CD19+CD24-CD38hi B细胞在浆细胞型特发性多中心型Castleman病发病中的作用及调控机制

Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder whose etiology remains unknown. The pathogenesis of plasma-cell subtype iMCD (PC-iMCD) might be related to dysregulation of B cells and/or plasma cells. Our preliminary study showed a significant increase of CD19+CD24-CD38hi B cells in the peripheral blood of PC-iMCD patients. We also found an increase of PD-1hiCXCR5-CD4+ T cells (Tph) in the peripheral blood of PC-iMCD patients which might also be an upstream regulator of CD19+CD24-CD38hi B cells. In order to explore the role of CD19+CD24-CD38hi B cells in the pathogenesis of PC-iMCD and as well as their driving factor, we would further delineate the distribution of CD19+CD24-CD38hi B cells in patients’ peripheral blood and tissue; analyze the gene expression profiles of CD19+CD24-CD38hi B cells; correlate this cell subset with patients’ clinical features and prognoses; investigate the role of its possible upstream driver of Tph; examine the secretion of immunoglobin G (IgG) of this cell subset after interleukin-6 (IL-6) stimulation. This study aims to identify the role of CD19+CD24-CD38hi B cells in the pathogenesis of PC-iMCD, to investigate the function of this cell subset and upstream driving factor, and to provide theoretical and experimental evidence so that this cell subset could be utilized as a biomarker and treatment target for PC-iMCD.

特发性多中心型Castleman病(iMCD)是一种病因未明的罕见淋巴增生性疾病。其浆细胞亚型(PC-iMCD)的发病可能与B细胞和/或浆细胞的异常有关。我们前期发现PC-iMCD患者外周血中CD19+CD24-CD38hiB细胞明显升高。还发现患者外周血PD-1hiCXCR5-CD4+T细胞(Tph)水平明显升高，可能是前者的上游调控因素。为探讨CD19+CD24-CD38hiB细胞在PC-iMCD发病中的作用及调控机制，我们将分析PC-iMCD患者外周血与组织中该细胞的分布，分析其表达谱，了解其与患者临床表现及预后的相关性；探索其是否受到Tph细胞调控，以及该群细胞是否能在白细胞介素-6刺激下分泌免疫球蛋白。本研究将证实CD19+CD24-CD38hiB细胞在PC-iMCD发病中的作用，揭示其功能和上游调控因素，从而为将该群细胞作为PC-iMCD的生物标志物及治疗靶点提供理论和实验依据

背景：特发性多中心性Castleman病(iMCD)是一种罕见的淋巴增殖性疾病，该病的疗效评估体系较为复杂，需要从症状、淋巴结、生化指标等多个维度进行，亟需探索能够更好评价疗效的血清学标志物，以便更加精准的评估治疗效果。.主要研究内容：收集iMCD患者的临床资料，和疾病活动期及缓解期血清。首先通过蛋白质组学分析，找到与疾病活动度相关的特征性蛋白分子。之后通过ELISA法测定相应蛋白水平，分析其与疾病活动及TCP（沙利度胺-环磷酰胺-泼尼松）方案一线治疗疗效的相关性。.重要结果：首先通过蛋白质组学筛选，发现血清富亮氨酸α2糖蛋白1（LRG1）水平在疾病活动期和缓解期的患者中存在表达差异。后续扩大样本量，共纳入81例iMCD患者的110个血清样本，其中TAFRO患者10例，重型患者40例。采用ELISA法测定疾病活动期和缓解期标本中的LRG1水平：110个血清样本中活动（Flare）期（n=76）患者的血清LRG1水平为113.5±14.27μg/mL，血清学PR（部分缓解）期（n=16）为 47.48±14.23μg/mL，血清学CR（完全缓解）期（n=18）为 14.4±1.18μg/mL；三种疾病状态之间的差异显著（Flare vs PR，p = 0.0019；Flare vs CR，p < 0.0001；PR vs CR，p = 0.0349)。20例患者治疗前后配对样本中的缓解期（PR或CR）血清LRG1水平比活动期平均下降-35.36±5.94μg/mL（p < 0.0001）。另外，部分iMCD-TAFRO患者的疾病活动期血清CRP水平不高，但血清LRG1水平升高。在38例以TCP为一线治疗方案的患者中，20例活动期 LRG1 > 57.75μg/mL患者的中位至下次治疗时间仅为10个月，较18例 LRG1 < 57.75μg/mL患者（30个月）显著更短（HR: 2.254, 95% CI:1.052-4.828，p = 0.0277）。 .科学意义：血清LRG1水平随疾病缓解而显著下降，能够用于治疗疗效监测。可能特别适用于血清CRP水平不高的iMCD-TAFRO患者。基线LRG1 > 57.75μg/mL还可作为TCP方案长期疗效的预测指标。综上，该研究有望为iMCD患者提供一个全新的疗效评估指标。