The effect of ageing on phenotype and function of monocyte-derived Langerhans cells

Background With increasing age the immune system shows functional decline. In the skin this is associated with an increased incidence of epidermal malignancies and infections. Epidermal Langerhans cells (LCs) act as sentinels of the immune system, recognizing, processing and presenting antigen and inducing T-cell responses. Previous investigations have demonstrated a reduction in the number of epidermal LCs in elderly subjects. Moreover, the ability of LCs to migrate in response to tumour necrosis factor (TNF)-α, but not interleukin (IL)-1β, is significantly impaired in the elderly. Objectives To characterize further the changes in LC function that are associated with increasing chronological age, we have evaluated age-related changes in the response of monocyte-derived LCs (mLCs) to IL-1β and TNF-α. Methods The phenotype and function of mLCs were compared in six young (> 30 years) and six aged (a 70 years) healthy individuals using a combination of flow cytometry, cytokine and chemokine array, and a Transwell migration assay. Results Monocytes from aged individuals were able to differentiate into LCs. There were no significant differences in expression of activation markers, or in baseline or inducible cytokine secretion, by mLCs derived from aged or young subjects. Furthermore, migration in response to a chemokine ligand, CCL19, was equivalent in both age groups. Conclusions These data demonstrate that changes in LC function in the elderly are not associated with changes in systemic dendritic cell phenotype and function. Conditioning of LCs in situ by the epidermal microenvironment is likely to be more important. © 2011 The Authors. BJD © 2011 British Association of Dermatologists 2011

LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery

Neurotransmitter receptor trafficking during synaptic plasticity requires the concerted action of multiple signaling pathways and the protein transport machinery. However, little is known about the contribution of lipid metabolism during these processes. In this paper, we addressed the question of the role of cholesterol in synaptic changes during long-term potentiation (LTP). We found that N-methyl-d-aspartate-type glutamate receptor (NMDAR) activation during LTP induction leads to a rapid and sustained loss or redistribution of intracellular cholesterol in the neuron. A reduction in cholesterol, in turn, leads to the activation of Cdc42 and the mobilization of GluA1-containing α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) from Rab11-recycling endosomes into the synaptic membrane, leading to synaptic potentiation. This process is accompanied by an increase of NMDAR function and an enhancement of LTP. These results imply that cholesterol acts as a sensor of NMDAR activation and as a trigger of downstream signaling to engage small GTPase (guanosine triphosphatase) activation and AMPAR synaptic delivery during LTP.Peer Reviewe

HLA-DR+ leukocytes acquire CD1 antigens in embryonic and fetal human skin and contain functional antigen-presenting cells

Adequate numbers and functional maturity are needed for leukocytes to exhibit a protective role in host defense. During intrauterine life, the skin immune system has to acquire these prerequisites to protect the newborn from infection in the hostile external environment after birth. We investigated the quantitative, phenotypic, and functional development of skin leukocytes and analyzed the factors controlling their proliferation and trafficking during skin development. We show that CD45+ leukocytes are scattered in embryonic human skin and that their numbers continuously increase as the developing skin generates an environment that promotes proliferation of skin resident leukocytes as well as the influx of leukocytes from the circulation. We also found that CD45+HLA-DRhighCD1c+ dendritic cells (DCs) are already present in the epidermis and dermis at 9 wk estimated gestational age (EGA) and that transforming growth factor β1 production precedes Langerin and CD1a expression on CD45+CD1c+ Langerhans cell (LC) precursors. Functionally, embryonic antigen-presenting cells (APCs) are able to phagocytose antigen, to up-regulate costimulatory molecules upon culture, and to efficiently stimulate T cells in a mixed lymphocyte reaction. Collectively, our data provide insight into skin DC biology and the mechanisms through which skin DCs presumably populate the skin during development

Epidemiologie und Verlauf kritisch kranker Patienten mit komorbiden rheumatischen Erkrankungen auf der Intensivstation – eine retrospektive Datenanalyse

Abweichender Titel laut Übersetzung der Verfasserin/des VerfassersDiplomarbeit Medizinische Universität Wien 202

CD34+ Cell-Derived CD14+ Precursor Cells Develop into Langerhans Cells in a TGF-β1-Dependent Manner

AbstractLangerhans cells (LC) are CD1a+E-cadherin (E-cad)+Birbeck granule+ but CD11b−CD36−factor XIIIa (FXIIIa)− members of the dendritic cell (DC) family. Evidence holds that LC originate from CD1a+CD14− rather than CD14+CD1a− progenitors, both of which arise from GM-CSF/TNF-α-stimulated CD34+ stem cells. The CD14+CD1a− progenitors, on the other hand, can give rise to a separate DC type characterized by its CD1a+CD11b+CD36+FXIIIa+E-cad−BG− phenotype (non-LC DC). Although GM-CSF/TNF-α are important for both LC and non-LC DC differentiation, TGF-β1 is thought to preferentially promote LC development in vitro and in vivo. However, the hemopoietic biology of this process and the nature of TGF-β1-responsive LC precursors (LCp) are not well understood. Here we show that CD14+ precursors in the presence, but not in the absence, of TGF-β1 give rise to a progeny that fulfills all major criteria of LC. In contrast, LC development from CD1a+ progenitors was TGF-β1 independent. Further studies revealed that CD14+ precursors contain a CD11b+ and a CD11b− subpopulation. When either subset was stimulated with GM-CSF/TNF-α and TGF-β1, only CD14+CD11b− cells differentiated into LC. The CD11b+ cells, on the other hand, acquired non-LC DC features only. The higher doubling rates of cells entering the CD14+ LCp rather than the CD1a+ LCp pathway add to the importance of TGF-β1 for LC development. Because CD14+CD11b− precursors are multipotent cells that can enter LC or macrophage differentiation, it is suggested that these cells, if present at the tissue level, endow a given organ with the property to generate diverse cell types in response to the local cytokine milieu.</jats:p