Glucocorticoids—All-Rounders Tackling the Versatile Players of the Immune System

Glucocorticoids regulate fundamental processes of the human body and control cellular functions such as cell metabolism, growth, differentiation, and apoptosis. Moreover, endogenous glucocorticoids link the endocrine and immune system and ensure the correct function of inflammatory events during tissue repair, regeneration, and pathogen elimination via genomic and rapid non-genomic pathways. Due to their strong immunosuppressive, anti-inflammatory and anti-allergic effects on immune cells, tissues and organs, glucocorticoids significantly improve the quality of life of many patients suffering from diseases caused by a dysregulated immune system. Despite the multitude and seriousness of glucocorticoid-related adverse events including diabetes mellitus, osteoporosis and infections, these agents remain indispensable, representing the most powerful, and cost-effective drugs in the treatment of a wide range of rheumatic diseases. These include rheumatoid arthritis, vasculitis, and connective tissue diseases, as well as many other pathological conditions of the immune system. Depending on the therapeutically affected cell type, glucocorticoid actions strongly vary among different diseases. While immune responses always represent complex reactions involving different cells and cellular processes, specific immune cell populations with key responsibilities driving the pathological mechanisms can be identified for certain autoimmune diseases. In this review, we will focus on the mechanisms of action of glucocorticoids on various leukocyte populations, exemplarily portraying different autoimmune diseases as heterogeneous targets of glucocorticoid actions: (i) Abnormalities in the innate immune response play a crucial role in the initiation and perpetuation of giant cell arteritis (GCA). (ii) Specific types of CD4+ T helper (Th) lymphocytes, namely Th1 and Th17 cells, represent important players in the establishment and course of rheumatoid arthritis (RA), whereas (iii) B cells have emerged as central players in systemic lupus erythematosus (SLE). (iv) Allergic reactions are mainly triggered by several different cytokines released by activated Th2 lymphocytes. Using these examples, we aim to illustrate the versatile modulating effects of glucocorticoids on the immune system. In contrast, in the treatment of lymphoproliferative disorders the pro-apoptotic action of glucocorticoids prevails, but their mechanisms differ depending on the type of cancer. Therefore, we will also give a brief insight into the current knowledge of the mode of glucocorticoid action in oncological treatment focusing on leukemia

Characterization of regulatory T cells in urban newborns

© 2009 Ly et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells

Dendritic cells from patients with hyper-IgE syndrome less efficiently generate induced regulatory T cells

Vitamin D intake in mid-pregnancy and child allergic disease – a prospective study in 44,825 Danish mother-child pairs

Background: Past studies suggest that maternal vitamin D intake during pregnancy may protect against child wheeze but studies on asthma are limited. Our objective was to examine the relation between intake of vitamin D in mid-pregnancy and child asthma and allergic rhinitis at 18 months and 7 years. Methods: We examined data from 44,825 women enrolled during pregnancy in the longitudinal Danish National Birth Cohort (1996–2002). We estimated vitamin D intake from diet and supplements based on information from a validated food frequency questionnaire completed in gestational week 25. At 18 months, we evaluated child asthma using data from phone interviews. We assessed asthma and allergic rhinitis by self-report at age 7 and asthma by using records from national registries. Current asthma at age 7 was defined as lifetime asthma diagnosis and wheeze in the past 12 months. We calculated multivariable risk ratios with 95% CIs comparing highest vs. lowest quintile of vitamin D intake in relation to child allergic disease outcomes. Results: The median (5%-95%ile) intake of total vitamin D was 11.7(3.0-19.4) μg/day (68% from supplements). In multivariable analysis, mothers in the highest (vs. lowest) quintile of total vitamin D intake were less likely to have children classified with current asthma at 7 years (Q5 vs. Q1: 0.74, 95% CI: 0.56, 0.96, P = 0.02) and they were less likely to have children admitted to the hospital due to asthma (Q5 vs. Q1: 0.80, 95% CI: 0.64, 1.00, P = 0.05). We found no associations with child asthma at 18 months or with allergic rhinitis at 7 years. Conclusions: Our findings suggest a weak inverse relationship between high total vitamin D and asthma outcomes in later, but not early, childhood. The data did not suggest a clear threshold of vitamin D intake above which risk of asthma was reduced

Phenotype and function of CD25+ regulatory T cells in infants and adults

Active suppression by CD4+CD25+FOXP3+ regulatory T cells (Treg) is essential for the maintenance of peripheral tolerance to both self antigens and environmental antigens. Absence of these cells in human newborns leads to autoimmune and inflammatory disorders as well as allergic disease. Thus, Treg are probably necessary for down-regulating autoimmune as well as allergic immune reactions. The aim of this thesis was to examine if Treg from birch pollen-allergic patients were able to suppress birch pollen-induced proliferation and cytokine production and if their suppressive function was affected following specific immunotherapy (SIT) against birch pollen allergy. Moreover, it aimed to describe the expression of FOXP3, homing receptors and maturation markers on Treg at various time points during the first 3 years of life compared with the expression seen in adults. We found that pollen-allergic patients and non-allergic controls had similar proportions of Treg cells in the circulation and that Treg were equally able to potently suppress birch pollen-induced proliferation and production of IFN-γ. However, Treg cells isolated during birch pollen-season from allergic patients were not able to down-regulate birch-pollen induced production of IL-13 and IL-5, in contrast to those from non-allergic controls. Likewise, Treg from birch pollen-allergic patients who had undergone SIT for 6 months were unable to suppress IL-5 production, while their ability to suppress proliferation and IFN-γ production was retained and similar as in untreated allergic controls. Of note, we found that IL-10 was produced at higher levels in SIT patients than controls, but only when CD25neg cells and Treg were cultured together and not when the CD25neg or Treg cells were cultured separately. This indicates that both Treg and CD25neg T cells are important and need to be present for an increased production of IL-10 to occur after SIT. When examining the expression of FOXP3, homing receptors and maturation markers on Treg in infants we observed a rapid increase in the proportion of Treg in the circulation during the first days of life, indicating conversion to suppressive Treg from CD25high Treg precursors. An appropriate localisation of these cells is essential for their ability to suppress immune responses and their migration to different tissues is determined by homing receptors. We found that that a homing receptor switch from the gut homing receptor 4β7 to the extra-intestinal homing receptor CCR4 on Treg started as late as between 18 months and 3 years of age and was associated with maturation of the Treg. Moreover, the homing receptor expression on Treg corresponded to their actual migration properties, since Treg from cord blood migrated foremost towards the gut-associated chemokine CCL25. In conclusion, our results indicate that Treg from allergic individuals are unable to suppress Th2 responses, but not Th1 responses, during birch-pollen season and that SIT is unable to restore the ability of Treg to suppress Th2 responses in vitro in spite of an increased production of IL-10. Moreover, Treg cells in infants up to 18 months of age express 47 and migrate towards gut-homing chemokines, while at 3 years the cells have started to mature and to switch into extra-intestinal homing receptors

Interleukin-4 suppresses the cytotoxic potential of in vitro generated, adaptive regulatory CD4+ T cells by down-regulation of granzyme B

Regulatory CD4+ T cells (Tregs) control immune responses using secretion of anti-inflammatory cytokines and/or cytotoxic mechanisms and play a central role in the outcomes of several immune pathologies. Previous studies suggest an impaired function of Tregs in allergy, especially during allergen seasons, but the underlying mechanism is not known. Therefore, we analysed the impact of the T helper type 2 cytokine interleukin (IL)-4 on in vitro generated adaptive Tregs (aTregs), which have been reported to use the granzyme B (GrB)/perforin pathway to kill autologous immune cells. aTregs were generated by co-ligation of CD3 and CD46 on CD4+ T lymphocytes and granzyme expression was analysed using flow cytometry. To quantify GrB and perforin expression as well as IL-10 secretion in response to IL-4, specific enzyme-linked immunosorbent assays were performed in cell lysates and/or culture supernatants. Using a flow cytometry-based cytotoxicity assay the impact of IL-4 on the cytotoxic potential of aTregs was investigated. While IL-4 did not affect IL-10 secretion and perforin expression in aTregs, a significant suppression of GrB synthesis was detected in the presence of IL-4. In addition, IL-4-mediated suppression of GrB led to impaired cytotoxicity of aTregs against K562 target cells. In conclusion, our data suggest that IL-4 might play a role in impaired aTreg function in allergy