Pathomechanism of atopic dermatitis in the perspective of T cell subsets and skin barrier functions – “Which comes first, the chicken or the egg?”

AbstractAtopic dermatitis (AD) is a common skin condition that is characterized by a complex, heterogeneous pathogenesis. The possible candidates for its pathogenesis include skin barrier abnormality and allergy/immunology aspects. It has long been asked, “Which comes first, the barrier dysfunction or the allergy/immunology abnormality?” Recently, direct evidence of a link between the incidence of AD and loss-of-function mutations in the gene encoding Filaggrin has been discovered. This finding suggests that barrier dysfunction is a primary cause of AD. It has also been widely recognized that T cells play an important role in the development of AD in the perspective of the Th1/Th2 paradigm. Recently, however, new T cell subsets, Th17, T22, and regulatory T cells have been identified. In this review, we will update the roles of T cell subsets in AD and ascertain how skin barrier abnormality and allergy/immunology interact in a highly interdisciplinary manner

Uncovering the Mysteries of Langerhans Cells, Inflammatory Dendritic Epidermal Cells, and Monocyte-Derived Langerhans Cell-Like Cells in the Epidermis

The identity of Langerhans cells (LCs) has been called into question of late due to the increasing evidence that LCs originate from macrophage lineage instead of dendritic cell (DC) lineage as previously thought. For many years, LCs have been assumed to be DCs due to its migratory capabilities. However, recent studies have demonstrated that LCs are from macrophage lineage of the adult fetal liver (FL) progenitor. Bona fide LCs are now considered tissue-resident macrophages as they originate from the FL as shown by fate mapping models. In recent years, studies have shown that there are three types of antigen-presenting cells present in the epidermis, such as LCs, monocyte-derived LC-like cells, and inflammatory dendritic epidermal cells (IDECs). Of these, LC-like cells have been characterized in both human and mouse studies, while IDECs have only been described in human studies. This has shed a new light on the area of epidermal macrophages, suggesting that there might be a misidentification and misclassification of LCs. IDECs and LC-like cells have been shown to be present in both steady state and inflammatory state, but they are present in more significant amounts under inflammatory conditions such as atopic dermatitis, ultra violet injury, and psoriasis. In this review, we discuss what is already known and discuss the possible roles of LCs, LC-like cells, and IDECs during inflammation. Most intriguingly, we discuss the possibility of LCs having a dual identity as both a macrophage and a DC. This is shown as LCs are the only tissue-resident macrophage to have shown migratory property-like DCs

Interaction of Psoriasis and Bullous Diseases

Patients with psoriasis are frequently complicated with autoimmune bullous diseases, especially, pemphigoid diseases. It has been known that one-third cases of anti-laminin gamma1 pemphigoid, formerly anti-p200 pemphigoid, are associated with psoriasis whereas bullous pemphigoid is the most frequently associated bullous disease in psoriasis cases regardless of the lack of detectable levels of the accompanying anti-laminin gamma1 autoantibodies. Despite several suggestions, however, the definitive reason of the striking association of psoriasis and these autoimmune bullous diseases remains elusive. In this review, we look over the epidemiological evidence of the association of psoriasis and autoimmune bullous diseases and the information of genetic susceptibilities of each disease, and discuss the possible mechanisms of their complication with reference to the recent understandings of each pathogenesis

Immune Control by TRAF6-Mediated Pathways of Epithelial Cells in the EIME (Epithelial Immune Microenvironment)

In the protective responses of epithelial tissues, not only immune cells but also non-immune cells directly respond to external agents. Epithelial cells can be involved in the organization of immune responses through two phases. First, the exogenous harmful agents trigger the primary responses of the epithelial cells leading to various types of immune cell activation. Second, cytokines produced by the immune cells that are activated directly by the external agents and indirectly by the epithelial cell products elicit the secondary responses giving rise to further propagation of immune responses. TRAF6 is a ubiquitin E3 ligase, which intermediates between various types of receptors for exogenous agents or endogenous mediators and activation of subsequent transcriptional responses via NF-kappaB and MAPK pathways. TRAF6 ubiquitously participates in many protective responses in immune and non-immune cells. Particularly, epithelial TRAF6 has an essential role in the primary and secondary responses via driving type 17 response in psoriatic inflammation of the skin. Consistently, many psoriasis susceptibility genes encode the TRAF6 signaling players, such as ACT1 (TRAF3IP2), A20 (TNFAIP3), ABIN1 (TNIP1), IL-36Ra (IL36RN), IkappaBzeta (NFKBIZ), and CARD14. Herein, we describe the principal functions of TRAF6, especially in terms of positive and regulatory immune controls by interaction between immune cells and epithelial cells. In addition, we discuss how TRAF6 in the epithelial cells can organize the differentiation of immune responses and drive inflammatory loops in the epithelial immune microenvironment, which is termed EIME

Neural Correlates of Attitude Change Following Positive and Negative Advertisements

Understanding changes in attitudes towards others is critical to understanding human behaviour. Neuropolitical studies have found that the activation of emotion-related areas in the brain is linked to resilient political preferences, and neuroeconomic research has analysed the neural correlates of social preferences that favour or oppose consideration of intrinsic rewards. This study aims to identify the neural correlates in the prefrontal cortices of changes in political attitudes toward others that are linked to social cognition. Functional magnetic resonance imaging (fMRI) experiments have presented videos from previous electoral campaigns and television commercials for major cola brands and then used the subjects' self-rated affinity toward political candidates as behavioural indicators. After viewing negative campaign videos, subjects showing stronger fMRI activation in the dorsolateral prefrontal cortex lowered their ratings of the candidate they originally supported more than did those with smaller fMRI signal changes in the same region. Subjects showing stronger activation in the medial prefrontal cortex tended to increase their ratings more than did those with less activation. The same regions were not activated by viewing negative advertisements for cola. Correlations between the self-rated values and the neural signal changes underscore the metric representation of observed decisions (i.e., whether to support or not) in the brain. This indicates that neurometric analysis may contribute to the exploration of the neural correlates of daily social behaviour