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

先天性和后天性宿主防御和皮肤组织损伤的机制

• 批准号: 7992592
• 负责人: Delphine J Lee
• 金额: $ 15.43万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992592
• 关键词: Acute; Antigens; Bacteria; Cells; Clinical; Cutaneous; Data; Developing Countries; Development; Disease; Disease Outcome; Disorder by Site; Doctor of Philosophy; E-Selectin; Economic Burden; Erythema Nodosum; Gene Expression; Goals; Host Defense; Host Defense Mechanism; Human; Immune; Immune response; Immune system; Immunity; Immunologic Receptors; Immunologics; Infection; Infectious Skin Diseases; Inflammation; Inflammatory; Injury; Instruction; Interleukin-4; Investigation; Lead; Leprosy; Lesion; Life; Ligands; Link; Mediating; Mentors; Modeling; Molecular Profiling; Mycobacterium leprae; Neutrophil Infiltration; Paper; Pathogenesis; Pathway interactions; Patients; Pattern; Predisposition; Process; Prunella vulgaris; Public Health; Publishing; Reaction; Regulation; Resistance; Role; Skin; Study models; T cell response; TLR2 gene; TLR8 gene; Testing; Therapeutic Intervention; Time; Tissues; Training; Tuberculoid leprosy; antimicrobial; base; cytokine; health economics; immunoregulation; insight; interest; microbial; mycobacterial; novel; pathogen; programs; public health relevance; receptor; response; skin disorder; skin lesion

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.

描述（由申请人提供）： 该提案的最终目标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。麻风病为研究皮肤全身和局部免疫反应之间的相互作用提供了一个模型，因为其多样化的临床表现与宿主对病原体麻风分枝杆菌的免疫反应相关。在结核样（T-lep）疾病形式中，感染是自愈性的，少数皮肤病变中细菌很少，而在麻风病（L-lep）形式中，感染是进行性的，在播散性皮肤病变中细菌载量很高。此外，患者会出现免疫反应，从而可以随着时间的推移研究急性炎症。我们选择关注 Th17 细胞，最近确定了 Th22 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麻风病自限性形式的 Th17 细胞、结核样 (T-lep) 和 Th22 细胞与急性炎症反应状态麻风结节性红斑 (ENL) 联系起来。这些发现构成了我们中心假设的基础，即 Th17 细胞有助于宿主防御皮肤微生物感染，而相比之下，Th22 细胞则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) 先天免疫系统识别麻风分枝杆菌并触发诱导 Th17 与 Th22 细胞的机制，2) Th17 和 Th22 细胞促进宿主防御的机制，3) 诱导 Th17 和 Th22 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组织的关键因素 受伤。通过研究 Th17 和 Th22 细胞在麻风病谱系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反应影响与人类微生物感染背景下宿主防御和组织损伤相关的适应性反应，并且我们希望能够提供预测疾病结果的能力，并导致针对各种疾病开发新的免疫调节治疗方法。 传染病和皮肤病。 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，并且还提供了一个非凡的模型来研究人类对微生物病原体的免疫反应，因为它是一种皮肤病，因此可以很容易地利用病变部位来研究疾病部位的免疫过程。我们的初步数据证明了麻风病研究中对人类免疫反应的独特见解，包括有助于对进行性感染进行抵抗与易感性的生物/免疫途径。对宿主防御机制这些方面的研究将为人类免疫系统带来新的见解，并为针对各种传染病和皮肤病的治疗干预提供新的靶点。