C型凝集素受体DC-SIGN在特应性皮炎发病中的作用机制研究
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摘要
特应性皮炎(atopic dermatitis, AD)是一种具有代表性的过敏性疾病,一种常见的慢性、复发性、炎症性皮肤病,主要表现为皮肤干燥、湿疹样皮疹和顽固瘙痒。在过去的三十年间,该病的发病率快速攀升,目前该病在儿童中发病率已占到15-30%,在成人中的发病率也达到了2-10%[21。AD的发病机制涉及到很多因素,包括遗传素质、环境因素、免疫功能异常和皮肤屏障功能障碍等。天然免疫系统和适应性免疫系统均参与AD发病,在病情急性发作及疾病持续发展中起重要的作用。AD患者因瘙痒反复搔抓加重皮肤屏障破坏,过敏原及病原微生物抗原更易透过皮肤产生过敏反应。树突状细胞(dendritic cells, DCs)广泛分布于皮肤和粘膜中,是机体功能最强的专职抗原递呈细胞(Antigen presenting cells, APC),它能高效地摄取、加工处理和递呈抗原。未成熟DC具有较强的迁移能力,成熟DC能有效激活初始T细胞,处于启动、调控、并维持免疫应答的中心环节。DCs识别和递呈抗原是诱导获得性免疫反应发生的首要阶段。近几年来,人们认识到天然免疫系统的活化首先是通过抗原递呈细胞表面的模式识别受体(pattern-recognition receptor, PRRs)来介导的。DCs表面表达多种PRRs,包括C凝集素受体(C-type lectin receptors, CLRs), Toll样受体(Toll-like receptors)和核苷酸结合寡聚化蛋白受体(nucleotide-binding oligomerization domain proteins, NODs)等。其中,CLRs通过识别病原体或过敏原表面的“糖指纹”,来传递外源信号,活化免疫细胞。在众多的CLRs中,DC-SIGN(DC-specific ICAM-grabbing non-integrin, DC-SIGN)日益受到人们的关注,主要表达于髓样DC和巨噬细胞表面,作为DCs的模式识别和黏附受体,DC-SIGN可在DCs黏附迁移及炎症反应、激活天然T细胞及启动免疫应答,以及病原体与肿瘤的免疫逃逸等诸多方面发挥重要作用,并可能是DCs执行和调控天然免疫与获得性免疫反应的一个重要的分子介导基础。
DC-SIGN的胞外区糖识别域(CRDs)可识别结合特定的糖类抗原,如ManLAM和LewisX等。在生理条件下,DC-SIGN可通过促进DC捕获病原体胞壁成分糖蛋白,调节DC抗原处理和递呈功能。DC-SIGN与TLR家族在调节DC激活T细胞应答中也存在串话,这种串话通过细胞内信号分子改变而调节T细胞应答产生免疫活化或免疫抑制,诱导免疫应答趋于平衡,维持内环境稳定。研究发现,不同的病原体或抗原与DC-SIGN结合,诱导分泌的细胞因子不同,如胃幽门螺杆菌与DC-SIGN结合诱导Th2型细胞因子分泌增加；脑膜炎奈瑟氏菌变异体通过与DC-SIGN结合促进T细胞向Thl反应；乳酸杆菌与DC-SIGN结合可诱导调节性T细胞的分化。在诱导耐受方面也发现,妊娠期女性胎盘中DC-SIGN受体阳性的树突状细胞介导了母体免疫系统对胎儿抗原的免疫耐受；Huang等用严重食物过敏的小鼠动物模型研究发现,Man51-BSA选择性的作用于小鼠的肠道内的表达SIGNR1(DC-SIGN的同源性受体)的固有层树突状(lamina propria dendritic cell, LPDC)细胞,参与诱导致敏食物口服耐受。以上的发现均支持DC-SIGN在免疫调节方面的重要角色,是一种免疫调节受体。
很多AD患者易感的病原微生物和过敏原都富含多糖结构,但是目前尚不清楚它们具体是如何通过DC-SIGN而活化DC,从而诱导特定型别T细胞免疫反应的。因此,从以下几方面研究DC-SIGN在AD患者的免疫功能异常中发挥的功能作用具有重要意义：①确定AD病人皮损处DC-SIGN表达情况；②富含多糖结构的病原菌或过敏原与可溶性DC-SIGN受体和细胞膜表达的DC-SIGN受体结合情况；③尘螨被DC-SIGN识别、内吞,及介导DCs活化后产生哪些细胞因子,从而诱导哪些型别的T细胞分化?
本研究针对以上方面进行了系统研究,期望发现DC-SIGN受体在AD的发病中的作用。首先,采集AD患者皮损,并以银屑病皮损和正常人皮肤作为对照,免疫组化实验方法检测AD患者和对照组皮肤内DC-SIGN表达差异情况。其次,验证表达于DCs细胞上的DC-SIGN是否参与了变应原及病原菌的识别、内吞及递呈?通过ELISA.流式细胞技术及激光共聚焦显微镜技术检测数种过敏原与可溶性DC-SIGN蛋白及细胞表达的DC-SIGN受体的结合能力。再次,当过敏原经DC-SIGN通路诱导DCs活化成熟后,通过检测DC细胞培养上清及DC细胞表面标志,检查DC细胞活化、成熟状态。最后,将经过敏原刺激的成熟DC细胞与初始T细胞共培养,检测过敏原通过DC-SIGN介导DCs活化后对指导T细胞极化作用的影响。
通过本实验发现,①DC-SIGN在AD患者皮肤内表达量增高,推测DC-SIGN可能在特应性皮炎的发病中起到一定的作用。②通过ELISA方法初步验证过敏原／病原菌与可溶性DC-SIGN受体的结合能力及最佳结合浓度。③以构建表达DC-SIGN受体的HEK293T细胞和体外诱导树突状细胞为模型模拟体内情况,运用流式细胞技术和激光共聚焦显微技术等方法验证了DC-SIGN受体介导了过敏原的结合及内吞。④尘螨刺激单核细胞诱导的树突状细胞(Monocyte derived dendritic cells, MDDCs)24h后,检测比较DC-SIGN受体和／或Toll样受体阻断组的细胞培养上清前炎症细胞因子及细胞表面标志,发现DC-SIGN受体阻断较其他组CD83表达受到抑制,培养上清中肿瘤坏死因子TNF-α和IL-6表达量降低,故得出DCs可通过DC-SIGN受体介导致活化和成熟。⑤最后将户尘螨过敏原刺激的成熟DCs与初始T细胞共培养,检测发现培养上清液中的IL-4和IL-22表达升高,间接证实了户尘螨通过DC-SIGN刺激DCs细胞活化后,进一步诱导了初始T细胞向Th2和Th22型免疫反应极化。
本研究课题对进一步阐明过敏性皮肤病的发病机制和干预环节提供了重要的理论依据,也为开辟过敏性疾病发病机制研究的新领域和发展新的治疗策略提供理论和实验基础。
Atopic dermatitis (AD) is a chronic, relapsing, inflammatory disease, characterized by the presence of eczematous lesions and pruritus. AD affects nearly15-30%of children and2-10%of the adult population worldwide. Innate and adaptive immunity have definitive roles in the development, maintenance and flare-up of AD. Skin barrier dysfunctions of AD make the entry of antigens and pathogens into the skin possible. Once they come into skin, they would interact with DCs, and then create a milieu that shapes the immune response to allergy reaction Dendritic cells (DCs) which are the most powerful antigen presenting cells(APCs) mainly distributed in sub-epidermal and mucosal, where in those places, DCs are easy to attach allergens, then uptake, processing and presenting antigens in the draining lymph node, where they become able to stimulate naive T cells. Recently, the pattern-recognition receptor(PRRs) on APC surface were found one after another including C-type lectin receptors (CLRs), Toll-like receptors, or nucleotide-binding oligomerization domain proteins(NODs), and CLRs is one of an important PRRs among them that suggest to functionally interact with allergens and are critical in controlling immune response.
DC-SIGN is a type Ⅱ membrane receptor that was expressed on immature DCs in peripheral tissue and mature DCs in lymphoid tissues, initially cloned and characterized from human placenta as a receptor for the HIV envelope glycoprotein gp120. However, it was not until much later that DC-SIGN was rediscovered as a cell-adhesion receptor as well as antigen uptake and signaling, that supports primary immune responses and enhanced HIV infection of CD4+T cell.
The primary function of DC-SIGN is the recognition of glycans through its carbohydrate recognition domain (CRD). The CRD of DC-SIGN is a C-type lectin-like domain with an EPN motif that binds fucose and mannose and has two Ca2+coordination sites. Thus, DC-SIGN recognizes fucosylated glycans, such as the blood-type Lewis antigens and high-mannose structures. This relatively broad glycan specificity confers on the receptor the ability to recognize a wide variety of ligands, pathogens, self-glycoproteins, Fc portion of immunoglobulins and allergens. Internalization of DC-SIGN into the classical endolysosomal pathway is initially described to mediate efficient antigen processing and presentation into MHC class Ⅱ. DC-SIGN cross-presentation of allergens is enhanced by the simultaneous triggering of Toll-like receptors (TLRs). DC-SIGN is not only an antigen-uptake receptor, but also facilitates the intercellular adhesion of DCs with T cells. DC-SIGN also behaves as a signaling receptor.
Recent studies displayed different pathogens interactions between DC-SIGN would be delivered to promote secretion of different cytokines. Such as Helicobacter pylori interaction with DC-SIGN promoted secretion of Th2-type pro-cytokines. While, Neisseria meningitidis variants delivered by DC-SIGN biased toward Thl-type immune response. Interestingly, Bacillus acidi lactic interacted with DC-SIGN promotes Treg polarization. The appearance of DC-SIGN+cells in the decidua was a pregnancy-associated event involved in maternal immune system accepted the allogeneic embryo.Huang reported oral delivery of Man51-BSA targed SIGNR-1reduced the BSA-induced anaphylactic response.
Common allergens and pathogens that associated with the onset of AD were rich in polysaccharides, and the cellular basis of allergens uptake and processing by DCs through DC-SIGN and mechanisms of inducing naive T cells polarization were largely unknown. In this study, we had carried intensive investigations on the following aspects:①Clarified the expressed level of DC-SIGN within the lesions of AD patients;②ested the hypothesis that glycan-containing allergens and pathogens were natural ligands for DC-SIGN;③Determined the role of DC-SIGN to induce innate and adaptive immune responses.
These studies promoted us to investigate the efficiency and specificity of the allergen-DC-SIGN interaction might be important in determining the immune outcomes of AD. Firstly, we analysed the DC-SIGN expression levels within lesions from AD patients and same samples from healthy individuals and psoriasis patients were used as controls at the same time. Secondly, because of the restricted expression of DC-SIGN on DCs, we speculated that DC-SIGN participate in antigens recognition, uptake, processing and presenting. We conducted a series of researches on the binding ability of DC-SIGN with allergens and pathogens. ELISA-based binding assay were performed to determine the binding activity of purified allergens and pathogens with soluble DC-SIGN. DC-SIGN transfected HEK-293T cells and human monocyte-derived DCs (MDDCs) were investigated as models for testing the cellular binding activity and functional effects of allergen-DC-SIGN interaction by using confocal microscopy and flow cytometry. Thirdly, we assessed the contribution of DC-SIGN and TLRs to DCs activation and maturation after Der p2stimulation, including the activation molecular markers (CD86/CD80and CD83) and proimflamation cytokines(TNF-α、IL-1β、IL-6and IL-12). Finally, in order to make clear the polarization of T cells, we co-cultured Der p2allergens stimulated DCs with naive T cells, and tested some cytokines (IL-4/IFN-y/IL-22/IL-17A) related with T cell types.
Our studies found that①The expression of DC-SIGN within AD lesions was higher than that of healthy controls and psoriasis;②The best concentration for binding of allergens with Soluble DC-SIGN by Titration test was1ug/ml;③DC-SIGN mediated the internalization of Der p2and Gal d2from house dust mite and egg white through their carbohydrate moieties, DC-SIGN expressed on HEK293T cells and human MDDCs was the major receptor for Der p2and Gal d2recognition and endocytosis. These effects were dose-dependent and could be inhibited for the most part by DC-SIGN blocking antibody or mannan pretreatment;⑤CD86/CD80/CD83were predominantly expressed on MDDCs stimulated with crude extracts of house dust mite and egg white from AD patients for24h and the expression was partly inhibited by DC-SIGN blocking antibody and/or MyD88blocking antibody. The supernatant of proinflammatory cytokines in cultured DCs activated by house dust mite were assayed. Significantly increased TNF-a and IL-6productions in the supernatant were noted, and pretreated by DC-SIGN blocking antibody and/or MyD88blocking antibody could partly inhibit their productions.⑤When actived mature DCs were co-cultured with naive T cells, the IL-4and IL-22expression levels were increased significantly, and these effects could be inhibited by DC-SIGN blocking antibody also. Early events at the interface of DCs and allergens were clearly of great importance in determining T cell polarization. Our work demonstrated a major role for DC-SIGN in glycoallergen recognition and in the regulation of Th2/Th22responses.
This study may provided evidences for the pathogenesis of atopic dermatitis and possible intervention for AD treatment.
DC-SIGN的胞外区糖识别域(CRDs)可识别结合特定的糖类抗原,如ManLAM和LewisX等。在生理条件下,DC-SIGN可通过促进DC捕获病原体胞壁成分糖蛋白,调节DC抗原处理和递呈功能。DC-SIGN与TLR家族在调节DC激活T细胞应答中也存在串话,这种串话通过细胞内信号分子改变而调节T细胞应答产生免疫活化或免疫抑制,诱导免疫应答趋于平衡,维持内环境稳定。研究发现,不同的病原体或抗原与DC-SIGN结合,诱导分泌的细胞因子不同,如胃幽门螺杆菌与DC-SIGN结合诱导Th2型细胞因子分泌增加；脑膜炎奈瑟氏菌变异体通过与DC-SIGN结合促进T细胞向Thl反应；乳酸杆菌与DC-SIGN结合可诱导调节性T细胞的分化。在诱导耐受方面也发现,妊娠期女性胎盘中DC-SIGN受体阳性的树突状细胞介导了母体免疫系统对胎儿抗原的免疫耐受；Huang等用严重食物过敏的小鼠动物模型研究发现,Man51-BSA选择性的作用于小鼠的肠道内的表达SIGNR1(DC-SIGN的同源性受体)的固有层树突状(lamina propria dendritic cell, LPDC)细胞,参与诱导致敏食物口服耐受。以上的发现均支持DC-SIGN在免疫调节方面的重要角色,是一种免疫调节受体。
很多AD患者易感的病原微生物和过敏原都富含多糖结构,但是目前尚不清楚它们具体是如何通过DC-SIGN而活化DC,从而诱导特定型别T细胞免疫反应的。因此,从以下几方面研究DC-SIGN在AD患者的免疫功能异常中发挥的功能作用具有重要意义：①确定AD病人皮损处DC-SIGN表达情况；②富含多糖结构的病原菌或过敏原与可溶性DC-SIGN受体和细胞膜表达的DC-SIGN受体结合情况；③尘螨被DC-SIGN识别、内吞,及介导DCs活化后产生哪些细胞因子,从而诱导哪些型别的T细胞分化?
本研究针对以上方面进行了系统研究,期望发现DC-SIGN受体在AD的发病中的作用。首先,采集AD患者皮损,并以银屑病皮损和正常人皮肤作为对照,免疫组化实验方法检测AD患者和对照组皮肤内DC-SIGN表达差异情况。其次,验证表达于DCs细胞上的DC-SIGN是否参与了变应原及病原菌的识别、内吞及递呈?通过ELISA.流式细胞技术及激光共聚焦显微镜技术检测数种过敏原与可溶性DC-SIGN蛋白及细胞表达的DC-SIGN受体的结合能力。再次,当过敏原经DC-SIGN通路诱导DCs活化成熟后,通过检测DC细胞培养上清及DC细胞表面标志,检查DC细胞活化、成熟状态。最后,将经过敏原刺激的成熟DC细胞与初始T细胞共培养,检测过敏原通过DC-SIGN介导DCs活化后对指导T细胞极化作用的影响。
通过本实验发现,①DC-SIGN在AD患者皮肤内表达量增高,推测DC-SIGN可能在特应性皮炎的发病中起到一定的作用。②通过ELISA方法初步验证过敏原／病原菌与可溶性DC-SIGN受体的结合能力及最佳结合浓度。③以构建表达DC-SIGN受体的HEK293T细胞和体外诱导树突状细胞为模型模拟体内情况,运用流式细胞技术和激光共聚焦显微技术等方法验证了DC-SIGN受体介导了过敏原的结合及内吞。④尘螨刺激单核细胞诱导的树突状细胞(Monocyte derived dendritic cells, MDDCs)24h后,检测比较DC-SIGN受体和／或Toll样受体阻断组的细胞培养上清前炎症细胞因子及细胞表面标志,发现DC-SIGN受体阻断较其他组CD83表达受到抑制,培养上清中肿瘤坏死因子TNF-α和IL-6表达量降低,故得出DCs可通过DC-SIGN受体介导致活化和成熟。⑤最后将户尘螨过敏原刺激的成熟DCs与初始T细胞共培养,检测发现培养上清液中的IL-4和IL-22表达升高,间接证实了户尘螨通过DC-SIGN刺激DCs细胞活化后,进一步诱导了初始T细胞向Th2和Th22型免疫反应极化。
本研究课题对进一步阐明过敏性皮肤病的发病机制和干预环节提供了重要的理论依据,也为开辟过敏性疾病发病机制研究的新领域和发展新的治疗策略提供理论和实验基础。
Atopic dermatitis (AD) is a chronic, relapsing, inflammatory disease, characterized by the presence of eczematous lesions and pruritus. AD affects nearly15-30%of children and2-10%of the adult population worldwide. Innate and adaptive immunity have definitive roles in the development, maintenance and flare-up of AD. Skin barrier dysfunctions of AD make the entry of antigens and pathogens into the skin possible. Once they come into skin, they would interact with DCs, and then create a milieu that shapes the immune response to allergy reaction Dendritic cells (DCs) which are the most powerful antigen presenting cells(APCs) mainly distributed in sub-epidermal and mucosal, where in those places, DCs are easy to attach allergens, then uptake, processing and presenting antigens in the draining lymph node, where they become able to stimulate naive T cells. Recently, the pattern-recognition receptor(PRRs) on APC surface were found one after another including C-type lectin receptors (CLRs), Toll-like receptors, or nucleotide-binding oligomerization domain proteins(NODs), and CLRs is one of an important PRRs among them that suggest to functionally interact with allergens and are critical in controlling immune response.
DC-SIGN is a type Ⅱ membrane receptor that was expressed on immature DCs in peripheral tissue and mature DCs in lymphoid tissues, initially cloned and characterized from human placenta as a receptor for the HIV envelope glycoprotein gp120. However, it was not until much later that DC-SIGN was rediscovered as a cell-adhesion receptor as well as antigen uptake and signaling, that supports primary immune responses and enhanced HIV infection of CD4+T cell.
The primary function of DC-SIGN is the recognition of glycans through its carbohydrate recognition domain (CRD). The CRD of DC-SIGN is a C-type lectin-like domain with an EPN motif that binds fucose and mannose and has two Ca2+coordination sites. Thus, DC-SIGN recognizes fucosylated glycans, such as the blood-type Lewis antigens and high-mannose structures. This relatively broad glycan specificity confers on the receptor the ability to recognize a wide variety of ligands, pathogens, self-glycoproteins, Fc portion of immunoglobulins and allergens. Internalization of DC-SIGN into the classical endolysosomal pathway is initially described to mediate efficient antigen processing and presentation into MHC class Ⅱ. DC-SIGN cross-presentation of allergens is enhanced by the simultaneous triggering of Toll-like receptors (TLRs). DC-SIGN is not only an antigen-uptake receptor, but also facilitates the intercellular adhesion of DCs with T cells. DC-SIGN also behaves as a signaling receptor.
Recent studies displayed different pathogens interactions between DC-SIGN would be delivered to promote secretion of different cytokines. Such as Helicobacter pylori interaction with DC-SIGN promoted secretion of Th2-type pro-cytokines. While, Neisseria meningitidis variants delivered by DC-SIGN biased toward Thl-type immune response. Interestingly, Bacillus acidi lactic interacted with DC-SIGN promotes Treg polarization. The appearance of DC-SIGN+cells in the decidua was a pregnancy-associated event involved in maternal immune system accepted the allogeneic embryo.Huang reported oral delivery of Man51-BSA targed SIGNR-1reduced the BSA-induced anaphylactic response.
Common allergens and pathogens that associated with the onset of AD were rich in polysaccharides, and the cellular basis of allergens uptake and processing by DCs through DC-SIGN and mechanisms of inducing naive T cells polarization were largely unknown. In this study, we had carried intensive investigations on the following aspects:①Clarified the expressed level of DC-SIGN within the lesions of AD patients;②ested the hypothesis that glycan-containing allergens and pathogens were natural ligands for DC-SIGN;③Determined the role of DC-SIGN to induce innate and adaptive immune responses.
These studies promoted us to investigate the efficiency and specificity of the allergen-DC-SIGN interaction might be important in determining the immune outcomes of AD. Firstly, we analysed the DC-SIGN expression levels within lesions from AD patients and same samples from healthy individuals and psoriasis patients were used as controls at the same time. Secondly, because of the restricted expression of DC-SIGN on DCs, we speculated that DC-SIGN participate in antigens recognition, uptake, processing and presenting. We conducted a series of researches on the binding ability of DC-SIGN with allergens and pathogens. ELISA-based binding assay were performed to determine the binding activity of purified allergens and pathogens with soluble DC-SIGN. DC-SIGN transfected HEK-293T cells and human monocyte-derived DCs (MDDCs) were investigated as models for testing the cellular binding activity and functional effects of allergen-DC-SIGN interaction by using confocal microscopy and flow cytometry. Thirdly, we assessed the contribution of DC-SIGN and TLRs to DCs activation and maturation after Der p2stimulation, including the activation molecular markers (CD86/CD80and CD83) and proimflamation cytokines(TNF-α、IL-1β、IL-6and IL-12). Finally, in order to make clear the polarization of T cells, we co-cultured Der p2allergens stimulated DCs with naive T cells, and tested some cytokines (IL-4/IFN-y/IL-22/IL-17A) related with T cell types.
Our studies found that①The expression of DC-SIGN within AD lesions was higher than that of healthy controls and psoriasis;②The best concentration for binding of allergens with Soluble DC-SIGN by Titration test was1ug/ml;③DC-SIGN mediated the internalization of Der p2and Gal d2from house dust mite and egg white through their carbohydrate moieties, DC-SIGN expressed on HEK293T cells and human MDDCs was the major receptor for Der p2and Gal d2recognition and endocytosis. These effects were dose-dependent and could be inhibited for the most part by DC-SIGN blocking antibody or mannan pretreatment;⑤CD86/CD80/CD83were predominantly expressed on MDDCs stimulated with crude extracts of house dust mite and egg white from AD patients for24h and the expression was partly inhibited by DC-SIGN blocking antibody and/or MyD88blocking antibody. The supernatant of proinflammatory cytokines in cultured DCs activated by house dust mite were assayed. Significantly increased TNF-a and IL-6productions in the supernatant were noted, and pretreated by DC-SIGN blocking antibody and/or MyD88blocking antibody could partly inhibit their productions.⑤When actived mature DCs were co-cultured with naive T cells, the IL-4and IL-22expression levels were increased significantly, and these effects could be inhibited by DC-SIGN blocking antibody also. Early events at the interface of DCs and allergens were clearly of great importance in determining T cell polarization. Our work demonstrated a major role for DC-SIGN in glycoallergen recognition and in the regulation of Th2/Th22responses.
This study may provided evidences for the pathogenesis of atopic dermatitis and possible intervention for AD treatment.
引文
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