Effective therapeutic interventions for chronic, idiopathic lung diseases remain elusive. Normalized T-cell function is an important contributor to spontaneous resolution of pulmonary sarcoidosis. ...Up-regulation of inhibitor receptors, such as programmed death-1 (PD-1) and its ligand, PD-L1, are important inhibitors of T-cell function.
To determine the effects of PD-1 pathway blockade on sarcoidosis CD4(+) T-cell proliferative capacity.
Gene expression profiles of sarcoidosis and healthy control peripheral blood mononuclear cells were analyzed at baseline and follow-up. Flow cytometry was used to measure ex vivo expression of PD-1 and PD-L1 on systemic and bronchoalveolar lavage-derived cells of subjects with sarcoidosis and control subjects, as well as the effects of PD-1 pathway blockade on cellular proliferation after T-cell receptor stimulation. Immunohistochemistry analysis for PD-1/PD-L1 expression was conducted on sarcoidosis, malignant, and healthy control lung specimens.
Microarray analysis demonstrates longitudinal increase in PDCD1 gene expression in sarcoidosis peripheral blood mononuclear cells. Immunohistochemistry analysis revealed increased PD-L1 expression within sarcoidosis granulomas and lung malignancy, but this was absent in healthy lungs. Increased numbers of sarcoidosis PD-1(+) CD4(+) T cells are present systemically, compared with healthy control subjects (P < 0.0001). Lymphocytes with reduced proliferative capacity exhibited increased proliferation with PD-1 pathway blockade. Longitudinal analysis of subjects with sarcoidosis revealed reduced PD-1(+) CD4(+) T cells with spontaneous clinical resolution but not with disease progression.
Analogous to the effects in other chronic lung diseases, these findings demonstrate that the PD-1 pathway is an important contributor to sarcoidosis CD4(+) T-cell proliferative capacity and clinical outcome. Blockade of the PD-1 pathway may be a viable therapeutic target to optimize clinical outcomes.
Hair plays a major role in perception within a society. It provides information about gender, age, health, and social status. It is therefore not surprising that those affected are exposed to great ...suffering due to the widespread occurrence of hair loss. As a result, the demand for new products to remedy this problem is not diminishing. Hair grows in cycles, and a hair follicle goes through several phases called the hair cycle. The active growth phase (anagen phase) lasts 2–6 years. In this state a hair follicle shows a growth of about 1 cm per month. In order to improve the existing hair status, hair should be kept in the active anagen phase as long as possible, or the transition to anagen should be stimulated. A number of reviews already describe the influence of individual active ingredients on hair growth. However, the following review describes existing studies of complex dietary supplements with their experimental weaknesses and strengths and their influence on hair loss. Also, for the determination of hair loss, it is important to use a valid method with high acceptance by the test persons. In this context, the TrichoScale® is a validated and non-invasive tool for quantifying hair loss/hair growth. Thus, it is an ideal measuring instrument to objectively quantify the effectiveness of a hair loss treatment.
Sarcoidosis pathogenesis is characterized by peripheral anergy and an exaggerated, pulmonary CD4(+) Th1 response. In this study, we demonstrate that CD4(+) anergic responses to polyclonal TCR ...stimulation are present peripherally and within the lungs of sarcoid patients. Consistent with prior observations, spontaneous release of IL-2 was noted in sarcoidosis bronchoalveolar lavage CD4(+) T cells. However, in contrast to spontaneous hyperactive responses reported previously, the cells displayed anergic responses to polyclonal TCR stimulation. The anergic responses correlated with diminished expression of the Src kinase Lck, protein kinase C-θ, and NF-κB, key mediators of IL-2 transcription. Although T regulatory (Treg) cells were increased in sarcoid patients, Treg depletion from the CD4(+) T cell population of sarcoidosis patients did not rescue IL-2 and IFN-γ production, whereas restoration of the IL-2 signaling cascade, via protein kinase C-θ overexpression, did. Furthermore, sarcoidosis Treg cells displayed poor suppressive capacity indicating that T cell dysfunction was a global CD4(+) manifestation. Analyses of patients with spontaneous clinical resolution revealed that restoration of CD4(+) Th1 and Treg cell function was associated with resolution. Conversely, disease progression exhibited decreased Th1 cytokine secretion and proliferative capacity, and reduced Lck expression. These findings implicate normalized CD4(+) T cell function as a potential therapeutic target for sarcoidosis resolution.
Bacterial infections and inflammation of the uterus are common in dairy cattle after parturition. In particular, pathogenic bacteria that cause endometritis have been the focus of research in cattle ...reproduction in the last ten years. The aim of the present study was to identify commensal lactobacilli in the bovine uterus and to examine their influence on the synthesis of pro-inflammatory factors in bovine endometrial epithelial cells in vitro. Lactobacillus species were isolated from healthy bovine uteri and further characterised. Bovine endometrial epithelial cells in the second passage (n = 5 animals) were co-cultured with the autochthonous isolates L. buchneri, L. ruminis and L. amylovorus as well as with a commercially available L. vaginalis in different multiplicities of infection (MOI = 1, 5 and 10, respectively). Endometrial epithelial cells cultured without bacteria served as controls. At distinct points in time (2, 4 and 6 h) total RNA was extracted from co-cultured epithelial cells and subjected to reverse transcription quantitative PCR of pro-inflammatory factors. Furthermore, the release of such factors by co-cultured epithelial cells was measured by ELISA or EIA after 24 and 48 h. L. ruminis and L. amylovorus induced increased interleukin (IL) IL1A, IL6, IL8 and prostaglandin-endoperoxide synthase 2 mRNA levels and the release of IL8 and prostaglandin F(2α) in endometrial epithelial cells compared with control cells. In contrast, L. buchneri did not significantly influence the expression and release of these factors. Toll-like receptors 2 and 6 transcripts were found unchanged in co-cultured and untreated epithelial cells in vitro. However, endometrial epithelial cells of each animal showed individual differences in the response to bacterial load. These results suggest that Lactobacillus species are present in the bovine uterus, revealing immunomodulatory properties.
Messaging surrounding skin cancer prevention has previously focused on the general public and emphasized how or when activities should be undertaken to reduce solar ultraviolet radiation (UVR) ...exposure. Generic messages may not be applicable to all settings, and should be tailored to protect unique and/or highly susceptible subpopulations, such as outdoor workers. The primary objective of this study was to develop a set of tailored, practical, harm-reducing sun safety messages that will better support outdoor workers and their employers in reducing the risk of solar UVR exposure and UVR-related occupational illnesses.
We adapted a core set of sun safety messages previously developed for the general population to be more applicable and actionable by outdoor workers and their employers. This study used an integrated knowledge translation approach and a modified Delphi method (which uses a survey-based consensus process) to tailor the established set of sun safety messages for use for outdoor worker populations.
The tailored messages were created with a consideration for what is feasible for outdoor workers, and provide users with key facts, recommendations, and tips related to preventing skin cancer, eye damage, and heat stress, specifically when working outdoors.
The resulting tailored messages are a set of evidence-based, expert- approved, and stakeholder-workshopped messages that can be used in a variety of work settings as part of an exposure control plan for employers with outdoor workers.
Background: Messaging surrounding skin cancer prevention has previously focused on the general public and emphasized how or when activities should be undertaken to reduce solar ultraviolet radiation ...(UVR) exposure. Generic messages may not be applicable to all settings, and should be tailored to protect unique and/or highly susceptible subpopulations, such as outdoor workers. The primary objective of this study was to develop a set of tailored, practical, harm-reducing sun safety messages that will better support outdoor workers and their employers in reducing the risk of solar UVR exposure and UVR-related occupational illnesses. Methods: We adapted a core set of sun safety messages previously developed for the general population to be more applicable and actionable by outdoor workers and their employers. This study used an integrated knowledge translation approach and a modified Delphi method (which uses a survey-based consensus process) to tailor the established set of sun safety messages for use for outdoor worker populations. Results: The tailored messages were created with a consideration for what is feasible for outdoor workers, and provide users with key facts, recommendations, and tips related to preventing skin cancer, eye damage, and heat stress, specifically when working outdoors. Conclusion: The resulting tailored messages are a set of evidence-based, expert- approved, and stakeholder-workshopped messages that can be used in a variety of work settings as part of an exposure control plan for employers with outdoor workers.
Rationale
Sarcoidosis is a granulomatous disease of unknown etiology. Many patients with sarcoidosis demonstrate antigen-specific immunity to mycobacterial virulence factors. Th-17 cells are crucial ...to the immune response in granulomatous inflammation, and have recently been shown to be present in greater numbers in the peripheral blood and bronchoalveolar lavage (BAL) fluid (BALF) of sarcoidosis patients than healthy controls. It is unclear whether Th-17 cells in sarcoidosis are specific for mycobacterial antigens, or whether they have similar functionality to control Th-17 cells.
Methods
Flow cytometry was used to determine the numbers of Th-17 cells present in the peripheral blood and BALF of patients with sarcoidosis, the percentage of Th-17 cells that were specific to the mycobacterial virulence factor ESAT-6, and as well as to assess IFN-γ expression in Th-17 cells following polyclonal stimulation.
Results
Patients with sarcoidosis had greater numbers of Th-17 cells in the peripheral blood and BALF than controls and produced significantly more extracellular IL-17A (
p
= 0.03 and
p
= 0.02, respectively). ESAT-6 specific Th-17 cells were present in both peripheral blood and BALF of sarcoidosis patients (
p
< 0.001 and
p
= 0.03, respectively). After polyclonal stimulation, Th-17 cells from sarcoidosis patients produced less IFN-γ than healthy controls.
Conclusions
Patients with sarcoidosis have mycobacterial antigen-specific Th-17 cells peripherally and in sites of active sarcoidosis involvement. Despite the Th1 immunophenotype of sarcoidosis immunology, the Th-17 cells have reduced IFN-γ expression, compared to healthy controls. This reduction in immunity may contribute to sarcoidosis pathogenesis.
Abstract Background Atherosclerosis is widely accepted as an inflammatory disease involving both innate and adaptive immunity. B cells and/or antibodies have previously been shown to play a ...protective role against atherosclerosis. Aside from their ability to bind to antigens, antibodies can influence inflammatory responses by interacting with various Fcγ receptors on the surface of antigen presenting cells. Although studies in mice have determined that stimulatory Fcγ receptors contribute to atherosclerosis, the role of the inhibitory Fcγ receptor IIb (FcγRIIb) has only recently been investigated. Methods and results To determine the importance of FcγRIIb in modulating the adaptive immune response to hyperlipidemia, we generated FcγRIIb-deficient mice on the apoE-deficient background (apoE/FcγRIIb−/− ). We report that male apoE/FcγRIIb−/− mice develop exacerbated atherosclerosis that is independent of lipid levels, and is characterized by increased antibody titers to modified LDL and pro-inflammatory cytokines in the aorta. Conclusions These findings suggest that antibodies against atherosclerosis-associated antigens partially protect against atherosclerosis in male apoE−/− mice by conveying inhibitory signals through the FcγRIIb that downregulate pro-inflammatory signaling via other immune receptors. These data are the first to describe a significant in vivo effect for FcγRIIb in modulating the cytokine response in the aorta in male apoE−/− mice.
Atherosclerosis is a chronic inflammatory disease characterized by dyslipidemia and accumulation of lipids in the arterial intima, with activation of both innate and adaptive immunity. Reciprocally, ...dyslipidemia associated with atherosclerosis can perturb normal immune function. Natural killer T (NKT) cells are a specialized group of immune cells that share characteristics with both conventional T cells and natural killer cells. However, unlike these cells, NKT cells recognize glycolipid antigens and produce both pro- and anti-inflammatory cytokines upon activation. Because of these unique characteristics, NKT cells have recently been ascribed a role in the regulation of immunity and inflammation, including cardiovascular disease. In addition, NKT cells represent a bridge between dyslipidemia and immune regulation. This review summarizes the current knowledge of NKT cells and discusses the interplay between dyslipidemia and the normal functions of NKT cells and how this might modulate inflammation and atherosclerosis.
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