IgA inducing peptide

描述(申请人提供)：免疫球蛋白是大多数哺乳动物的粘膜分泌物中的主要免疫球蛋白亚型，因此是防止病原体进入的理想定位。我们利用牛的大量粘膜组织，包括淋巴结和Peyer‘s斑块，开发了一个cDNA文库，以探索调节IgA表达的因素。我们在牛体内发现了一种新的影响体外产生IgA的因子，并将该因子命名为IgA诱导蛋白或IGIP。这项为期两年的创新计划的总体目标是将我们对这一新因子的研究扩展到人类，并阐明IGIP影响IgA产生的机制。我们对该项目的工作假设是，间质树突状细胞衍生的IGIP在哺乳动物物种中是保守的，是诱导表达IgA的细胞的T依赖和独立途径的重要组成部分。我们还假设，树突状细胞和/或B细胞中IGIP调节的改变是选择性IgA缺陷的一个因素。检验这一假说的具体目的是：1)利用建立的体外模型确定IGIP在表达IgA的人B细胞分化中的作用；2)鉴定外周血白细胞包括树突状细胞、T细胞、B细胞和单核/巨噬细胞在内的IGIP转录和蛋白的细胞来源；3)比较选择性IgA缺陷患者外周血白细胞IGIP转录和蛋白的表达及其对IGIP的反应性。这项拟议中的研究将首次建立机制(S)，通过这种机制，最近发现的一种独特的因子与已知的因子如转化生长因子-β或白介素10协同作用，促进免疫球蛋白A应答，并应有助于澄清人类树突状细胞在免疫球蛋白应答调节中的作用。此外，拟议的研究将开始检查确定IGIP与临床IgA产生异常之间的潜在关系。

DESCRIPTION (provided by applicant): IgA is the predominant Ig isotype in mucosal secretions of most mammalian species and is thus ideally localized to prevent pathogen entry. We took advantage of the large quantities of mucosal tissues, including lymph nodes and Peyer's patches in cattle to develop a cDNA library to probe for factors that regulate IgA expression. We identified a novel factor in the bovine, which impacts IgA production in vito and designated the factor, IgA Inducing Protein or IGIP. The general goal of this two-year innovative proposal is to extend our studies of this novel factor to humans and to elucidate the mechanisms by which IGIP influences IgA production. Our working hypothesis for the project is that interstitial dendritic cell derived- IGIP is conserved across mammalian species and is an essential component of T-dependent and independent pathways for induction of IgA-expressing cells. We also hypothesize that altered IGIP regulation in dendritic cells and/or B cells is a factor in selective IgA deficiency. The specific aims that will test this hypothesis are: 1) Use an established in vitro model to determine the role of IGIP in differentiation of IgA-expressing human B cells; 2) Identify the cellular sources of IGIP transcripts and protein in peripheral blood leukocytes including dendritic cells, T cells, B cells and monocyte/macrophages from normal individuals; 3) Compare the expression of IGIP transcripts and protein and the responsiveness to IGIP of peripheral blood leukocytes from patients with selective IgA deficiency. The proposed studies will be the first to establish the mechanism(s) by which a unique, recently identified factor acts in concert with known factors such as TGF-beta or IL-10 to promote IgA responses and should help clarify the role of human DC in the regulation of the IgA responses. In addition, the proposed studies will begin to examine determine the potential relationship between IGIP and clinical abnormality in IgA production.