Immunobiology of Leprosy

由麻风分枝杆菌(MLEP)引起的皮肤病麻风为研究皮肤免疫反应提供了一个特殊的模型，至少有三个原因：i)麻风仍然是一个全球性的健康和经济负担；ii)皮肤病变很容易进行免疫学研究；iii)这种疾病形成了一种谱系，其临床表现与对病原体的免疫反应类型有关。我们建议检验这一总体假设，即不同的IFN不同地调节人类基因程序，包括维生素D依赖的抗菌途径，从而有助于麻风对进行性感染的耐药性和易感性。本应用的主要主题是了解I型和II型干扰素途径在调节皮肤炎症中的作用。所提出的模型包括识别诱导I型和II型IFN的mLEP抗原/配体，抗菌活性和免疫抑制的诱导及其下游(项目1，莫德林)阐明I型和II型干扰素基因程序与麻风病的发病部位有关，并有助于疾病中不同的功能结果(项目2，程)，了解干扰素基因程序的基因簇和转录调控与维生素D在调节这些反应中的作用的关系(项目3，男性)；以及，在生物信息学核心(Pellegrini)的协助下，研究IFN在调节维生素D新陈代谢和下游宿主防御机制中的作用(项目4，ADAMS)。行政核心通过以下方式促进项目之间的研究互动：i)研究研讨会、充实计划和与专家咨询委员会的会议；ii)通过试点和可行性项目计划扩大研究基础；并利用加州大学洛杉矶分校的资源和环境，包括核心设施、CTSI(CTSA)和针对医学和研究生以及博士后研究员的培训计划。

The skin disease leprosy, caused by the Intracellular pathogen Mycobacterium leprae (mLEP), provides an extraordinary model to study cutaneous immune responses for at least three reasons: i) the disease is still a global health and economic burden, ii) the skin lesions are readily accessible for immunologic study; and, iii) the disease forms a spectrum in which the clinical manifestation correlate with the type of immune response to the pathogen. We propose to test the overall hypothesis that distinct IFNs differentially regulate human gene programs, including the vitamin D-dependent antimicrobial pathway, and thereby contribute to resistance vs. susceptibility to progressive infection in leprosy. The major thematic focus of this application is to understand the role of Type I vs. Type ll IFN pathways in regulatin cutaneous inflammation. The proposed model includes the identification of the mLEP antigens/ligands that induce Type I vs. Type II IFNs, the and downstream induction of antimicrobial activity and immune suppression (Project 1, Modlin) elucidation of the Type I vs. Type II IFN gene programs as related to the site of disease in leprosy and contributing to the distinct functional outcomes in the disease (Project 2, Cheng), understanding the gene clusters and transcriptional control of the IFN gene programs with relationship to the role of vitamin D in modulating these responses (Project 3, Smale); and, investigation of the role of IFNs in regulating vitamin D metabolism and downstream host defense mechanisms (Project 4, Adams), all through the assistance of a Bioinformatics Core (Pellegrini). The Administrative Core to facilitate research interactions between the projects through: i) research seminars, an Enrichment Program and meeting with an expert Advisory Board; ii), extend the research base through a Pilot and Feasibility Project Program; and leverage the resources and environment at UCLA including core facilities, the CTSI (CTSA) and training programs for medical and graduate students as well as those for postdoctoral fellows.