Abstract
IntroductionRheumatoid 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.MethodsTNF 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.ResultsAfferent 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.ConclusionsAsymmetric 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.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease with episodic flares in affected joints
Afferent lymph flow to collapsed nodes was significantly lower (P < 0.05) than flow to expanding nodes by near infrared imaging of injected indocyanine green (NIR-ICG) imaging, and this occurred ipsilaterally. While both collapsed and expanding popliteal lymph node (PLN) and iliac lymph node (ILN) had a significant increase (P < 0.05) of B cells in inflamed nodes (B-in) compared to wild type (WT) and pre-arthritic tumor necrosis factor transgenic (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
Assessment of the images, analysis of the contrast-enhanced magnetic resonance imaging (CE-magnetic resonance imaging (MRI)) data presented in Table 1 revealed non-overlapping threshold values (LN CE = 5 arbitrary unit (AU) and LNcap = 30 AU) that were subsequently used as objective criteria to define the PLN as expanding or collapsed
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease with episodic flares in affected joints. 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. One potential key variable in the development of arthritic flare is regional efferent lymphatic flow from RA joints It has been known for almost 75 years that lymphatic vessels proliferate at sites of inflammation [10], but the contribution of lymph clearance has been largely overlooked until recently [11]. Case reports with lymphoscintigraphy have posited that patients with tenosynovial inflammation and normal lymphatic drainage demonstrate improved pharmacologic responses and improved clinical outcomes compared to patients with chronic lymphatic vascular damage and persistent oedema [16,17], this theory has yet to be tested in animal models or clinical trials
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