AMCase and BRP-39 in Th2 Inflammation and Asthma

描述（由申请人提供）：多条证据表明，Th 2炎症和重塑是哮喘和抗寄生虫反应发病机制的重要组成部分。几丁质是生物学中第二丰富的糖聚合物，是寄生虫和真菌壁的组成部分，它保护它们免受环境中潜在有害方面的影响。含有几丁质的生物体也产生几丁质酶以允许它们蜕皮和生长。因此，几丁质酶的产生是低等生命形式对寄生虫和感染因子的免疫反应的重要组成部分。有趣的是，人类中并不存在几丁质和几丁质合成酶，然而，一些几丁质酶和几丁质酶样基因最近在人类中被发现。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，如乳腺退化蛋白-39（BRP-39）。有趣的是，AMCase和BRP-39都在Th 2炎症部位有效诱导。然而，人们对AMCase的作用知之甚少，对BRP-39在人类生物学中的作用几乎一无所知。 我们推测在抗寄生虫Th 2炎症和重塑中起关键作用的元素在哮喘Th 2应答中也起重要作用。为了验证这一点，我们研究了AMCase和BRP-39在过敏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Th 2炎症部位的巨噬细胞和上皮细胞中被显著诱导。他们还证明，AMCase具有突出的几丁质酶活性，以Th 2特异性方式诱导，并且用抗AMCase抗血清治疗显著降低了空气变应原诱导的Th 2炎症和IL-13效应子途径活化。相反，BRP-39诱导不是Th 2特异性的，并且用抗BRP-39抗血清处理不改变IL-13诱导的炎症。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提出以下假设：（1）原型几丁质酶AMCase和原型几丁质酶样蛋白BRP-39是Th 2炎症位点的主要基因产物;（2）AMCase在Th 2炎症的发病机制中起关键作用，其中它是最佳IL-13效应子途径活化所需的，和（3）BRP-39在Th 2-Th 3炎症的发病机制中起关键作用。诱导组织重塑。为了验证这些假设，我们建议： AIM岛表征抗原激发和转基因肺中AMCase和BRP-39的表达、定位和调控。 AIM II.描述AMCase在Th 2炎症、生理失调和重塑中的作用。 AIM III.表征BRP-39在Th 2炎症、生理失调和重塑中的作用。

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.