CD56 expression in all lymphocyte populations was noted in the coeliac gut. These findings demonstrate a sustained aberrant innate lymphocyte profile in coeliac disease patients of all ages, persisting even after elimination of gluten from the diet. This may lead to impaired immunity, and could potentially account for the increased incidence of autoimmune co-morbidity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Down syndrome (DS) is the most common genetic syndrome associated with immune defects. The extent of immune dysregulation in DS is substantial, spanning the innate and adaptive systems and including ...anomalies in: T and B cells, monocytes, neutrophil chemotaxis, circulating cytokines, and suboptimal antibody responses which all contribute to an increased risk of infections, poorer clinical outcomes and chronic inflammation in this vulnerable cohort. Other aspects of innate immunity may also be abnormal and contribute to the increased morbidity and warrant further interrogation such as: gamma delta T cell function, the inflammasome, Toll-like receptors and their pathways. Pharmacotherapies such as pavilizumab, pneumococcal and influenza immunizations, as well as potential immunoprophylactic agents such as pidotimod, azithromycin and Broncho-Vaxom may help alleviate the infectious consequences. Children with DS need to be managed with a heightened sense of awareness and urgency in the setting of sepsis and signs of chronic inflammation need regular screening and appropriate follow up.
PDF
