Mechanisms of Innate and Acquired Host Defense and Tissue Injury in Skin

描述（由申请人提供）： 本研究的最终目的是深入了解宿主对皮肤感染反应中的免疫、炎症和组织损伤机制。麻风病提供了一个模型，研究全身和局部皮肤免疫反应之间的相互作用，因为它的不同的临床表现与宿主的病原体，麻风分枝杆菌的免疫反应。在结核样（T-lep）形式的疾病中，感染是自愈的，在少数皮肤病变中具有很少的细菌，而在麻风瘤（L-lep）形式中，感染是进行性的，在播散性皮肤病变中具有高细菌负荷。此外，患者会产生免疫反应，从而允许随着时间的推移研究急性炎症。我们选择专注于Th 17和最近发现的Th 22细胞及其在麻风病中的作用，因为我们令人兴奋的初步数据将自限性形式的麻风病，结核样（T-lep）和Th 22细胞的疾病部位的Th 17细胞与急性炎症反应状态，麻风结节性红斑（ENL）联系起来。这些发现形成了我们的中心假设的基础，即Th 17细胞有助于宿主防御皮肤中的微生物感染，而相反，Th 22细胞有助于急性炎症和免疫介导的组织损伤。修订后的具体目标是研究：1）先天免疫系统识别M。2）Th 17和Th 22细胞有助于宿主防御的机制，和3）诱导Th 17和Th 22触发中性粒细胞募集的机制，中性粒细胞募集是急性炎症和免疫介导的组织损伤中的关键因素。通过研究Th 17和Th 22细胞在整个麻风病谱中的皮肤病变中的不同作用作为模型，我们希望能够全面了解先天免疫应答影响适应性应答，并与人类微生物感染背景下的宿主防御和组织损伤相关，我们希望，将提供预测疾病结果的能力，并且还导致开发用于各种传染病和皮肤病的新的免疫调节治疗。 公共卫生相关性： 麻风病仍然是发展中国家的主要健康和经济负担，并且还提供了研究人类对微生物病原体的免疫反应的非凡模型，因为它是一种皮肤病，因此病变很容易用于研究疾病部位的免疫过程。我们的初步数据显示了对麻风病研究中人类免疫反应的独特见解，包括有助于抵抗与易感性进行性感染的生物/免疫途径。宿主防御机制的这些方面的调查将产生对人类免疫系统的新见解，以及提供针对各种传染病和皮肤病的治疗干预的新靶点。

DESCRIPTION (provided by applicant): The ultimate goal of this proposal is to gain insight into the mechanisms of immunity, inflammation and tissue injury in the host response to cutaneous infection. Leprosy provides a model for studying the interaction between the systemic and local immune responses in skin, because its diverse clinical manifestations correlate with the host immune response to the pathogen, Mycobacterium leprae. In the tuberculoid (T-lep) form of disease, the infection is self-healing, with few bacteria in few skin lesions, while in the lepromatous (L-lep) form, the infection is progressive, with high bacterial loads in disseminated skin lesions. Furthermore, patients develop immunologic reactions, permitting the study of acute inflammation over time. We have elected to focus on the Th17 and recently identified Th22 cells and their role in leprosy, given our exciting preliminary data linking Th17 cells at the site of disease in the self-limited form of leprosy, tuberculoid (T-lep) and Th22 cells to the acute inflammatory reactional state, erythema nodosum leprosum (ENL). These findings form the basis for our central hypothesis that Th17 cells contribute to host defense in response to microbial infection in skin, whereas in contrast, Th22 cells contribute to acute inflammation and immune-mediated tissue injury. The revised specific aims are to investigate: 1) the mechanisms by which the innate immune system recognizes M. leprae and triggers the induction of Th17 vs. Th22 cells, 2) the mechanisms by which Th17 and Th22 cells contribute to host defense, and, 3) the mechanisms inducing Th17 and Th22 to trigger neutrophil recruitment, a key factor in acute inflammation and immune-mediated tissue injury. By studying the differential role of Th17 and Th22 cells in skin lesions from across the spectrum of leprosy as model, we hope to target an integrated understanding by which the innate immune response influences the adaptive response with relevance to host defense and tissue injury in the context of microbial infection in humans, and, we would hope, would provide the ability to predict disease outcome and also lead to the development of new immunomodulatory treatments for a variety of infectious and skin diseases. PUBLIC HEALTH RELEVANCE: Leprosy continues as a major health and economic burden in developing countries and also provides an extraordinary model to study human immune responses to a microbial pathogen because it is a skin disease, such that the lesions are readily accessible for study of immune processes at the site of disease. Our preliminary data demonstrate unique insights into human immune responses from the study of leprosy, including the biologic/immunologic pathways that contribute to resistance vs. susceptibility to progressive infection. The investigation of these aspects of host defense mechanisms will yield new insights into the human immune system as well as provide novel targets for therapeutic intervention against a variety of infectious and skin diseases.