Class I Molecules and Autoimmunity

描述（由申请人提供）：IgG是导致多种自身免疫性疾病的主要抗体同种型。因此，一个主要目标是了解如何控制自身免疫性疾病个体中致病性IgG抗体的水平。在我们最近的基因靶向和转基因实验中达到高潮的研究表明，MHC I类IgG保护受体FcRn在维持所有年龄段的哺乳动物的内源性IgG浓度中起着关键作用。我们的研究表明，FcRn是IgG介导的免疫应答的关键控制点。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将确定哪些自身免疫性疾病在各种自身免疫性疾病中通过FcRn缺乏而改善（或加重）。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。在这样做时，它应该定义可能适合抗FcRn治疗策略的自身免疫性疾病。虽然在健康成年小鼠中仅检测到较低水平的FcRn蛋白，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，目的2将确定FcRn表达水平的增加是否有助于自身免疫性疾病。这些结果应该提供重要的见解，为什么FcRn上调，以及FcRn上调是否是建立和维持高丙种球蛋白血症的主要因素。虽然FcRn的IgG保存功能已得到充分确立，但体内监测FcRn的困难阻碍了有关其体内生物学的主要问题的解决。为了确定在正常和自身免疫情况下FcRn表达并保护IgG免受卡替的组织位点，Aim 3因此将采用Cre-Lox技术用FcRn-GFP融合构建体替换正常FcRn基因。该构建体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保护的解剖学，并且更一般地，将促进对FcRn生理学的许多其他方面的研究。

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.