Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thromboembolism is a common occurrence in patients with the antiphospholipid syndrome (APS). The mechanism responsible for this phenomenon is unclear; there are several theories. One possibility is that a pathogenic interaction exists between antiphospholipid antibodies and platelets, leading to their activation. This study examined the expression of the platelet activation markers CD62 and CD63 by flow cytometry in 20 patients with the primary antiphospholipid syndrome (PAPS). Levels of soluble P-selectin were also assayed. Reticulated platelets were measured as an indicator of increased platelet production and/or turnover. Median CD63 expression was significantly increased in patients (14.3%) compared to a group of healthy controls (10.1%, P = 0.0008). There was no significant difference in median CD62 expression or percent reticulated platelets between the two groups. The median level of soluble P-selectin was significantly higher in PAPS patients (35.5 ng/ml) compared to controls (18.8 ng/ml, P = 0.0028). Patients receiving aspirin had lower median CD63 values (13.1%) when compared to those patients who were not (18.0%, P = 0.023). However, aspirin therapy did not prevent significant platelet activation occurring in some individual patients. Our data suggest that although not excessive, there is a degree of increased platelet activation in some PAPS patients, which is not always suppressed by antiplatelet therapy with aspirin.
Lupus 1998
PMID:Platelet activation and turnover in the primary antiphospholipid syndrome. 969 37

Platelets play an important part in normal haemostasis, and are likely to be involved in the thromboembolism seen in the primary antiphospholipid syndrome (PAPS). Evidence exists for platelet activation in this disorder, and new flow cytometric techniques have made it possible to detect low levels of activation. We have previously studied the expression of the platelet activation markers CD62p and CD63, percentage of reticulated platelets, and levels of soluble P-selectin in a group of PAPS patients. Median platelet CD63 expression and plasma soluble P-selectin levels were significantly increased in PAPS patients compared to a group of controls; there was no difference in reticulated platelet percentages between the two groups. Additional assays of platelet activation (PAC-1 expression, Annexin V binding, platelet microparticles and complexes) are being developed and assessed with respect to disease activity, thrombosis risk and effects of antithrombotic therapy.
Lupus 1998
PMID:Platelet activation markers and the primary antiphospholipid syndrome (PAPS). 981 73

Lupus erythematosus tumidus (LET) is a disease with characteristic clinical and histopathologic features that has not always been considered a subset of cutaneous lupus erythematosus (CLE). Although LET was first mentioned in the literature in 1930, it has rarely been documented, and immunohistochemical studies have never been performed. The aim of the present study was to characterize the inflammatory infiltrate and to analyze the expression of endothelial cell adhesion molecules in skin specimens from patients with LET and to compare the results with those from patients with other variants of CLE, such as discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE). Cryostat sections of lesional skin specimens from ten patients with LET demonstrated an infiltrate composed of more than 75% CD4+, CD8+, and HLA-DR+ cells. Interestingly, CD45RO+ cells, in contrast to CD45RA+ cells, were the prevailing inflammatory cell population. Compared with skin specimens from patients with DLE and SCLE, the mean expression of CD4+ and CD8+ cells was higher (but not significantly so) in LET, and no differences were observed with the other three antibodies. Furthermore, in contrast to controls, intercellular adhesion molecule-1, vascular adhesion molecule-1, E-selectin, and P-selectin showed the same expression pattern in skin specimens from patients with DLE, SCLE, and LET. In conclusion, the inflammatory infiltrate of LET primarily consists of CD4+/CD8+ lymphocytes. Furthermore, expression of endothelial cell adhesion molecules was equally upregulated in LET compared with the expression in DLE and SCLE, suggesting a similar immunopathomechanism of these subtypes of CLE.
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PMID:Characterization of the inflammatory infiltrate and expression of endothelial cell adhesion molecules in lupus erythematosus tumidus. 1207 Nov 56

The association of antiphospholipid (aPL) antibodies with thrombosis in patients with antiphospholipid syndrome (APS) is well documented in humans and in animal studies. However, the mechanisms by which aPL antibodies induce thrombosis are the subject of much current study. It has been suggested that aPL may activate endothelial cells (ECs), thus creating a hypercoagulable state that precedes and contributes to thrombosis in patients with APS. Several studies have shown that aPL upregulate ECs' adhesion molecules (CAMs): intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin (E-sel) or induce tissue factor (TF) in monocytes in vitro. Similarly, the incubation of EC with antibodies reacting with beta2glycoprotein I (beta2GPI) has been shown to induce EC activation with concomitant upregulation of CAMs, IL-6 production and alteration of prostaglandin metabolism. Our group has shown that aPL-mediated upregulation of adhesion molecules on ECs correlates with an increased adhesion of leukocytes to endothelium in the microcirculation of mouse cremaster muscle, a n indication of EC activation in vivo, andwith enhanced thrombosis in vivo. In another series of studies, investigators have shown that upregulation of expression of adhesion molecules by some murine monoclonal anti-beta2glycoprotein I (anti-beta2GPI) antibodies correlated with fetal resorption in mice in vivo. More recently, one study showed that the anti-hypercholesterolaemic drug fluvastatin inhibited the aPL-mediated enhanced adhesion of monocytes to ECs in vitro. Data from our laboratories indicate that fluvastatin also reverses thrombus formation and activation of EC induced by aPL in an in vivo mouse model. As additional support for the hypothesis that aPL antibodies activate ECs and may create an hypercoagulable state in APS patients, two recent studies indicated that levels of soluble ICAM-1 and VCAM-1 were significantly increased in the plasma of patients with APS and recurrent thrombosis. Furthermore, studies utilizing knockout mice and specific monoclonal anti-VCAM-1 antibodies have demonstrated that expression of ICAM-1, P-selectin, E-selectin and VCAM-1 are important in in vivo aPL-mediated thrombosis and EC activation in mice. Recent data suggests that aPL antibodies also induce expression of TF not only in monocytes but in ECs. Hence, the interference of aPL with the TF mechanism may be another important mechanism by which these antibodies create a hypercoagulable state and prone patients to thrombosis. Specifically, how aPL alters EC activation state and the molecular and intracellular mechanisms involved have not yet been defined. APL may interact with specific cell surface receptors (proteins and/or lipids) induce signals that have consequences downstream, and that ultimately will result in upregulation of cell surface proteins (i.e., CAMs and TF) and subsequently induce EC activation. In that regard, our group recently showed that aPL-mediated upregulation of adhesion molecules in ECs is preceded by activation of the nuclear factor kappa B (NFkappaB). Other intracellular mechanisms triggered by aPL are not completely understood and are the subject of current investigation. In conclusion, studies suggest that activation of ECs by aPL is an important mechanism that may precede thrombus formation in patients with APS. Hence, the interplay between aPL antibodies and ECs is important inthe pathogenesis of thrombosis in APS.
Lupus 2003
PMID:Probing antiphospholipid-mediated thrombosis: the interplay between anticardiolipin antibodies and endothelial cells. 1289 95

IL-12 and IFN-gamma play key roles in murine lupus and planted antigen models of glomerulonephritis. However, their roles in renal organ-specific autoimmunity are unknown. To establish the roles of endogenous IFN-gamma and IL-12 in experimental autoimmune anti-glomerular basement membrane (GBM) glomerulonephritis (EAG), EAG was induced in normal C57BL/6 mice (WT), IL-12p40-deficient (IL-12p40-/-) mice, and IFN-gamma-deficient (IFN-gamma-/-) mice by immunization with alpha3-alpha5(IV)NC1 heterodimers. At 13 wk, WT mice developed EAG with linear mouse anti-GBM antibody deposition, histologic injury, proteinuria, and mild tubulointerstitial disease. Compared with WT mice, IL-12p40-/- mice had decreased histologic injury and trends to decreased leukocyte infiltrates. In contrast, 40% (4 of 10) of IFN-gamma-/- mice developed significant crescent formation and focal or diffuse interstitial infiltrates (WT, 0 of 8). Compared with WT and/or IL-12p40-/- mice, IFN-gamma-/- mice developed increased injury: histologic injury, total glomerular cell numbers, leukocytes in glomeruli, and renal expression of P-selectin and intercellular adhesion molecule 1. All groups developed similar serum anti-alpha3-alpha5(IV)NC1 antibodies and glomerular Ig deposition, but IFN-gamma-/- mice had decreased anti-alpha3-alpha5(IV)NC1 IgG2a. Therefore, IFN-gamma-/- mice developed increased cellular reactants despite a potentially less damaging antibody response. Dermal delayed-type hypersensitivity was increased in alpha3-alpha5(IV)NC1 immunized IFN-gamma-/- mice and was suppressed by recombinant murine IFN-gamma. CD4+ cells from draining nodes of immunized IFN-gamma-/- mice showed increased proportions of proliferating CD4+ cells but similar numbers of apoptotic cells. These studies demonstrate that in renal organ-specific autoimmunity, IL-12 is pathogenetic but IFN-gamma is protective. They lend weight to the hypothesis that depending on the context/severity of the nephritogenic immune response IFN-gamma has different effects.
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PMID:Experimental autoimmune anti-glomerular basement membrane glomerulonephritis: a protective role for IFN-gamma. 1521 64

Mycophenolate mofetil (MMF) has been reproducibly shown to inhibit lymphocyte adhesion and penetration of endothelial cell surfaces. The mechanism is not yet elucidated. In vitro studies on the effects of MMF on cell adhesion molecules (CAM) using human umbilical vein endothelial cells (HUVEC) have shown conflicting results. Different studies have independently shown that MMF increased, decreased or had no effect on intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1). Several studies suggest MMF may reduce the endothelial expression of E-selectin. Recent studies have been unable to replicate initial work, which suggested that MMF impaired glycosylation of lymphocyte CAM. The same studies concluded that MMF had no effect on the surface expression of lymphocyte CAM, but altered the binding ability of these molecules. ICAM-1/LFA-1 (lymphocyte function-associated antigen-1), VCAM-1/VLA-4 (very late antigen-4) and P-selectin/PSGL-1 (P-selectin glycoprotein ligand-1) ligand pairs are most likely to be involved. Few in vivo and no conclusive human studies have been carried out. The literature relevant to cell adhesion molecules in systemic lupus erythematosus (SLE) is reviewed in detail.
Lupus 2005
PMID:Adhesion molecules, mycophenolate mofetil and systemic lupus erythematosus. 1580 27

Individuals with lupus anticoagulants (LA) are at risk for thromboembolism (TE). Chronic inflammation is an important characteristic in LA patients which may dispose for TE. Platelets play a key role in inflammation and TE. We therefore investigated gene polymorphisms as well as plasma levels of platelet receptors as predictors of TE in 107 LA patients. We compared 74 patients with a history of thromboembolic disease (TE+), 56 with venous thrombosis (VT), 12 with arterial thrombosis (AT), and six patients who had both, with 33 LA patients without previous thrombosis (TE-). The P-selectin Pro715 allele was slightly more frequent in VT (OR = 3.167,95% CI 0.955-10.503; p = 0.0594), but no patient with AT had this allele (OR = 0.099, 95 % CI 0.001-0.790; p = 0.0238) which therefore may protect from AT. Plasma levels of P-selectin, collected a median of 35 months (range 2-329 months) after the last thrombotic event, were higher in patients withVT (p = 0.0096) than in TE-, but not with AT (p = 0.4713). These high P-selectin levels were not explained by the P-selectin polymorphism. The CA repeat polymorphism in the 3'-noncoding region of CD154 was significantly associated with the development of AT (OR = 4.035,95 % CI 1.329-12.249; p = 0.0138). Plasma levels of CD154 were not significantly different among the subgroups. Thus, the Thr715Pro polymorphism of P-selectin and CA repeats of CD154 are differentiating between the risk for VT and AT. Further, soluble P-selectin is elevated in LA patients with previous VT, but its role to predict VT needs to be evaluated in prospective studies.
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PMID:The risk for thromboembolic disease in lupus anticoagulant patients due to pathways involving P-selectin and CD154. 1739 20

Renal pathology in systemic lupus erythematosus involves both autoantibody deposition and a cellular inflammatory response, both of which are mediated by effector CD4 T cells. MRL(lpr) mice spontaneously develop massive perivascular infiltrates, but the pathways that regulate the development, trafficking, and effector functions of kidney-infiltrating T cells are poorly defined. To address these questions, we first surveyed inflammatory chemokine protein levels in nephritic kidneys from lupus-prone MRL(lpr) mice. After identifying highly elevated levels of the CXCR3 ligand CXCL9, we found that kidney-infiltrating effectors are enriched for expression of CXCR3, as well as P-selectin ligand and ICOS. Using genetic ablation, we demonstrate that ICOS plays an essential role in the establishment of renal perivascular infiltrates, although a small number of infiltrating cells remain around the blood vessels. Interestingly, though IgG autoantibody production is substantially reduced in Icos(-/-) MRL(lpr) mice, the progression of immune complex glomerulonephritis is only modestly diminished and the production of inflammatory chemokines, such as CXCL9, remains high in the kidney. We find that Icos(-/-) effector cell numbers are only slightly reduced and these have normal expression of CXCR3 and P-selectin ligand with intact migration to CXCL9. However, they have impaired production of inflammatory cytokines and fail to show evidence of efficient proliferation in the kidney. Thus, while dispensable for acquisition of renal trafficking receptor expression, ICOS is strictly required for local inflammatory functions of autoreactive CD4 T cells in murine lupus.
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PMID:ICOS controls effector function but not trafficking receptor expression of kidney-infiltrating effector T cells in murine lupus. 1929 5

Lupus anticoagulants (LACs) are associated with thromboembolic complications (TECs). LACs can be detected by their anticoagulant properties in thrombin generation assays, by the peak height (PH) and lag time (LT). To assess the thrombotic risk in LAC-positive patients, we have expressed the LAC activity quantitatively by PH/LT calibration curves, constructed for mixtures of monoclonal antibodies against beta2-glycoprotein I (beta2GPI) and prothrombin, spiked in normal plasma. PH/LT was determined in LAC patients, with (n = 38) and without (n = 21) TECs and converted into arbitrary LAC units. LAC titers ranged from 0 to 200 AU/mL, with 5 of 59 patients being negative. In the positive LAC titer population (54 of 59), LAC and anti-beta2GPI immunoglobulin G (IgG) titers correlated with TECs, with odds ratios of 3.54 (95% CI, 1.0-1.7) and 10.0 (95% CI, 1.98-50.6), respectively. In patients with single or combined low titers, useful predictions on thrombosis could be made only after additional measurements of soluble P-selectin and factor VII. This layered strategy yielded positive and negative predictive values, sensitivity, and specificity values approximately 90% in this subgroup. Hence, LAC and anti-beta2GPI IgG titers, when combined with selected markers of the hypercoagulable state, allow a relevant thrombotic risk assessment in nearly all patients with LACs.
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PMID:Thrombotic risk assessment in the antiphospholipid syndrome requires more than the quantification of lupus anticoagulants. 1996 29

The aims of this study are to investigate the cytokine, chemokine and adhesion molecule profiles in cerebrospinal fluid from patients with neuropsychiatric systemic lupus erythematosus and systemic lupus erythematosus with central nervous system infection. Experimental sets were established which included 108 patients and 132 cerebrospinal fluid samples. The patients were grouped as neuropsychiatric systemic lupus erythematosus (n = 54), systemic lupus erythematosus with central nervous system infection (n = 16), systemic lupus erythematosus controls (n=20), and non-inflammatory neurological disease (n=18). The dynamic changes of 21 patients in the neuropsychiatric systemic lupus erythematosus group before and after induction therapy were further analyzed. IL-1 beta, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, TNFalpha, IFN gamma, IP-10, MCP-1, RANTES, VCAM-1, and P-selectin were measured in cerebrospinal fluid samples by using a fluorescent bead-based assay. Cerebrospinal fluid levels of IL-8, MCP-1, P-selectin and VCAM-1 were significantly increased in neuropsychiatric systemic lupus erythematosus compared with systemic lupus erythematosus controls. IL-6, IL-17, IL-8 and VCAM-1 were higher in systemic lupus erythematosus with central nervous system infection than in systemic lupus erythematosus controls. Among systemic lupus erythematosus with central nervous system infection, the IL-6, IL-17, IL-8 and IP-10 levels were higher than those in neuropsychiatric systemic lupus erythematosus. After sufficient induction therapy, IL-8, MCP-1, P-selectin, VCAM-1 and IL-6 in patients with neuropsychiatric systemic lupus erythematosus decreased significantly. Levels of all molecules tested in non-inflammatory central nervous system disease were not different from those of systemic lupus erythematosus controls. From our data, the intrathecal cytokine/chemokine profile is different among patients with neuropsychiatric systemic lupus erythematosus, systemic lupus erythematosus complicated with central nervous system infection and systemic lupus erythematosus controls. IL-8, MCP-1, VCAM-1, P-selectin and IL-6 in cerebrospinal fluid are effective parameters to monitor neuropsychiatric systemic lupus erythematosus disease activity and response to treatment. Significantly elevated IL-17, IL-6, and to a lesser extent, IL-8, favors central nervous system infection in systemic lupus erythematosus.
Lupus 2010 May
PMID:Intrathecal cytokine and chemokine profiling in neuropsychiatric lupus or lupus complicated with central nervous system infection. 2017 68


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