Fc gamma RIIB and Inflammation-Related Vascular Disease

描述（由申请人提供）：Fc受体（FcR）典型地调节免疫系统中B细胞和其他效应细胞对IgG的反应。我们发现，抑制性FcR，Fc？RIIB在内皮中是丰富的，并且它通过IgG、C-反应蛋白（CRP）和血清淀粉样蛋白P组分（SAP）介导内皮NO合酶（eNOS）拮抗作用，SAP是小鼠中的CRP等效物。eNOS拮抗作用通过抑制Akt和eNOS活化磷酸化而发生。由于在小鼠内皮细胞Akt和eNOS活化磷酸化同样衰减与肥胖诱导的高血压（HTN），全球Fc？将RIIB-/-小鼠置于高脂饮食（HFD）中，发现尽管体重增加等于Fc？RIIB+/+，裸小鼠被保护免于肥胖诱导的HTN。该提案的总体目标是确定如何Fc？RIIB有助于肥胖诱导的HTN的发病机制。目的1是确定内皮细胞Fc？RIIB参与了这种疾病。使用无线电遥测，BP将在野生型小鼠与内皮细胞特异性Fc？正常食物与HFD的RIIB缺失。将在这些组中评价HFD诱导的血管Akt和eNOS磷酸化状态的变化，并将在内皮中选择性表达组成型活性Akt的小鼠中评估HTN的潜在保护作用。抗Fc抗体RIIB阻断抗体将用于确定靶向受体的干预是否能预防HTN。目的2是确定Fc？RIIB配体介导肥胖诱导的HTN。我们已经发现，在HFD小鼠中SAP增加，并且从HFD喂养的小鼠中分离的IgG有效地拮抗培养的内皮细胞中的eNOS，而来自正常饮食喂养的小鼠的IgG则没有。因此，将在野生型与SAP-/-和免疫球蛋白u重链缺失小鼠中研究HFD诱导的HTN，这些小鼠缺乏B细胞和IgG。如果这项工作涉及IgG，则将使用B细胞耗竭抗体和增强IgG降解的FcRn导向剂来确定是否存在降低Fc？RIIB配体丰度防止肥胖诱导的HTN。目的3是确定如何Fc？RIIB影响具有升高的正五聚蛋白水平或肥胖的人类中HTN的发展。常见的单核苷酸多态性（SNP）在Fc？RIIB和HTN事件将在女性基因组健康研究中进行评估，这是一项超过25，000名女性的前瞻性队列研究。推动力包括发现Fc？在达拉斯心脏研究中，对CRP> 2.0 mg/L的受试者进行了初步调查;在基因型频率提供足够统计学把握度的非裔美国人中，功能丧失变异与较低的收缩压相关。通过实现这些目标，新的概念将被测试，Fc？内皮细胞中的RIIB和FcR配体参与HTN的发病机制。独特的预防或治疗措施，以打击HTN，复杂的肥胖和其他慢性炎症性疾病将可能遵循。

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.