Key research advances in atopic dermatitis (AD) suggest the complexity of its endotypes. A comprehensive serum biomarker panel revealed at least 4 types of AD. Some represent classic TH2-dominant AD ...with filaggrin mutations commonly reported in Europeans, a simultaneously activated multipolar axis of cytokines often reported in Asian individuals, and an intrinsic type characterized by TH2 inferiority. Innate lymphoid cells, including natural killer cells, natural killer T cells, and fibroblasts, play a role in AD development and heterogeneity. Here, we discuss the endotypes of AD from the perspective of antigen types (hapten vs protein antigens), barrier function, and a novel set of immune cells. Endotypic stratification of AD may lead to the development of customized therapeutic strategies in the future.
Abstract
Atopic dermatitis (AD) is a common T-cell-mediated inflammatory disease of the skin. Signatures of AD are characterized by an impaired skin barrier, aberrant Th2-type cytokine production and ...intensive pruritus. Transcriptomic analysis, however, has revealed a heterogeneous pathogenesis and the co-existence of multiple cytokine axes of Th17, Th22 and Th1 types, especially in intrinsic (a subtype of AD without skin barrier impairment), pediatric and Asian types of AD. Furthermore, the therapeutic effect of anti-IL-4 receptor α against AD was not as high as that of IL-17 blockage against psoriasis, which implies a modification of the disease spectrum by non-Th2-type cytokine axes in AD. These lines of evidence indicate a need for personalized or precision medicine appropriate for each subtype of AD.
Photosynthetic water oxidation is catalyzed by the Mn
CaO
cluster of photosystem II (PSII) with linear progression through five S-state intermediates (S
to S
). To reveal the mechanism of water ...oxidation, we analyzed structures of PSII in the S
, S
, and S
states by x-ray free-electron laser serial crystallography. No insertion of water was found in S
, but flipping of D1 Glu
upon transition to S
leads to the opening of a water channel and provides a space for incorporation of an additional oxygen ligand, resulting in an open cubane Mn
CaO
cluster with an oxyl/oxo bridge. Structural changes of PSII between the different S states reveal cooperative action of substrate water access, proton release, and dioxygen formation in photosynthetic water oxidation.
Advances in atopic dermatitis in 2015 Nomura, Takashi, MD, PhD; Kabashima, Kenji, MD, PhD
Journal of allergy and clinical immunology,
12/2016, Letnik:
138, Številka:
6
Journal Article
Recenzirano
Odprti dostop
This review aims to highlight recently published articles on atopic dermatitis (AD). Updated are the insights into epidemiology, pathology, diagnostics, and therapy. Epidemiologic studies have ...revealed a positive correlation between AD and systemic conditions, such as rheumatoid arthritis, inflammatory bowel disease, and neonatal adiposity. Pathologic findings highlight the involvement of novel barrier factors (desmoplakin and claudin), novel immune cell subsets (pathogenic effector TH 2 cells and group 2 innate lymphoid cells), and differential skewing of helper T cells (eg, TH 17 dominance in Asians with AD). As diagnostics, noninvasive examinations of the transepidermal water loss of neonates, the density of epidermal Staphylococcus species, and the gut flora might prognosticate the onset of AD. As for therapy, various methods are proposed, including conventional (petrolatum and UV) and molecule-oriented regimens targeting Janus kinase, signal transducer and activator of transcription 3, extracellular signal-regulated kinase, sirtuin 1, or aryl hydrocarbon receptor.
Atopic dermatitis (AD) is a heterogeneous disease with unique clinical manifestations across age groups and race/ethnicities. Characteristic molecular mechanisms, known as endotypes, including IgE ...level, status of epidermal barrier genes, and differential cytokine axes activation in the background of T
2 upregulation, are also implicated. In adults, the T
22, T
17, and T
1 pathways are involved, and a weakened epidermal barrier is characteristic. In contrast, pediatric patients exhibit less T
1 activation, and defects in epidermal lipid metabolism contribute to their barrier defect. European American patients are characterized by higher differential T
2/T
22 activation, lower expression of the T
1/T
17 axes, and suppression of filaggrin (FLG) and loricrin gene expressions. Asian patients have accentuated polarity of the T
22/T
17 pathways, and also exhibit epidermal barrier defects despite relative maintenance of FLG and loricrin expression. African American patients do not exhibit FLG mutations and have distinct attenuation of T
17/T
1 axes activation. Dissecting the molecular basis of AD endotypes has provided an important framework upon which targeted therapeutics are being developed. An increased understanding of these subtypes and the alteration of biomarkers that correlate with disease can ultimately push AD treatment in an era of personalized medicine.
Summary
Atopic dermatitis (AD) is a chronic skin disorder characterized by pruritus and recurrent eczematous lesions that are accompanied by T‐helper (Th)2‐dominated inflammation. AD Etiology is not ...yet completely understood, but it is multifactorial. Moreover, the disease is characterized by complex interactions between genetic and environmental factors, such as skin barrier dysfunctions, allergy/immunity, and pruritus. For example, filaggrin is a key protein involved in skin barrier function. Th2 cells produce interleukin (IL)‐31, which provokes pruritus, and other Th2 cytokines decrease filaggrin expression by keratinocytes. Dupilumab has recently been developed for AD treatment; its mechanism of action is to bind to IL‐4 receptor α and inhibit downstream signaling induced by IL‐4 and IL‐13. This review summarizes the etiopathogenesis of AD and provides the rationale for selecting a novel targeted therapy.
Innate lymphoid cells (ILCs) harbor tissue-resident properties in border zones, such as the mucosal membranes and the skin. ILCs exert a wide range of biological functions, including inflammatory ...response, maintenance of tissue homeostasis, and metabolism. Since its discovery, tremendous effort has been made to clarify the nature of ILCs, and scientific progress revealed that progenitor cells of ILC can produce ILC subsets that are functionally reminiscent of T-cell subsets such as Th1, Th2, and Th17. Thus, now it comes to the notion that ILC progenitors are considered an innate version of naïve T cells. Another important discovery was that ILC progenitors in the different tissues undergo different modes of differentiation pathways. Furthermore, during the embryonic phase, progenitor cells in different developmental chronologies give rise to the unique spectra of immune cells and cause a wave to replenish the immune cells in tissues. This observation leads to the concept of layered immunity, which explains the ontology of some cell populations, such as B-1a cells, γδ T cells, and tissue-resident macrophages. Thus, recent reports in ILC biology posed a possibility that the concept of layered immunity might disentangle the complexity of ILC heterogeneity. In this review, we compare ILC ontogeny in the bone marrow with those of embryonic tissues, such as the fetal liver and embryonic thymus, to disentangle ILC heterogeneity in light of layered immunity.
Abstract Objective Rapid eye movement (REM) sleep behavior disorder (RBD) may be a risk factor for dementia development in patients with Parkinson’s disease (PD); however, the role of subclinical RBD ...remains unknown. Patients with PD and clinical RBD, subclinical RBD, or with normal REM sleep were examined in a cross sectional study and a longitudinal follow-up. Methods Interviews regarding RBD symptoms and polysomnographies were performed on 82 PD patients divided into RBD subcategories based on the presence/absence of REM sleep without atonia (RWA) and/or RBD symptoms. Descriptive variables were compared and patients were followed-up longitudinally for 21.4 ± 10.8 months. Results The existence of RBD, but not subclinical RBD, was associated with orthostatic hypotension and levodopa dose equivalents (LDEs) in patients with PD. Kaplan–Myer curves indicated that the occurrence of dementia in the PD group with clinical RBD was significantly faster than in the PD group with normal REM sleep ( p = 0.013). A Cox hazard regression analysis revealed that development to PD with dementia was only significantly associated with the presence of clinical RBD (hazard ratio: 14.1, p = 0.017). Conclusion Clinical RBD symptoms, but not subclinical RBD, were associated with the development of dementia in PD.
This report shows that interleukin (IL) 17-producing T helper type 17 (Th17) cells predominantly express CC chemokine receptor (CCR) 6 in an animal model of rheumatoid arthritis (RA). Th17 cells ...induced in vivo in normal mice via homeostatic proliferation similarly express CCR6, whereas those inducible in vitro by transforming growth factor beta and IL-6 additionally need IL-1 and neutralization of interferon (IFN) gamma and IL-4 for CCR6 expression. Forced expression of RORgamma t, a key transcription factor for Th17 cell differentiation, induces not only IL-17 but also CCR6 in naive T cells. Furthermore, Th17 cells produce CCL20, the known ligand for CCR6. Synoviocytes from arthritic joints of mice and humans also produce a large amount of CCL20, with a significant correlation (P = 0.014) between the amounts of IL-17 and CCL20 in RA joints. The CCL20 production by synoviocytes is augmented in vitro by IL-1beta, IL-17, or tumor necrosis factor alpha, and is suppressed by IFN-gamma or IL-4. Administration of blocking anti-CCR6 monoclonal antibody substantially inhibits mouse arthritis. Thus, the joint cytokine milieu formed by T cells and synovial cells controls the production of CCL20 and, consequently, the recruitment of CCR6+ arthritogenic Th17 cells to the inflamed joints. These results indicate that CCR6 expression contributes to Th17 cell function in autoimmune disease, especially in autoimmune arthritis such as RA.
Enhancement of the Seebeck coefficient (S ) without reducing the electrical conductivity (sigma) is essential to realize practical thermoelectric materials exhibiting a dimensionless figure of merit ...(ZT=S2 x sigma x T x kappa-1) exceeding 2, where T is the absolute temperature and kappa is the thermal conductivity. Here, we demonstrate that a high-density two-dimensional electron gas (2DEG) confined within a unit cell layer thickness in SrTiO(3) yields unusually large |S|, approximately five times larger than that of SrTiO(3) bulks, while maintaining a high sigma2DEG. In the best case, we observe |S|=850 microV K-1 and sigma2DEG=1.4 x 10(3) S cm-1. In addition, by using the kappa of bulk single-crystal SrTiO(3) at room temperature, we estimate ZT approximately 2.4 for the 2DEG, corresponding to ZT approximately 0.24 for a complete device having the 2DEG as the active region. The present approach using a 2DEG provides a new route to realize practical thermoelectric materials without the use of toxic heavy elements.
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