Nitration immunology

描述(由申请人提供)：呼吸道蛋白质上的酪氨酸残基硝化已被证明发生在炎症性肺部疾病中，包括哮喘、慢性阻塞性肺疾病、囊性纤维化和毛细支气管炎闭塞症。硝基酪氨酸的形成是无机的，但也是由多形核白细胞的酶催化的，包括嗜酸性粒细胞过氧化物酶和中性粒细胞髓过氧化物酶。硝基酪氨酸熊在结构和化学上与许多著名的半抗原有明显的相似之处--低分子化合物，当与蛋白质共价结合时，会激发免疫反应。我们假设，硝基酪氨酸--在天然免疫过程的早期蛋白质硝化过程中形成--作为半抗原发挥作用，是启动针对其结合的蛋白质的获得性免疫反应的关键因素。我们计划初步评估关于吸入性过敏原硝化的这一假说。我们将确定天然和重组尘螨蛋白硝化的最佳化学条件，并将这些条件与普通感冒等炎症期间在呼吸道中发现的条件进行比较。在支持初步数据的基础上，我们将同时通过评估人外周血单个核细胞在暴露于硝化变应原与非硝化变应原时的体外增殖反应来研究硝化变应原增强免疫反应的潜力。此外，我们将通过皮肤测试和血清检测来检测硝化蛋白的特异性抗体，以寻求人类对硝化变应原的免疫反应。我们预计，与初步数据一致，蛋白质的硝化将启动和增强免疫反应。然后，当硝化蛋白质从组织中移除时，促炎信号应该被消除。这一新的项目可能有助于阐明先天免疫和后天免疫之间的一个重要联系--识别一种激发和调节免疫反应的高度新颖的机制。

DESCRIPTION (provided by applicant): Nitration of tyrosine residues on proteins in the respiratory tract has been shown to occur during inflammatory lung diseases including asthma, chronic obstructive pulmonary disease, cystic fibrosis, and bronchiolitis obliterans. Formation of nitrotyrosine occurs inorganically, but also is catalyzed by enzymes of polymorphonuclear leukocytes including eosinophil peroxidase and neutrophil myeloperoxidase. Nitrotyrosine bears pronounced structural and chemical similarity to many well-described haptens--low molecular weight compounds that when covalently bound to proteins incite immune responses. We hypothesize that nitrotyrosine--formed during nitration of proteins early during innate immune processes--functions as a hapten and is a key factor initiating acquired immune responses against the protein in which it is bound. We plan initially to evaluate this hypothesis with respect to nitration of inhaled allergens. We will determine optimum chemical conditions for nitration of natural and recombinant dust mite proteins, and compare these conditions to those found in the airways during inflammation such as occurs with the common cold. Expanding upon supportive preliminary data, we will concurrently investigate the potential of nitrated allergen to augment immune responses by evaluating in vitro the proliferative responses of human peripheral blood mononuclear cells upon exposure to nitrated allergen in comparison to non-nitrated allergen. Further, we will seek immune responses to nitrated allergen in humans by assaying for specific antibody to nitrated proteins with skin testing and serum assays. We anticipate that, consistent with preliminary data, nitration of proteins will initiate and augment immune responses. The pro-inflammatory signals should then be eliminated as nitrated proteins are removed from the tissue. This novel project may serve to elucidate an important link between innate and acquired immunity--identifying a highly novel mechanism for both inciting and regulating immune responses.