AMCase and BRP-39 in Th2 Inflammation and Asthma

描述(由申请人提供)：多条证据表明，Th2炎症和重构是哮喘和抗寄生虫反应发病机制中的重要组成部分。甲壳素是生物学中含量第二丰富的糖共聚物，是寄生虫和真菌壁的不可或缺的组成部分，在那里它可以保护它们免受环境的潜在有害方面的影响。含有甲壳素的生物体也会产生几丁质酶，使它们能够蜕皮和生长。因此，几丁质酶的产生是对低等生命形式的寄生虫和感染性病原体的免疫反应的重要组成部分。有趣的是，人类并不存在甲壳素和甲壳素合成酶。然而，最近在人类中发现了许多几丁质酶和几丁质酶样基因。这包括真正的几丁质酶，如酸性哺乳动物几丁质酶(AMCase)和缺乏几丁质酶活性的成员，如乳腺回归蛋白-39(BRP-39)。有趣的是，AMCase和BRP-39都是在Th2炎症部位被有效诱导的。然而，人们对AMCase的作用知之甚少，也几乎对Brp-39在人类生物学中的作用一无所知(S)。 我们推测，在抗寄生虫Th2炎症和重塑中起关键作用的因素也在哮喘Th2反应中发挥重要作用。为了验证这一点，我们研究了AMCase和BRP-39在变态反应性炎症和重塑中的调节和作用。我们的研究表明，AMCase和BRP-39在Th2炎症部位的巨噬细胞和上皮细胞中显著诱导。他们还证明了AMCase具有显著的几丁质酶活性，是以Th2特异的方式诱导的，抗AMCase抗血清治疗显著减少了空气变应原诱导的Th2炎症和IL-13效应通路的激活。相反，BRP-39的诱导不是Th2特异性的，用抗BRP-39抗血清治疗不能改变IL-13诱导的炎症反应。然而，它确实减少了IL-13诱导的组织重塑。这些观察结果使我们得出如下假设：(1)原型几丁质酶AMCase和原型几丁质酶样蛋白BRP-39是Th2炎症部位的重要基因产物；(2)AMCase在Th2炎症的发病机制中发挥关键作用，其中它是最佳IL-13效应途径激活所必需的；(3)BRP-39在Th2诱导的组织重塑的发病机制中发挥关键作用。为了检验这些假设，我们建议： 目的I.研究AMCase和BRP-39在抗原攻击和转基因肺中的表达、定位和调控。 目的II.研究AMCase(S)在Th2型炎症、生理失调和重塑中的作用。 目的III.研究酪氨酸蛋白-39(S)在Th2型炎症、生理失调和重构中的作用。

DESCRIPTION (provided by applicant): Multiple lines of evidence suggest that Th2 inflammation and the remodeling are essential components in the pathogenesis of asthma and anti-parasite responses. Chitin, the second most abundant glycopolymer in biology, is an integral component of the walls of parasites and fungi where it protects them from potentially deleterious aspects of their environment. Chitin containing organisms also produce chitinases to allow them to molt and grow. As a result, chitinase production is an essential part of the immune response to parasites and infectious agents in lower life forms. Interestingly, chitin and chitin synthase do not exist in man. However, a number of chitinase and chitinase-like genes have recently been appreciated in man. This includes true chitinases such as acidic mammalian chitinase (AMCase) and members that lack chitinase activity like breast regression protein-39 (BRP-39). Interestingly, AMCase and BRP-39 are both potently induced at sites of Th2 inflammation. However, very little is known about the effects of AMCase and virtually nothing is known about the role(s) of BRP-39 in human biology. We speculated that elements that are critical in anti-parasite Th2 inflammation and remodeling also play essential roles in asthmatic Th2 responses. To test this we studied the regulation and roles of AMCase and BRP-39 in allergic inflammation and remodeling. Our studies demonstrate that AMCase and BRP-39 are prominently induced in macrophages and epithelial cells at sites of Th2 inflammation. They also demonstrate that AMCase has prominent chitinase activity, is induced in a Th2-specific manner and that treatment with anti-AMCase antiserum markedly decreases aeroallergen-induced Th2 inflammation and IL-13 effector pathway activation. In contrast, BRP-39 induction was not Th2 specific and treatment with anti-BRP-39 antiserum did not alter IL-13 induced inflammation. It did, however, decrease IL-13 induced tissue remodeling. These observations led us to the following hypotheses: (1) the prototypic chitinase, AMCase, and the prototypic chitinase-like protein, BRP-39 are prominent gene products at sites of Th2 inflammation; (2) AMCase plays a key role in the pathogenesis of Th2 inflammation where it is required for optimal IL-13 effector pathway activation and (3) BRP-39 plays a key role in the pathogenesis of Th2-induced tissue remodeling. To test these hypotheses we propose to: AIM I. Characterize the expression, localization, and regulation of AMCase and BRP-39 in the antigen challenged and transgenic lung. AIM II. Characterize the role(s) of AMCase in Th2 inflammation, physiologic dysregulation and remodeling. AIM III. Characterize the role(s) of BRP-39 in Th2 inflammation, physiologic dysregulation and remodeling.