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: 8500211
• 负责人: Delphine J Lee
• 金额: $ 37.82万
• 依托单位: SAINT JOHN'S CANCER INSTITUTE
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500211
• 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; Genes; Goals; Host Defense; Host Defense Mechanism; Human; Immune; Immune response; Immune system; Immunity; Immunologic Receptors; Immunologics; Infection; Infectious Skin Diseases; Inflammation; Inflammatory; Injury; Instruction; Interferons; 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; 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.

描述（由申请人提供）：