The online version of this article (doi:10.1186/ar3452) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
JL performed most of the experiments, analyzed the data and participated in the manuscript draft. QZ participated in part of the ICG-NIR lymphatics imaging and data analysis. IK helped with flow cytometry. RWW, AB, LX and CTR provided scientific input and helped with manuscript editing. EMS designed the study, and drafted and finalized the manuscript. All authors read and approved the final manuscript.
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+/CD21hi 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.
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.
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.
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.
Brunner HI, Lovell DJ, Finck BK, Giannini EH: Preliminary definition of disease flare in juvenile rheumatoid arthritis. J Rheumatol. 2002, 29: 1058-1064. PubMed
Bingham CO, Pohl C, Woodworth TG, Hewlett SE, May JE, Rahman MU, Witter JP, Furst DE, Strand CV, Boers M, Alten RE: Developing a standardized definition for disease "flare" in rheumatoid arthritis (OMERACT 9 Special Interest Group). J Rheumatol. 2009, 36: 2335-2341. 10.3899/jrheum.090369. CrossRefPubMed
Ringold S, Bittner R, Neogi T, Wallace CA, Singer NG: Performance of rheumatoid arthritis disease activity measures and juvenile arthritis disease activity scores in polyarticular-course juvenile idiopathic arthritis: Analysis of their ability to classify the American College of Rheumatology pediatric measures of response and the preliminary criteria for flare and inactive disease. Arthritis Care Res (Hoboken). 2010, 62: 1095-1102. 10.1002/acr.20205. CrossRef
Gio-Fitman J: The role of psychological stress in rheumatoid arthritis. Medsurg Nurs. 1996, 5: 422-426. PubMed
Pullinger BD, Florey HW: Proliferation of lymphatics in inflammation. J Pathol Bacteriol. 1937, 45: 157-170. 10.1002/path.1700450115. CrossRef
Olszewski WL, Pazdur J, Kubasiewicz E, Zaleska M, Cooke CJ, Miller NE: Lymph draining from foot joints in rheumatoid arthritis provides insight into local cytokine and chemokine production and transport to lymph nodes. Arthritis Rheum. 2001, 44: 541-549. 10.1002/1529-0131(200103)44:3<541::AID-ANR102>3.0.CO;2-6. CrossRefPubMed
Grillet B, Dequeker J: Rheumatoid lymphedema. J Rheumatol. 1987, 14: 1095-1097. PubMed
Zhang Q, Guo R, Lu Y, Zhao L, Zhou Q, Schwarz EM, Huang J, Chen D, Jin ZG, Boyce BF, Xing L: VEGF-C, a lymphatic growth factor, is a RANKL target gene in osteoclasts that enhances osteoclastic bone resorption through an autocrine mechanism. J Biol Chem. 2008, 283: 13491-13499. 10.1074/jbc.M708055200. PubMedCentralCrossRefPubMed
Guo R, Zhou Q, Proulx ST, Wood R, Ji RC, Ritchlin CT, Pytowski B, Zhu Z, Wang YJ, Schwarz EM, Xing L: Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritis. Arthritis Rheum. 2009, 60: 2666-2676. 10.1002/art.24764. PubMedCentralCrossRefPubMed
Troyan SL, Kianzad V, Gibbs-Strauss SL, Gioux S, Matsui A, Oketokoun R, Ngo L, Khamene A, Azar F, Frangioni JV: The FLARE intraoperative near-infrared fluorescence imaging system: a first-in-human clinical trial in breast cancer sentinel lymph node mapping. Ann Surg Oncol. 2009, 16: 2943-2952. 10.1245/s10434-009-0594-2. PubMedCentralCrossRefPubMed
Proulx ST, Kwok E, You Z, Papuga MO, Beck CA, Shealy DJ, Ritchlin CT, Awad HA, Boyce BF, Xing L, Schwarz EM: Longitudinal assessment of synovial, lymph node, and bone volumes in inflammatory arthritis in mice by in vivo magnetic resonance imaging and microfocal computed tomography. Arthritis Rheum. 2007, 56: 4024-4037. 10.1002/art.23128. PubMedCentralCrossRefPubMed
Li J, Kuzin I, Moshkani S, Proulx ST, Xing L, Skrombolas D, Dunn R, Sanz I, Schwarz EM, Bottaro A: Expanded CD23(+)/CD21(hi) B cells in inflamed lymph nodes are associated with the onset of inflammatory-erosive arthritis in TNF-transgenic mice and are targets of anti-CD20 therapy. J Immunol. 2010, 184: 6142-6150. 10.4049/jimmunol.0903489. PubMedCentralCrossRefPubMed
Ji H, Ohmura K, Mahmood U, Lee DM, Hofhuis FM, Boackle SA, Takahashi K, Holers VM, Walport M, Gerard C, Ezekowitz A, Carroll MC, Brenner M, Weissleder R, Verbeek JS, Duchatelle V, Degott C, Benoist C, Mathis D: Arthritis critically dependent on innate immune system players. Immunity. 2002, 16: 157-168. 10.1016/S1074-7613(02)00275-3. CrossRefPubMed
Tsutsumi R, Hock C, Bechtold CD, Proulx ST, Bukata SV, Ito H, Awad HA, Nakamura T, O'Keefe RJ, Schwarz EM: Differential effects of biologic versus bisphosphonate inhibition of wear debris-induced osteolysis assessed by longitudinal micro-CT. J Orthop Res. 2008, 26: 1340-1346. 10.1002/jor.20620. PubMedCentralCrossRefPubMed
- CD23+/CD21hi B-cell translocation and ipsilateral lymph node collapse is associated with asymmetric arthritic flare in TNF-Tg mice
Ronald W Wood
Christopher T Ritchlin
Edward M Schwarz
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II