title: Efficacy of B cell depletion therapy for murine joint arthritis flare is associated with increased lymphatic flow.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Rochester School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Yawen
authors.initials: Y
authors.lastname: Ju
authors.forename: Echoe M
authors.initials: EM
authors.lastname: Bouta
authors.forename: Lianping
authors.initials: L
authors.lastname: Xing
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Wood
authors.forename: Igor
authors.initials: I
authors.lastname: Kuzin
authors.forename: Andrea
authors.initials: A
authors.lastname: Bottaro
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Ritchlin
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000473:pathology / Q000628:therapy*; D001402:B-Lymphocytes; D039481:CD11b Antigen; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007719:Knee Joint / Q000473:pathology*; D008198:Lymph Nodes; D042601:Lymphatic Vessels / Q000473:pathology*; D008212:Lymphocyte Depletion / Q000379:methods*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D013585:Synovitis / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D039481:CD11b Antigen; C509295:ITGAM protein, human