Immune tolerance to both self-antigens and innocuous non–self-antigens is essential to protect the host against chronic inflammatory diseases and tissue damage. A wide range of cell types and ...suppressive molecules are involved in induction and maintenance of tolerance. In addition to their key function in the production of immunoglobulins, B cells can regulate immune responses through their surface molecules and secretion of cytokines. Regulatory B (Breg) cells are characterized by their immunosuppressive capacity, which is often mediated through IL-10 secretion. However, IL-35 and TGF-β have also been associated with B cell–mediated immunosuppression. Several types of murine and human Breg cells have been described, such as mouse CD5+ CD1dhi B10 cells, CD21hi CD23hi CD24hi transitional stage 2–like B cells, and CD138+ plasma cells and plasmablasts. Human Breg cell types include CD27+ CD24high B10 cells, CD24hi CD38hi immature transitional B cells, and CD73− CD25+ CD71+ BR 1 cells and a subset of plasma cells. Support for the in vivo existence of allergen-specific human Breg cells comes from direct detection of their increase during the course of allergen-specific immunotherapy, as well as their increased expression in nonallergic but high-dose allergen–exposed beekeepers. Human BR 1 cells selectively upregulate IgG4 antibodies on differentiation to plasma cells. This suggests an additional immune regulatory role because of the noninflammatory and blocking antibody function of IgG4 . Taken together, Breg cells appear to be involved in mediating allergen tolerance, but many open questions remain to be answered.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
2.
Role of IgG4 in IgE-mediated allergic responses van de Veen, Willem, PhD; Akdis, Mübeccel, MD, PhD
Journal of allergy and clinical immunology,
11/2016, Volume:
138, Issue:
5
Journal Article
Peer reviewed
Open access
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
There have been extensive developments on cellular and molecular mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic ...infections during the last few years. Better understanding the functions, reciprocal regulation, and counterbalance of subsets of immune and inflammatory cells that interact through interleukins, interferons, TNF-α, and TGF-β offer opportunities for immune interventions and novel treatment modalities in the era of development of biological immune response modifiers particularly targeting these molecules or their receptors. More than 60 cytokines have been designated as interleukins since the initial discoveries of monocyte and lymphocyte interleukins (called IL-1 and IL-2, respectively). Studies of transgenic or gene-deficient mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided essential information about their functions. Here we review recent developments on IL-1 to IL-38, TNF-α, TGF-β, and interferons. We highlight recent advances during the last few years in this area and extensively discuss their cellular sources, targets, receptors, signaling pathways, and roles in immune regulation in patients with allergy and asthma and other inflammatory diseases.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background Distinct human IL-10–producing B-cell subsets with immunoregulatory properties have been described. However, the broader spectrum of their direct cellular targets and suppressive ...mechanisms has not been extensively studied, particularly in relation to direct and indirect IL-10–mediated functions. Objective The aim of the study was to investigate the effects of IL-10 overexpression on the phenotype and immunoregulatory capacity of B cells. Methods Primary human B cells were transfected with hIL-10, and IL-10–overexpressing B cells were characterized for cytokine and immunoglobulin production by means of specific ELISA and bead-based assays. Antigen presentation, costimulation capacity, and transcription factor signatures were analyzed by means of flow cytometry and quantitative RT-PCR. Effects of IL-10–overexpresing B cells on Toll-like receptor–triggered cytokine release from PBMCs, LPS-triggered maturation of monocyte-derived dendritic cells, and tetanus toxoid–induced PBMC proliferation were assessed in autologous cocultures. Results IL-10–overexpressing B cells acquired a prominent immunoregulatory profile comprising upregulation of suppressor of cytokine signaling 3 (SOCS3), glycoprotein A repetitions predominant (GARP), the IL-2 receptor α chain (CD25), and programmed cell death 1 ligand 1 (PD-L1). Concurrently, their secretion profile was characterized by a significant reduction in levels of proinflammatory cytokines (TNF-α, IL-8, and macrophage inflammatory protein 1α) and augmented production of anti-inflammatory IL-1 receptor antagonist and vascular endothelial growth factor. Furthermore, IL-10 overexpression was associated with a decrease in costimulatory potential. IL-10–overexpressing B cells secreted less IgE and potently suppressed proinflammatory cytokines in PBMCs, maturation of monocyte-derived dendritic cells (rendering their profile to regulatory phenotype), and antigen-specific proliferation in vitro. Conclusion Our data demonstrate an essential role for IL-10 in inducing an immunoregulatory phenotype in B cells that exerts substantial anti-inflammatory and immunosuppressive functions.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Allergen-specific immunotherapy (AIT) was described as a therapeutic option for the treatment of allergies > 100 years ago. It is based on administration of allergen extracts and leads to the ...development of clinical allergen tolerance in selected patients. According to current knowledge, AIT results in the restoration of immune tolerance toward the allergen of interest. It is mainly accompanied by the induction of regulatory and suppressive subsets of T and B cells, the production of IgG4 isotype allergen-specific blocking antibodies, and decreased inflammatory responses to allergens by effector cells in inflamed tissues. Currently, AIT is mainly applied subcutaneously or sublingually and is suitable for both children and adults for pollen, pet dander, house dust mite, and venom allergies. It not only affects rhinoconjunctival symptoms but also has documented short- and long-term benefits in asthma treatment. Clinically, a fast onset of tolerance is achieved during desensitization, with a tolerable amount of side effects. The disease modification effect leads to decreased disease severity, less drug usage, prevention of future allergen sensitizations, and a long-term curative effect. Increasing safety while maintaining or even augmenting efficiency is the main goal of research for novel vaccine development and improvement of treatment schemes in AIT. This article reviews the principles of allergen-specific immune tolerance development and the effects of AIT in the clinical context.
There is an overall complication rate of 6.3%-10% after bariatric surgery. After ruling out anatomic/physical causes, there is a substantial group of patients who develop unexplained postsurgical ...abdominal pain.
To inventory the prevalence of unexplained abdominal pain after laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy and to determine predictive factors for unexplained abdominal pain.
Obesity Center Amsterdam, Amsterdam, the Netherlands.
A retrospective study in a prospective database was performed. Baseline characteristics and postoperative course were evaluated.
A total of 1788 patients underwent laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy between November 2007 and April 2015. The average follow-up consisted of 33.5 months, without loss to follow-up. Abdominal pain was presented in 387 patients (21.6%). The study population consisted of 337 women (87.1%) and 50 men (12.9%); the mean age was 43.3 years (standard deviation 10.1) and the median preoperative body mass index was 43.7 kg/m². An explanation for abdominal pain was found in 246 of 387 patients (63.6%), whereas no explanation was found in 133 patients (34.4%). Revisional surgery was a significant predictor for unexplained pain (odds ratio 1.7; confidence interval 1.0-2.8; P = 0.037).
A total of 133 patients (7.4%) experienced unexplained abdominal pain after laparoscopic bariatric surgery. Revisional surgery was found to be a significant predictive factor for this outcome. Present study results suggest that postoperative unexplained abdominal pain is a significant morbidity and should be part of the informed consent. More research is needed regarding further diagnosis and management and treatment.
Objective To assess the safety of the Manchester Triage System in pediatric emergency care for children who require admission to the intensive care unit (ICU). Study Design Between 2006 and 2013, 50 ...062 consecutive emergency department visits of children younger than the age of 16 years were included. We determined the percentage of undertriage, defined as the proportion of children admitted to ICU triaged as low urgent according to the Manchester Triage System, and diagnostic performance measures, including sensitivity, specificity, and diagnostic OR. Characteristics of undertriaged patients were compared with correctly triaged patients. In a logistic regression model, risk factors for undertriage were determined. Results In total, 238 (28.7%) of the 830 children admitted to ICU during the study period were undertriaged. Sensitivity of high Manchester Triage System urgency levels to detect ICU admission was 71% (95% CI 68%-74%) and specificity 85% (95% CI 85%-85%). Severity of illness was lower in undertriaged children than correctly triaged children admitted to ICU. Risk factors for undertriage were age <3 months, medical presenting problem, comorbidity, referral by a medical specialist or emergency medical services, and presentation during the evening or night shift. Conclusion The Manchester Triage System misclassifies a substantial number of children who require ICU admission. Modifications targeted at young children and children with a comorbid condition could possibly improve safety of the Manchester Triage System in pediatric emergency care.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Advancing our understanding of mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections could lead to effective and ...targeted therapies. Subsets of immune and inflammatory cells interact via ILs and IFNs; reciprocal regulation and counter balance among T h and regulatory T cells, as well as subsets of B cells, offer opportunities for immune interventions. Here, we review current knowledge about ILs 1 to 37 and IFN-γ. Our understanding of the effects of ILs has greatly increased since the discoveries of monocyte IL (called IL-1) and lymphocyte IL (called IL-2); more than 40 cytokines are now designated as ILs. Studies of transgenic or knockout mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided important information about IL and IFN functions. We discuss their signaling pathways, cellular sources, targets, roles in immune regulation and cellular networks, roles in allergy and asthma, and roles in defense against infections.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background IL-10–producing regulatory B cells suppress immune responses, and lack of these cells leads to exacerbated symptoms in mouse models of chronic inflammation, transplantation, and chronic ...infection. IgG4 is a blocking antibody isotype with anti-inflammatory potential that is induced in human high-dose antigen tolerance models. Objective We sought to characterize human inducible IL-10–secreting B regulatory 1 (BR 1) cells and to investigate their immunoregulatory capacity through suppression of cellular immune responses and production of anti-inflammatory immunoglobulins. Methods Highly purified IL-10–secreting B cells were phenotypically and functionally characterized by means of whole-genome expression analysis, flow cytometry, suppression assay, and antibody production. B cells specific for the major bee venom allergen phospholipase A2 (PLA) were isolated from beekeepers who displayed tolerance to bee venom antigens and allergic patients before and after specific immunotherapy. Results Human IL-10+ BR 1 cells expressed high surface CD25 and CD71 and low CD73 levels. Sorting of CD73− CD25+ CD71+ B cells allowed enrichment of human BR 1 cells, which produced high levels of IL-10 and potently suppressed antigen-specific CD4+ T-cell proliferation. IgG4 was selectively confined to human BR 1 cells. B cells specific for the major bee venom allergen PLA isolated from nonallergic beekeepers show increased expression of IL-10 and IgG4 . Furthermore, the frequency of IL-10+ PLA-specific B cells increased in allergic patients receiving allergen-specific immunotherapy. Conclusion Our data show the characterization of IL-10+ BR 1 cells and in vivo evidence for 2 essential features of allergen tolerance: the suppressive B cells and IgG4 -expressing B cells that are confined to IL-10+ BR 1 cells in human subjects.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Natural killer (NK) cells not only exert cytotoxic activity against tumor cells or infected cells but also act to regulate the function of other immune cells through secretion of cytokines and ...chemokines or cell contact–dependent mechanisms. NK cells are able to polarize in vitro into 2 functional distinct subsets, NK1 or NK2 cells, which are analogous to the T-cell subsets TH 1 or TH 2. In addition, a regulatory NK cell subset has been described that secretes IL-10, shows antigen-specific T-cell suppression, and suppresses IgE production. Although it has been demonstrated that NK cells play important roles in autoimmunity, cancer, transplantation, and pregnancy, the role of NK cells in allergy has not been extensively discussed. This review aims to discuss our understanding of NK cells and NK cell subsets in allergic inflammation and IgE regulation.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PDF
