降钙素基因相关肽在皮肤免疫中作用的研究进展

降钙素基因相关肽(CGRP)是一种主要由感觉神经合成的神经肽,是皮肤的重要感觉神经递质。研究证实其在皮肤免疫中发挥重要作用,CGRP可促进皮肤角质形成细胞及血管内皮细胞增殖,分泌多种细胞因子;CGRP可增强朗格汉斯细胞对Th2型免疫反应的提呈作用,调控朗格汉斯细胞的迁移与分化,抑制朗格汉斯细胞向T细胞呈递HIV-1抗原;CGRP可促进局部CD4+T细胞聚集,通过活化CAMP及蛋白激酶A,促进CD4+T分泌IL-4。CGRP导致局部皮肤增厚、血管扩张、炎性细胞浸润等皮肤炎性皮损的形成,在银屑病、特应性皮炎等多种皮肤炎症性疾病的发生中起重要作用。     

C型凝集素受体Langerin的研究进展

朗格汉斯细胞是存在于上皮能提呈抗原的树突细胞.Birbeck颗粒是其电子显微镜下的特征性细胞器,Langerin(CD207)是其细胞表型特征.Langerin除了表达于朗格汉斯细胞表面,也表达在真皮的树突细胞和机体其他组织细胞.近年来研究发现,Langerin能降低HIV-1感染的风险、抗真菌感染、调节接触超敏反应、辅助朗格汉斯细胞相关疾病的诊断及增强疫苗功效,希望能为探索相关皮肤疾病新的预防和治疗手段提供思路.     

朗格汉斯细胞靶向免疫研究进展

朗格汉斯细胞是机体重要的抗原呈递细胞。朗格汉斯细胞靶向免疫是将外源性基因和抗原转入朗格汉斯细胞,诱导机体产生特异性体液和细胞免疫,目前主要的免疫方法为基因免疫和抗原免疫。综述了朗格汉斯细胞的特点,免疫的靶向性、安全性及免疫效果。     

朗格汉斯细胞靶向免疫研究进展

朗格汉斯细胞是机体重要的抗原呈递细胞。朗格汉斯细胞靶向免疫是将外源性基因和抗原转入朗格汉斯细胞，诱导机体产生特异性体液和细胞免疫，目前主要的免疫方法为基因免疫和抗原免疫。综述了朗格汉斯细胞的特点，免疫的靶向性、安全性及免疫效果。     

朗格汉斯细胞在特应性皮炎免疫机制和治疗中的作用

特应性皮炎是一种涉及多种免疫细胞的慢性复发性炎症性皮肤病,朗格汉斯细胞在其发病中起着重要作用。研究表明朗格汉斯细胞在发病早期迁移至皮肤淋巴结,活化并主导Th2型免疫反应。治疗方面,倍他米松、大环内酯类抗生素可以抑制朗格汉斯细胞诱导Th2型炎症,而焦油和组胺4受体拮抗剂则可抑制朗格汉斯细胞表达CCL17和CCL22。本文对朗格汉斯细胞在特应性皮炎免疫机制和治疗中的作用进行了综述。     

朗格汉斯细胞与人类乳头瘤病毒感染

朗格汉斯细胞是表皮中的抗原提呈细胞，在免疫系统中起着重要作用。人类乳头瘤病毒感染后，朗格汉斯细胞在免疫识别阶段未能有效地启动细胞介导的免疫反应，成为人类乳头瘤病毒感染后发生免疫逃逸的部分原因，综述朗格汉斯细胞在人类乳头瘤病毒感染免疫逃逸机制中的作用。     

细胞因子与表皮朗格汉斯细胞的成熟和迁移

朗格汉斯细胞是存在于上皮组织中的一种抗原递呈细胞，在人体的防御系统中起着极为重要的作用。朗格汉斯细胞从表皮向引流淋巴结迁移的过程,亦是朗格汉斯细胞成熟的过程。朗格汉斯细胞的迁移和成熟在激发皮肤免疫反应过程中起着重要的作用，是抗原特异性致敏反应过程中必不可少的一步，许多细胞因子在这一过程中发挥着重要的调节作用。     

朗格汉斯细胞与人类乳头瘤病毒感染

朗格汉斯细胞是表皮中的抗原提呈细胞,在免疫系统中起着重要作用。人类乳头瘤病毒感染后,朗格汉斯细胞在免疫识别阶段未能有效地启动细胞介导的免疫反应,成为人类乳头瘤病毒感染后发生免疫逃逸的部分原因,综述朗格汉斯细胞在人类乳头瘤病毒感染免疫逃逸机制中的作用。     

甘草甜素对小鼠朗格汉斯细胞的影响

目的 探讨甘草甜素对小鼠皮肤朗格汉斯细胞的影响。方法 甘草甜素、生理盐水和地塞米松每日1次腹腔注射后在不同时间点获取耳部皮肤。用免疫组化技术检测小鼠表皮中的朗格汉斯细胞。结果 ①甘草甜素5 mg/kg、10 mg/kg及地塞米松1 mg/kg用药3 d后和1周后与用药0 d相比,朗格汉斯细胞密度显著降低。②甘草甜素80 mg/kg用药3 d后和1周后与用药0 d相比,朗格汉斯细胞密度显著升高。③用药4周后甘草甜素对朗格汉斯细胞密度的影响渐弱。结论 甘草甜素对朗格汉斯细胞密度具有双相调节作用。低剂量使朗格汉斯细胞密度降低,高剂量使朗格汉斯细胞密度升高。     

细胞因子与表皮朗格汉斯细胞的成熟和迁移

朗格汉斯细胞是存在于上皮组织中的一种抗原递呈细胞 ,在人体的防御系统中起着极为重要的作用。朗格汉斯细胞从表皮向引流淋巴结迁移的过程 ,亦是朗格汉斯细胞成熟的过程。朗格汉斯细胞的迁移和成熟在激发皮肤免疫反应过程中起着重要的作用 ,是抗原特异性致敏反应过程中必不可少的一步 ,许多细胞因子在这一过程中发挥着重要的调节作用     

Imiquimod, a topical immune response modifier, induces migration of Langerhans cells

Langerhans cells are bone marrow derived dendritic cells that represent the major antigen-presenting cells in the skin. Langerhans cells take up and process antigen within the epidermis and present processed antigen to T lymphocyte in the regional lymph nodes and thus form an integral part of the cutaneous immune response. The cutaneous immune response can be modified by a number of pharmacologic agents, including corticosteroids, cyclosporine, and retinoids as well as physical agents, such as ultraviolet light. For the most part these agents act by suppressing immune function. A topical immune response modifier, imiquimod has been shown to enhance the cutaneous immune response. Imiquimod has anti-viral and anti-tumor effects in animal models and has been approved for the topical treatment of external genital and perianal warts in humans. The biologic activity of imiquimod in part is due to its effect as a cytokine inducer. Preliminary data suggested that imiquimod could have an effect on Langerhans cells. In order to clarify this effect on Langerhans cells, we examined Langerhans cell morphology and migration in imiquimod-treated skin. The density of Ia + cells decreased 2 d after treatment, falling to approximately 43% by day 10. The Ia positive in cells remaining in the skin appeared larger and more dendritic suggesting an activated state. ATPase staining of epidermal sheet confirmed the decreased number of Langerhans cells. To clarify status of Langerhans cells, the activation of B7 was examined. Activation of B7-1 or B7-2 was not detected. Imiquimod, however, did enhance Langerhans cell migration from skin to draining lymph nodes. This enhanced Langerhans cell migration was also associated with an enhanced allergic contact hypersensitivity. These results suggest that the mechanism of modulation of immune response by imiquimod is in part due to effects on Langerhans cells.     

Acute immobilization stress induces clinical and neuroimmunological alterations in experimental murine cutaneous leishmaniasis

Background The skin is an important component of the neuroendocrine‐immune axis. Several studies have shown that stress exacerbates skin disorders, affecting the function of sebaceous glands, keratinocytes, epidermal Langerhans cells and other cells, having an impact on the pathogenesis of many immunologically associated skin diseases. In American cutaneous leishmaniasis, we have shown the importance of the epidermis as a regulatory site, with the key participation of Langerhans cells. Objectives To analyse the effect of acute immobilization stress on Langerhans cells, substance P (SP), calcitonin gene‐related peptide (CGRP) and the natural course of infection in a murine model of cutaneous leishmaniasis. Methods BALB/c mice, susceptible to Leishmania infection, were placed under acute stress by immobilization (confinement) for 2 or 8 h before inoculation with L. mexicana (MHOM/BZ/82/BEL21). An avidin–biotin immunoperoxidase technique was used for cell and neuropeptide identification. Results The stressed animals became more susceptible to the parasite infection, which was manifested by acceleration and exacerbation of the lesions. In addition, the stressed animals showed morphological alterations (spherical bodies and shortened dendrites) and decreased numbers of epidermal Langerhans cells, when compared with control L. mexicana‐infected mice. Mice stressed for 8 h showed greater and antidromic immunoreactivity to CGRP and SP at the time of infection. Moreover, the single inoculation of parasites caused a decrease of CGRP innervation. Conclusions Acute immobilization stress induces an immunosuppressive state that further favours Leishmania invasion in susceptible animals.     

Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems

Abstract: The interaction between components of the nervous system and multiple target cells in the cutaneous immune system has been receiving increasing attention. It has been observed that certain skin diseases such as psoriasis and atopic dermatitis have a neurogenic component. Neuropeptides released by sensory nerves that innervate the skin and often contact epidermal and dermal cells can directly modulate functions of keratinocytes, Langerhans cells (LC), mast cells, dermal microvascular endothelial cells and infiltrating immune cells. Among these neuropeptides the tachykinins substance P (SP) and neurokinin A (NKA), calcitonin gene related peptide (CGRP), vasoactive intestinal peptide (VIP) and somato statin (SOM) have been reported to effectively modulate skin and immune cell functions such as cell proliferation, cytokine production or antigen presentation under physiological or pathophysiological conditions. Expression and regulation of their corresponding receptors that are expressed on a variety of skin cells as well as the presence of neuropeptidespecific peptidases such as neutral endopeptidase (NEP) or angiotensinconverting enzyme (ACE) determine the final biological response mediated by these peptides on the target cell or tissue. Likewise, skin cells like keratinocytes or fibroblasts are a source for neurotrophins such as nerve growth factor that are required not only for survival and regeneration of sensory neurons but also to control responsiveness of these neurons to external stimuli. Therefore, neuropeptides, neuropeptide receptors, neuropeptidedegrading enzymes and neurotrophins participate in a complex, interdependent network of mediators that modulate skin inflammation, wound healing and the skin immune system. This review will focus on recent studies demonstrating the role of tachykinins, CGRP, SOM and VIP and their receptors and neuropeptide-degrading enzymes in mediating neurogenic inflammation in the skin.     

The effect of neuropeptides/hormones on Langerhans cells.

Neuropeptides/hormones have been shown to regulate the various functions of many immunocompetent cells. A number of neuropeptides/hormones has been demonstrated to be present in the skin and a close anatomical association between calcitonin gene-related peptide (CGRP)-containing nerves and Langerhans cells (LC) has been reported. In addition to the CGRP receptor, receptors for several neuropeptides including pituitary adenylate cyclase activating polypeptide (PACAP) and gastrin releasing peptide (GRP) are found on LC, suggesting these neuropeptides might have some effects on LC. CGRP inhibits alloantigen presentation and stimulation of a specific-antigen responsive T-cell clone by LC. Pre-treatment of LC with CGRP also inhibits the elicitation of delayed type hypersensitivity (DTH) in tumor immune mice. Upregulation of B7-2 expression on LC is suppressed by CGRP, which might be, in part, responsible for the inhibitory effect of CGRP in the functional assay. The production of some inflammatory cytokines such as IL-10 by LC-like cell line XS52 is regulated by CGRP and the functional effect of CGRP appears to be at least partially mediated through the autocrine regulation of IL-10. Alpha-MSH is another neuropeptide, the effect of which has been well studied in the cutaneous immune system. Pre-treatment of mice with alpha-MSH produces inhibitory effects in contact hypersensitivity (CHS). IL-10 has been suggested to be involved in the inhibitory effect of alpha-MSH. The receptors and the functional effects of other proopiomelanocortin (POMC)-derived peptides including beta-endorphin and catecholamines on LC are under investigation.     

Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide as modulators of innate and adaptive immunity

Significant evidence suggests that the nervous and immune systems have regulatory interactions within the skin. Langerhans cells (LCs) are dendritic antigen-presenting cells that reside within the epidermis. By laser confocal scanning microscopy, LCs in human skin have been found to be frequently in anatomic association with epidermal nerves. Additionally, a minority of LCs have been found by immunohistochemistry to have the neuropeptide calcitonin gene-related peptide (CGRP) on or near their cell surfaces. Functional studies have demonstrated that CGRP, pituitary adenylate cyclase-activating polypeptide, and vasoactive intestinal peptide inhibit antigen presentation by LCs, at least in some assays. Epinephrine and norepinephrine also have been shown to inhibit LC antigen presentation in vitro . Some of these agents appear to exert their effects through regulation of the expression of cytokines and costimulatory molecules. Furthermore, some of these agents inhibit the acquisition of contact hypersensitivity after intradermal administration. As a whole, these findings suggest a regulatory locus of interaction between the immune system and the nervous system within the skin.     

In vivo UVA-1 and UVB irradiation differentially perturbs the antigen-presenting function of human epidermal Langerhans cells

Ultraviolet B (UVB, 290-320 nm) radiation is known to suppress the immune function of epidermal Langerhans cells. We have recently described that in vitro UVB irradiation perturbs the antigen-presenting cell function of Langerhans cells by inhibiting their expression of functional B7 costimulatory molecules (B7-1, B7-2). The aim of this study was to determine wavelength-specific UV effects on Langerhans cells function in vivo, specifically UVB and UVA-1. To address this issue, volunteers were irradiated on the sun protected volar aspects of their forearms with 3 x minimal erythema dose of UVB (Philips TL-12) and UVA-1 (UVASUN 5000 Mutzhaas). Langerhans cells were isolated from suction blister roofs immediately following irradiation. Langerhans cells isolated from UVB- but not from UVA-1-irradiated skin failed to activate na?ve resting allogeneic T cells (mixed epidermal cell leukocyte reaction) or primed tetanus toxoid reactive autologous T cells. Langerhans cells isolated from sham-irradiated or UVA-1-irradiated skin strongly upregulated B7-2 molecules during short-term tissue culture. By contrast, Langerhans cells from UVB-irradiated skin did not upregulate B7-2 molecules. Furthermore, exogenous stimulation of the B7 pathway by anti-CD28 stimulatory monoclonal antibodies restored the capacity of UVB-irradiated Langerhans cells to activate both alloreactive and tetanus toxoid-reactive T cells, implying suppressed antigen-presenting cell activities and perturbed B7 expression of Langerhans cells isolated from UVB-irradiated skin are related. Those studies demonstrate that in vivo UVB, but not UVA-1, interferes with the activation-dependent upregulation of B7 molecules on Langerhans cells, which in turn is of functional relevance for the perturbed antigen-presenting cell function of Langerhans cells within UVB- but not UVA-1-irradiated skin.     

Expression of ICAM-3/CD50 in normal and diseased skin

ICAM-3 is a newly recognized adhesion molecule, which is a member of the immunoglobulin supergene family of ICAMs. and has been shown to be identical with the CD50 antigen. Recent functional studies have shown that ICAM-3 is a ligand for LFA-1, and plays an important part in immune reactions. To date, very few data exist in the literature concerning its expression in the skin. In the present study, we investigated the expression of ICAM-3 in normal skin and in 98 biopsy specimens of various inflammatory and neoplastic dermatoses. ICAM-3 was found to be expressed by epidermal CD la⁺ Langerhans cells, by cells of Langerhans cell hisliocytosis, by T and B lymphocytes infiltrating the dermis in cutaneous lymphomas and in a wide spectrum of inflammatory dermaloses. Epidermal keralinocytes were consistently negative: endothelial expression of ICAM-3 was observed in six of the 48 cases. These results show that ICAM-3 is constitutively and widely expressed by cells participating in inflammatory dermaloses (including Langerhans cells and T and B lymphocytes), and that it can be albeit rarely, induced on endothelial cells and dermal dendrocytes. These results highlight the important part that ICAM-3 may play in cutaneous inflammatory and immune reactions.     

A strikingly constant ratio exists between Langerhans cells and other epidermal cells in human skin. A stereologic study using the optical disector method and the confocal laser scanning microscope

Langerhans cells play an important part in the immune surveillance of the human epidermis. Therefore, a certain distribution and numerical relationship to other epidermal cells can be expected. To quantify epidermal Langerhans cells population extensive studies have been performed using two-dimensional quantification methods on vertical sections or epidermal sheet preparations. Whereas methods using vertical sections were complicated considerably by the sampling procedure, the dendritic shape, and the suprabasal, nonrandom distribution of Langerhans cells, epidermal sheet preparations have their limitations regarding the numerical relationship of Langerhans cells to total epidermal cells and the epidermal morphology as such. In order to improve the validity of data the three-dimensional dissector method combined with confocal laser scanning microscopy has been applied to quantify the number of Langerhans cells and other epidermal cell nuclei per volume unit in cryosections of 24 punch biopsies of normal breast skin of eight women. Furthermore, the ratio of Langerhans cells to other epidermal cells, their number per biopsy, and per skin surface area were calculated. To minimize the bias by shrinkage the reference volume was estimated using Cavalieri's principle. A constant ratio of one Langerhans cells to 53 other epidermal cells was identified in breast skin (interindividual correlation coefficient: 0.952, p < 0.0001). Thus, Langerhans cells represent 1.86% of all epidermal cells; however, a wide interindividual range was found for the number of Langerhans cells per mm2 (912-1806; mean +/- SD 1394 +/- 321) and other epidermal cells per mm2 (47,315-104,588; mean +/- SD 73,952 +/- 19,426). This explains the conflicting results achieved by conventional morphometric assessments relating cell numbers to skin surface area, ignoring the varying thickness of the epidermis. The surprisingly constant relationship of Langerhans cells to other epidermal cells stresses the hypothesis of an epidermal Langerhans cells unit where one Langerhans cells seems to be responsible for the immune surveillance of 53 epidermal cells.     

Epidermal langerhans cell depletion after artificial ultraviolet B irradiation of human skin in vivo: apoptosis versus migration

Ultraviolet B radiation can suppress cellular immunity. One of the mechanisms related to this immunosuppression is the disappearance of Langerhans cells from the epidermis. The aim of this study was to establish the mechanism of ultraviolet B-induced Langerhans cell disappearance in healthy individuals. The two most likely mechanisms for Langerhans cell disappearance are apoptosis and migration. Apoptosis was assessed in vivo by exposing buttock skin of 10 healthy volunteers to six minimal erythema doses of ultraviolet B. Only very few apoptotic Langerhans cells could be observed in sections from the ultraviolet B-exposed skin. Migration of Langerhans cells cannot be established in skin sections and suction blisters were therefore raised in an attempt to trap migrating Langerhans cells in the sub-basal membrane blister fluid. Blisters were raised on the flexor side of the lower arm of 30 healthy volunteers at several time points after exposure of the skin to six minimal erythema doses of ultraviolet B. Blister fluid was collected and blister roofs were removed to check for Langerhans cell disappearance. Langerhans cells were detected in the blister fluid of the ultraviolet B-exposed skin and not of the unexposed skin. The number of Langerhans cells in the blister fluid peaked at about 18 h after ultraviolet exposure, which coincided with the largest depletion of Langerhans cells in the blister roof. A fraction (20-30%) of the Langerhans cells in the blister fluid stained positive for DNA damage (cyclobutyl pyrimidine dimers), showing that they originated from the epidermis. Ultraviolet B-induced Langerhans cell disappearance appears to be mainly attributable to migration.     

朗格汉斯细胞功能的新认识

朗格汉斯细胞是位于皮肤表皮的组织特异性不成熟树突细胞,其感知、传递外界环境的信号刺激并指导后续的免疫应答.早期研究显示,朗格汉斯细胞具有强大的诱导免疫应答的能力,在启动T细胞特异性免疫应答中起着重要的作用.而最近的一系列研究提示,朗格汉斯细胞的主要作用可能是诱导免疫耐受,其机制可能与特异性T细胞的清除、调节性T细胞的产生、协同刺激因素等相关.因此,朗格汉斯细胞不仅是免疫反应的哨兵,更是人体皮肤环境平衡的维护者.