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...

Objective-We have previously shown that intravenous apolipoprotein A-I/phosphatidylcholine (apoA-I/PC) discs increase plasma pre-␤ HDL concentration and stimulate reverse cholesterol transport (RCT) in humans. We have now investigated the associated changes in the following 3 HDL components that play key roles in RCT: lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), and phospholipid transfer protein (PLTP he inverse relationship between plasma HDL cholesterol concentration and incidence of coronary heart disease (CHD) is well documented. 1,2 Although the mechanism of the antiatherogenic effect of HDLs is unclear, their role in reverse cholesterol transport (RCT) seems to explain at least part of the effect. 3 The HDLs are composed of numerous subpopulations that undergo continuous remodelling by enzymes and lipid transfer proteins that are associated with the particles. These include lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), and phospholipid transfer protein (PLTP). 4 -6 During RCT, small lipid-poor apolipoprotein (apo) A-I containing pre-␤ HDLs in tissue fluid take up free cholesterol (FC) from peripheral cells. The FC is esterified in plasma by LCAT, and the resultant cholesteryl esters (CEs) enter the cores of spheroidal ␣HDLs. 7 In some species (including humans), some CEs are transferred from ␣HDLs to apoBcontaining lipoproteins by CETP and are then taken up by hepatocytes as a consequence of receptor-mediated catabolism of remnant and LDLs. Other CEs in ␣HDLs are transferred directly to hepatocytes via SR-BI receptors. 8 Phospholipid transfer protein is thought to play an important role in RCT by catalyzing the transfer of phospholipids to ␣HDLs from triglyceride-rich lipoproteins and by inducing fusion of ␣HDLs, generating pre-␤ HDLs in the process. 9 -11 Increased potential for pre-␤ HDL production has been described in mice with stable or transient adenovirusmediated expression of human PLTP. 12,13 The extent to which the actions of PLTP, LCAT, and CETP might be coordinately regulated to facilitate RCT is not known. Nor is there information on the degree to which they are influenced by variations in nascent HDL secretion rate.

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Abstract-When cultured cells are exposed to plasma, the initial acceptors of unesterified cholesterol are small lipid-poor apolipoprotein A-I (apoA-I)-containing high density lipoproteins (HDLs) with pre-␤ electrophoretic mobility. These are converted by lecithin:cholesterol acyltransferase into larger spheroidal cholesteryl ester-rich HDLs with ␣ mobility. To study the determinants of the concentration of small pre-␤ HDLs in tissue fluids, we collected prenodal peripheral lymph from 34 fasted normal men. By crossed immunoelectrophoresis, the concentration of pre-␤ HDLs in lymph averaged 20% of that in plasma. On multiple regression analysis, pre-␤ apoA-I concentration in lymph was directly related to pre-␤ apoA-I concentration in plasma and independently to ␣ apoA-I concentration in lymph. Similar results were obtained when the same apoA-I-containing particles were quantified by size exclusion chromatography. Lymph pre-␤ apoA-I concentration was low in a subject with familial lecithin:cholesterol acyltransferase deficiency, despite a normal plasma pre-␤ apoA-I concentration, but was normal in a subject with familial lipoprotein lipase deficiency. These results suggest that the concentration of small pre-␤ HDLs in human tissue fluids is determined only in part by the transfer of pre-␤ HDLs across capillary endothelium from plasma.

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 ؎ Conclusion. High lymph concentrations of cyto-