重症脓毒症外周浆细胞的产生机制、免疫调节功能及临床意义研究

Severe sepsis is developed from sepsis and defined as systemic manifestations of infection with the presence of organ dysfunction. Severe sepsis is the leading cause of mortality in most intensive care units (ICUs) with the death rate ranging from 25% to 50%. The heterogeneity of the disease encompasses a diverse interplay between pathogens and host immune responses which vary in degree from patient to patient. Currently there are no specific drugs for the treatment of severe sepsis beyond supportive care. Thus, severe sepsis represents an unmet medical need. The course of sepsis can be defined as early "pro-inflammatory response phase" and late "immune suppressive phase", and immune suppression is the key reason for the death of severe sepsis patients. However, there is limited study to decipher the immune regulatory mechanisms in severe sepsis. To this end, we have applied a novel systemic strategy to study the immune status of severe sepsis. To our surprise, we have found a large numbers of plasma cells present both in peripheral blood of patients and in spleens of mice with severe sepsis. Based on these findings, the current research project is dedicated to perform the following studies: 1) to characterize the key signaling pathways and relevant mechanisms responsible for the rapid generation of large numbers of plasma cells in severe sepsis; 2) to study the potential immune regulatory roles and clinical significance of these plasma cells in severe sepsis; 3) to evaluate the values of plasma cells and relevant parameters as prognostic biomarkers for severe sepsis. In short, this project will not only provide critical information to help to uncover the complex nature of immune disorder of severe sepsis, but also could constitute a strong basis to develop novel strategies for the prevention and treatment of this severe disease.

重症脓毒症(Severe Sepsis) 由脓毒症发展而来，是一种病情凶险的重症感染性疾病，病死率高达25%-50%，严重危害人类健康。脓毒症早期表现为 "高炎性应答阶段"，随后进入"免疫抑制阶段"，而免疫抑制是导致临床重症脓毒症患者死亡的重要原因。目前对于重症脓毒症免疫调控机制的研究尚不深入，为此，我们应用新建的细胞免疫学整体研究策略对重症脓毒症进行研究，结果意外的发现重症脓毒症患者外周血和重症脓毒症小鼠脾脏中存在大量的浆细胞，其数量与病情呈正相关。在此基础上，本项目拟开展如下研究:1)鉴定出重症脓毒症诱导产生大量浆细胞的关键信号途径，阐明其生成机制;2)研究重症脓毒症浆细胞的免疫调节作用及机理，明确其病理生理意义；3) 探索浆细胞及其相关免疫指标作为重症脓毒症预后标志物的价值。本研究不但对于阐明重症脓毒症的免疫状态及其调节机制有着重要的意义，而且也可为重症脓毒症的诊治提供新的线索。

脓毒症(Sepsis) 是病原微生物侵入血循环后生长繁殖而引起的一类严重感染性疾病，部分脓毒症患者给予足量的液体复苏后仍然伴有无法纠正的持续性低血压，则进一步发展成脓毒症休克 (Septic shock)。脓毒症病情凶险，特别是老年人由于免疫力低下，老年脓毒症及脓毒症休克发病率逐年上升，尽管抗感染治疗和器官功能支持技术取得了长足的进步，但老年脓毒症和脓毒症休克患者的死亡率常超过50%，且致残率和再入院率也非常高，对家庭和社会造成了沉重的负担。. 目前对于脓毒症和脓毒症休克的治疗手段主要是采用纠正脓毒症引起的病理生理后果的支持治疗，缺乏根本性突破，而几乎所有的临床试验宣告失败，其核心原因在于脓毒症的发病和免疫调控机制尚未完全阐明，因此如何解析脓毒症的免疫应答特征是当前迫切需要解决的一个关键科学问题。本研究针对上述关键科学问题，以老年脓毒症患者浆细胞为主要研究对象，取得了以下的研究成果：(1) 发现与健康对照和肺炎对照相比，老年脓毒症患者外周循环浆细胞数量和比例显著上升；(2) 发现与健康对照外周浆细胞相比，老年脓毒症外周浆细胞具有独特的基因表达谱，蛋白合成和代谢通路等发生异常活化；(3) 老年脓毒症外周浆细胞具有免疫调节作用，可促进CD4+ T细胞增殖和分泌IFN-g和IL-17；(4) 明确了老年脓毒症外周浆细胞的预后价值，其数量增高是指示脓毒症休克患者预后良好的一个潜在标志物；(5) 拓展研究中发现，活动性系统红斑狼疮患者外周浆细胞和未成熟B细胞增高，并且I型干扰素可促进未成熟B细胞的生存和炎性应答；另外人类肝癌组织中浆细胞增高是患者预后良好的一个免疫指标。以上研究不但拓展了对浆细胞在人类疾病中的认识，也为炎性疾病的诊断和病情预后提供了新的思路。本项研究按计划总体执行良好，已在国际期刊Nature Reviews Immunology, Immunity, Cellular Molecular Immunology, Oncoimmunology等杂志发表论文4篇，中文核心期刊发表论文3篇，另有2篇英文论文投稿中，后续研究也正在积极进行。.