Increased numbers of CD23⁺CD21^hi Bin‐like B cells in human reactive and rheumatoid arthritis lymph nodes

Abstract

A unique population of CD23+ CD21high B cells in inflamed nodes (Bin) has been shown to accumulate in lymph nodes (LNs) draining inflamed joints of TNF-transgenic (TNF-tg) mice. Bin cells contribute to arthritis flare in mice by distorting node architecture and hampering lymphatic flow, but their existence in human inflamed LNs has not yet been described. Here, we report the characterization of resident B-cell populations in fresh popliteal lymph nodes (PLNs) from patients with severe lower limb diseases (non-RA) and rheumatoid arthritis (RA) patients, and from banked, cryopreserved reactive and normal human LN single cell suspension samples. Bin-like B cells were shown to be significantly increased in reactive LNs, and strikingly elevated (>30% of total) in RA samples. Histopathology and immunofluorescence analyses were consistent with B follicular hyperplasia and histological alterations in RA vs. non-RA PLNs. This is the first description of Bin-like B cells in human inflamed LNs. Consistent with published mouse data, this population appears to be associated with inflammatory arthritis and distortion of LN architecture. Further analyses are necessary to assess the role of CD23+CD21hi Bin-like B cells in RA pathogenesis and arthritic flare.

Ex vivo Demonstration of Functional Deficiencies in Popliteal Lymphatic Vessels from TNF-Tg Mice with Inflammatory Arthritis

“…Recent investigations suggest a contribution from circulating IgD + immature B lymphocytes and PRIME cells, as well as synovial macrophage populations (8,9). These novel observations are also consistent with our model of lymphatic dysfunction in RA flare 7, as: 1) the circulating IgD + B-cells may be the Bin cells that we observe within the lymphatic sinuses (20,21,35), 2) the circulating PDPN + PRIME cells may be lymphatic endothelial progenitors that are mobilized to repair damaged lymphatic vessels, and 3) the activated adherent macrophages in the lumen of degenerated PLVs (42) are likely from the afferent inflamed synovium (35,43).…”

“…These longitudinal imaging studies combining contrast enhanced (CE) MRI of the synovium and popliteal lymph node (PLN) (12), with quantification of lymphatic drainage via near infrared (NIR) imaging of an injected dye (indocyanine green, ICG) (15), demonstrated that prior to detectable synovial hyperplasia in the knee, the adjacent PLN expands. This PLN expansion is associated with increased lymphangiogenesis, elevated volume, CD11b + macrophage infiltration, and the accumulation of a unique subset of IgD + /CD23 + /CD21 hi B cells in inflamed nodes (B-in) (15)(16)(17)(18)(19)(20)(21). This asymptomatic "expansion" phase is followed by a sudden "collapse" of the PLN, which is objectively defined by quantitative CE-MRI or power Doppler ultrasound (PD-US) imaging of the PLN (12,22).…”

Brief Report: Treatment of Tumor Necrosis Factor–Transgenic Mice With Anti–Tumor Necrosis Factor Restores Lymphatic Contractions, Repairs Lymphatic Vessels, and May Increase Monocyte/Macrophage Egress

“…Previously, we demonstrated that progression of arthritis in the knee joints of TNF-transgenic mice is paralleled by dramatic changes in the draining lymph nodes (LNs) (6)(7)(8). Those longitudinal imaging studies combining contrast-enhanced magnetic resonance imaging (CE-MRI) of the synovium and popliteal LNs (6) with quantitation of lymphatic drainage via near-infrared (NIR) imaging of an injected dye (indocyanine green [ICG]) (9) demonstrated that prior to detectable synovial hyperplasia in the knee, the adjacent popliteal LN expands due to increased lymphangiogenesis, lymphatic fluid accumulation, CD11b1 macrophage infiltration, and the expansion of a unique subset of CD231/CD21 high B cells in inflamed nodes (5,(9)(10)(11)(12)(13)(14). This asymptomatic "expansion" phase is followed by a sudden "collapse" of the popliteal LN, which is identified by CE-MRI or power Doppler imaging of the popliteal LN (6,15).…”

Power Doppler ultrasonographic assessment of the joint-draining lymph node complex in rheumatoid arthritis: a prospective, proof-of-concept study on treatment with tumor necrosis factor inhibitors

“…This phenomenon is related to translocation of specific B-cell subsets (Bin, B cells in inflamed nodes) in the paracortical sinuses, and is coupled to decreased PD signal and defective lymphatic flow [ 47 , 48 ]. Of relevance, LN Bin, whose presence in humans has been proved recently [ 49 ], can be removed by systemic B-cell depletion [ 47 ], but are marginally affected by anti-TNF [ 50 ]. Introduction of treatment in a phase in which a central lymphatic road-block is active might thus limit some of the beneficial effects of anti-TNF that include peripheral lymphangiogenesis [ 51 ] and increased lymphatic contraction [ 50 ].…”