Immunobiology of Leprosy

由胞内病原体麻风分枝杆菌（Mycobacterium leprae，mLEP）引起的皮肤病麻风病为研究皮肤免疫应答提供了一个非凡的模型，至少有三个原因：i）该疾病仍然是全球健康和经济负担，ii）皮肤病变易于进行免疫学研究;和iii）所述疾病形成一个谱，其中临床表现与对病原体的免疫应答类型相关。我们建议测试的总体假设，不同的干扰素差异调节人类基因程序，包括维生素D依赖性抗菌途径，从而有助于抵抗与易感性进行性感染麻风病。本申请的主要主题焦点是了解I型与II型IFN途径在调节皮肤炎症中的作用。所提出的模型包括鉴定诱导I型与II型IFN的mLEP抗原/配体、抗微生物活性和免疫抑制的下游诱导（项目1，Modlin）阐明I型与II型IFN基因程序与麻风病的发病部位相关，并有助于疾病的不同功能结局（项目2，Cheng），了解基因簇和IFN基因程序的转录控制与维生素D在调节这些反应中的作用的关系（项目3，Smale）;研究干扰素在调节维生素D代谢和下游宿主防御机制中的作用（项目4，亚当斯），所有通过一个生物信息学核心（佩莱格里尼）的援助。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，丰富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展研究基础;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.