The Role of BATF in Allergic Inflammation and Anti-Helminth Immunity

BATF 在过敏性炎症和抗蠕虫免疫中的作用

• 批准号: 9212620
• 负责人: Richard Lee Reinhardt
• 金额: $ 18.02万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9212620
• 关键词: Affect; Allergic; Allergic Disease; Allergic inflammation; Asthma; Automobile Driving; Binding; Biochemical; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Chromatin; Chromatin Structure; DNA Methylation; Data; Defect; Development; Disease; Epigenetic Process; Foundations; Generations; Genetic; Health; Helminths; Helper-Inducer T-Lymphocyte; Human; Hypersensitivity; IL4 gene; IgE; Immunity; Incidence; Individual; Infection; Interleukin-13; Interleukin-17; Interleukin-4; Intestines; Locus Control Region; Lung; Lymphoid Cell; Maintenance; Mediating; Mission; Molecular; Mouse Strains; Mus; Nippostrongylus; Nucleic Acid Regulatory Sequences; Pathology; Patient Care; Pharmaceutical Preparations; Plant Roots; Play; Prevention; Process; Production; Public Health; Recruitment Activity; Recurrence; Reporter; Research; Role; Seminal; Steroids; System; T-Lymphocyte; Testing; Th2 Cells; Transcription Factor AP-1; United States; United States National Institutes of Health; Vaccination; Work; atopy; attenuation; bisulfite sequencing; care burden; cell type; chromosome conformation capture; cytokine; design; disorder control; effective therapy; histone modification; immune function; in vivo; innovation; interest; methylation pattern; new therapeutic target; novel; prevent; programs; promoter; research study; response; selective expression; standard of care; symptom treatment; targeted treatment; therapeutic target; therapy development; transcription factor

 DESCRIPTION (provided by applicant): Allergic disease represents a spectrum of disorders including allergy, asthma, and parasitic helminth infections, which afflict more than 3 billion individuals worldwide. Current treatment options (steroids in the case of allergy and asthma; de-worming drugs for helminth infection) focus on treating the symptoms rather than prevention or the root cause of the underlying disease. Thus, the current standard of care in most cases is not curative, does not prevent secondary attacks or infections, and requires frequent treatments to control disease recurrence. Because most allergic disorders share many of the same underlying features and allergic hallmarks, there is great interest in identifying novel disease targets, whic are central to the development and maintenance of allergic inflammation, and therefore, when targeted, can provide long-term protection against a broad spectrum of allergic diseases. Preliminary data provided in the proposal has identified the AP-1 transcription factor BATF as one such candidate factor. BATF-deficient mice and novel reporter systems designed to explore allergic immunity in vivo have revealed that BATF is essential for the induction of allergic inflammation and immunity to the parasitic helminth Nippostrongylus brasiliensis. Furthermore, these initial studies indicate that BATF likely regulates the function and/or development of three essential cell types critical for the induction of allergic immunity to intestinal helminths. These cell types are T-helper type 2 (Th2) cells, follicular T cells (Tfh), and group 2 innate lymphoid cells (ILC2). The objective of this proposal is to identify the cellular and molecular mechanisms by which BATF regulates allergic immunity. Our central hypothesis is that BATF regulates Interleukin-4 (IL-4) and IL-13 production in Tfh, Th2, and ILC2 by modulating chromatin accessibility and long-range intrachromosomal interactions between the locus control region in the rad50 gene and the IL-4 and IL-13 promoters. IL-4 and IL-13 are two cytokines absolutely required for development of the allergic pathology. The central hypothesis will be tested in two specific aims: 1) Determine the role of BATF in anti-helminth immunity; 2) Define the molecular mechanism by which BATF regulates Type-2 cytokine production. The proposed project is innovative because it uses novel, in vivo reporter mouse strains and molecular and biochemical approaches to reveal the significance of a hitherto unknown molecular mechanism central to the control of allergic inflammation, and challenges the status quo that BATF has a limited role in Th2 and ILC2 cell function. This proposal is significant as it is expected to bridge a fundamental gap in our understanding of the underlying mechanisms inducing allergic disease. Bridging of this gap helps to integrate our current understanding of AP-1 transcription factors in allergic disease, and represents a major advancement for the development of therapies effective at ameliorating a spectrum of allergic disorders. This proposal also lays the foundation for exploring whether enhancement of BATF during vaccination is capable of providing more effective long-term immunity to helminth infection.

 描述(由申请人提供)：过敏性疾病是一系列疾病，包括过敏、哮喘和寄生虫感染，全球有30多亿人患有过敏性疾病。目前的治疗选择(过敏和哮喘的类固醇；蠕虫感染的驱虫药物)侧重于治疗症状，而不是预防或根本原因。因此，在大多数情况下，目前的护理标准是不能治愈的，不能预防二次发作或感染，需要经常治疗才能控制疾病复发。由于大多数过敏性疾病具有许多相同的潜在特征和过敏性特征，因此人们对确定新的疾病靶点非常感兴趣，这些靶点对过敏性炎症的发展和维持至关重要，因此，当有针对性时，可以针对广泛的过敏性疾病提供长期保护。提案中提供的初步数据已确定AP-1转录因子BATF是这样的候选因子之一。BATF基因缺陷的小鼠和探索体内变态反应免疫的新型报告系统表明，BATF在诱导对寄生虫巴西纤毛虫的变态反应性炎症和免疫方面是必不可少的。此外，这些初步研究表明，BATF可能调节三种基本细胞类型的功能和/或发育，这些细胞类型对于诱导对肠道蠕虫的过敏免疫至关重要。这些 细胞类型包括辅助性T细胞2型(Th2)、滤泡T细胞(TFH)和第二组先天淋巴样细胞(ILC2)。这项建议的目的是确定BATF调节过敏免疫的细胞和分子机制。我们的中心假设是，BATF通过调节染色质的可及性以及Rad50基因的位点控制区与IL-4和IL-13启动子之间的远程染色体内相互作用来调节Tfh、Th2和ILC2中IL-4和IL-13的产生。IL-4和IL-13是过敏性病变发生发展过程中必不可少的两种细胞因子。中心假说将在两个具体目标上得到检验：1)确定BATF在抗蠕虫免疫中的作用；2)确定BATF调节2型细胞因子产生的分子机制。这项拟议的项目具有创新性，因为它使用了新的体内报告小鼠品系以及分子和生化方法来揭示迄今未知的分子机制对控制变态反应性炎症的重要性，并挑战了BATF在Th2和ILC2细胞功能中的有限作用的现状。这一建议意义重大，因为它有望弥合我们对导致过敏性疾病的根本机制的理解上的根本差距。这一差距的弥合有助于整合我们目前对AP-1转录因子在过敏性疾病中的理解，并代表着开发有效改善一系列过敏性疾病的治疗方法的重大进展。这项建议也为探讨疫苗接种期间加强BATF能否对蠕虫感染提供更有效的长期免疫奠定了基础。