Systemic Vasculitis: Host Factors in Tissue Injury

描述（由申请人提供）： 在系统性血管炎中，最近基于遗传和机制的观察强调了抗神经细胞胞质自身抗体（ANCA）作为炎性、促炎性、致病性介质的作用。ANCA可以激活中性粒细胞和单核吞噬细胞，这在血管炎组织损伤的发展中是至关重要的。虽然ANCA自身抗体的产生和体内血管损伤的过程无疑是复杂的，但对人类Fc？与ANCA相互作用的受体使关键的新研究领域成为明确的焦点。FC？R介导的触发在启动细胞功能中是重要的，包括细胞因子的粘附、合成和释放以及颗粒内容物（包括ANCA靶）和炎症介质（活性氧中间体）的释放。我们在进展和初步数据中提出的工作清楚地确定了每个激活Fc γ R在ANCA介导的中性粒细胞活化中的贡献，并且我们已经显示了这些受体中的等位基因变体对ANCA介导的中性粒细胞活化的定量重要性。我们还显示了抑制性Fc γ R在中性粒细胞上的表达，并且我们已经定义了CR 1（CD 35）对ANCA介导的中性粒细胞活化的新型抑制活性。这些激活性和抑制性受体中的每一种在人类中是多态的。 因此，正如进展和初步数据所支持的那样，本提案的具体目标是：1）建立Fc？RIIb和CR 1作为ANCA的负调节因子在体外诱导吞噬细胞活化，以表征受影响的细胞程序并鉴定作用机制。2)通过建立每个Fc对ANCA诱导的小鼠血管炎的贡献来测试我们的ANCA假设？受体类型，并使用缺乏单个配体结合α链（激活剂和抑制剂）的小鼠在体内测试嗜中性粒细胞的作用。3)通过使用在进展和目标1和2中鉴定的靶分子中具有功能意义的多态性来检验我们在人类中的ANCA假设（Fc γ R，CR 1和由ANCA调节的粘附分子）以建立这些变体与人类疾病表型之间的相关性，以及4）建立用肽和Fc γ RIIb表达诱导剂进行新干预的基础，所述肽中断ANCA对吞噬细胞的激活下调ANCA介导的激活。 鉴于我们目前关于ANCA-PMN活化途径中关键受体的独特功能和遗传特征的数据，以及靶向干预的明确潜力，这些研究可能会定义疾病易感的重要风险因素，并导致靶向治疗策略的发展。

DESCRIPTION (provided by applicant): In the systemic vasculitides, recent genetic and mechanism-based observations have emphasized the role of antineutrophil cytoplasmic autoantibodies (ANCA) as phlogistic, pro-inflammatory, pathogenic mediators. ANCA can activate neutrophils and mononuclear phagocytes, which are critical in the development of tissue injury in vasculitis. While the generation of ANCA autoantibodies and the process of vascular injury in vivo is no doubt complex, new insights into the genetics, structure and function of human Fc? receptors which interact with ANCA have brought critical new areas of research into clear focus. Fc?R-mediated triggering is important in initiating cell functions including adhesion, synthesis and release of cytokines and release of both granule contents (including ANCA targets) and inflammatory mediators (reactive oxygen intermediates). Our work presented in Progress and Preliminary Data clearly establishes the contributions of each activating FcyR in ANCA-mediated neutrophil activation and we have shown the quantitative importance of allelic variants in these receptors to ANCA-mediated neutrophil activation. We have also shown expression of the inhibitory FcyR on neutrophils and we have defined a novel inhibitory activity of CR1 (CD35) on ANCA-mediated neutrophil activation. Each of these activating and inhibitory receptors is polymorphic in humans. Therefore, as supported by Progress and Preliminary Data, the specific aims of this proposal are 1) to establish Fc?RIIb and CR1 as negative regulators of ANCA induced phagocyte activation in vitro, to characterize the cell programs affected and to identify the mechanism(s)of action. 2) to test our ANCA hypothesis by establishing the contribution to ANCA-induced murine vasculitis of each Fc? receptor type in vivo using mice deficient in individual ligand-binding a-chains (both activators and inhibitor) and to test the role of neutrophils in vivo using mice deficient in granule contents. 3) to test our ANCA hypothesis in humans by using functionally significant, polymorphisms in target molecules identified in Progress and in Aims 1 and 2 (FcyR, CR1 and adhesion molecules modulated by ANCA) to establish a correlation between these variants and the human disease phenotype and 4) to establish the basis for novel interventions with peptides that interrupt the activation of phagocytes by ANCA and with inducers of FcyRIIb expression to downregulate ANCA-mediated activation. Given our current data on the unique functional and genetic profile of key receptors in the ANCA-PMN activation pathway, and the clear potential for targeted intervention, these studies may define important risk factors predisposing for disease and lead to the development of targeted therapeutic strategies.