Modulation of Cutaneous Autoimmunity by Staphylococcus Aureus

金黄色葡萄球菌对皮肤自身免疫的调节

基本信息

批准号：
10263361
负责人：
JANET A FAIRLEY
金额：
$ 19.87万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10263361
关键词：
Abbreviations Acute Affect Age Age of Onset Antibiotic Therapy Antibiotics Antibody titer measurement Area Atopic Dermatitis Autoantibodies Autoimmune Autoimmunity Biopsy Blood Bulla Bullous Pemphigoid Cell Adhesion Molecules Clinical Trials Collagen Type XVII Cutaneous Data Development Disease Disease remission Doctor of Philosophy Dose Elderly Enrollment Enterotoxins Environment Exhibits Flare Forearm Funding Opportunities Gene Cluster General Population Generations Geographic Locations Geography Goals Health Healthcare Histocompatibility Antigens Class II Hospitalization Immune Immunity Immunosuppression Incidence Infection Inflammation Inflammatory Investigation Iowa Knowledge Lateral Lesion Letters Life Link Liquid substance Location Measures Medical History Mission Morbidity - disease rate Pathogenesis Pathogenicity Pathologic Patient Care Patient-Focused Outcomes Patients Play Pneumonia Population Prevalence Production Race Research Respiratory System Risk Role Sampling Sepsis Severity of illness Site Skin Skin Tissue Soft Tissue Infections Staphylococcus aureus Superantigens Systemic disease Systemic infection T Chain T-Cell Activation T-Cell Receptor T-cell receptor repertoire Testing Therapeutic Therapeutic immunosuppression Toxic Shock Syndrome Toxic Shock Syndrome Toxin-1 Toxin United States National Institutes of Health Universities Virulence Factors aged aging population clinical remission commensal bacteria cost effective cytokine efficacy evaluation ethnic minority population improved improved outcome innovation microbiota mortality novel pathogenic bacteria pathogenic virus peripheral blood racial and ethnic response sex skin disorder standard care targeted treatment therapeutic target therapy outcome

项目摘要

PROJECT SUMMARY There is a fundamental gap in our understanding of the pathogenic mechanisms of Bullous pemphigoid (BP), an autoimmune blistering disease of the elderly. Thus, standard treatment consists of high dose immunosuppression, which is associated with significant morbidity and mortality. Our long-term goal is to identify the pathogenic mechanisms of BP so that targeted therapies can be developed, resulting in improved efficacy, decreased off-target effects, and a reduced healthcare burden. The objective of this proposal is to define the role of bacterial colonization with Staphylococcus aureus in the pathogenesis of BP. S. aureus is a leading cause of skin and soft tissue infection and systemic disease. An estimated 30% of the general population is colonized with S. aureus, leading to an increased risk of pathologic infection. Further, S. aureus has been implicated in a host of inflammatory and autoimmune skin diseases resulting from the local or systemic effects of secreted virulence factors, known as superantigens (SAg). Our central hypothesis is that S. aureus colonization plays an important role in pathogenesis BP. The rationale for the proposed research is that establishing a role for S. aureus in the pathogenesis of BP will immediately impact patient care through the addition of antibiotic therapy to the first line of treatment for BP in order to reduce immunosuppressive burden and improve patient outcomes. Guided by our robust preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Establish the prevalence of S. aureus colonization and define SAg profiles in geographically and demographically diverse BP patients. The studies in Aim 1 will determine the impact of race or geographic location on the rate of S. aureus colonization in BP patients, and controls matched by age, sex and race, through two enrollment sites in Iowa and Georgia. The rate of S. aureus colonization, SAg expression, and protective antibody titers will be assessed in relation to measures of BP disease activity. The studies in Aim 2 will determine if S. aureus colonization promotes cutaneous autoimmunity by inducing skin- specific changes in cytokine profiles and Vβ-TCR repertoire. These studies are relevant to the NIH's mission aimed at enhancing health, lengthening life and reducing illness, and relevant to Funding Opportunity PA-18- 739 aimed at evaluating changes in microbiota and its influence in health and disease in the elderly, including those of racial/ethnic minorities, and understanding the underlying mechanisms of microbiota in aged subjects as related to health and disease. This approach innovative because it represents a substantial departure from the current paradigms of BP pathogenesis. The proposed studies are significant because they will advance and expand our understanding of the basic mechanisms of cutaneous autoimmunity in the elderly and will lay the groundwork for mechanistic studies geared toward understanding the role of S. aureus in the propagation of autoimmunity and generation of the initial autoantibody response in BP.

项目概要我们对大疱性类天疱疮（BP）致病机制的理解存在根本性差距，因此，标准治疗包括高剂量。免疫抑制与显着的发病率和死亡率相关，我们的长期目标是确定BP的致病机制，以便开发靶向治疗，从而改善血压该提案的目标是提高疗效、减少脱靶效应并减轻医疗负担。定义金黄色葡萄球菌定植在 BP 发病机制中的作用。导致皮肤和软组织感染及全身性疾病，估计占一般的30%。人群定植有金黄色葡萄球菌，导致病理感染的风险增加。与局部或局部引起的一系列炎症和自身免疫性皮肤病有关分泌的毒力因子（称为超抗原（SAg））的全身效应我们的中心假设是 S. 金黄色葡萄球菌定植在 BP 发病机制中发挥着重要作用本研究的基本原理是：确定金黄色葡萄球菌在 BP 发病机制中的作用将通过以下方式立即影响患者护理：在 BP 的一线治疗中添加抗生素治疗，以减轻免疫抑制负担在我们可靠的初步数据的指导下，这一假设将得到检验。追求两个具体目标：1) 确定金黄色葡萄球菌定植的流行情况并定义 SAg 谱目标 1 中的研究将确定种族的影响。 BP 患者和按年龄、性别匹配的对照中金黄色葡萄球菌定植率的影响和种族，通过爱荷华州和佐治亚州的两个登记点金黄色葡萄球菌定植率，SAg。将根据 BP 疾病活动的测量来评估表达和保护性抗体滴度。目标 2 中的研究将确定金黄色葡萄球菌定植是否通过诱导皮肤- 细胞因子谱和 Vβ-TCR 库的具体变化这些研究与 NIH 的使命相关。旨在增强健康、延长寿命和减少疾病，并与资助机会 PA-18-相关第739章旨在评估微生物群的变化及其对老年人健康和疾病的影响，包括少数种族/族裔的微生物群，并了解老年受试者微生物群的潜在机制这种方法具有创新性，因为它与健康和疾病有关。所提出的研究具有重要意义，因为它们将推动 BP 发病机制的发展。扩大我们对老年人皮肤自身免疫基本机制的认识，将为我们奠定基础旨在了解金黄色葡萄球菌在传播中的作用的机制研究的基础 BP 中自身免疫的发生和初始自身抗体反应的产生。