Innate Immune Response Patterns to Autoantigen-Associated RNA

描述（由申请人提供）： 该提案的重点是抗RNP自身免疫中的肺部疾病，这是混合性结缔组织病死亡的主要原因，也是RNP+狼疮的重要临床问题。基于抗RNP自身免疫小鼠模型和人类研究的初步数据，我们假设一个亚群的CD 11 c + CD 11bhigh CD 103-髓样树突状细胞通过TLR诱导的TRIF介导的途径发挥作用，在抗RNP自身免疫性肺病的发病机制中发挥核心作用。在本提案中，我们将通过动物模型的研究来验证这一假设。在目标1中，我们将通过TRIF-/-小鼠的直接免疫和过继转移研究来评估TRIF与抗RNP肺病的相关性。在目标2中，我们将使用氯膦酸盐或DC表面标志物抗体的耗竭研究评估CD 11b + mDC与抗RNP肺病的相关性，我们将测试靶向抗RNP肺病中表达CD 11b的细胞的新型免疫抑制治疗剂的治疗效果。这些研究将导致更好的理解和潜在的新的治疗方法，目前的治疗方法尚未有效的自身免疫性疾病谱。

DESCRIPTION (provided by applicant): This proposal focuses on lung disease in anti-RNP autoimmunity, the leading cause of death in Mixed Connective Tissue Disease, and a significant clinical issue in RNP+ lupus. Based on preliminary data in a murine model of anti-RNP autoimmunity and human studies, we hypothesize that a subset of CD11c+ CD11bhigh CD103- myeloid dendritic cells acting through TLR-inducible TRIF-mediated pathways play a central role in the pathogenesis of anti-RNP autoimmune lung disease. In this proposal, we will test this hypothesis with studies in animal models. In Aim 1, we will assess the relevance of TRIF to anti-RNP lung disease by direct immunization and adoptive transfer studies with TRIF-/- mice. In Aim 2, we will assess the relevance of CD11b+ mDC's to anti-RNP lung disease using depletion studies with clodronate or antibodies to DC surface markers, and we will test the therapeutic efficacy of a novel immunosuppressive therapeutic agent that targets CD11b-expressing cells in anti-RNP lung disease. These studies will lead to improved understanding and potentially to novel treatment approaches for a spectrum of autoimmune disease for which current treatments have not been efficacious.