Li Jie, Ju Yawen, Bouta Echoe M, Xing Lianping, Wood Ronald W, Kuzin Igor, Bottaro Andrea, Ritchlin Christopher T, Schwarz Edward M
University of Rochester School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York 14642, USA.
Arthritis Rheum. 2013 Jan;65(1):130-8. doi: 10.1002/art.37709.
B cell depletion therapy ameliorates rheumatoid arthritis by mechanisms that are incompletely understood. Arthritis flare in tumor necrosis factor (TNF)-transgenic mice is associated with efferent lymph node (LN) "collapse," triggered by B cell translocation into lymphatic spaces and decreased lymphatic drainage. The aim of this study was to examine whether the efficacy of B cell depletion therapy is associated with restoration of lymphatic drainage due to removal of obstructing nodal B cells.
We used contrast-enhanced magnetic resonance imaging, indocyanine green near-infrared imaging, and intravital immunofluorescence imaging to longitudinally assess synovitis, lymphatic flow, and cell migration in lymphatic vessels in TNF-transgenic mice. We conducted tests to determine whether the efficacy of B cell depletion therapy is associated with restoration of lymphatic draining and cell egress from arthritic joints.
Unlike active lymphatics to normal and prearthritic knees, afferent lymphatic vessels to collapsed LNs in inflamed knees do not pulse. Intravital immunofluorescence imaging demonstrated that CD11b+ monocyte/macrophages in lymphatic vessels afferent to expanding LNs travel at high velocity (mean±SD 186±37 μm/second), while these cells are stationary in lymphatic vessels afferent to collapsed popliteal LNs. B cell depletion therapy for arthritis flares in TNF-transgenic mice significantly decreased knee synovium volume (by 50% from the baseline level) and significantly increased lymphatic clearance compared with placebo (P<0.05). This increased lymphatic drainage restored macrophage egress from inflamed joints without recovery of the lymphatic pulse.
These results support a novel mechanism in which B cell depletion therapy for joint arthritis flares lessens inflammation by increasing lymphatic drainage and subsequent migration of cells and cytokines from the synovial space.
B细胞清除疗法改善类风湿性关节炎的机制尚不完全清楚。肿瘤坏死因子（TNF）转基因小鼠的关节炎发作与传出淋巴结（LN）“塌陷”有关，这是由B细胞转移到淋巴管腔隙以及淋巴引流减少所触发的。本研究的目的是探讨B细胞清除疗法的疗效是否与因清除阻塞性淋巴结B细胞而恢复淋巴引流有关。
我们使用对比增强磁共振成像、吲哚菁绿近红外成像和活体免疫荧光成像，纵向评估TNF转基因小鼠的滑膜炎、淋巴流动以及淋巴管中的细胞迁移。我们进行了测试，以确定B细胞清除疗法的疗效是否与恢复淋巴引流以及炎性关节中的细胞流出有关。
与正常和关节炎前期膝关节的活跃淋巴管不同，炎症膝关节中塌陷淋巴结的传入淋巴管不搏动。活体免疫荧光成像显示，流入肿大淋巴结的淋巴管中的CD11b+单核细胞/巨噬细胞快速移动（平均±标准差为186±37μm/秒），而这些细胞在流入腘窝淋巴结塌陷处的淋巴管中是静止的。与安慰剂相比，针对TNF转基因小鼠关节炎发作的B细胞清除疗法显著降低了膝关节滑膜体积（从基线水平降低50%），并显著增加了淋巴清除率（P<0.05）。这种增加的淋巴引流恢复了巨噬细胞从炎症关节的流出，而淋巴管搏动未恢复。
这些结果支持了一种新机制，即针对关节关节炎发作的B细胞清除疗法通过增加淋巴引流以及随后细胞和细胞因子从滑膜腔的迁移来减轻炎症。
