蛋白激酶受体2在瘙痒性皮肤病中的机制研究进展

瘙痒性皮肤病以皮肤炎症和瘙痒为主要表现,包括湿疹、荨麻疹、特应性皮炎、药疹及血管性水肿等。对瘙痒性皮肤病的发病机制的研究很多,目前主要集中于神经免疫生理学方面。肥大细胞是重要的免疫效应细胞,是连接神经系统和免疫系统的重要节点;蛋白激酶受体（protease-activated receptor,PAR）2是类胰蛋白酶受体,分布于肥大细胞、角质细胞及周围感觉神经末梢的神经细胞等细胞膜表面,激活后可直接或间接引起瘙痒。该文综述了PAR2在瘙痒中的机制研究进展,对深入认识特应性皮炎等瘙痒性皮肤病发病机制,发现相关的治疗靶点有重要意义。     

特应性皮炎病因及发病机制的研究进展

特应性皮炎是一种血清IgE增高，常伴发哮喘和过敏性鼻炎的慢性，复发,瘙痒性，炎症性皮肤病，其发病机制较为复杂，与遗传，环境，免疫和对生理药理介质反应异常等因素有关，对特应性皮炎发病机制的研究，进一步明确与其发病机理直接相关的效应细胞及效应分子，包括局部细胞因子的释放，辅助T细胞的分化，IgE的多种效应，感染因素以及超抗原等，以及深入了解它们在特应性皮炎炎症过程中的作用，对改善 临床治疗效果有重要意义。     

特应性皮炎病因及发病机制的研究进展

特应性皮炎是一种血清IgE增高、常伴发哮喘和过敏性鼻炎的慢性、复发性、瘙痒性、炎症性皮肤病。其发病机制较为复杂 ,与遗传、环境、免疫和对生理药理介质反应异常等因素有关。对特应性皮炎发病机制的研究 ,进一步明确与其发病机理直接相关的效应细胞及效应分子 ,包括局部细胞因子的释放、辅助T细胞的分化、IgE的多种效应、感染因素以及超抗原等 ,以及深入了解它们在特应性皮炎炎症过程中的作用 ,对改善临床治疗效果有重要意义     

特应性皮炎中的细胞因子异常与Th2细胞亚群优势

综述细胞因子特别是Ｔｈ细胞亚群相关细胞因子（白介素２，４，５，６，１０，１３，γ－干扰素）与特应性皮炎的关系，认为特应性皮炎皮损和外周血Ｔ细胞中存在（类）Ｔｈ２细胞优势亚群，特应性皮炎免疫发病机制可能是一种以Ｔｈ２细胞介导为主的皮肤免疫炎症反应。     

特应性皮炎的合并症及相关的综合征

特应性皮炎是一种不仅局限于皮肤的炎症性疾病。除皮肤损害外,患者常合并哮喘、过敏性鼻炎和食物过敏,其皮肤对细菌和病毒的易感性增加,一些免疫缺陷综合征常伴有特应性皮炎表现。近年还发现,特应性皮炎与注意缺陷多动障碍等行为异常密切相关,其机制尚不完全清楚。进一步阐明特应性皮炎与躯体或精神障碍合并症之间的潜在生物学机制,可能会增加临床医师对特应性皮炎发病机制的理解,并有助于研发靶向干预特应性皮炎的治疗或预防措施。     

固有淋巴样细胞2与特应性皮炎的研究进展

特应性皮炎是一种慢性炎症性疾病,在儿童中多见,且多有哮喘、过敏性鼻炎等疾病的家族史.该病的发病机制尚不明确,与皮肤屏障缺损、遗传易感性、环境危险因素及免疫调节异常等多个因素相关.研究发现,特应性皮炎与固有淋巴样细胞所介导的免疫反应相关,特别是2型固有淋巴样细胞,与该型细胞相关的白介素4、5和13等一系列细胞因子在特应性皮炎的发病过程中发挥重要作用,这一进展可为特应性皮炎提供新的治疗靶点.     

特应性皮炎中的细胞因子异常与Th2细胞亚群优势

综述细胞因子特别是Th细胞亚群相关细胞因子(白介素2、4、5、6、10、13、γ-干扰素)与特应性皮炎的关系,认为特应性皮炎皮损和外周血T细胞中存在(类)Th2细胞优势亚群,特应性皮炎免疫发病机制可能是一种以Th2细胞介导为主的皮肤免疫炎症反应。     

特应性皮炎的体外3D皮肤模型

特应性皮炎是一种慢性炎症性皮肤病,其病理机制涉及表皮屏障功能破坏、皮肤微生物组异常和2型炎症免疫失调之间复杂的相互作用.随着组织工程技术发展,3D皮肤模型已与正常人体皮肤结构接近.通过模拟特应性皮炎的病理机制,许多研究者成功构建出特应性皮炎的3D皮肤模型.该模型被应用于特应性皮炎的病理机制研究、药物筛选方面,是进行特应...     

皮肤微生物群与特应性皮炎

皮肤的微生物群与机体保持着稳态关系,影响皮肤的屏障和免疫功能。皮肤微生物群的构成受多种因素的影响,具有多样性和特异性。以金黄色葡萄球菌为优势菌和皮肤微生物群的多样性降低是特应性皮炎的主要特点。金黄色葡萄球菌的过度繁殖 加重了特应性皮炎的炎症反应。表皮葡萄球菌虽然也是特应性皮炎优势菌,但通过树突细胞、分泌IL?17A的Th17细胞/IL?17通路调节皮肤屏障免疫反应,拮抗金黄色葡萄球菌过度繁殖,发挥保护性免疫防御作用。马拉色菌可以通过定植、致敏和交叉反应等多种机制诱导和加重特应性皮炎的炎症反应。皮肤益生菌的研究有望为特应性皮炎的治疗提供新的方向。     

精神应激在特应性皮炎中的作用

特应性皮炎是一种慢性、复发性、炎症性皮肤疾病,发病机制不明。特应性皮炎病情的复发与精神应激事件密切相关。本文综述了精神应激在特应性皮炎发病中的作用,一方面通过复杂的神经内分泌免疫网络影响炎症细胞的功能,另一方面,精神应激破坏皮肤屏障功能,诱发级联免疫反应,加重病情。     

Mast cell chymase is increased in chronic atopic dermatitis but not in psoriasis

Mast cell chymase is a chymotrypsin-like serine proteinase primarily stored in secretory mast cell granules. Mast cell chymase has various effects on angiotensin, metalloproteases, lipoproteins, procollagen, neuropeptides and cytokines. Recent studies have demonstrated that chymase inhibitors inhibit skin inflammation. In this study we sought to determine the role of mast cell chymase in atopic dermatitis (AD) in comparison with its role in psoriasis and normal skin. Skin biopsy specimens were obtained from non-lesional and lesional skin of patients with chronic AD and psoriasis and from normal skin of non-atopic and non-psoriatic controls. The number of mast cells containing chymase was determined by immunohistochemistry using a chymase-specific monoclonal antibody. A significantly (P<0.05) enhanced number of chymase-positive cells was found in lesional AD skin as compared to normal skin as well as to lesional and non-lesional skin of patients with psoriasis. A significant (P<0.05) increase in the number of chymase-positive cells was also found in non-lesional AD skin in comparison to psoriasis. An enhanced, albeit not statistically significant difference was noted in non-lesional AD skin as compared to normal skin. In conclusion, these results suggest that mast cell chymase may play an integral part in eliciting and maintaining cutaneous inflammation in AD but not in psoriasis. The increased proteinase activity of mast cell chymase may also be involved in promoting a skin barrier defect in AD, which subsequently enhances the skins permeability to allergens and microbes and thereby aggravates the eczema.     

β-endorphin modulates lipogenesis in human sebocytes

Proteinase-activated receptors are G-protein-coupled receptors with seven-transmembrane domains activated by serine proteinases. PAR-2 is a receptor for mast cell tryptase, house dust mite allergens, bacterial antigens and trypsin, for example, indicating a role of PAR-2 during inflammation and immune responses. In the skin, PAR-2 is expressed by keratinocytes, endothelial cells, certain immune cells and nerves, suggesting a broad regulatory role of proteases in the skin. Recently, PAR-2 has been demonstrated to be involved in neurogenic inflammation. Therefore, we examined whether neuronal PAR-2 may be involved in pruritus of human skin. The endogenous PAR-2 agonist tryptase was increased up to fourfold in atopic dermatitis (AD) patients. PAR-2 was markedly enhanced on primary afferent nerve fibres in skin biopsies of AD patients. Intracutaneous injection of endogenous PAR-2 agonists provoked enhanced and prolonged itch when applied intralesionally. Interestingly, itch upon mast cell degranulation prevailed despite local antihistamines in AD patients only. Thus, we identified enhanced PAR-2 signalling as a new link between inflammatory and sensory phenomena in AD patients. PAR-2 antagonists, thus, represent a promising therapeutic target for the treatment of cutaneous neurogenic inflammation and pruritus.     

Mast cells,nerves and neuropeptides in atopic dermatitis and nummular eczema

The association between mast cells and sensory nerves and the distribution of the neuropeptides substance P (SP), vasoactive intestinal polypeptide (VIP) and calcitonin gene-related peptide (CGRP) were studied immunohistochemically in lesional and nonlesional skin of 26 atopic dermatitis (AD) and 23 nonatopic nummular eczema (NE) patients. Mast cell-nerve contacts were counted morphometrically and confirmed by confocal laser scanning microscopy. Neuropeptide positivity was assessed semiquantitatively. Dermal contacts between mast cells and nerves were increased in number in both lesional and nonlesional samples of AD and NE when compared to those in normal controls, although only the values in lesional AD reached statistical significance ( P<0.05). Nerve-mast cell contacts in the basement membrane zone were seen practically only in lesional NE. SP and CGRP fibres were prominently increased in lesional samples when compared to their nonlesional controls both in AD and NE in the epidermis and in the papillary dermis. In both AD and NE, only small differences were found regarding VIP positivity in lesional and nonlesional biopsies. The epidermis was devoid of VIP positivity. In conclusion, SP and CGRP but not VIP fibres were more frequent in lesional than in nonlesional papillary dermis of both AD and NE. Since mast cells are also increased in number in lesions of AD and NE, they are able to maintain neurogenic inflammation through activation by SP and CGRP. The increased SP/CGRP nerves in the epidermis of AD and NE lesions may stimulate keratinocytes to release cytokines which affect various cell types enhancing inflammation.     

Interaction of peripheral nerves and mast cells,eosinophils, and basophils in the development of pruritus

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.     

Mast cells in psoriatic skin are strongly positive for interferon-gamma

The increased number and early activation of cutaneous mast cells is a typical feature of psoriatic inflammation. Interferon-gamma (IFN-gamma) is believed to be one of the important mediators in the cytokine cascade of psoriasis. Human mast cells have been previously reported to release various cytokines upon stimulation including interleukin (IL) -4, IL-5, IL-6, IL-8, IL-13 and tumour necrosis factor-alpha. Here we report that human mast cells synthesize also IFN-gamma at mRNA and protein level and that the number of IFN-gamma producing mast cells is significantly increased in the psoriatic skin. IFN-gamma immunoreactivity in mast cells was demonstrated by staining non-lesional and lesional skin sections from 21 patients with psoriasis. Ten patients with atopic dermatitis (AD) and five healthy persons served as control groups. The percentage (mean +/- SD) of IFN-gamma + mast cells in lesional compared with non-lesional psoriatic skin was 67 +/- 18% vs. 44 +/- 17% (P < 0.0001, paired t-test), respectively, but only 9 +/- 6% vs. 10 +/- 7% in corresponding skin samples of AD. In the skin of healthy controls, only 12 +/- 12% of the mast cells were IFN-gamma +. Using immunoelectron microscopy, we confirmed the ultrastructural localization of IFN-gamma within the granules of mast cells in psoriatic skin. In addition, stimulation of a human mast cell line HMC-1 with phorbol myristate acetate (PMA) (100 nmol/L) for periods of 2-24 h induced expression of IFN-gamma mRNA, which peaked at 24 h. When HMC-1 cells were stimulated with PMA (100 nmol/L) for periods of 0-3 days, the cells released IFN-gamma protein, peaking on day 1. These results provide further evidence for the important role of mast cells in the pathogenesis of psoriasis.     

Quantitative analysis of bikunin-laden mast cells in follicular eruptions and chronic skin lesions of atopic dermatitis

Bikunin, an inhibitor of serine proteases, is widely distributed in human tissues, including the skin, and may inhibit tryptase and modulate allergic inflammation. The purpose of the present study was to compare follicular eruptions (FE), so-called atopic skin or perifollicular accentuation, with atopic dermatitis (AD) lesions (ADL) by immunohistochemical analysis using antibodies to bikunin and tryptase. Immunohistochemically, bikunin was colocalized with tryptase in dermal mast cells, and a small quantity of bikunin was also deposited in the intercellular spaces in FE and ADL. The number of bikunin-laden mast cells per 0.78 mm(2) of skin was 78.1+/-7.1 (mean+/-SEM, n=14) in FE, 25.4+/-2.3 (n=10) in normal skin from children and infants, 91.3+/-11.8 (n=10) in ADL, 25.6+/-4.8 (n=5) in nonlesional skin of AD, and 27.8+/-2.0 (n=13) in normal adult skin. The difference between FE and normal control skin from children and infants, between FE and nonlesional skin of AD, and between lesional and nonlesional skin of AD were significant. Based on the above findings and the occasional presence of spongiosis and lymphocyte infiltration, in FE moderate inflammation is apparent histopathologically even though little inflammation is apparent clinically.     

Abundant immunoglobulin E‐positive cells in skin lesions support an allergic etiology of atopic dermatitis in the elderly

Background/Objectives Atopic dermatitis (AD) in the elderly is gradually increasing in industrialized countries in association with the aging of society. We report herein four cases of elderly AD {three extrinsic [immunoglobulin (Ig)E‐mediated allergy]; one intrinsic (non‐IgE‐allergy)} in which we investigated the presence of IgE+ cells in lesional skin. Methods/Results Single immunohistochemical and double immunofluorescence stainings were performed for skin biopsy specimens from AD patients and non‐atopic control subjects with chronic eczema. In the lesional lichenified skin of patients with extrinsic elderly AD, numerous IgE+ cells were found among inflammatory cells infiltrates in the upper dermis. Comparative analysis of single immunohistochemistry results using serial paraffin and/or frozen sections found that many IgE+ cells showed identical distributions to tryptase+ mast cells. IgE+ cells coincident with CD1a+ Langerhans cells in the epidermis were found in small numbers only in frozen sections. Double immunofluorescence staining for IgE and CD11c revealed cells coexpressing IgE and CD11c with a dendritic morphology in the papillary and upper dermis. These IgE+ mast cells and IgE+ CD11c+ cells were also found in cured normal‐looking skin from a patient with extrinsic elderly AD after successful treatment. Although only a few weakly positive IgE+ cells were detected, no IgE+CD11c+ cells were found in specimens from patients with intrinsic elderly AD or non‐atopic chronic eczema. Conclusion IgE‐mediated allergic inflammation may play an important role in the pathobiology of elderly AD, similar to other age groups of AD.     

Further exploring the brain-skin connection: stress worsens dermatitis via substance P-dependent neurogenic inflammation in mice

A neurogenic component in atopy and allergy is evident and potentially of great pathogenic relevance. Stress was recently shown to activate elements of this component and is vividly discussed as a cause of exacerbation. However, to date, scientific proof of stress-induced neuronal plasticity and neuro-immune interaction in atopy or allergy remains lacking. Here we show early evidence that exposure to sound stress and atopic dermatitis-like allergic dermatitis (AD) equipotently raise the number of cutaneous nerve fibers containing the prototypic stress neuropeptide substance P (SP) in mice. Stress increases AD readout parameters by at least 30% (eosinophil infiltration, vascular cell adhesion molecule-positive blood vessels, epidermal thickness). This dramatic pathologic exacerbation is associated with increased neurogenic inflammation (degranulated mast cells; interstitial neuropeptidergic dense core granules, mast cell apoptosis, endothelial gaping). Key features of AD exacerbation could not be induced in mice lacking the neurokinin-1 SP receptor (NK1). Interestingly, stress had no significant additional effect on CD4+ cell number, but shifted the cytokine profile toward TH2 in skin. Thus, we conclude that stress primarily exacerbates AD via SP-dependent cutaneous neurogenic inflammation and subsequent local cytokine shifting and should be considered as a therapeutic target, while it offers a convincing pathogenic explanation to affected patients and their frustrated physicians alike.     

Topical adelmidrol 2% emulsion, a novel aliamide, in the treatment of mild atopic dermatitis in pediatric subjects: a pilot study

Recent studies have shown a correlation between an increased number of mast cells in patients with atopic dermatitis (AD) resulting in raised plasma levels of nerve growth factor (NGF), pointing to a possible key role of their interaction in the pathogenesis of AD. It is well known that mast cells synthesize, store and release NGF. Mast cells and NGF both appear to be involved in tissue inflammation and neuroimmune interactions, with NGF acting as a general "alert" molecule capable of recruiting and priming both local tissue and systemic defense processes following stressful events. Also, NGF has been demonstrated to increase mast cell histamine content and intracellular tryptase activity in a dose- and time-dependent fashion. Endogenous aliamides are capable of down-regulating mastocyte reactivity by their action through the vanilloid (VR1) receptors, and keratinocytes, and through the CB1 and CB2 cannabinoid receptors linked to G-protein, also expressed by sensitive nerve endings, macrophages, and epithelial cells. Therefore, aliamide action should be regarded as a multifaceted mechanism interfering with the inflammatory process occurring in AD further beyond the known and controversial anti-histamine pharmacologic effect. In this regard, the reduction of mast cell degranulation by adelmidrol, as demonstrated by in vitro and in vivo investigations in animals, would interfere with the release of other inflammatory mediators, including NGF. Based on these considerations, a pilot study aimed to assess the efficacy and safety of twice daily application of a topical emulsion containing adelmidrol 2%, a novel aliamide, in a series of 20 patients (11 male and 9 female, mean age 8 (range 3-16) years) affected by mild AD was performed. Complete resolution with no side effects was observed in 16 (80%) patients after 4 weeks of treatment, with no relapses at 8-week follow up. Six patches in six subjects with multiple lesions that had not been treated and served as controls showed no improvement. Controlled clinical studies in larger series are warranted to confirm the efficacy of aliamide in the management of AD.