title: CD23(+)/CD21(hi) B-cell translocation and ipsilateral lymph node collapse is associated with asymmetric arthritic flare in TNF-Tg mice.
abstract: BACKGROUND
  Rheumatoid arthritis (RA) is a chronic autoimmune disease with episodic flares in affected joints. However, how arthritic flare occurs only in select joints during a systemic autoimmune disease remains an enigma. To better understand these observations, we developed longitudinal imaging outcomes of synovitis and lymphatic flow in mouse models of RA, and identified that asymmetric knee flare is associated with ipsilateral popliteal lymph node (PLN) collapse and the translocation of CD23(+)/CD21(hi) B-cells (B-in) into the paracortical sinus space of the node. In order to understand the relationship between this B-in translocation and lymph drainage from flaring joints, we tested the hypothesis that asymmetric tumor necrosis factor (TNF)-induced knee arthritis is associated with ipsilateral PLN and iliac lymph node (ILN) collapse, B-in translocation, and decreased afferent lymphatic flow.
  
  
  METHODS
  TNF transgenic (Tg) mice with asymmetric knee arthritis were identified by contrast-enhanced (CE) magnetic resonance imaging (MRI), and PLN were phenotyped as "expanding" or "collapsed" using LNcap threshold = 30 (Arbitrary Unit (AU)). Inflammatory-erosive arthritis was confirmed by histology. Afferent lymphatic flow to PLN and ILN was quantified by near infrared imaging of injected indocyanine green (NIR-ICG). The B-in population in PLN and ILN was assessed by immunohistochemistry (IHC) and flow cytometry. Linear regression analyses of ipsilateral knee synovial volume and afferent lymphatic flow to PLN and ILN were performed.
  
  
  RESULTS
  Afferent lymph flow to collapsed nodes was significantly lower (P < 0.05) than flow to expanding nodes by NIR-ICG imaging, and this occurred ipsilaterally. While both collapsed and expanding PLN and ILN had a significant increase (P < 0.05) of B-in compared to wild type (WT) and pre-arthritic TNF-Tg nodes, B-in of expanding lymph nodes (LN) resided in follicular areas while B-in of collapsed LN were present within LYVE-1+ lymphatic vessels. A significant correlation (P < 0.002) was noted in afferent lymphatic flow between ipsilateral PLN and ILN during knee synovitis.
  
  
  CONCLUSIONS
  Asymmetric knee arthritis in TNF-Tg mice occurs simultaneously with ipsilateral PLN and ILN collapse. This is likely due to translocation of the expanded B-in population to the lumen of the lymphatic vessels, resulting in a dramatic decrease in afferent lymphatic flow. PLN collapse phenotype can serve as a new biomarker of knee flare.
authors: Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA.
authors: Jie
authors: J
authors: Li
authors: Quan
authors: Q
authors: Zhou
authors: Ronald W
authors: RW
authors: Wood
authors: Igor
authors: I
authors: Kuzin
authors: Andrea
authors: A
authors: Bottaro
authors: Christopher T
authors: CT
authors: Ritchlin
authors: Lianping
authors: L
authors: Xing
authors: Edward M
authors: EM
authors: Schwarz
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D002469:Cell Separation; D005434:Flow Cytometry; D007839:Functional Laterality / Q000502:physiology; D007150:Immunohistochemistry; D008196:Lymph; D008198:Lymph Nodes / Q000276:immunology* / Q000473:pathology; D042601:Lymphatic Vessels / Q000473:pathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017464:Receptors, Complement 3d / Q000276:immunology; D017455:Receptors, IgE / Q000276:immunology; D013055:Spectrophotometry, Infrared; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D017464:Receptors, Complement 3d; D017455:Receptors, IgE; D014409:Tumor Necrosis Factor-alpha