嗜碱性粒细胞在狼疮性肾炎Th1/Th2应答失衡以及病理分型中的作用

Imbalance of Th1/Th2 response is closely related to systemic lupus erythematosus (SLE). As known, basophils (Ba) can affect Th1/Th2 balance and involved in a variety of autoimmune diseases. However, few studies focus on SLE. Our previous study showed that the relative and absolute amount of Ba in peripheral significantly decreased, and activation associated immune phenotype changes turned up in active SLE patients. Moreover, the changes of the numbers of Ba and activation associated immune phenotype are not consistent in LN with different pathological types, suggesting that Ba maybe involved in the the development of LN through affecting Th1/Th2 balance and affect pathological type. The current project aims to further investigate the effects of basophiles in the imbalance of Th1/Th2 response and pathological type of lupus nephritis via studying in vitro and vivo experiments and detecting clinical specimens. Details are as follows. First, we will further clarify the correlation of the numbers of Ba in peripheral and associated changes of immune phenotype with disease activity and pathological type of LN in SLE patients by analyzing more clinical specimens. Second, we plan to study the activation mechanism of Ba in LNs with different pathological types and the effects of activated Ba on Th1/Th2 balance. Third, we will investigate the influence of regulation of numbers and activation of Ba on the progress of murine lupus disease in vivo experiments. This project will help to further clarify the pathogenesis of LN.

Th1/Th2应答失衡与系统性红斑狼疮(SLE)发病密切相关。已知嗜碱性粒细胞(Ba)可影响Th1/Th2平衡而参与多种免疫性疾病发病，但在SLE方面研究极少。我们预实验发现：活动期SLE患者外周血Ba相对及绝对数量均显著下降，而活化程度升高，但不同病理类型狼疮性肾炎(LN)患者外周血Ba数量变化却不同，提示Ba可能通过影响Th1/Th2参与LN发生发展并影响病理分型。本项目拟进一步采用临床标本、体外细胞和动物实验相结合的方案，研究Ba在LN Th1/Th2应答失衡以及病理分型中的作用，具体为：⑴增加样本，进一步明确外周血Ba数量和活化后相关的免疫表型变化与SLE疾病活动以及LN病理分型的关系；⑵体外研究在不同病理类型LN中Ba的活化机制，以及活化后对外周和次级淋巴器官Th1/Th2偏移的影响；⑶调控Ba数量和活化对狼疮小鼠疾病进展的影响。研究结果将有助于进一步明确LN发病机制。

系统性红斑狼疮(systemic lupus erythematosus, SLE)常累及肾脏，即狼疮肾炎((lupus nephritis, LN)。LN患者IV型以Th1应答为主，而V型以Th2应答为主，活化的嗜碱性粒细胞(Basophils, Ba)除可影响Th1/Th2应答失衡和LN病理分型外，对SLE B细胞产生自身抗体的影响尚不明确。本研究发现，SLE患者外周Ba高度活化(多个活化标记物显著上调)，且显著减少；自身反应性IgE及其免疫复合物是Ba活化的主要诱因(V型LN患者肾脏IgE沉积强度显著高于IV型)；体外，SLE患者活化的Ba可促进B细胞产生自身抗体；动物体内实验发现，清除Ba可显著延缓狼疮小鼠的疾病进展。有望为靶向Ba及其活化通路延缓SLE和LN疾病进展提供新的治疗策略。