Lymph draining from foot joints in rheumatoid arthritis provides insight into local cytokine and chemokine production and transport to lymph nodes

Abstract

Objective Rheumatoid arthritis (RA) is characterized by inflammatory reactions in joints and adjacent tissues unaccompanied by clinically evident changes in lymphatics and lymph nodes draining the inflamed areas. The explanation for this phenomenon, which contrasts with infectious processes in joints and soft tissues that evoke major changes in the lymphatic system, is unclear. To determine which inflammatory factors produced in the joints of RA patients are transported in lymph to lymph nodes, we measured levels of immunoglobulins, cytokines, and chemokines in prenodal lymph from the foot joints of RA patients and quantified their rate of transport to regional lymph nodes. Methods Lymph was collected from the cannulated lymphatics draining the foot joints, tendons, fascia, and skin of 20 RA patients. Lymph flow rate and concentrations of proteins and immunoglobulins were measured. Cytokine and chemokine levels were quantified by enzyme‐linked immunosorbent assays. Results were compared with those obtained in 20 control subjects. Results In the cannulated vessel, the mean ± SEM lymph flow rate in RA patients was almost 2‐fold that in control subjects (22.6 ± 3.2 ml/24 hours versus 13.2 ± 1.1 ml/24 hours; P < 0.01). Lymph concentrations of total protein, IgG, and IgM were 1.80 ± 0.14 gm/dl, 384 ± 45 mg/dl, and 32.0 ± 1.5 mg/dl, respectively, in RA patients and 1.66 ± 0.14 gm/dl, 238 ± 32 mg/dl, and 15.0 ± 1.3 mg/dl, respectively, in control subjects. The corresponding lymph:serum (L:S) ratios were 0.21 ± 0.02, 0.22 ± 0.02, and 0.15 ± 0.02, respectively, in RA patients and 0.22 ± 0.02, 0.19 ± 0.02, and 0.11 ± 0.02, respectively, in control subjects. The L:S ratios of <1 and the absence of significant differences between groups suggested a lack of local production of immunoglobulins. In RA patients, lymph concentrations (in pg/ml) were as follows: interleukin‐1β (IL‐1β) 14.8 ± 3.9, IL‐6 511 ± 143, tumor necrosis factor α (TNFα) 9.9 ± 1.1, IL‐1 receptor antagonist (IL‐1Ra) 4,274 ± 737, IL‐10 13.3 ± 4.4, IL‐8 846 ± 174, IL‐15 6.2 ± 0.9, granulocyte–macrophage colony‐stimulating factor (GM‐CSF) 2.30 ± 0.15, vascular endothelial growth factor (VEGF) 80.4 ± 8.6, and macrophage inflammatory protein 1α (MIP‐1α) 171 ± 34. In control subjects, these values were as follows: IL‐1β 1.50 ± 0.25, IL‐6 79.0 ± 14.6, TNFα 4.4 ± 1.1, IL‐1Ra 208 ± 52, IL‐10 0.0, IL‐8 216 ± 83, IL‐15 5.00 ± 0.45, GM‐CSF 0.40 ± 0.05, VEGF 42.0 ± 2.4, and MIP‐1α 3.4 ± 1.7 (P < 0.05 versus RA patients for all except IL‐15). The L:S ratio was >1 in all RA patient samples for IL‐1β, IL‐6, IL‐1Ra, IL‐8, GM‐CSF, IL‐10, IL‐15, TNFα, and MIP‐1α, indicating local production of cytokines. Great variability in lymph cytokine concentrations, presumably reflecting differences in the intensity of local inflammation, was not reflected in serum cytokine concentrations. Intravenously infused methylprednisolone decreased lymph cytokine levels to normal within 12 hours. In contrast, their concentrations in serum showed little or no change. Conclusion High lymph c...

Cutting Edge: Rapid Accumulation of Epidermal CCL27 in Skin-Draining Lymph Nodes following Topical Application of a Contact Sensitizer Recruits CCR10-Expressing T Cells

“…This vessel was cannulated and lymph was collected by retrograde flow over 24 h (to minimize differences in capillary filtration rate due to positioning effects) into heparinized tubes at 2-h intervals as described (15,16). All human subject experiments were performed with the approval of institutional authorities by two of the authors (W.L.O.…”

Simulation of Monoclonal Antibody Pharmacokinetics in HumansUsing a Minimal Physiologically Based Model

“…By making the (31,27). In order to achieve a steady-state interstitial space: plasma ratio as high as 0.17 it was necessary to use a reflection coefficient of 0.62.…”

“…The baseline plasma level of TNF-α in subjects with rheumatoid arthritis (R max =4.4E-6 μM; CV 30%) and values for the degradation rate of TNF-α (k deg ) (0.877 1/h; CV 30%) were taken from published values (27,28). The TNF-α synthesis rate (k syn ) was calculated for each subject using the relationship R max ×k deg , and the degradation of the adalimumab-TNF-α complex was assumed to be the same as the degradation rate of endogenous TNF-α.…”

“…Various values of σ v were tried in the model. With the values used for lymph flow in the model it was found that a value of 0.62 was needed for this parameter to give a reasonable interstitial concentration of endogenous IgG (steady-state interstitial space: plasma ratio of 0.17) compared with experimental data (27,31).…”

Oedema, infiltration and drainage of connective tissue in rheumatoid arthritis – a preliminary report

“…In 2001, Olszewski et al [24] reported to have found that the average lymph flow rate from cannulated prenodal lymphatic vessels in RA patients doubled as compared with healthy individuals in the control group. They reported the standard cell concentration in the lymph to be 5-120/µl and double in RA patients.…”