Complement Receptor 2 as a Biomarker for Systemic Lupus Erythematosus

描述(申请人提供)：补体受体2(CR2/CD21)是狼疮NZM2410小鼠模型SLelc狼疮易感区间中最强的候选基因，基于其蛋白产物的结构和功能变化。在人类中，CR2位于一个共生遗传区间，该区间也与狼疮易感性有关。人类CR2近端启动子的多态性改变了其转录活性，这可能是先前在系统性红斑狼疮(SLE)患者中描述的CR2 B细胞表达降低的原因之一。我们假设，CR2表达的改变，无论是通过遗传还是后天手段，反映了人类SLE的疾病活动，跟踪CR2表达和/或识别改变其功能的多态性可以帮助SLE患者的管理和治疗。我们的具体目的是确定狼疮患者B细胞CR2水平是否与疾病活动性相关，确定狼疮患者CR2水平降低的机制，以及确定特定的CR2等位基因是否影响CR2水平与疾病活动性的相关性。患有活动期SLE、非活动期SLE、类风湿性关节炎或无自身免疫性疾病的成年人(每组15人)将在为期一年的时间里每3个月进行一次评估，并对狼疮发作进行中期评估。在每次就诊时，将进行病史和体检，评估疾病活动，并采集60毫升外周血。将分离外周血单个核细胞，用于制备基因组DNA用于基因分型，用于流式细胞仪分析B细胞在B细胞亚群上CR2的表达，并用于纯化B细胞，从中制备mRNA用于定量逆转录酶聚合酶链式反应。将获得额外的血液，用于测量疾病活动性的血清学参数。将进行尿液分析，并采集尿液以测定蛋白质和肌酐。CR2水平将与疾病活动性相关，并将确定导致水平下降的机制。这些研究将揭示监测CR2水平作为狼疮疾病活动性的生物标志物的价值，这将有助于狼疮的诊断和治疗，并改善在临床试验中测试的新疗法的评估。此外，它们将促进我们对CR2在SLE发病机制中的作用的理解，并为促进这种疾病的发展提供洞察力。

DESCRIPTION (provided by applicant): Complement receptor 2 (CR2/CD21) is the strongest candidate gene for lupus susceptibility in the Slelc lupus susceptibility interval of the NZM2410 mouse model of lupus, based on structural and functional alterations in its protein products. In humans, CR2 is located in a syntenic genetic interval that is also linked and associated with lupus susceptibility. A polymorphism in the proximal promoter of human CR2 alters its transcriptional activity, potentially contributing to the decreased B cell expression of CR2 that has been previously described in patients with systemic lupus erythematosus (SLE). We hypothesize that alterations in CR2 expression, whether by genetic or acquired means, reflect disease activity in human SLE, and that tracking CR2 expression and/or identifying polymorphisms that alter its function can assist in the management and treatment of patients with SLE. Our specific aims are to determine whether B cell CR2 levels in lupus patients are correlated with disease activity, to determine the mechanism by which CR2 levels are decreased in lupus patients, and to determine whether a specific CR2 allele affects the correlation of CR2 levels with disease activity. Adults with active SLE, inactive SLE, rheumatoid arthritis, or no autoimmune disease (15 each group) will be evaluated every 3 months for 1 year, with interim evaluation for lupus flares. At each visit, history and physical exam will be performed, disease activity assessed, and 60 milliliters of peripheral blood obtained. Peripheral blood mononuclear cells will be isolated for preparation of genomic DNA for genotyping, for flow cytometric analyses of B cell expression of CR2 on B cell subsets, and for purification of B cells from which mRNA will be prepared for quantitative reverse transcriptase PCR. Additional blood will be obtained for measurement of serologic parameters of disease activity. Urinalysis will be performed and urine collected for measurement of protein and creatinine. CR2 levels will be correlated with disease activity, and the mechanisms underlying decreased levels will be defined. These studies will reveal the value of monitoring CR2 levels as a biomarker for lupus disease activity, which would assist in diagnosis and treatment of lupus and improve the evaluation of new therapies tested in clinical trials. In addition, they will advance our understanding of the role of CR2 in the pathogenesis of SLE and provide insight into the mechanisms that contribute to the development of this disease.