AMCase and BRP-39 in Th2 Inflammation and Asthma

描述（由申请人提供）：多种证据表明Th2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共聚物，是寄生虫和真菌壁的一个组成部分，它保护它们免受环境潜在有害方面的影响。含有几丁质的生物体也会产生几丁质酶，使它们能够蜕皮和生长。因此，几丁质酶的产生是低等生物对寄生虫和传染性病原体的免疫反应的重要组成部分。有趣的是，几丁质和几丁质合成酶在人体内并不存在。然而，最近在人类中发现了一些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，如乳腺退化蛋白-39 （BRP-39）。有趣的是，AMCase和BRP-39都在Th2炎症部位被有效诱导。然而，我们对AMCase的影响知之甚少，对BRP-39在人类生物学中的作用几乎一无所知。

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.