Complement protein synthesis and activation by human mast cells

描述(由申请人提供)：肥大细胞参与大多数过敏事件通常是由于IgE介导的此类细胞的激活。然而，最近的研究表明，肥大细胞在先天性免疫和获得性免疫中都发挥着重要的作用。补体激活也发生在先天免疫和后天免疫过程中。在小鼠的系统中，C3和C5缺乏以各种方式影响肥大细胞，例如减少细胞因子的释放和它们杀死细菌的效率。我们的初步数据显示，人类肥大细胞合成补体C3、C4和C5，并表达补体调节蛋白CD46、CD55、CD59和CR1。具体目标1将分析人肥大细胞的补体合成，包括细胞因子和其他刺激物对皮肤MCTC细胞和肺MCT细胞合成补体的影响(S)，内源性补体蛋白如何在脱颗粒、细胞因子释放、趋化因子释放和产生活性氧方面影响肥大细胞的激活，以及补体调节蛋白是否影响肥大细胞的激活。特定目的2将分析哪些基质金属蛋白酶激活人肥大细胞上的补体。肥大细胞和补体系统之间的相互作用可能对补体和肥大细胞均被激活的疾病有重要意义，如哮喘和慢性自身免疫性荨麻疹。公共卫生相关性：哮喘是美国和世界的一个主要问题。肥大细胞和补体都参与了哮喘的发病机制。这项建议的目标是更好地了解人类补体途径如何与人类肥大细胞相互作用。

DESCRIPTION (provided by applicant): Mast cell involvement in most allergic events typically occurs due to IgE-mediated activation of such cells. However, recent progress reveals that mast cells play important roles in innate as well as acquired immunity. Complement activation also occurs during both innate and acquired immunity. In the murine system, C3 and C5 deficiencies affect mast cells in various ways, such as reducing cytokine release and the efficiency with which they kill bacteria. Our preliminary data show that human mast cells synthesize complement C3, C4 and C5, and express complement regulatory proteins, CD46, CD55, CD59 and CR1. Specific Aim 1 will analyze complement synthesis by human mast cells, including the effect(s) of cytokines and other stimulants on complement synthesis by skin MCTC cells and lung MCT cells, how endogenous complement proteins affect mast cell activation with respect to degranulation, cytokine release, chemokine release and production of reactive oxygen species and whether complement regulatory proteins affect mast cell activation. Specific Aim 2 will analyze which matrix metalloproteases activate complement on human mast cells. The interactions between mast cells and the complement system may have important implications for disorders in which both complement and mast cells are activated, such as asthma and chronic autoimmune urticaria. PUBLIC HEALTH RELEVANCE: Asthma is a major problem in the United States and also in the world. Both mast cells and complement are involved in the pathogenesis of asthma. The goal of this proposal is to better understand how the human complement pathway interacts with human mast cells.