Fc gamma RIIB and Inflammation-Related Vascular Disease

描述(由申请人提供)：Fc受体(FCR)经典地调节免疫系统中B细胞和其他效应细胞对Ig G的反应。我们发现抑制性FCR Fc？RIIb在血管内皮细胞中含量丰富，并通过免疫球蛋白G、C反应蛋白(CRP)和血清淀粉样蛋白P成分(SAP)介导内皮型一氧化氮合酶(ENOS)拮抗作用。ENOS的拮抗作用是通过抑制Akt和eNOS激活磷酸化来实现的。由于在肥胖诱导的高血压(HTN)中，内皮细胞Akt和eNOS激活的磷酸化作用同样减弱，全球Fc？RIIb-/-小鼠被置于高脂饮食(HFD)中，发现尽管体重增加与Fc？RIIb/-小鼠相同，但空白小鼠可免受肥胖诱导的HTN的影响。该提案的总体目标是确定Fc？RIIb在肥胖诱导的HTN发病机制中的作用。目的1是确定内皮细胞Fc？RIIb是如何参与该疾病的。利用无线电遥测技术，将野生型小鼠与内皮细胞特异性Fc？RIIb缺失的小鼠的血压在正常饮食与高血压病之间进行比较。在这些组中，将评估HFD诱导的血管Akt和eNOS磷酸化状态的变化，并将评估HTN对在内皮细胞中选择性表达结构性活性Akt的小鼠的潜在保护作用。一种抗Fc？RIIb封闭抗体将被用来确定针对受体的干预是否可以阻止HTN。目的2鉴定介导肥胖诱导的HTN的Fc？RIIb配体(S)。我们已经发现，服用HFD的小鼠的SAP增加，从喂养HFD的小鼠中分离出的免疫球蛋白能有效地拮抗培养的内皮细胞中的eNOS，而从正常喂养的小鼠中分离出的免疫球蛋白不能。因此，HFD诱导的HTN将在野生型与SAP-/-和免疫球蛋白u重链缺失小鼠中进行研究，这些小鼠缺乏B细胞和Ig G。如果这项研究牵涉到免疫球蛋白G，一种B细胞耗竭抗体和一种FcRN导向的促进免疫球蛋白降解的药物将被用来确定降低Fc？RIIb配体丰度的干预措施是否可以预防肥胖诱导的HTN。目标3是确定Fc？RIIb如何影响五肽水平升高或肥胖患者的HTN发展。女性基因组健康研究将评估FC？RIIb中常见的单核苷酸多态(SNP)与HTN事件之间的关联，这是一项对25,000多名女性进行的前瞻性队列研究。推动因素包括在达拉斯心脏研究中发现了一种不能拮抗eNOS的Fc？RIIb变异，以及对C反应蛋白和gt；2.0 mg/L受试者的初步质疑；在基因频率提供了足够统计力量的非裔美国人中，功能丧失变异与较低的收缩压相关。通过这些目标的实现，将检验内皮Fc？RIIb和FCR配体参与HTN发病的新概念。可能会出现独特的预防或治疗措施，以对抗使肥胖和其他慢性炎症性疾病复杂化的HTN。

DESCRIPTION (provided by applicant): Fc receptors (FcR) classically modulate responses to IgG in B cells and other effector cells in the immune system. We discovered that the inhibitory FcR, Fc?RIIB, is abundant in endothelium, and that it mediates endothelial NO synthase (eNOS) antagonism by IgG, C-reactive protein (CRP) and serum amyloid P component (SAP), which is the CRP-equivalent in mice. The eNOS antagonism occurs via inhibition of Akt and eNOS activating phosphorylation. Since in mice endothelial Akt and eNOS activating phosphorylation are similarly attenuated in association with obesity-induced hypertension (HTN), global Fc?RIIB-/- mice were placed on high-fat diet (HFD) and it was discovered that despite weight gain equal to that of Fc?RIIB+/+, the null mice are protected from obesity-induced HTN. The OVERALL GOAL of the proposal is to determine how Fc?RIIB contributes to the pathogenesis of obesity-induced HTN. Aim 1 is to determine how endothelial cell Fc?RIIB participates in the disorder. Using radiotelemetry, BP will be compared in wild-type mice vs. mice with endothelial cell-specific Fc?RIIB deletion on normal chow vs. HFD. HFD-induced changes in vascular Akt and eNOS phosphorylation state will be evaluated in these groups, and potential protection from the HTN will be assessed in mice expressing constitutively-active Akt selectively in endothelium. An anti-Fc?RIIB blocking antibody will be used to determine if an intervention targeting the receptor prevents the HTN. Aim 2 is to identity the Fc?RIIB ligand(s) mediating obesity-induced HTN. We've discovered that SAP increases in mice on HFD, and that IgG isolated from HFD-fed mice potently antagonizes eNOS in cultured endothelium, whereas IgG from normal chow-fed mice does not. HFD-induced HTN will therefore be studied in wild-type vs. SAP-/- and immunoglobulin u heavy-chain null mice deficient in B cells and IgG. If this work implicates IgG, a B cell depleting antibody and an FcRn-directed agent that enhances IgG degradation will be used to determine if interventions that decrease Fc?RIIB ligand abundance prevent obesity-induced HTN. Aim 3 is to determine how Fc?RIIB influences the development of HTN in humans with elevated pentraxin levels or obesity. The association between common single nucleotide polymorphisms (SNP) in Fc?RIIB and incident HTN will be evaluated in the Women's Genome Health Study, which is a prospective cohort study of over 25,000 women. Impetus includes the discovery of an Fc?RIIB variant incapable of eNOS antagonism and a preliminary query of subjects with CRP>2.0mg/L in the Dallas Heart Study; in African Americans in whom genotype frequency provided sufficient statistical power, the loss-of-function variant was associated with lower systolic BP. By accomplishing these aims, the novel concept will be tested that Fc?RIIB in endothelium and FcR ligands participate in the pathogenesis of HTN. Unique preventative or treatment measures to combat the HTN that complicates obesity and other chronic inflammatory conditions will potentially follow.