Act1 in CD40-/BAFFR-Mediated B Cell Survival

描述（由申请人提供）：在整个发育，成熟和激活过程中，B细胞持续暴露于两种主要的相反力量。首先是驱动产生和维持具有高度多样化的免疫受体的B细胞，这些免疫受体能够识别外源抗原的多样性。第二是必须避免对自身成分的破坏性免疫反应。这两种力量的平衡确保无法对自身抗原作出反应，同时保留对病原体的防御。CD40-CD40L和BAFF-BAFFR细胞因子通路已被证明在B细胞存活和分化中发挥重要作用。我们研究了一种名为Act1的新型接头分子在CD40和baffr介导的B细胞存活中的调节机制。我们发现CD40和baff介导的存活在缺乏act1的B细胞中显著增加。与这一发现一致的是，act1缺陷小鼠外周血B细胞普遍增加，最终导致淋巴结病变、脾肿大和自身抗体的形成。Act1通过直接影响CD40和BAFF介导的即时信号事件，在B细胞存活中发挥负调控作用。缺乏act1的B细胞表现出CD40L-和baff诱导的IkappaB磷酸化和NF-kappaB2加工增强（pl00/p52）。基于这些发现，我们假设Act1通过减弱CD40和BAFFR信号，调节体液免疫反应，是B细胞稳态的重要调节因子。为了验证这一假设，我们将首先阐明Act1负调控CD40-和baffr介导的信号传导的机制（Specific Aim 1）。然后，我们将研究act1调控通路对B细胞存活和体液免疫反应的生理和病理影响（Specific Aim 2）。这些拟议的研究将为我们提供对Act1功能的机制见解，揭示Act1如何协调调节CD40-和baffr介导的途径，从而发挥其对B细胞存活和调节体液免疫反应的影响。这些发现将有助于我们阐明B细胞稳态的详细调控机制，并为干预免疫系统开辟新的可能性。

DESCRIPTION (provided by applicant): Throughout development, maturation and activation, B cells are continuously exposed to two major opposing forces. The first is the drive to generate and maintain B cells with highly diverse immune receptors able to recognize the diversity of exogenous antigens. The second is the necessity to avoid damaging immune responses against self-components. The balance of these two forces ensures an inability to react to self-antigens while preserving defenses against pathogens. CD40-CD40L and BAFF-BAFFR cytokine pathways have been shown to play essential roles in B cell survival and differentiation. We investigated the regulatory mechanism of a novel adaptor molecule, termed Act1 in CD40 and BAFFR-mediated B cell survival. We found that CD40- and BAFF-mediated survival is significantly increased in Act1-deficient B cells. Consistent with this finding, Act1-deficient mice revealed a general increase in peripheral B cells, culminating in lymphadenopathy, splenomegaly, and the formation of autoantibodies. Act1 exerts its negative regulatory function in B cell survival through its direct impact on the immediate signaling events mediated by CD40 and BAFF. Act1-deficient B cells displayed enhanced CD40L- and BAFF-induced IkappaB phosphorylation and processing of NF-kappaB2(pl00/p52). Based on these findings, we hypothesize that Act1 is an important regulator for the homeostasis of B cells by attenuating CD40 and BAFFR signaling, modulating humoral immune responses. To test this hypothesis, we will first elucidate the mechanism by which Act1 negatively regulates the CD40- and BAFFR-mediated signaling (Specific Aim 1). We will then examine Investigate the physiological and pathological impact of the Act1-regulated pathways on B cell survival and humoral immune responses (Specific Aim 2). These proposed studies will provide us with the mechanistic insight for Act1's function, revealing how Act1 coordinately regulates CD40- and BAFFR-mediated pathways, thereby exerting its impact on B cell survival and modulating humoral immune responses. These findings will help us to elucidate the detailed regulatory mechanism for B cell homeostasis and opens new possibility to intervene the immune system.