From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins.
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Rheumatoid arthritis is a common and debilitating autoimmune disease whose cause and mechanism remain a mystery. We recently described a T cell receptor transgenic mouse model that spontaneously develops a disease with most of the clinical, histological, and immunological features of rheumatoid arthritis in humans. Disease development in K/BxN mice is initiated by systemic T cell self-reactivity; it requires T cells, as expected, but B cells are also needed, more surprisingly. Here, we have identified the role of B cells as the secretion of arthritogenic immunoglobulins. We suggest that a similar scenario may unfold in some other arthritis models and in human patients, beginning with pervasive T cell autoreactivity and ending in immunoglobulin-provoked joint destruction. (+info)
Fibroblast-like synoviocytes from rheumatoid arthritis patients have intrinsic properties of follicular dendritic cells.
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The production of IgG rheumatoid factors in the inflamed synovium of many patients with rheumatoid arthritis (RA) implies that local sites exist where plasma cell precursors undergo isotype switching and affinity maturation by somatic mutation and selection. Lymphonodular infiltrates of the synovium-containing germinal centers (GCs), are candidates to fulfill such function in the rheumatoid patient. It has been suggested that these GCs are organized around, obviously ectopic, follicular dendritic cells (FDCs). The present study attempts to find out whether these putative FDCs 1) are specific for RA, 2) have the same phenotype and functional capacity as FDCs in lymphoid organs, and 3) may locally differentiate from fibroblast-like synoviocytes (FLS). Synovial biopsies from patients with RA versus non-RA, yet arthritic backgrounds, were compared. Cells with the FDC phenotype were found in both RA and non-RA tissues as well as in single cell suspensions thereof. When FLS were cultured in vitro, part of these cell lines could be induced with IL-1beta and TNF-alpha to express the FDC phenotype, irrespective of their RA or non-RA background. By contrast, the FDC function, i.e., stable binding of GC B cells and switching off the apoptotic machinery in B cells, appeared to be the prerogative of RA-derived FLS only. The present data indicate that FDC function of FLS in RA patients is intrinsic and support the idea that synovial fibroblast-like cells have undergone some differentiation process that is unique for this disease. (+info)
The beta2-adrenergic agonist salbutamol is a potent suppressor of established collagen-induced arthritis: mechanisms of action.
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The therapeutic potential of salbutamol, a beta2-adrenergic agonist, was explored in collagen-induced arthritis. This study was based on a report that salbutamol, by elevating intracellular cAMP, inhibits IL-12 production by macrophages and dendritic cells, thus preventing Th1 development. Ten-week-old male DBA/1 mice were immunized by intradermal injection of type II collagen in CFA. Arthritis developed 15-30 days later and the mice were treated after onset of disease with salbutamol, 200 microgram i.p. After 10 days, the mice were sacrificed, and the hind paws were evaluated histologically. Salbutamol, 200 microgram daily or every other day, had a profound therapeutic effect on the clinical progression of arthritis, as assessed by clinical score and paw thickness. The therapeutic effect was dose dependent. Daily administration of 200 microgram of salbutamol offered the best protection against joint damage, as assessed by histology. In vitro, salbutamol reduced IL-12 and TNF-alpha release by peritoneal macrophages in a dose-dependent manner, as well as TNF release by synovial cells from arthritic mice. Ex vivo, draining lymph node cells of the salbutamol-treated arthritic mice showed a diminished CII-specific IFN-gamma production and proliferation. In vivo, salbutamol specifically blocked mast cell degranulation in joint tissues. In conclusion, salbutamol has important effects on the immunoinflammatory response and a significant therapeutic action in collagen-induced arthritis. (+info)
High pleural fluid hyaluronan concentrations in rheumatoid arthritis.
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Previous studies have shown that high pleural fluid (Pf) hyaluronan (HYA) concentrations may be due not only to malignant mesothelioma but also to inflammatory diseases. The objective of this study was to evaluate Pf-HYA in various nonmalignant inflammatory pleural disorders. A radiometric assay was used to determine HYA in Pf and serum (S) of 126 patients, 12 of whom had rheumatoid arthritis (RA), 22 tuberculosis, 22 pneumonia, 41 lung cancer, 10 malignant mesothelioma and 19 congestive heart failure. Pf-HYA values were correlated with values for Pf-tumour necrosis factor (TNF)-alpha and Pf-interleukin (IL)-1beta, as determined by radioimmunoassay. The highest median Pf-HYA (125.6 mg x L(-1), range 0.04-386.5 mg x L(-1)) occurred in patients with malignant mesothelioma. Among patients with nonmalignant inflammatory diseases, significantly higher median Pf-HYA were observed in those with rheumatoid arthritis (64.2 mg x L(-1), range 25.8-106.9 mg x L(-1)) than in those with tuberculosis (25.5 mg x L(-1), range 14.9-57.1 mg x L(-1), p<0.0005) or pneumonia (20.9 mg x L(-1), range 9.5-129.4 mg x L(-1), p<0.005). There was no correlation between Pf-HYA and S-HYA. Pf-HYA correlated positively with Pf-TNF-alpha (r=0.62) and Pf-IL-1beta (r=0.52). High pleural fluid hyaluronan occurs not only in malignant mesothelioma, but also in certain nonmalignant inflammatory diseases, especially rheumatoid arthritis. One explanation for the increase in pleural fluid hyaluronan may be local production of proinflammatory cytokines, such as tumour necrosis factor-alpha and interleukin-1beta. (+info)
Synovial fluid T cells from patients with rheumatoid arthritis are refractory to the T helper type 2 differentiation-inducing effects of interleukin-4.
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The balance between T helper type 1 (Th1) and Th2 cytokines is thought to be important in the initiation and outcome of autoimmune diseases. The goal of the present study was to compare the production of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) by synovial fluid (SF) and peripheral blood (PB) CD4+ and CD8+ cells from patients with rheumatoid arthritis (RA) using three-colour immunofluorescence staining and flow cytometry, and to investigate the capacity of IL-4, IL-10 and IL-12 to modify the cytokine production profile of SF T cells. The frequency of IFN-gamma-producing CD4+ and CD8+ cells was significantly increased in SF when compared with PB. In contrast to IFN-gamma, the expression of IL-4 in SF and PB T cells was comparable. The majority of IL-4-producing cells in SF belonged to Th0/T cytotoxic (Tc) type 0 phenotype, whereas there were significantly more Th2/Tc2 cells in PB than in SF. Interestingly, IL-4 was unable to induce differentiation of non-adherent SF mononuclear cells (SFMC) into Th2 cells, whereas PB mononuclear cells (PBMC) under similar culture conditions differentiated into cells producing high levels of IL-4, IL-10 and IL-13. In contrast, there were no major differences in the effects of IL-10 and IL-12 on the cytokine production profile of SFMC when compared with PBMC. Taken together, the present results suggest that SF T cells from patients with RA are terminally differentiated into Th1/Tc1-like phenotype, and Th2/Tc2 differentiation-inducing agents, such as IL-4, may not be able to reverse the inflammatory process occurring in the joints. (+info)
Interleukin-4 regulation of human monocyte and macrophage interleukin-10 and interleukin-12 production. Role of a functional interleukin-2 receptor gamma-chain.
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Interleukin-4 (IL-4) is the prototypic type 2 immunoregulatory cytokine that can suppress the production of many monocyte and macrophage pro-inflammatory mediators. In this study we investigated the regulation by IL-4 of IL-12 and IL-10 production. While IL-4 suppressed lipopolysaccharide (LPS)-induced IL-12 and IL-10 production by human peripheral blood monocytes, IL-4 suppressed LPS-induced IL-12, but not IL-10, production by synovial fluid mononuclear cells from patients with rheumatoid arthritis. IL-4 also suppressed IL-12, but not IL-10 production, by LPS-stimulated in vitro monocyte-derived macrophages. Similarly, IL-4 cannot suppress LPS-induced tumour necrosis factor-alpha (TNF-alpha) production by synovial fluid cells and monocyte-derived macrophages. The failure of IL-4 to regulate IL-10 production is not due to the failure of IL-4 to suppress TNF-alpha, and vice versa. The data suggest that the IL-4 receptor subunit, gammac, is essential for IL-4 regulation of LPS-induced IL-10 production and that a correlation exists between duration of monocyte culture, reduction in gammac mRNA in cultured cells and hyporesponsiveness of monocyte-derived macrophages to IL-4 for regulation of LPS-induced IL-10 production. This study highlights the importance of investigating responses to IL-4, as a potential therapeutic anti-inflammatory agent, by cells isolated from inflammatory sites and not by the more easily accessible blood monocytes. This study emphasizes the involvement of signalling from gammac in IL-4 regulation of LPS-induced IL-10 production by monocytes and macrophages. (+info)
Sustained elevated levels of VCAM-1 in cultured fibroblast-like synoviocytes can be achieved by TNF-alpha in combination with either IL-4 or IL-13 through increased mRNA stability.
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Rheumatoid arthritis is characterized by hyperplasia of the synovial lining and invasion of cartilage and bone by a subset of resident synovial cells named fibroblast-like synoviocytes. They are characterized by elevated expression of the vascular cell adhesion molecule-1 (VCAM-1). The intensity of VCAM-1 expression correlates with the degree of inflammation of the synovial joint. Differential VCAM-1 expression may determine inflammatory cell accumulation through its interaction with leukocytes that express the counterreceptor integrins alpha4beta1 and alpha4beta7. Elevated levels of VCAM-1 expression are thought to be a consequence of the presence of inflammatory mediators, in particular IL-1beta and TNF-alpha. Fibroblast-like synoviocytes rapidly up-regulate VCAM-1 expression in response to IL-1beta and TNF-alpha, but also to IL-4. However, we now show that the response to IL-1beta or TNF-alpha is of a brief transient nature, even when applied continuously over a period of 12 days, whereas the response to IL-4 or IL-13 is sustained. Great synergy is obtained by combining either IL-4 or IL-13 with TNF-alpha, which results in a highly elevated but also sustained expression of VCAM-1. The mechanism by which IL-4 or IL-13 prolongs VCAM-1 expression can be explained by a dramatic increase in the half-life of VCAM-1 mRNA. (+info)
Expression of receptor tyrosine kinase Axl and its ligand Gas6 in rheumatoid arthritis: evidence for a novel endothelial cell survival pathway.
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Angiogenesis and synovial cell hyperplasia are characteristic features of rheumatoid arthritis (RA). Many growth and survival factors use receptors belonging to the tyrosine kinase family that share conserved motifs within the intracellular catalytic domains. To understand further the molecular basis of cellular hyperplasia in RA, we have used degenerate primers based on these motifs and RNA obtained from the synovium of a patient with RA to perform reverse transcriptase-polymerase chain reaction. We report detection of the receptor tyrosine kinase (RTK) Axl in RA synovium and we document the expression pattern of Axl in capillary endothelium, in vascular smooth muscle cells of arterioles and veins, and in a subset of synovial cells in RA synovial tissue. Gas6 (for growth arrest-specific gene 6), which is a ligand for Axl and is related to the coagulation factor protein S, was found in synovial fluid and tissue from patients with RA and osteoarthritis. Axl expression and function was studied in human umbilical vein endothelial cells (HUVECs). Gas6 bound to HUVECs; soluble Axl inhibited this binding. Exogenous Gas6 protected HUVECs from apoptosis in response to growth factor withdrawal and from TNFalpha-mediated cytotoxicity. These findings may reveal a new aspect of vascular physiology, which may also be relevant to formation and maintenance of the abnormal vasculature in the rheumatoid synovium. (+info)