早期类风湿关节炎B细胞活化生物标志及靶向B细胞生物制剂早期治疗

HLA-DRβ1 alleles are closely related to rheumatoid arthritis (RA), and participate in the production of anticyclic citrullinated peptide antibody (ACPA). ACPA is a special diagnosis marker of RA. CD20, BAFF and the receptors of BAFF play important role in B lymphocytes activation. Could HLA-DRB1, ACPA, CD20, BAFF and the receptors of BAFF be considered as special biomarkers for early dignosis in early RA? And could HLA-DRB1, ACPA, CD20, BAFF and the receptors of BAFF be considered as surrogate endpoint of efficacy evaluation of drugs? Is it more effective to prevent joint damage to select biological agents targeting B cell activity? The relevant documents have not being seen at present. In this study, techniques such as fluorescence quantity PCR, image, flow cytometry,Magnetic Activated Cell Sorting (MACS) and so on will be used in RA patients and animal model. The relations between HLA-DRB1 or ACPA or CD20 or BAFF or the receptors of BAFF and synovitis or DAS28 will be illustrated in early RA; Clinical effects Rituximab and Belimumaband in different phases in mice with collagen induced arthritis will be observed, and the changes of indexes such as ACPA, CD20, BAFF and the receptors of BAFF will be also observed. It will be illustrated that ACPA, CD20, BAFF and receptors of BAFF be considered as surrogate endpoint of efficacy evaluation of drugs. The rationality of early therapy for early RA will be illustrated. This study will provide new markers of diagnosis for early RA, and will provide theory for early therapy in early RA.

HLA-DRβ1等位基因与类风湿关节炎（RA）密切相关，并参与抗环瓜氨酸肽抗体（ACPA）产生。ACPA是RA诊断特异指标。CD20和BAFF及其受体在B细胞活化中起重要作用。HLA-DRB1、ACPA、CD20和BAFF及其受体能否作为早期RA特异标志物，实现早期诊断？能否作为药物疗效评价的替代终点？靶向B细胞生物制剂早期治疗能否更有效阻止关节破坏？目前未见相关文献报道。本研究通过RA患者和动物模型，采用定量PCR、影像学、流式术、免疫磁珠等，研究RA早期HLA-DRB1、ACPA、CD20和BAFF及其受体与滑膜炎、DAS28相关性；探讨胶原性关节炎小鼠不同病程Rituximab和Belimumab药物治疗后，ACPA等指标变化与滑膜炎的相关性，明确ACPA等指标作为药物疗效评价的替代终点，阐明RA早期治疗的合理性。该研究为RA早期诊断提供新的诊断标志物，为RA早期治疗提供理论依据。

类风湿关节炎(rheumatoid arthritis, RA)是以多关节破坏为主要特征的慢性、系统性自身免疫病。寻找早期RA诊断特异性和敏感性高的生物标志物，选择合理靶向B细胞生物制剂治疗至关重要。本研究以RA患者和动物模型为研究对象，研究早期RA患者HLA-DRB1等位基因、BAFF及其受体与疾病活动性的相关性；观察靶向B细胞生物制剂对人B细胞增殖活化功能及B细胞中CD20、BAFF受体表达的影响；研究小鼠CIA不同炎症阶段靶向B细胞生物制剂治疗前后CD19、CD20、CD27、BAFF及BAFF受体表达变化情况及与临床疗效的关系；分析靶向B细胞生物制剂对CIA的治疗情况，比较相同病程中生物制剂和CP-25之间的疗效情况。研究发现RA患者TNFR2基因rs1061622该位点G等位基因频率与DAS28评分具有相关性；血清IL-1α、IL-1β、MCP-1、IFN-α、TNF-α、IFN-γ等水平升高。RA患者血清BAFF及其受体水平升高，B细胞异常活化，BAFF通过其受体介导NF-κB信号通路参与RA B细胞增殖活化。利妥昔单抗和依那西普通过抑制BAFF/ BAFFR介导的NF-κB信号通路和TNF-α/ TNFR介导的TRAF2-NF-κB信号通路调控B细胞功能。依那西普改善RA病人临床症状、下降实验室指标，下调外周血总B细胞、记忆细胞、浆细胞水平，抑制B细胞异常活化。CP-25对实验性关节炎治疗作用与其调节免疫应答和免疫细胞功能密切相关。CP-25的作用与其调控TNF-α和BAFF介导的信号转导通路交叉联系密切相关。该研究明确了HLA-DRB1等位基因、BAFF、CD20、BAFF受体可作为诊断早期 RA特异性生物标志物。明确CD20、BAFF及其受体为利妥昔单抗疗效评价的替代终点。CP-25作用特点可能是对信号通路中关键调控分子如GRK2、TRAF2活性的调控，提示CP-25可能是具有“炎症免疫反应软调节”作用的新型药物。该研究为 RA 早期诊断提供新的诊断标志物，为开发新的抗炎免疫调节药物提供新思路。