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INDUCTION OF IG C EPSILON & C GAMMA 1 BY IL4 & CD40L

IG C Epsilon 感应

基本信息

批准号：
6510760
负责人：
Janet M. Stavnezer
金额：
$ 26.2万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-01 至 2003-05-31
项目状态：
已结题

项目摘要

After immunization or infection, B cells undergo immunoglobulin (Ig) class switching, which results in expression of a new heavy chain constant region (C/H) region gene. Class switching allows the humoral immune response to adaptively respond to a variety of different infectious organisms to produce the best antibody for each pathogen. This proposal will investigate the mechanism of regulation of class switching to IgG1 and IgE, using the mouse a model system. This proposal will investigate the mechanism of regulation of class switching to IgG1 and IgE, using the mouse as a model system. Both IgG1 and IgE are produced in response to T dependent antigens, although IgG1 in much greater abundance that IgE. IgG1 in effective against bacterial, viral and nematode infections due to its ability to active complement and to bind to FcRgammaIII on macrophages, neutrophils, mast cells and NK cells. IgE helps to eliminate parasitic helminths, although it does not appear to be essential for this immune response and in industrial societies is generally more dangerous than protective, as it causes allergy, including asthma. Thus, the ability to increase IgG1 and decrease IgE responses would be useful medically. Numerous studies have established that transcription of the C/H gene to which cells will switch is induced prior to switching by cytokines and B cell activators, and that this transcription is required for class switching. This proposal is to investigate the mechanism of regulation of germline gamma1 and epsilon transcription by cytokines and B cell activators known to regulate class switching to IgG1 and IgE. The proposal will specifically investigate and compare the regulation of the germline gamma1 and epsilon transcripts by three transcription factors/families which are involved in induction of transcription by IL-4 and CD40 signaling: Stat6, NF-kappaB/Rel proteins, and b-Zip proteins. We have shown that Stat6 and NF-kappaB directly bind each other and have evidence suggesting this is the mechanism whereby IL-4 and CD40 signaling synergistically induce transcription. This proposal will directly address whether this binding is necessary for their synergy and analyze the mechanism of their interaction. A b-Zip binding site which binds Ap-1 is also required for the ability of Stat6 to induce transcription, but the requirement for the Ap-1 binding site is not understood. We will investigate whether this requirement is due to the inability of Stat6 to bind to chromatin in vivo in the absence of AP-1. The promoters for the gamma1 and epsilon germline transcripts have similar binding sites for Stat6, NF-kappaB and AP-1 (or for C/EBP), but these sites are differentially arranged. We will determine if it is the differential arrangement and/or different binding proteins at the b-Zip element which regulates their different responses to IL-4 and B cell activators.

免疫或感染后，B细胞经历免疫球蛋白（IG）类转换，导致表达新的重链常数区域（C/H）基因。类转换使得体液免疫适应性地应对各种不同的传染病生物体产生最好的抗体每一种病原体。这项建议将研究类转换为IgG 1的调节机制和免疫球蛋白E，使用小鼠作为模型系统。该提案将调查调节IgG 1和IgE类别转换的机制，使用以老鼠为模型。IgG 1和IgE都是对T 依赖性抗原，尽管IgG 1的丰度比IgE大得多。IgG1 由于其具有抗细菌、病毒和线虫感染作用，激活补体并结合巨噬细胞上的FcR γ III的能力，嗜中性粒细胞、肥大细胞和NK细胞。IgE有助于消除寄生虫蠕虫，虽然它似乎并不是这种免疫所必需的，在工业社会中，一般来说，保护，因为它会引起过敏，包括哮喘。因此，增加IgG 1和降低IgE应答在医学上是有用的。许多研究已经证实，C/H基因的转录，在细胞因子和B的转换之前，细胞激活剂，并且这种转录是类切换本研究旨在探讨调节的机制，细胞因子和B细胞对生殖系γ 1和γ 2转录的影响已知调节IgG 1和IgE类别转换的激活剂。该提案将专门研究和比较生殖系的调节，三个转录因子/家族的γ 1和γ 2转录物参与IL-4和CD 40的转录诱导信号传导：Stat 6、NF-κ B/Rel蛋白和b-Zip蛋白。我们有显示Stat 6和NF-κ B直接相互结合，并有证据表明提示这是IL-4和CD 40信号传导的机制，协同诱导转录。该提案将直接针对这种结合是否对它们的协同作用是必要的，并分析他们的互动机制。结合Ap-1的b-Zip结合位点是也是Stat 6诱导转录的能力所必需的，但是对Ap-1结合位点的要求尚不清楚。我们将调查这一要求是否是由于Stat 6无法在缺乏AP-1的情况下，在体内结合染色质。The Promoters for the γ 1和γ 2生殖系转录物具有相似的结合位点， Stat 6、NF-κ B和AP-1（或C/EBP），但这些位点是不同的安排。我们将确定是否是差异在b-Zip元件处的不同排列和/或不同的结合蛋白，调节它们对IL-4和B细胞活化剂的不同应答。