Mechansim of activation of innate immunity by ISS-DNA

ISS-DNA激活先天免疫的机制

• 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
• 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

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）：HMGB 1和Ku蛋白先前被认为作为结合DNA并增强转录的核因子发挥作用。遗传学证据表明，Ku蛋白的缺失在很大程度上消除了DNA双链断裂（DSB）修复，并导致B和T细胞发育的严重缺陷，而HMGB 1的缺失导致出生后致死的表型，原因不明。此外，最近的发现表明Ku 70是康氏立克次体的哺乳动物受体，HMGB 1作为介导对感染、损伤和炎症的反应的关键细胞因子，从而建立了HMGB 1和Ku蛋白以及先天免疫之间的联系。然而，HMGB 1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应答，其以TLR 9依赖和独立的方式参与SLE的免疫发病机制。有趣的是，HMGB 1和Ku蛋白都是SLE的自身抗原，并且在一些SLE患者的血清中存在针对这两种蛋白的自身抗体。HMGB 1和Ku蛋白在SLE抗体/抗原/DNA复合物介导的炎症反应和I型IFN反应中是否发挥作用？我们的研究结果表明，HMGB 1和Ku蛋白是重要的促炎细胞因子和I型IFN免疫刺激单链DNA（ISS-DNA）的反应。然而，分子机制的细节仍然缺失。因此，我们制定了三个具体的目标，以阐明HMGB 1和Ku蛋白所需的先天免疫应答ISS-DNA的机制。我们相信，我们的研究将提供一个更好地了解HMGB 1和Ku自身抗原是如何参与细胞因子对DNA的反应，以及TLR 9是如何被ISS-DNA激活。此外，我们的研究将揭示TLR 9依赖和非依赖途径之间的联系。最后，我们的研究将提供新的见解信息，设计更好的佐剂，疫苗对过敏，哮喘，癌症和感染性疾病，同时提供更好的抑制剂治疗系统性红斑狼疮。