权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Class I Molecules and Autoimmunity

I 类分子和自身免疫

基本信息

批准号：
7095832
负责人：
Derry Charles Roopenian
金额：
$ 33.83万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-05-01 至 2007-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): IgG is the major antibody isotype responsible for a wide diversity of autoimmune diseases. A major goal would thus be to understand how one controls the levels of pathogenic IgG antibodies in individuals with autoimmune disease. Studies culminating in our recent gene targeting and transgenic experiments have suggested that the MHC class I-like IgG protection receptor, FcRn, plays a key role in maintaining endogenous IgG concentrations in mammals of all ages. Our studies indicate that FcRn is a key control point for IgG-mediated immune responses. The overall goal of the proposed studies is thus to elucidate the biology and function of FcRn in normal and autoimmune states. Our new results provide the first direct evidence that FcRn is an important molecule for humoral autoimmunity. Aim 1 will determine which autoimmune diseases are ameliorated (or exacerbated) by an FcRn deficiency in a variety of autoimmune diseases. The results will suggest the diseases in which increased serum IgG concentrations are deleterious or protective. In doing so, it should define the autoimmune diseases that might be amenable to anti-FcRn therapeutic strategies. While FcRn protein is detected only at low levels in healthy adult mice, our new results indicate that FcRn protein increases substantially as mice develop SLE. Aim 2 will thus determine whether an increased level of FcRn expression contributes to autoimmune disease. These results should provide important insights into why FcRn is upregulated and whether FcRn upregulation is a major factor in establishing and maintaining hypergammaglobulinemia. While the IgG conserving function of FcRn is well established, the difficulties in monitoring FcRn in vivo have impeded the resolution of major issues concerning its in vivo biology. To determine the tissue sites in which FcRn expresses and operates to protect IgG from catabolism under normal and autoimmune situations, Aim 3 will thus employ Cre-Lox technology to replace the normal FcRn gene with an FcRn-GFP fusion construct. The expression of this construct under normal regulation and under tissue specific regulation will clarify the anatomy of FcRn-mediated protection of IgG, and, more generally, will facilitate many other aspects of investigation into the physiology of FcRn.

描述（由申请人提供）：IgG是引起多种自身免疫性疾病的主要抗体同型。因此，一个主要的目标将是了解如何控制自身免疫性疾病患者的致病性IgG抗体水平。我们最近的基因靶向和转基因实验的研究结果表明，MHC i类IgG保护受体FcRn在维持所有年龄哺乳动物内源性IgG浓度方面起着关键作用。我们的研究表明，FcRn是igg介导的免疫反应的关键控制点。因此，拟议研究的总体目标是阐明FcRn在正常和自身免疫状态下的生物学和功能。我们的新结果提供了第一个直接证据，证明FcRn是体液自身免疫的重要分子。目的1将确定在各种自身免疫性疾病中，FcRn缺乏会改善（或加重）哪些自身免疫性疾病。结果将提示血清IgG浓度升高的疾病是有害的还是保护性的。在此过程中，它应该确定可能适用于抗fcrn治疗策略的自身免疫性疾病。虽然FcRn蛋白仅在健康成年小鼠中检测到低水平，但我们的新结果表明，随着小鼠发生SLE， FcRn蛋白大幅增加。因此，Aim 2将确定FcRn表达水平升高是否与自身免疫性疾病有关。这些结果应该为FcRn上调的原因以及FcRn上调是否是建立和维持高γ球蛋白血症的主要因素提供重要的见解。虽然FcRn保存IgG的功能已被证实，但在体内监测FcRn的困难阻碍了其体内生物学重大问题的解决。为了确定在正常和自身免疫情况下FcRn表达和保护IgG免于分解代谢的组织位点，Aim 3将采用Cre-Lox技术，用FcRn- gfp融合构建体取代正常的FcRn基因。该结构在正常调节和组织特异性调节下的表达将阐明FcRn介导的IgG保护的解剖结构，并且更一般地说，将促进对FcRn生理学的许多其他方面的研究。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease.

DOI：
10.1172/jci18838
发表时间：
2004-05
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
S. Akilesh;Stefka B. Petkova;T. Sproule;D. Shaffer;G. Christianson;D. Roopenian
通讯作者：
S. Akilesh;Stefka B. Petkova;T. Sproule;D. Shaffer;G. Christianson;D. Roopenian

Efficient mucosal vaccination mediated by the neonatal Fc receptor.

新生儿FC受体介导的有效粘膜疫苗接种。