Innate cytokine responses that regulate autoimmunity

描述(由申请人提供)：由这笔资金资助的研究进展导致发现，骨桥蛋白基因通过单一OPN RNA物种的差异翻译指定了两种不同的异构体：T细胞中的一种细胞因子和树突状细胞中表达的一种关键的细胞内蛋白。我们已经证明，OPN在浆细胞样树突状细胞中的表达对于该细胞标志性细胞因子-干扰素α的产生是必不可少的。我们最近发现，强大的Th17反应依赖于新定义的细胞内opn异构体-opn-I-抑制DC分泌IL-27的能力。我们还定义了一种依赖于opn-I的相互作用，它阻止了Th17反应的有效发展。依赖干扰素α/β受体(IFNAR)抑制OPN-I的表达，释放对IL-27分泌的刹车，并抑制Th17对自体肽的反应。IFNAR：OPN-I轴对Th1和Th17反应的影响的定义为干扰素-I治疗多发性硬化症和其他Th17疾病的疗效提供了新的见解，并为采用这一IFNAR：OPN-I途径的新治疗方法提供了理论基础。我们提出的实验(1)确定导致DC和T细胞中OPN-I和OPN-S表达的遗传机制，(2)确定OPN-I与血浆细胞样树突状细胞中MyD88信号模块的相互作用，从而导致IFN1表达和促进Th1的发育；(3)分析调节抗原提呈和Th17发育的常规DC中的opn依赖的相互作用；(4)建立选择性表达不同opn亚型的小鼠，以便我们可以在实验性自身免疫性脑脊髓炎(EAE MU MS模型)的背景下确定OPN亚型在免疫应答中的作用。公共卫生相关性：骨桥蛋白(OPN)基因通过与不同细胞类型的相互作用在包括免疫反应、血管形成和骨形成在内的多种生物学过程中发挥重要作用。我们最近发现的不同的On分泌和细胞内亚型对Th17和Th1亚群的产生的贡献填补了在理解正常和自身免疫反应中这些亚群的起源方面的一个重要空白。我们将产生表达细胞内或分泌的opn异构体的突变小鼠，用于分析每种异构体在多发性硬化症小鼠模型中对再次感染和保护的贡献。

DESCRIPTION (provided by applicant): Progress in the research funded by this grant has led to the discovery that the Osteopontin gene specifies two distinct isoforms through differential translation of a single Opn RNA species: a cytokine in T cells and a critical intracellular protein expressed in dendritic cells. We have shown that Opn expression in plasmacytoid dendritic cells is essential for production of this cell's signature cytokine- interferon alpha. We have recently discovered that robust Th17 responses depend on the ability of a newly-defined intracellular Opn isoform- Opn-i - to inhibit secretion of IL-27 by DC. We have also defined an Opn-i-dependent interaction that prevents efficient development of Th17 responses. Interferon alpha/beta receptor (IFNAR)-dependent inhibition of Opn-i expression releases the brakes on IL-27 secretion and inhibits the Th17 response to self-peptides. Definition of the impact of this IFNAR:Opn-i axis on the Th1 and Th17 response has provided new insight into the basis for the therapeutic effects of IFN-I in Multiple Sclerosis and other Th17 diseases, as well as a rationale for new therapeutic approaches that engage this IFNAR:Opn-i pathway. We propose experiments (1) to define the genetic mechanism resulting in generation of Opn-i and Opn-s expression in DC and T cells; (2) to define the interaction between Opn-i and the MyD88 signaling module in plasmacytoid DC leading to IFN1 expression and enhanced Th1 development; (3) to analyze Opn-dependent interactions in conventional DC that regulate antigen presentation and Th17 development and (4) to generate mice that selectively express distinct Opn isoforms so that we may determine the contribution of Opn isoforms to the immune response to foreign and self antigens in the context of Experimental Autoimmune Encephalomyelitis (EAE mu model of MS. PUBLIC HEALTH RELEVANCE: The Osteopontin (Opn) gene is important in diverse biological processes, including immune responses, vascularization and bone formation, through its interaction with different cell types. Our recent discovery of the contribution of distinct secreted and intracellular isoforms of Opn to the generation of Th17 and Th1 subsets fills an important gap in understanding the genesis of these subsets in normal and autoimmune responses. We will generate mutant mice that express the intracellular or secreted Opn isoform for analysis of the contribution of each to protection again infection and in a murine model of Multiple Sclerosis.