B类I型清道夫受体的缺失致小鼠自身免疫疾病相关性淋巴瘤生成的机制研究

Links between systemic autoimmune diseases and increased incidence of lymphoma have been indicated based on series of clinical studies. So it is of great importance to study the association and find out the risk factors. Our previous researches demonstrated that the aged SR-BI-/- mice develop autoimmunity and large lymph nodes. The enlarged nodes are the results of increased B cell-derived lymphocytes, especially the B220low group, while the HE staining of lymph nodes shows the absence of "stars" in lymphoid nodules. Moreover, the B lymphocytes in SR-BI-/- mice have been indicated to be over-activated and hyper-proliferated. Thus our hypothesis is that deficiency of SR-BI induces increased incidences of lymphoma, which is associated to autoimmunity. To accomplish this, we plan to demonstrate the clonal expansion and malignancy of B cell employing experiments both in vivo and in vitro, and study the mechanisms both intracellular and extracellular. Using CFSE, cell cycle and Western Blot, we explore the effects of SR-BI on cell proliferation, apoptosis, cell cycle, and signal transduction. Using high fat and probucol feeding, we expose the influences of dysfunctional HDL on lymphoid phenotype. The aim of this subject is to establish the role of SR-BI in the association of autoimmunity and lymphoma. Our studies provide a new insight into the prevention and therapy of lymphoma in patients with autoimmune diseases.

大量临床资料汇总发现系统性自身免疫性疾病患者淋巴瘤发病风险增高。因此研究两者的相关性并寻找这类患者淋巴瘤的高危因素具有重要意义。我们的前期工作发现"老龄SR-BI基因敲除小鼠具有自身免疫性疾病的表现；且易出现异常增大的淋巴结；其中以B细胞来源的增生细胞为主，尤其是B220low亚群；其淋巴滤泡丧失"满天星"的现象"。因此我们提出假说：SR-BI缺失导致自身免疫相关性淋巴瘤的发病风险增加。我们拟"通过体内、外实验进一步确定SR-BI-/-小鼠淋巴瘤细胞的克隆源性及恶性表型；进而用CFSE、细胞周期、Western Blot等证明SR-BI对细胞增殖凋亡、细胞周期和信号通路的影响机制；并改变血清HDL水平观察SR-BI通过胞外环境对淋巴细胞的影响"。从而确立SR-BI的缺失是自身免疫疾病和淋巴瘤高发的共同危险因素，为自身免疫性疾病患者的淋巴瘤的防治提供新的线索和理论依据。

B类I型清道夫受体（Scavenger receptor class B type I, SR-BI）是公认的高亲和力的HDL受体。人SR-BI主要在肝脏和类固醇的组织中表达，乳腺组织中极少表达。既往实验证明B类I型清道夫受体（scavenger receptor class B type I，SR-BI）与乳腺癌的发生和发展相关，但其表达在乳腺癌中的临床意义尚不清楚。本实验中我们应用免疫组化染色检测150例乳腺癌组织中SR-BI的表达。在所有乳腺癌病例中，SR-BI的高表达占54%，且与肿瘤分期晚（P = 0.002），肿瘤体积较大（P = 0.023），淋巴结转移（P = 0.012），和ER阴性（P = 0.014）显著相关。Kaplan-Meier生存分析显示SR-BI高表达的患者有总生存（OS）较短（P = 0.004）。此外，多因素分析证实SR-BI高表达是患者的一个独立的预后危险因素（P = 0.017）。综上所述，我们的研究表明，乳腺癌SR-BI的高表达与一些传统意义上的恶性指标显著相关。脂质代谢是肿瘤研究领域的一个热点，而SR-BI作为脂代谢的一个重要的调控分子在肿瘤细胞中的高表达，暗示了其在肿瘤发生发展中起到了一定作用。乳腺癌组织SR-BI可作为乳腺癌的一个新的预后指标和潜在的治疗靶点。.本课题历时三年，发表SCI收录文章4篇，申请3项专利并获授权，按时达到预期目标。.