瘦素对原发性干燥综合征B细胞的免疫调节和机制

Primary sjogren's syndrome (pSS) is a kind of autoimmune disease which not only offends systemic exocrine gland organ, but also injures multiple organ systems. B cells' abnormal activation and immune tolerance of deletion are of great consequence in pSS. Our previous studies in pSS found that patients' B cell activating factor (BAFF) levels were abnormal and correlated with disease activities, which suggested B cell abnormalities counted a great deal in the pathogenesis of pSS. Leptin is kind of protein hormone mainly secreted by adipose tissue, which plays an important role in immune response. Leptin can regulate growth, apoptosis and function of B cell via the BAFF, Bcl-2 and cyclin D1. Our previous studies have found that the serum soluble leptin and leptin receptor expression abnormalities in pSS were related with activities, and the levels of leptin were positively correlated with the levels of serum BAFF. This research will investigate the immune regulatory effect and mechanism of leptin accommodating B-cell in primary Sjogren's syndrome, therapeutic effect and immune regulation and cell cycle and apoptosis of B cell in NOD/LtJ rats infused by leptin and leptin antibody and the influence of leptin on BAFF, Bcl-2, cyclin D1 through the detection of leptin levels and leptin receptor on B cell. The research intends to explore the pathogenesis of pSS and to provide a theoretical basis for the new treatment of pSS.

原发性干燥综合征（pSS）是一类侵犯全身外分泌腺器官，累及多脏器的自身免疫病。B细胞在pSS疾病发生中起了重要作用。前期研究发现pSS患者B细胞活化因子（BAFF）水平异常，与疾病活动相关，提示了pSS中B细胞存在异常。瘦素是一种主要由脂肪组织分泌的蛋白质类激素，在免疫中发挥重要作用。瘦素通过调控BAFF、Bcl-2、cyclin D1调控B细胞发育、凋亡及功能。前期研究发现pSS患者血清瘦素和瘦素受体异常，与疾病活动相关，瘦素水平与BAFF水平显著正相关。本研究通过检测pSS患者B细胞上瘦素及瘦素受体的表达，了解瘦素及瘦素抗体输注对干燥鼠（NOD/LtJ鼠）的疗效及对B细胞的免疫调节、细胞周期及凋亡的作用机制，瘦素对BAFF、Bcl-2、cyclin D1的影响，通过上述研究了解瘦素对pSS的B细胞的作用机制, 探讨pSS的发病机制，为寻找治疗pSS治疗新方法提供理论。

原发性干燥综合症（Primary sjögren’s syndrome，pSS）是一种以淋巴细胞浸润为特征的系统性自身免疫疾病。临床表现为口眼干燥，常可累及多系统，如肺脏、肾脏、甲状腺及肝脏等，出现间质性肺炎、胆汁性肝硬化、肾小管酸中毒、淋巴瘤等多种疾病。本项目中我们检测了干燥综合症病人的瘦素和瘦素受体的表达水平差异，发现病人中瘦素和受体表达的显著性升高，以此推测瘦素和瘦素受体可能参与了干燥综合症的发病机制。为了进一步研究瘦素和瘦素受体在干燥综合症病理进程中的作用机制，本项目利用NOD/LtJ小鼠干燥综合症疾病模型，结合分离培养的B淋巴细胞与颌下腺上皮细胞共培养模型，采用腺相关病毒介导的基因沉默，抗体中和等技术，证实了瘦素和瘦素受体促进了干燥综合症的病理进程，并揭示了调控新机制，验证了在立项初所提出的瘦素与瘦素受体参与干燥综合症的科学假设。本研究中揭示了：（1）明确了在干燥综合症患者及干燥综合征模型小鼠体内瘦素及其受体的表达及其重要意义；（2）揭示了颌下腺中的瘦素和瘦素受体的信号通路在干燥综合症模型小鼠的病理进程中的重要作用；（3）证明了瘦素和瘦素受体对B细胞的免疫调控及其干燥综合征中的作用； (4) 发现了颌下腺B细胞浸润及其分泌的白介素4细胞因子作为关键分子在颌下腺内皮细胞凋亡中的重要作用；这些研究发现丰富了对干燥综合征的发病机制和保护策略的认识，对发展治疗干燥综合征的手段方法提供了参考依据。