Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Asymmetric Arthritic Flare in the Knees of TNF-Tg Mice Is Mediated by Expansion of CD23/CD21hi B Cells and Ipsilateral Collapse of Lymph Nodes in Series.
Li, Jie, Kuzin, Igor, Ritchlin, Christopher, Sanz, Ignacio, Bottaro, Andrea, Xing, Lianping, Schwarz, Edward
The efficacy of TNF antagonists and anti-CD20 therapy has demonstrated a critical role for TNF and B cells in the pathogenesis of rheumatoid arthritis (RA). However, the mechanism underlying arthritic flare and asymmetric arthritis in particular joints is still unknown. Previously, we used contrast-enhancement (CE) MRI and near infrared (NIR) indocyanine green (ICG) lymphatic imaging to evaluate arthritis in TNF-Tg mice, and demonstrated that arthritic progression from the ankle to the knee joint occurs following a sudden decrease in lymphatic flow from the lower limb to the adjacent popliteal lymph node (PLN). This decrease in lymphatic flow to "expanding" PLNs with high lymphatic drainage capacity (LNcap) lead to a "collapsed" PLN phenotype characterized by a marked decreases in LNcap, and translocation of CD23+/CD21hi B cells in inflamed nodes (Bin) from the follicles into the sinus space. Interestingly, this pathology is asymmetric in time to occurrence and incidence, and some TNF-Tg mice never develop bilateral knee arthritis. Since lymph from the ankle drains to PLN and lymph from knee joint drains to the iliac lymph node (ILN), we hypothesized that the correlation of PLN collapse and arthritic flare in the adjacent knee is caused by inhibited lymph drainage of the lower limb due to simultaneous collapse of ipsilateral PLN and ILN, and tested this in our murine model.
57 month old TNF-Tg mice with expanding or collapsed PLNs were identified by longitudinal CE-MRI, and their knees were phenotyped for arthritic flare (defined as synovial volume >3mm3). PLNs (n>10) and ILNs (n>10) were harvested from the TNF-Tg, and their WT littermate controls, for flow cytometry or immunohistochemistry (IHC) to quantify Bin and their location within the node. Lymphatic draining function of PLN and ILN were measured by NIR of ICG injected into the footpad or knee cavity respectively.
Flow cytometry of ILNs revealed a significant (p<0.05) 2.8-fold expansion of the Bin population from 7.2% in WT to 19.8% in TNF-Tg, which was consistent with the significant (p<0.05) 3.3-fold increase from 10% to 33.2% observed in WT and TNF-Tg PLN respectively. While Bin numbers were similar in both expanding and collapsed PLNs, IHC revealed that ILN ipsilateral to collapsed PLN have similar lymphoid architecture in which Bin are depleted from the follicular region, and reside in paracotical LYVE+ lymphatic sinuses. NIR-ICG imaging revealed that lymph flow to ILN ipsilateral to expanding PLNs (S-max=255) is 1.7-fold greater than that of ILN ipsilateral to collapsed PLNs (S-max=151.4).
Our results showed that ipsilateral ILN and PLN function in series. The decrease of lymphatic flow from the lower limb and Bin translocation from the follicles into lymphatic sinuses of draining LNs occur simultaneously. This finding supports a novel mechanism of the asymmetric arthritic flare that is triggered by Bin translocation in draining LN, which results in decreased afferent lymph flow from the inflamed joint. Future studies aimed establish this Bin "clogging" phenomena in mice and RA patients will be discussed.
To cite this abstract, please use the following information:
Li, Jie, Kuzin, Igor, Ritchlin, Christopher, Sanz, Ignacio, Bottaro, Andrea, Xing, Lianping, et al; Asymmetric Arthritic Flare in the Knees of TNF-Tg Mice Is Mediated by Expansion of CD23/CD21hi B Cells and Ipsilateral Collapse of Lymph Nodes in Series. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1710