2013-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/657787摘要：異位性皮膚炎是一種慢性、過敏性、發炎性皮膚疾病，因為它也是一種全身性(systemic)過敏反應，所以異位性皮膚炎病人具有體內E型免疫球蛋白(Immunoglobulin E)上升及時常合併過敏性鼻炎、過敏性氣喘等呼吸道過敏。目前雖然對於異位性皮膚炎有相當的瞭解，然而其詳細致病機轉仍未清楚，此外，異位性皮膚炎會時常反覆發作，更嚴重者全身皮膚都有病灶(lesion)，厲害的抓癢會嚴重影響病人的生活品質。皮膚作為人體表面積最大的器官，並且直接與外界接觸，所以也有相當大的機會與外界的過敏原接觸。傳統上認為致敏反應(allergic sensitization)大多與吸入或是吃入過敏原有關，很容易忽略了另一個重要的途徑---經皮致敏反應(epicutaneous sensitization)，也就是過敏原以穿透皮膚進入人體而引起全身性過敏反應，先從異位性皮膚炎開始，慢慢變成過敏性氣喘、過敏性鼻炎等，形成所謂的過敏進行曲(atopic march)。最近異位性皮膚炎的研究指出皮膚障蔽缺損(skin barrier defect)在異位性皮膚炎致病機轉扮演重要角色，認為破損的皮膚障蔽不僅容易被病原、過敏原等穿透，還容易引起蘭格罕細胞(Langerhans cell)的活化而引發過敏性發炎反應。我們據此推測在異位性皮膚炎的皮膚障蔽缺損的狀態下，經皮致敏反應成為引起全身性過敏反應最主要的路徑，其中的蘭格罕細胞(Langerhans cell)扮演相當的角色。C-type lectin receptor 最近被指出與過敏性疾病有關，包括它們具有醣類辨認區域(carbohydrate-recognition domain)可以與 mannose 結合而吸收(uptake)或吞入(endocytosis)含有 mannose 寡醣聚合體(oligosaccharide)的分子，包括 HIV 的 gp120 蛋白、白蛋白(ovalbumin)以及 Der p 1、Fel d 1、Ara h 1、Bla g 2、Can f 1 等常見的過敏原。我們據此提出假說在異位性皮膚炎的皮膚障蔽缺損的狀態下，蘭格罕細胞(Langerhans cell)利用C-type lectin receptor 吸收或吞入含有 mannose 寡醣聚合體(oligosaccharide)的過敏原，此一途徑引發經皮致敏反應，進而造成全身性過敏疾病。我們提出的計劃即是研究 Langerin (CD207)、Dectin-2、Mincle、DC-SIGN (CD209)等 C-type lectin receptor 在引發經皮致敏反應，進而造成異位性皮膚炎的致病機轉。我們先決定 Langerin (CD207)、Dectin-2、Mincle、DC-SIGN (CD209)等 C-type lectin receptor在異位性皮膚炎的表現量是否有增加，接著嘗試引起基因剃除鼠、探討其對異位性皮膚炎動物模式的影響，我們也在體外(in vitro)及體內(in vivo)利用單株抗體進行阻斷(blocking)實驗，最後我們探討 Langerin (CD207)、Dectin-2、Mincle、DC-SIGN (CD209)等 C-type lectin receptor 引發經皮致敏反應的 signal transduction。<br> Abstract: Atopic dermatitis (AD) is a chronic relapsing eczematous skin disorder that is frequentlyassociated with elevated serum IgE levels and a family history of AD, allergic rhinitis, and/orasthma. Although significant progress has been made in the understanding of AD, its cause isstill unknown, and much remains to be learned about the complex interrelationship of genetic,environmental, immunologic, and epidermal factors in this disease. However, the in vivosignificance of these in vitro findings of IgE-mediated Th2 allergic responses has beenquestioned in some clinical trials, as anti-IgE antibodies had controversial clinical benefits forpatients with AD.Skin is the largest organ of the body as determined by its wet weight or by its surfacearea. Recent findings have shown that disruption of epithelial barrier systems includingstratum corneum (SC) are involved in the pathogenesis of asthma and AD. Allergens thatrepeatedly come into close contact with the skin over extended periods of time are especiallylikely to induce sensitization through the skin. Thus, a non-invasive in vivo tool is essential toevaluate the histopathological changes of SC associated with abnormalities in skin barrierfunction of AD.Perturbation of the SC barrier not only allows allergen penetration throughout this barrier,but also triggers LC activation and facilitates subsequent uptake of antigens by LCs across theepidermal barrier. After antigen acquisition, LCs presumably migrate to draining lymph nodes(DLNs) and activate antigen-specific T cells. It is not yet clear how LCs uptake penetratedallergen, and the specific receptors other than IgE-FcεRI which are associated with Ag uptakeremain to be investigated.CLRs also appear to be involved in allergic disorders. Given the commonality ofmannosylated allergens from diverse sources, it is reasonable that allergen endocytosis byCLRs plays a central role in the development of Th2 responses. It is tempting to suggest thatthe counter structures of these carbohydrates on innate immune cells, namely MR and otherCLRs, could be targeted to prevent allergen uptake at the point of initial contact with innatebody defences.We hypothesized that percutaneous sensitization as an initial trigger of atopic cascades,which lead to the initiation of AD and development of atopic march. We aimed to evaluatethe role of CLRs on the allergic sensitization pathway and on the pathophysiology of AD. Wechoose CLRs with mannose-specificity, including Langerin (CD207), Dectin-2 (also knownas CLEC6A), Mincle (macrophage‑inducible C‑type lectin; also known as CLEC4E), andDC-SIGN (CD209), as our targeting molecules for analysis.異位性皮膚炎蘭格罕細胞經皮致敏反應atopic dermatitisCD207c-type lectin receptorepicutaneous sensitizationLangerhans cell