Functional role of serum amyloid A in periapical inflammation (R01 Renew)

项目总结/摘要 我们的血清淀粉样蛋白A（SAA）项目的长期目标是确定细胞/分子网络， 调节过度体脂肪状态下感染诱导的牙齿炎症/骨破坏的发展。 这项更新申请旨在测试一种新的病理学范式，即SAA是肥胖及其 通过改变高脂饮食（HFD）环境中的天然抗体（NAb）谱来治疗相关炎症。 肥胖是一个全球性的健康问题。肥胖加重根尖周炎（根尖周病变），导致 治疗成功率低。然而，了解肥胖患者根尖周病变的详细发病机制， 主机仍然不够。SAA在诸如肝脏、脂肪组织和巨噬细胞中是可诱导的， 炎症包括根尖周病变和肥胖。NA B是由B-1分泌的异源性免疫球蛋白 B细胞，无既往抗原经验（如感染）。NAb提供即时和非特异性 在一段时间内建立适应性免疫期间防止感染。此外，NAB是 在清除受损/凋亡细胞中很重要。相反，抗原与NAb（免疫复合物）复合， 丛）可通过补体激活和嗜中性粒细胞依赖性炎症引起组织损伤。 我们已经报道，在正常体脂状态下，SAA在诱导化疗中起着类似于精氨酸的作用。 在慢性根尖周炎的发展过程中，TLR-NF-kB轴的活化，但在骨中没有 杀伤性接下来，我们研究了SAA在HFD诱导的肥胖中根尖周病变中的作用。肥胖野生型 (WT)与瘦的对照相比，小鼠获得了>75%的更大的损伤尺寸。相比之下，HFD喂养的SAA阻断小鼠重新出现了免疫反应。 对肥胖和根尖周炎症都有抵抗力，没有导致体重增加，几乎没有根尖周 病变补体和免疫球蛋白的基因表达谱存在显著差异 可变基因未感染的肥胖WT小鼠具有NAb特征，其特征在于高滴度的IgG 1反应性抗体， 与人类牙髓病原体，而HFD喂养SAA阻断小鼠表现出高滴度的天然多反应性， IgM抗体SAA可能在天然抗体应答中起迄今未知的HFD依赖性作用。诸如补体 结论SAA可能是导致IgG免疫复合物损伤的致病因素， 仅对HFD环境中的WT小鼠。综上所述，总体假设是，SAA发挥了独特的作用， HFD依赖性病理作用通过改变NAb谱促进根尖周炎症和肥胖。 我们将通过以下具体目标来检验假设。 目标1.检查SAA对NAb在HFD环境中的作用的影响。 目标2.检测SAA是否导致HFD环境中IgG免疫复合物根尖周损伤。 目标3.探讨被动NAb转移对疾病发展的影响。 该项目的结果将导致肥胖患者根尖周病变发病机制的范式转变， 一种与传统疗法不同的新的治疗模式。

Project Summary/Abstract The long-term goal of our serum amyloid A (SAA) project is to determine the cellular/molecular networks that regulate the development of infection-induced dental inflammation/bone destruction in the over body fat status. This renewal application seeks to test a new pathological paradigm that SAA is responsible for obesity and its associated inflammations via altering the natural antibody (NAb) profile in a high-fat diet (HFD) environment. Obesity is a global health concern. Obesity exacerbates periapical periodontitis (periapical lesions), leading to a poor success rate of treatment. Yet, understanding of the detailed pathogenesis of periapical lesions in obese hosts is still insufficient. SAA is inducible in such as the liver, adipose tissue, and macrophages caused by inflammation including periapical lesions and obesity. NAb are heterogenous immunoglobulins secreted by B-1 B cells in the absence of prior antigenic experience (e.g. infection). NAb provides immediate and non-specific protection against infection during the establishment of adaptive immunity over some time period. Also, NAb is important in the clearance of damaged/apoptotic cells. In opposite, antigens complexed with NAb (immune com- plexes) may cause tissue injury via complement activation and neutrophil-dependent inflammation. We have reported that, under normal body fat status, SAA plays a cytokine-like role in the induction of chemo- taxis, activation of the TLR-NF-kB axis in the development of chronic periapical inflammation, but not in bone destruction. Next, we examined the role of SAA in periapical lesions in HFD-induced obesity. Obese wild-type (WT) mice gained >75% larger lesion size vs. lean controls. By contrast, HFD-fed SAA-blocked mice were re- sistant to both obesity and periapical inflammation, resulted in no body weight gain and almost no periapical lesions. Significant differences were observed in the gene expression profile of complement and immunoglobulin variable genes. Non-infected obese-WT mice had a NAb profile characterized by a high titer of IgG1 reactive with human endodontic pathogens, while HFD-fed SAA-blocked mice showed a high titer of natural polyreactive IgM. SAA probably plays a hitherto unknown HFD-dependent role in natural antibody response. As complement genes were locally expressed in obese-WT lesions, SAA may bring causal factors for IgG immune complex injury only to WT mice in a HFD environment. Taken together, the overarching hypothesis is that SAA plays a unique HFD-dependent pathologic role in promotion of periapical inflammation and obesity via changing of NAb profile. We will test the hypothesis through the following Specific Aims. Aim 1. To examine the effect of SAA on the role of NAb in a HFD environment. Aim 2. To examine whether SAA leads to IgG immune complex periapical injury in a HFD environment. Aim 3. To determine the effect of passive NAb transfer on the disease development. The outcome of this project will lead to a paradigm shift in the pathogenesis of periapical lesions in obesity and a new therapeutic paradigm in a different manner of conventional therapies.