UCL Centre for Nephrology, Royal Free Hospital, Renal and Vascular Inflammation Group, Imperial College London, Hammersmith Hospital and Centre for Rheumatology, University College London, London, UK.
Rheumatology (Oxford). 2014 Sep;53(9):1693-703. doi: 10.1093/rheumatology/keu136. Epub 2014 Apr 11.
B cells are central to the pathology of ANCA-associated vasculitis (AAV), a disease characterized by autoantibodies and effectively treated by rituximab. In addition to promoting inflammation, a subset of B cells act to suppress harmful autoimmune responses (Breg). The balance of effector and regulatory B cell subsets in AAV is not known. This study was conducted to assess the relative frequency of these subsets during different states of disease activity.
B memory (Bmem), naive (Bnaive) and regulatory (Breg) subsets were defined by their relative expression of CD24 and CD38. Function was assessed by cytokine production and suppressive action on CD4(+) Th1 activation evaluated in a co-culture system.
Compared with healthy controls, the frequency of Breg (CD24(hi)CD38(hi)) was significantly reduced during disease remission in both proteinase 3 (PR3)- and MPO-ANCA patients and during acute disease in PR3-ANCA patients, while the frequency of memory cells (CD24(hi)CD38(lo)) was reduced during active disease and restored during remission. Breg cell frequency showed a positive correlation, while Bmem had an inverse correlation with IL-10 production in vitro. B and T cell co-cultures revealed that memory and naive B cell subsets augmented Th1 activation in vitro, which was prevented by Breg, and this pattern did not differ between remission AAV patients and controls.
In remission there is a numerical, but not functional, deficiency in Breg and preservation of Bmem associated with reduced IL-10 production and increased Th1 activation in vitro. This imbalance may contribute to the high rate of relapse observed in AAV, especially in PR3-ANCA patients.
B 细胞是抗中性粒细胞胞浆抗体（ANCA）相关性血管炎（AAV）病理的核心，AAV 是一种以自身抗体为特征的疾病，利妥昔单抗对此病的治疗效果显著。除了促进炎症反应外，B 细胞的一个亚群还具有抑制有害自身免疫反应（Breg）的作用。AAV 中效应和调节性 B 细胞亚群的平衡尚不清楚。本研究旨在评估在不同疾病活动状态下这些亚群的相对频率。
通过相对表达 CD24 和 CD38 来定义 B 记忆（Bmem）、幼稚（Bnaive）和调节（Breg）亚群。通过细胞因子产生和在共培养系统中对 CD4+Th1 激活的抑制作用来评估功能。
与健康对照组相比，蛋白酶 3（PR3）-和髓过氧化物酶（MPO）-ANCA 患者疾病缓解期、PR3-ANCA 患者疾病急性期的 Breg（CD24hiCD38hi）频率均显著降低，而记忆细胞（CD24hiCD38lo）频率在疾病活动期降低，缓解期恢复。Breg 细胞频率与 IL-10 产生呈正相关，而 Bmem 与体外 IL-10 产生呈负相关。B 和 T 细胞共培养显示，记忆和幼稚 B 细胞亚群在体外增强了 Th1 的激活，而 Breg 可防止这种情况，这种模式在缓解期 AAV 患者和对照组之间没有差异。
在缓解期，Breg 存在数量上的而非功能上的缺陷，同时保留与体外 IL-10 产生减少和 Th1 激活增加相关的 Bmem。这种失衡可能导致 AAV 尤其是 PR3-ANCA 患者复发率较高。
