Mechansim of activation of innate immunity by ISS-DNA

描述(申请人提供)：HMGB1和Ku蛋白以前都被认为是结合DNA并增强转录的核因子。遗传学证据表明，Ku蛋白的丢失在很大程度上破坏了DNA双链断裂(DSB)的修复，导致B细胞和T细胞的严重发育缺陷，而HMGB1的丢失导致了一种原因不明的出生后死亡表型。此外，最近的发现表明，Ku70是哺乳动物的康氏立克次体受体，而HMGB1是一种重要的细胞因子，介导了对感染、损伤和炎症的反应，从而在HMGB1和Ku蛋白以及天然免疫之间建立了联系。然而，HMGB1和Ku蛋白在激活TLR途径中的生物学功能还没有被探索。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复合体诱导了促炎性和I型干扰素反应，并以TLR9依赖和独立的方式参与了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，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蛋白是否在抗体/抗原/DNA复合体介导的炎性和I型干扰素反应中发挥作用？我们的结果表明，HMGB1和Ku蛋白在促炎细胞因子和I型干扰素对免疫刺激单链DNA(ISS-DNA)的反应中起重要作用。然而，分子机制的细节仍然缺乏。因此，我们制定了三个特定的目标来阐明HMGB1和Ku蛋白在对ISS-DNA的先天性免疫反应中所需的机制。我们相信，我们的研究将更好地理解HMGB1和Ku自身抗原如何参与细胞因子对DNA的反应，以及TLR9是如何被ISS-DNA激活的。此外，我们的研究将揭示TLR9依赖和非独立通路之间的联系。最后，我们的研究将为设计更好的抗过敏、哮喘、癌症和传染病疫苗佐剂提供新的见解，同时为SLE的治疗提供更好的抑制剂。

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.