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：
7583102
负责人：
Wen-Ming Chu
金额：
$ 35.48万
依托单位：
BROWN UNIVERSITY
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 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7583102
关键词：
Adaptor Signaling Protein Adjuvant Adverse effects Affinity Affinity Chromatography Antibodies Antigens Asthma Autoantibodies Autoantigens Autoimmune Diseases 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 Development Double Strand Break Repair Equilibrium G22P1 gene Genetic Genetic Transcription Growth Factor HMGB1 Protein HMGB3 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 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.

描述（由申请人提供）：以前认为HMGB1和KU蛋白都是结合DNA并增强转录的核因子。遗传学证据表明，KU蛋白的丧失在很大程度上消除了DNA双链断裂（DSB）修复，并导致B和T细胞的发育严重缺陷，而HMGB1的丧失导致后期致死性的表型。此外，最近的发现表明，KU70是立克康罗伊的哺乳动物受体，而HMGB1充当至关重要的细胞因子，可介导对感染，损伤和炎症的反应，从而建立HMGB1和KU蛋白质和先天免疫的联系。但是，尚未探索HMGB1和KU蛋白在TLR途径激活中的生物学功能。此外，最近的发现表明，来自SLE患者血清的自身抗体/自身抗原/DNA复合物会诱导促炎和I型IFN反应，这与TLR9依赖性和独立的男人在SLE的免疫原理发生中有关。有趣的是，HMGB1和KU蛋白都是SLE的自身抗原，而对两者的自身抗体都存在于一些SLE患者的血清中。 HMGB1和KU蛋白可以在SLE中的抗体/抗原/DNA复合物介导的炎症和I型IFN反应中发挥作用吗？我们的结果表明，HMGB1和KU蛋白对于促炎性细胞因子和I型IFN对免疫刺激单链DNA（ISS-DNA）的反应很重要。但是，仍然缺少分子机制的细节。因此，我们制定了三个特定目标，以阐明HMGB1和KU蛋白具有先天免疫对ISS-DNA所必需的机制。我们认为，我们的研究将更好地了解HMGB1和KU自动抗原如何参与对DNA的细胞因子反应，以及如何通过ISS-DNA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，我们的研究将提供有关针对过敏，哮喘，癌症和感染性疾病的更好佐剂设计的新见解信息，同时为治疗SLE的治疗提供了更好的抑制剂。