Mechansim of activation of innate immunity by ISS-DNA

ISS-DNA激活先天免疫的机制

基本信息

批准号：
8240074
负责人：
Wen-Ming Chu
金额：
$ 33.08万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8240074
关键词：
Adaptor Signaling Protein Adjuvant Adverse effects Affinity Affinity Chromatography Antibodies Antigens Asthma Autoantibodies Autoantigens Autoimmune Diseases B-Cell Development Binding Proteins Biological Process Catalytic Domain Communicable Diseases Complex DNA DNA Binding DNA Double Strand Break DNA Sequence DNA-Binding Proteins DNA-PKcs DNA-dependent protein kinase Data Defect Double Strand Break Repair Equilibrium G22P1 gene Genetic Genetic Transcription Growth Factor HMGB1 Protein Heparin Hypersensitivity IRAK1 gene IRAK4 gene IkappaB kinase Immune response Immune system Infection Infectious Lung Disorder Inflammation Inflammatory Inflammatory Response Pathway Injury Interferon Type I Interferons Interleukin Receptor Interleukin-12 Interleukin-6 Ion Exchange Ku Protein Ku autoantigen Link Lupus MAP3K7 gene Malignant Neoplasms Mediating Mitogen-Activated Protein Kinases Molecular NF-kappa B Natural Immunity Nuclear PRKDC gene Pathway interactions Patients Phenotype Phosphorylation Play Protein Kinase Proteins Recruitment Activity Rickettsia conorii Role Serum Single-Stranded DNA Systemic Lupus Erythematosus T-Lymphocyte TLR9 gene TNF gene Testing Tumor Necrosis Factor Receptor Vaccine Adjuvant Vaccines XRCC5 gene cofactor cytokine design inhibitor/antagonist insight interferon regulatory factor-7 postnatal public health relevance receptor response

项目摘要

DESCRIPTION (provided by applicant): Both HMGB1 and Ku proteins were previously thought to function as nuclear factors that bind DNA and enhance transcription. Genetic evidence reveals that loss of Ku proteins largely abrogates DNA double-stranded breaks (DSBs) repair and results in a severe defect in the development of B and T cells, whereas loss of HMGB1 leads to a phenotype of postnatal lethality with an unidentified reason. In addition, recent discoveries demonstrate that Ku70 is a mammalian receptor for Rickettsia conorii, and HMGB1 acts as a crucial cytokine that mediates the response to infection, injury and inflammation, thereby establishing a link between HMGB1 and Ku proteins as well as innate immunity. However, the biological functions of HMGB1 and Ku proteins in activation of the TLR pathway have not been explored. Moreover, recent findings have suggested that autoantibody/autoantigen/DNA complexes from the serum of SLE patients induce the pro-inflammatory and type I IFN response, which is involved in the immunopathogenesis of SLE in TLR9-dependent and independent manners. Intriguingly, both HMGB1 and Ku proteins are autoantigens of SLE, and autoantibodies against both of them are present in the serum of some SLE patients. Could HMGB1 and Ku proteins play a role in the antibody/antigen/DNA complex-mediated inflammatory and type I IFN response in SLE? Our results indicate that HMGB1 and Ku proteins are important for the pro-inflammatory cytokine and type I IFN response to immunostimulatory single-stranded DNA (ISS-DNA). However, details of molecular mechanisms are still missing. Thus, we have formulated three specific aims to elucidate the mechanism by which HMGB1 and Ku proteins are required for the innate immune response to ISS-DNA. We believe that our study will provide a better understanding of how HMGB1 and Ku autoantigens are involved in the cytokine response to DNAs, and how TLR9 is activated by ISS-DNA. Moreover, our study will reveal a link between the TLR9- dependent and -independent pathways. Finally, our study will provide new insight information on design of better adjuvants for vaccine against allergy, asthma, cancer and infectious diseases, while providing better inhibitors for treatment of SLE. PUBLIC HEALTH RELEVANCE: Due to its powerful effects on inducing the Th1 response, CpG-DNA (ISS-DNA) has become a very attractive adjuvant in vaccine strategies against allergy, asthma, cancer and infectious disease. However, recent studies suggest that the autoantibody/autoantigen/DNA complex elicits the harmful inflammatory and type I IFN response in some autoimmune diseases including lupus. We identified that autoantigens such as DNA-PK and HMGB1 regulate the inflammatory and type I IFN response to CpG-DNA. To balance the benefits and side effects of CpG-DNA, we need to understand the molecular mechanisms by which DNAPK and HMGB1 activate the CpG- DNA pathway. We believe that our study will provide new insight information on design of better adjuvants for vaccine strategies against allergy, asthma, cancer and infectious disease, and provide better inhibitors for treatment of autoimmune diseases.

描述（由申请人提供）：HMGB1 和 Ku 蛋白先前被认为具有结合 DNA 并增强转录的核因子的功能。遗传证据表明，Ku 蛋白的缺失很大程度上破坏了 DNA 双链断裂 (DSB) 的修复，并导致 B 细胞和 T 细胞发育的严重缺陷，而 HMGB1 的缺失则导致产后致死的表型，原因不明。此外，最近的发现表明，Ku70是康氏立克次体的哺乳动物受体，而HMGB1作为介导感染、损伤和炎症反应的关键细胞因子，从而在HMGB1和Ku蛋白以及先天免疫之间建立了联系。然而，HMGB1 和 Ku 蛋白在 TLR 通路激活中的生物学功能尚未被探索。此外，最近的研究结果表明，SLE患者血清中的自身抗体/自身抗原/DNA复合物诱导促炎和I型IFN反应，其以TLR9依赖性和非依赖性方式参与SLE的免疫发病机制。有趣的是，HMGB1和Ku蛋白都是SLE的自身抗原，并且一些SLE患者的血清中存在针对这两种蛋白的自身抗体。 HMGB1 和 Ku 蛋白能否在 SLE 中抗体/抗原/DNA 复合物介导的炎症和 I 型 IFN 反应中发挥作用？我们的结果表明 HMGB1 和 Ku 蛋白对于促炎细胞因子和 I 型 IFN 对免疫刺激单链 DNA (ISS-DNA) 的反应很重要。然而，分子机制的细节仍然缺失。因此，我们制定了三个具体目标来阐明 ISS-DNA 先天免疫反应所需的 HMGB1 和 Ku 蛋白的机制。我们相信，我们的研究将有助于更好地了解 HMGB1 和 Ku 自身抗原如何参与 DNA 的细胞因子反应，以及 ISS-DNA 如何激活 TLR9。此外，我们的研究将揭示 TLR9 依赖性和非依赖性途径之间的联系。最后，我们的研究将为针对过敏、哮喘、癌症和传染病的疫苗设计更好的佐剂提供新的见解信息，同时为治疗系统性红斑狼疮提供更好的抑制剂。公共卫生相关性：由于其对诱导 Th1 反应的强大作用，CpG-DNA (ISS-DNA) 已成为针对过敏、哮喘、癌症和传染病的疫苗策略中非常有吸引力的佐剂。然而，最近的研究表明，自身抗体/自身抗原/DNA 复合物在包括狼疮在内的一些自身免疫性疾病中引发有害的炎症和 I 型干扰素反应。我们发现 DNA-PK 和 HMGB1 等自身抗原可调节对 CpG-DNA 的炎症反应和 I 型 IFN 反应。为了平衡 CpG-DNA 的益处和副作用，我们需要了解 DNAPK 和 HMGB1 激活 CpG-DNA 途径的分子机制。我们相信，我们的研究将为针对过敏、哮喘、癌症和传染病的疫苗策略设计更好的佐剂提供新的见解信息，并为治疗自身免疫性疾病提供更好的抑制剂。