Human skin and its immune cells provide essential protection of the human body from injury and infection. Recent studies reinforce the importance of keratinocytes as sensors of danger through alert systems such as the inflammasome. In addition, newly identified CD103 + dendritic cells are strategically positioned for cross-presentation of skin-tropic pathogens and accumulating data highlight a key role of tissue-resident rather than circulating T cells in skin homeostasis and pathology. This Review focuses on recent progress in dissecting the functional role of skin immune cells in skin disease.The skin, as the primary interface between the body and the environment, provides a first line of defence against microbial pathogens and physical and chemical insults. Immunosurveillance of such a large and exposed organ presents unique challenges for immune sentinels and effector cells. If an immune response is inadequate then overwhelming infections or tumours may ensue, but if an immune response is excessive then chronic inflammation and autoimmunity may develop. Controlling the extent of an immune response is thus a major challenge for maintaining skin integrity, which is of paramount importance for host survival. Therefore, both active defence mechanisms and tolerogenic pathways are used by the host to achieve immune homeostasis, ensuring that immune responses in the skin are properly adjusted to various challenges.Owing to its accessibility, the skin is an ideal organ system in which to study both tissue and whole-organism responses to local and systemic insults. A growing body of data supports the notion that the skin has essential immunological functions, both during tissue homeostasis and in various pathological conditions. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptAlthough early studies highlighted individual cell types in the skin, it was the visionary concept of the skin-associated lymphoid tissue (SALT), first described by Streilein in 1983 (REF. 1 ), and later the 'skin immune system' (REF. 2 ) that provided a modern interpretation and overall paradigm for investigators interested in cutaneous immunology. The initial SALT concept introduced the idea of distinct circuiting immune cells that continually traffic in a directed manner between the skin, the draining lymph nodes and the circulation, thereby providing optimal immunosurveillance.Although considerable attention was directed at the function of epidermal Langerhans cells 3 , it became apparent that other types of dendritic cells (DCs) and innate immune cells present in the dermis also have a relevant role, resulting in the emergence of the concept of a 'dermal immune system' (REF. 4 ). Human skin has two main compartments: the epidermis and the dermis (FIG. 1). The epidermis is the outer compartment and contains four strata. The stratum basale is the bottom layer of the epidermis and is responsible for constantly renewing the cells of the epidermis. This layer contains just one row of undifferentiated epidermal ...
Abnormal production of inflammatory mediators is believed to play an important role in the pathogenesis of psoriasis. Emerging data, both in mice and in humans, put the spotlight on a new subset of T helper (Th) cells, in part characterized by their production of IL-17 and accordingly named Th17 cells. Here, we review the development, characterization, and function of human Th17 cells as well as the crucial role of IL-23 in the context of Th17-cell-dependent chronic inflammation in psoriasis. We further discuss recent clinical trials targeting the IL-23/Th17 axis in psoriasis.
Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many expression quantitative trait locus (eQTL) studies, typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis effect on expression cannot be accounted for by common cis variants, a finding that reveals the contribution of low-frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene, and we identify several replicating trans variants that act predominantly in a tissue-restricted manner and may regulate the transcription of many genes
The aryl hydrocarbon receptor (AhR), for many years almost exclusively studied by the pharmacology/toxicology field for its role in mediating the toxicity of xenobiotics such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has more recently attracted the attention of immunologists. The evolutionary conservation of this transcription factor and its widespread expression in the immune system point to important physiological functions that are slowly being unraveled. In particular, the emphasis is now shifting from the role of AhR in the xenobiotic pathway toward its mode of action in response to physiological ligands. In this article, we review the current understanding of the molecular interactions and functions of AhR in the immune system in steady state and in the presence of infection and inflammation, with a focus on barrier organs such as the skin, the gut, and the lung.
Psoriasis is a common relapsing and remitting immune-mediated inflammatory disease that affects the skin and joints. This review focuses on current immunogenetic concepts, key cellular players, and axes of cytokines that are thought to contribute to disease pathogenesis. We highlight potential therapeutic targets and give an overview of the currently used immune-targeted therapies.
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