KFO 303: Pemphigoid Diseases - Molecular Pathways and their Therapeutic Potential

类天疱疮疾病（pemphigigoid， PD）是一组严重的、密切相关的、慢性的、自身抗体（AAb）诱导的、表皮下起疱性皮肤病，是由免疫应答引起的，免疫应答是针对特定的自身抗原，这些自身抗原在包括皮肤在内的鳞状上皮的真皮-上皮交界处（DEJ）的半粒间质锚定复合物中充当粘附分子。在这种免疫反应的效应期，炎症细胞被招募到真皮层并释放包括蛋白酶在内的介质，损害真皮与表皮的粘附。因此，皮肤出现水泡和腐蚀。pd主要影响老年人，死亡率高。随着发病率的上升，它们构成了一个日益严重的健康问题。治疗选择有限，往往会引起严重的不良反应。新的治疗策略的发展需要对帕金森病的发病机制有充分的了解。然而，驱动pd的分子机制尚不完全清楚。单独存在自身抗体，虽然是皮肤炎症的先决条件，但不足以启动效应期。因此，一个关键的问题是免疫效应细胞如何被激活、扩增并最终延续到真皮层。在治疗过程中有效和特异性地抑制效应细胞募集可能是控制帕金森病的关键。莱尔贝克大学皮肤科是世界上为数不多的专门从事皮肤病研究和治疗的学术中心之一。我们已经开发了独特的PD小鼠模型，并建立了一个重要的PD患者队列。这使我们对pd的发病机制有了一些了解，这比以前预期的要复杂得多。最近，我们有了新的令人兴奋的发现，特别是在pd的效应期，现在点燃了临床研究单位（CRU）的提议。我们的目标是揭示触发和驱动皮肤炎症的因素，并为pd的效应期提供一个全面的模型。我们将特别阐明启动、放大和延续效应细胞募集的机制，并将这些新见解转化为新的治疗方法、预防策略和生物标志物。在这种情况下，pd将作为阐明aab驱动的自身免疫性疾病的效应期的范例。与pd不同，大多数自身免疫性疾病的自身抗原是未知的，从而使大多数自身免疫性疾病的效应期的阐明复杂化，特别是在组织炎症刚刚出现的早期阶段。通过这个CRU，我们将在莱尔贝克大学建立一个永久性的转化研究单位，并将专门培训内科科学家。CRU将进一步加强<s:1>贝克大学感染与炎症研究重点。

Pemphigoid diseases (PD) are a group of severe, closely related, chronic, autoantibody (AAb)-induced, subepidermal blistering skin diseases caused by an immune response directed to defined autoantigens serving as adhesion molecules within in the hemidesmosomal anchoring complex at the dermal-epithelial junction (DEJ) of squamous epithelia, including the skin. In the effector phase of this immune response, inflammatory cells are recruited into the dermis and release mediators, including proteases, compromising dermal-epidermal adhesion. Consequently, skin blisters and erosions develop.PDs mainly affect elderly and are associated with a high mortality. With their incidence rising, they constitute a growing health concern. Treatment options are limited and often elicit severe adverse effects. Development of novel therapeutic strategies takes sound understanding of PD pathogenesis. The molecular mechanisms driving PDs, however, are only incompletely understood. The mere presence of AAbs alone, although a prerequisite for skin inflammation, is not sufficient to initiate the effector phase. A pivotal question therefore is how immune effector cell recruitment into the dermis is initiated, amplified, and finally perpetuated. Effectively and specifically blunting effector cell recruitment in a therapeutic effort is presumably key to control PD. The Department of Dermatology at the University of Lübeck is one of few academic centers worldwide specialized in both research and treatment of PDs. We have developed unique mouse models of PDs and have established a significant PD patient cohort. This has allowed us to shed some light on the pathogenesis of PDs, which has turned out to be more complex than previously anticipated. Recently, we have made new exciting discoveries, specifically on the effector phase of PDs, now kindling this Clinical Research Unit (CRU) proposal. Our goal is to uncover the factors triggering and driving skin inflammation and to provide a comprehensive model for the effector phase of PDs. We will particularly elucidate the mechanisms initiating, amplifying, and perpetuating effector cell recruitment, and we will translate these new insights into novel therapeutics, preventive strategies, and biomarkers. In this context, PDs will serve as paradigm for the elucidation of the effector phase of AAb-driven autoimmune diseases in general. Unlike in PDs, the autoantigens in the majority of autoimmune diseases are unknown, thus complicating the elucidation of the effector phase of most autoimmune diseases, especially its early stage when tissue inflammation is just emerging.By this CRU, we will establish a permanent translational research unit at the University of Lübeck and will train particularly physician scientists. The CRU will further strengthen the major research focus ¿Infection and Inflammation¿ of the University of Lübeck.