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

免疫或感染后，B细胞经历免疫球蛋白(Ig)类 开关，这导致了一个新的重链常数的表达 (C/H)区基因。类别转换允许体液免疫 对多种不同传染病的适应性反应 为每种病原体产生最好的抗体。这项建议 将研究类转换为IgG1的调节机制 和免疫球蛋白，使用鼠标建立模型系统.这项提案将调查 类转换为IgG1和IgE的调节机制，使用 以鼠标为模型系统。免疫球蛋白G_1和免疫球蛋白E是对T的反应而产生的 依赖抗原，尽管IgG1比IgE丰富得多。IgG1 对细菌、病毒和线虫感染有效，因为它的 巨噬细胞活化补体和与FcRGammaIII结合的能力 中性粒细胞、肥大细胞和NK细胞。免疫球蛋白有助于消除寄生虫 蠕虫，尽管它似乎不是这种免疫所必需的 在工业社会中的反应和反应通常比 保护性的，因为它会引起过敏，包括哮喘。因此，能够 提高IgG1和降低IgE反应在医学上是有用的。 许多研究已经证实，C/H基因转录到 哪些细胞会在细胞因子和B细胞转换之前被诱导转换 细胞激活剂，并且这种转录是课堂所必需的 正在切换。这项建议是为了研究监管的机制 细胞因子和B细胞对生殖系Gamma1和epsilon转录的影响 已知的激活剂可调节类向IgG1和IgE的转换。这项建议 将专门调查和比较生殖系的调节 三个转录因子/家族的Gamma1和epsilon转录本 参与IL-4和CD40诱导转录的基因 信号转导：STAT6、NF-kappaB/Rel蛋白和b-Zip蛋白。我们有 STAT6和NF-kappaB直接结合，有证据表明 这表明这是IL-4和CD40信号转导的机制 协同诱导转录。这项提案将直接解决 这种绑定是否对于它们的协同作用是必要的，并分析 它们相互作用的机制。与AP-1结合的b-Zip结合位点是 也是Stat6诱导转录能力所必需的，但 对AP-1结合位点的要求还不清楚。我们会 调查这一要求是否是由于Stat6无法 在没有AP-1的情况下，在体内与染色质结合。的发起人 Gamma1和epsilon生殖系转录本具有相似的结合位点 Stat6、NF-kappaB和AP-1(或C/EBP)，但这些位点是 不同的排列。我们将确定这是否是差异 B-Zip元件上的排列和/或不同的结合蛋白 调节它们对IL-4和B细胞激活剂的不同反应。

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.