Atopic dermatitis (AD) is characterized by chronic, eczematous, severe pruritic skin lesions. The knowledge on the pathogenesis of AD is driving the development of new drugs. From the research ...results, it has been revealed that Th2 cell-mediated immunity, skin barrier dysfunction, and pruritus cause a vicious cycle of AD. On the other hand, the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway are one of the essential signaling pathways in various inflammatory diseases including AD. In particular, TSLP, IL-4, IL-13 and IL-22 occupy an important position for Th2 cell-mediated immune reaction. Moreover, experimentally pan-JAK inhibitor suppress the STAT3 activation and improved the skin barrier function. Furthermore TSLP, IL-4, IL-13 and IL-31 contribute a lot to chronic pruritus of AD, and transmitted via JAK-STAT pathway. Therefore, JAK inhibitors are promising candidates for the treatment of severe AD. Here we review clinical trials of topical dergocitinib; a pan-JAK inhibitor, ruxolitinib; a JAK1 and JAK2 inhibitor, and tofacitinib; a JAK1, JAK2, and JAK3 inhibitor and oral baricitinib; a JAK1 and JAK2 inhibitor, abrocitinib and upadacitinib; JAK1 inhibitor. Significant improvements in the symptoms were obtained by each drug with low frequency of adverse events. In particular, oral JAK inhibitors have the ability to improve the pruritus and skin symptoms quickly. Therefore, the emergence of these topical and oral JAK inhibitors would be regarded as an innovation in the treatment of atopic dermatitis.
Melanoma, a skin cancer associated with high mortality rates, is highly radio- and chemotherapy resistant but can also be very immunogenic. These circumstances have led to a recent surge in research ...into therapies aiming to boost anti-tumor immune responses in cancer patients. Among these immunotherapies, neutralizing antibodies targeting the immune checkpoints T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are being hailed as particularly successful. These antibodies have resulted in dramatic improvements in disease outcome and are now clinically approved in many countries. However, the majority of advanced stage melanoma patients do not respond or will relapse, and the hunt for the "magic bullet" to treat the disease continues. This review examines the mechanisms of action and the limitations of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies which are the two types of checkpoint inhibitors currently available to patients and further explores the future avenues of their use in melanoma and other cancers.
Atopic dermatitis (AD) is characterized by chronic, eczematous, severe pruritic skin lesions caused by skin barrier dysfunction and T helper (Th)2 cell‐mediated immunity. Interleukin (IL)‐31 is a ...potent pruritogenic cytokine primarily produced by Th2 cells. Both IL‐31 transgenic mice and wild‐type mice treated with IL‐31 exhibit AD‐like skin lesions and scratching behaviour. IL‐31 receptor α‐chain (IL‐31RA) is also expressed in peripheral nerves and epidermal keratinocytes, and the roles of IL‐31 on pruritus and skin barrier have been investigated. Recently, an anti–IL‐31 receptor antibody was shown to significantly improve pruritus in AD patients. This review focuses on IL‐31 and IL‐31RA in AD.
The present review aims to provide readers with the latest updates on the biology and clinical management of cutaneous angiosarcoma (cAS).
The genomic alteration of cAS is heterogeneous. Mutations ...are enriched in the mitosis-activated kinase (MAPK) pathway. Functional analysis has identified molecules that may serve as potential markers and therapeutic targets of angiosarcoma. These molecules include survivin, HSP90, FOXM1, miR-497-5p, KCa3.1, and miR210.This body of knowledge has not yet transferred to clinical practice. The mainstay of treatment for cAS remains surgery followed by postoperative radiotherapy. The efficacy of paclitaxel as an adjuvant chemotherapy is suggested.For patients with advanced cAS, paclitaxel is the treatment of choice. There are also second-line treatment options that are supported by evidence of varying strength. A multikinase inhibitor, pazopanib, has been assessed in several studies, most of which support its efficacy for angiosarcoma. Bevacizumab monotherapy may be effective for angiosarcoma. The efficacy of eribulin mesylate and trabectedin for angiosarcoma is currently being assessed. Recent publications highlighted the role of the immune system in the biology of cAS.
Future research efforts should focus on the following aspects of cAS: drug development directed at recent molecular targets, clinical trials designed specifically for patients with cAS, and the role of immunotherapy for cAS.
Mast cells, eosinophils and basophils are central effector immune cells in allergic skin inflammation including atopic dermatitis (AD). Recent studies revealed that the bidirectional interaction ...between these three immune cell types (mast cells, eosinophils and basophils) and the nervous system is involved in the pathogenesis of neurogenic inflammation, pain and pruritus. Emerging evidence shows that these cells are the main source of pruritogens such as histamine, neuropeptides and cytokines, which are potential new therapeutic targets for drug development in chronic pruritus. For instance, many Th2 cytokines including interleukin (IL)‐4, 13 and 31 have been recognized as some of the most promising targets for the treatment of chronic pruritus in AD. In this review, we highlight the link between these three immune cell subsets and peripheral nerves, with emphasis on the development of chronic pruritus such as AD. We present cytokines and receptors of these three immune cells and peripheral nerves, and discuss the therapeutic potential of targeting these neuro‐immunological processes.
Background Barrier disruption and the resulting continuous exposure to allergens are presumed to be responsible for the development of atopic dermatitis (AD). However, the mechanism through which ...skin barrier function is disrupted in patients with AD remains unclear. Objectives Taking into account the fact that the TH 2 milieu impairs keratinocyte terminal differentiation, we sought to clarify our hypothesis that the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway plays a critical role in skin barrier function and can be a therapeutic target for AD. Methods We analyzed the mechanism of keratinocyte differentiation using a microarray and small interfering RNA targeting STATs. We studied the effect of the JAK inhibitor JTE-052 on keratinocyte differentiation using the human skin equivalent model and normal human epidermal keratinocytes. We applied topical JAK inhibitor onto NC/Nga mice, dry skin model mice, and human skin grafted to immunocompromised mice. Results IL-4 and IL-13 downregulated genes involved in keratinocyte differentiation. STAT3 and STAT6 are involved in keratinocyte differentiation and chemokine production by keratinocytes, respectively. Topical application of the JAK inhibitor suppressed STAT3 activation and improved skin barrier function, permitting increases in levels of terminal differentiation proteins, such as filaggrin, and natural moisturizing factors in models of AD and dry skin and in human skin. Conclusion STAT3 signaling is a key element that regulates keratinocyte differentiation. The JAK inhibitor can be a new therapeutic tool for the treatment of disrupted barrier function in patients with AD.
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.
Atopic dermatitis (AD) is a common chronic skin inflammatory disorder characterized by recurrent eczema accompanied by an intractable itch that leads to an impaired quality of life. Extensive recent ...studies have shed light on the multifaceted pathogenesis of the disease. The complex interplay among skin barrier deficiency, immunological derangement, and pruritus contributes to the development, progression, and chronicity of the disease. Abnormalities in filaggrin, other stratum corneum constituents, and tight junctions induce and/or promote skin inflammation. This inflammation, in turn, can further deteriorate the barrier function by downregulating a myriad of essential barrier-maintaining molecules. Pruritus in AD, which may be due to hyperinnervation of the epidermis, increases pruritogens, and central sensitization compromises the skin integrity and promotes inflammation. There are unmet needs in the treatment of AD. Based on the detailed evidence available to date, certain disease mechanisms can be chosen as treatment targets. Numerous clinical trials of biological agents are currently being conducted and are expected to provide treatments for patients suffering from AD in the future. This review summarizes the etiopathogenesis of the disease and provides a rationale for choosing the novel targeted therapy that will be available in the future.
Summary
Mast cells and basophils play a pathogenetic role in allergic, inflammatory, and autoimmune disorders. These cells have different development, anatomical location and life span but share many ...similarities in mechanisms of activation and type of mediators. Mediators secreted by mast cells and basophils correlate with clinical severity in asthma, chronic urticaria, anaphylaxis, and other diseases. Therefore, effective biomarkers to measure mast cell and basophil activation in vivo could potentially have high diagnostic and prognostic values. An ideal biomarker should be specific for mast cells or basophils, easily and reproducibly detectable in blood or biological fluids and should be metabolically stable. Markers of mast cell and basophil include molecules secreted by stimulated cells and surface molecules expressed upon activation. Some markers, such as histamine and lipid mediators are common to mast cells and basophils whereas others, such as tryptase and other proteases, are relatively specific for mast cells. The best surface markers of activation expressed on mast cells and basophils are CD63 and CD203. While these mediators and surface molecules have been associated to a variety of diseases, none of them fulfills requirements for an optimal biomarker and search for better indicators of mast cell/basophil activation in vivo is ongoing.
Basophils have been recognized as crucial players in allergic inflammation. Basophils have the potential to initiate and expand inflammation through the production of specific cytokines and ...proteases, and are associated with T helper 2 (Th2) immune responses. In addition, recent studies revealed the heterogeneity in basophil populations. Basophils have been clarified important roles in not only IgE-mediated allergic inflammation but also TSLP-mediated and IgE-independent inflammation. Moreover, basophils infiltrate in many human cutaneous diseases. Basophils are responsible for recruiting other inflammatory cells such as macrophages, eosinophils, and fibroblasts. In this review, we discuss recent advances in our understanding of basophil activation and migration in allergic inflammation.
PDF
