Class I Molecules and Autoimmunity

说明(申请人提供)：免疫球蛋白是导致多种自身免疫性疾病的主要抗体亚型。因此，一个主要目标将是了解一个人如何控制自身免疫性疾病患者的致病免疫球蛋白抗体水平。我们最近的基因打靶和转基因实验的结果表明，MHC-I类免疫球蛋白保护受体FcRN在维持所有年龄段哺乳动物的内源性免疫球蛋白浓度方面发挥着关键作用。我们的研究表明，FcRN是免疫球蛋白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。我们的新结果首次直接证明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，哪些自身免疫性疾病因FcRN缺陷而得到改善(或加重)。这一结果将提示，血清免疫球蛋白浓度升高的疾病是有害的或具有保护作用的。在这样做的过程中，它应该定义可能适用于抗FcRN治疗策略的自身免疫性疾病。虽然在健康的成年小鼠中只检测到低水平的FcRN蛋白，但我们的新结果表明，随着小鼠发生系统性红斑狼疮，FcRN蛋白显著增加。因此，目标2将确定FcRN表达水平增加是否有助于自身免疫性疾病。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丙种球蛋白血症的主要因素提供重要的见解。虽然FcRN的免疫球蛋白的保存功能已经确立，但体内监测FcRN的困难阻碍了有关其体内生物学的重大问题的解决。为了确定FcRN在正常和自身免疫情况下表达和运作以保护免疫球蛋白免受分解代谢的组织部位，Aim 3因此将使用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有助于阐明FcRN介导的免疫球蛋白保护的解剖学，更广泛地说，将有助于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.