Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies in our laboratory showed a dose-dependent and hormone-specific increase in CD154 expression in T cells from females with systemic lupus erythematosus (SLE). This present study investigates if the estrogen-dependent increase in CD154 expression is due to stabilization of the messenger RNA. T cells from female SLE patients and controls were cultured for 18 h in serum-free medium without and with estradiol 17-beta (10(-7) M). T cells were either unstimulated (resting) or were activated by further culture on anti-CD3 coated plates. Actinomycin D (25 microg/mL) was added to parallel cultures to inhibit new messenger RNA synthesis. CD154 messenger RNA stability was assessed by reverse-transcription polymerase chain amplification. Resting SLE (n = 10, P = 0.88) and normal (n = 7, P = 0.65) T cells showed no significant differences in message stability in response to estradiol. CD154 messenger RNA was also not significantly stabilized in activated SLE (n = 10, P = 0.15) or activated normal (n = 6, P = 0.077) T cells in response to estradiol. These findings indicate that the estrogen-dependent increase in CD154 in SLE T cells is not due to stability of the mRNA. These data are consistent with the postulate that estradiol stimulates CD154 transcription in SLE T cells.
Lupus 2006
PMID:Estrogen does not regulate CD154 mRNA stability in systemic lupus erythematosus T cells. 1721 90

T cells from patients with systemic lupus erythematosus (SLE) are characterized by heightened TCR-initiated free intracytoplasmic calcium responses. We demonstrate that activated T cells from SLE patients, but not from rheumatoid arthritis patients, displayed higher levels of the calcineurin-dependent transcription factor NF-ATc2 in the nucleus compared with control T cells. DNA NF-AT-binding activity was also increased, as was the amount of NF-ATc2 bound to the promoters of CD154 (CD40L) and IL-2 genes. Nevertheless, although high NF-ATc2 levels translated into higher CD154 transcription in SLE, IL-2 transcription was decreased. The absence of important transcriptional activators (AP-1, NF-kappaBeta) and the presence of transcriptional repressors (cAMP response element modulator) on the IL-2 promoter explain this dichotomous effect.
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PMID:Increased levels of NF-ATc2 differentially regulate CD154 and IL-2 genes in T cells from patients with systemic lupus erythematosus. 1723 47

B cell depletion may affect T cell activation and costimulation status in rituximab-treated patients with SLE. We examined whether rituximab administration in patients with active lupus nephritis is related to changes in mRNA expression of genes that define regulatory T cells (Tregs) in peripheral blood lymphocytes, measured by real-time PCR. At the early phase of B cell depletion mRNA levels of CD25, CTLA-4, GITR and the bona fide Treg functional marker FOXP3 increased significantly in all 7 patients examined. In contrast, mRNA levels of the costimulatory/activation T cell molecule CD40L were profoundly reduced, while mRNA levels of TGF-beta, a cytokine contributing to Treg induction, increased significantly in all. During follow-up, increased FOXP3 mRNA persisted in those patients in clinical remission, while in those patients with active disease subsequent decreases were noted. Further studies should examine whether modulation of Tregs by therapeutic B cell depletion contributes and/or predicts lupus disease remission.
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PMID:Increased expression of the FoxP3 functional marker of regulatory T cells following B cell depletion with rituximab in patients with lupus nephritis. 1727 13

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

SLE is a systemic autoimmune disease characterized by B cell hyperactivity. Evidence from the last years has shown that B cells play a key role in the development of the immune response. The interaction of CD40 on B cells with its ligand CD154 on activated T cells provides a costimulatory signal that induces T dependent B cell proliferation and differentiation with subsequent antibody production. Moreover, CD154 can act as a cytokine, in addition to its main role to mediate the interactions between T and CD40+ target cells. This review focuses on the multiple roles of CD154 in systemic lupus erythematosus and rheumatoid arthritis and its involvement in the humoral immunity disregulation of patients with these diseases. It also takes in consideration the most recent therapeutic perspectives regarding the use of monoclonal antibodies against CD154, which might be a powerful tool in the treatment of these diseases in the future.
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PMID:Costimulatory molecule CD154 in systemic lupus erythematosus and rheumatoid arthritis. Therapeutic perspectives. 1787 13

The aim was to explore the role of prolactin (PRL) in the lymphocyte activation process in systemic lupus erythematosus (SLE) patients in an in vitro model. Peripheral blood mononuclear cells (PBMCs) were isolated from SLE patients and healthy individuals. The mRNA for PRL and its receptor obtained by standard techniques, with an appropriate primer, were subjected to polymerase chain reaction (PCR) and visualized. The PBMCs were cultured with (a) medium alone as a negative control, (b) unspecific mitogen as a positive control, (c) PRL alone, (d) mitogen plus PRL, (e) mitogen plus antibody anti-PRL, and (f) mitogen plus a nonrelated antibody. Then CD69 and CD154 were determined by flow cytometry analysis. Twelve inactive and 15 active SLE patients were studied. Twenty-five percent of the active patients displayed hyperprolactinemia. Under basal conditions CD69 expression was associated with disease activity. The PBMCs activated in vitro were capable of producing and secreting PRL, measured by mRNA and Nb2 assay. In a similar way, the mRNA for the PRL receptor was visualized. Cells from SLE patients cultivated with PRL alone did not display increased CD69 and CD154 expression. The addition of PRL to the unspecific stimulated culture does not have an additive effect. In contrast, the addition of antibodies against PRL in order to block the autocrine PRL resulted in a striking reduction of CD69 and CD154 expression.
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PMID:Effect of prolactin on lymphocyte activation from systemic lupus erythematosus patients. 1789 82

Deficiency in complement proteins such as C1q is associated with the development of systemic lupus erythematosus (SLE). Here, we show that the differentiation of dendritic cells (DC) in the presence of C1q (C1qDC) gives rise to CD1a(+)/DC-SIGN(+) cells with high phagocytic capacity and low expression of CD80, CD83 and CD86. Further, when C1qDC were exposed to LPS, a significant reduction in the production of IL-6, TNF-alpha and IL-10 occurred with a limited up-regulation of CD80, CD83 and CD86. In addition, C1qDC were less responsive to activation by CD40L in terms of IL-12p70 secretion and CD86 expression. C1qDC showed an impaired ability to stimulate alloreactive T cells, with a reduced production of IFN-gamma. In conclusion, we have shown that C1q is a potent modulator of DC, resulting in cells characterized by an impaired capacity of cytokine production and an impaired up-regulation of costimulatory molecules, leading to a limited T cell response. Therefore, we hypothesize that, next to a pivotal role in the safe clearance of apoptotic cells, C1q regulates the threshold of DC activation and thereby prevents hyperactivation of the overall immune response.
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PMID:Immune modulation of human dendritic cells by complement. 1789 52

Allogeneic mixed chimerism achieved by low-dose total body irradiation (TBI) and anti-CD40L monoclonal antibody (mAb) with donor bone marrow transplantation (BMT) and host T cell depletion overcomes both allo- and autoimmunity. We investigated whether a similar regimen without T cell depletion cured diffuse proliferative glomerulonephritis. Male BXSB mice (H-2b) were injected with 20 x 10(6) BALB/c (H-2d) BM cells. When indicated, 3 Gy TBI on day -1 and anti-CD40LmAb (2 mg) on day 0 of BMT was given. Skin grafting was performed 1 day after BMT. BXSB mice were divided into four groups--I: BMT with TBI and anti-CD40LmAb; II: TBI; III: TBI and anti-CD40LmAb; and IV: no treatment. Chimerism in peripheral blood was analyzed. The kidney was examined histologically. TBI with anti-CD40LmAb and BMT allowed induction of multilineage mixed chimerism and donor-specific tolerance to skin grafts without graft-versus-host disease (GVHD). There was significant decrease in glomerular PAS-positive material deposition score, glomerular cell numbers, IgG, and C3 deposition in chimeric mice. All chimeric mice survived. Allogeneic mixed chimerism induced by a less toxic, nonlymphoablative regimen achieved allograft tolerance and cured glomerulonephritis in BXSB lupus mice.
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PMID:Allogenic mixed chimerism induced by nonlymphoablative regimen including donor BMT with low-dose TBI and anti-CD40L cured proliferative glomerulonephritis in lupus mice. 1791 51

Why systemic lupus erythematosus primarily affects women is unknown. Recent evidence indicates that human lupus is an epigenetic disease characterized by impaired T cell DNA methylation. Women have two X chromosomes; one is inactivated by mechanisms including DNA methylation. We hypothesized that demethylation of sequences on the inactive X may cause gene overexpression uniquely in women, predisposing them to lupus. We therefore compared expression and methylation of CD40LG, a B cell costimulatory molecule encoded on the X chromosome, in experimentally demethylated T cells from men and women and in men and women with lupus. Controls included TNFSF7, a methylation-sensitive autosomal B cell costimulatory molecule known to be demethylated and overexpressed in lupus. Bisulfite sequencing revealed that CD40LG is unmethylated in men, while women have one methylated and one unmethylated gene. 5-Azacytidine, a DNA methyltransferase inhibitor, demethylated CD40LG and doubled its expression on CD4(+) T cells from women but not men, while increasing TNFSF7 expression equally between sexes. Similar studies demonstrated that CD40LG demethylates in CD4(+) T cells from women with lupus, and that women but not men with lupus overexpress CD40LG on CD4(+) T cells, while both overexpress TNFSF7. These studies demonstrate that regulatory sequences on the inactive X chromosome demethylate in T cells from women with lupus, contributing to CD40LG overexpression uniquely in women. Demethylation of CD40LG and perhaps other genes on the inactive X may contribute to the striking female predilection of this disease.
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PMID:Demethylation of CD40LG on the inactive X in T cells from women with lupus. 1794 13

Lupus-prone NZB/W F1 mice develop glomerulonephritis after T helper cell-dependent isotype switching of autoantibody secretion from IgM to IgG at about 6 months of age. We compared innate immune natural killer (NK) T cells and conventional T cells for their capacity to help spontaneous in vitro immunoglobulin and autoantibody secretion of innate immune (B-1 and marginal zone) and conventional (follicular) B cell subsets from NZB/W F1 mice. We found that purified NKT cells not only increased spontaneous secretion of IgM and IgM anti-double-stranded (ds)DNA antibodies by B-1 and marginal zone B cells, but also facilitated secretion of IgG anti-dsDNA antibodies predominantly by B-1 B cells. Few IgM or IgG anti-dsDNA antibodies were secreted by follicular B cells, and conventional T cells failed to provide potent helper activity to any B cell subset. All combinations of T and B cell subsets from normal C57BL/6 mice failed to generate vigorous IgM and IgG secretion. NZB/W NKT cell helper activity was blocked by anti-CD1 and anti-CD40L mAb. In conclusion, direct interactions between innate immune T and B cells form a pathway for the development of IgM and IgG lupus autoantibody secretion in NZB/W mice.
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PMID:Natural killer T cells and innate immune B cells from lupus-prone NZB/W mice interact to generate IgM and IgG autoantibodies. 1805 Feb 73


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