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)

Activation-induced cell death (AICD) plays an important role in the regulation of the immune response by eliminating preactivated and potentially autoreactive cells. To elucidate possible abnormalities of AICD in human systemic lupus erythematosus (SLE), we studied AICD in activated T cells from patients with SLE and normal controls. CD3-mediated cell death was determined in short-term T cell lines by flow cytometry using propidium iodide staining and analysis of DNA subdiploid peak populations. It was found to be significantly lower in T cells from SLE patients compared to cells from normal controls. Anti-Fas mAb-mediated cell death was similar in SLE and control cell lines. CD3-mediated AICD could be blocked in control and SLE T cell lines by an IgG anti-Fas mAb. Indirect immunofluorescence analysis showed statistically significantly less intracellular TNF-alpha in SLE T cells than in control cells. These data show that activated T cells from patients with SLE are relatively resistant to a TCR-mediated death stimulus although they display intact anti-Fas mAb-mediated cell death. Defective antigen-mediated cell death can contribute to increased numbers of activated autoreactive cells in lupus patients.
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PMID:Defective CD3-mediated cell death in activated T cells from patients with systemic lupus erythematosus: role of decreased intracellular TNF-alpha. 893 8

Nitric oxide is involved as a messenger molecule in a large number of physiologic and pathologic responses. Local generation of high nitric oxide output through the expression of the calcium-independent, cytokine-inducible form of nitric oxide synthase (iNOS) can result in either protective or damaging effects. The development of drugs that specifically suppress iNOS expression or inhibit its activity may therefore provide an excellent therapeutic tool for treatment of a diverse set of dysfunctions, including asthma, inflammatory processes, and autoimmune disease. We show compelling evidence that linomide, an immunomodulator known to ameliorate autoimmune diseases, prevents accumulation in the macrophages of mRNA encoding iNOS in mice injected with LPS. This effect is partially mediated by the blocking of TNF-alpha and IL-beta production by activated macrophages. Here, we also present evidence that kidneys from MRL/Mp-lpr/lpr mice express high iNOS levels when the mice develop glomerulonephritis. The administration of linomide to MRL/Mp-lpr/lpr mice significantly decreases iNOS mRNA levels and prevents the development of glomerulonephritis, extending the half-life of mice of this strain. This linomide effect is compatible with its role in preventing the development of autoimmune disease and extends its possible use to other pathologic manifestations associated with iNOS expression, such as the systemic lupus erythematosus-associated glomerulonephritis present in MRL/Mp-lpr/lpr mice.
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PMID:Linomide administration to mice attenuates the induction of nitric oxide synthase elicited by lipopolysaccharide-activated macrophages and prevents nephritis in MRL/Mp-lpr/lpr mice. 901 85

We followed cytokine production from induction through disease progression in a murine model of experimental systemic lupus erythematosus (SLE). SLE was induced by immunization with the human monoclonal anti-DNA Ab that bears the common Id designated 16/6 Id. BALB/c and C3H.SW mice that are susceptible to SLE induction and C57BL/6 mice that are resistant were immunized with the 16/6 Id. Cytokine production was tested periodically for 7 mo. Increased production of IL-2 and IFN-gamma, the Th1-type cytokines, was detected in BALB/c and C3H.SW mice 2 to 4 mo following immunization. IL-4 and IL-10, the Th2-type cytokines predominated later in disease course, and peaked 5 mo following disease induction. At this stage the Th1 type cytokines dropped to levels below those observed in controls. IL-4 production also dropped rapidly to very low levels, while IL-10 production decreased but remained above control levels. The ratio of IgG2a/IgG1 of DNA and 16/6 Id-specific Abs peaked at 2 mo following disease induction and decreased later, in concordance with the higher production of Th2-type cytokines. Thus, the development of experimental SLE in mice involves two stages: increased production of Th1-type, followed by increased induction of Th2-type cytokines. High levels of the proinflammatory cytokines, TNF-alpha and IL-1, were maintained throughout disease course. No significant changes were detected in the cytokine profile of C57BL/6 immunocytes following immunization with the 16/6 Id, supporting the possible role of the cytokine network in SLE.
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PMID:Kinetics of cytokine production in experimental systemic lupus erythematosus: involvement of T helper cell 1/T helper cell 2-type cytokines in disease. 905 40

Estrogen has been suspected of causing changes in the lupus disease process by an as yet undetermined mechanism. In vitro apoptosis of peripheral blood mononuclear cells (PBMCs) in short-term unstimulated cultures of systemic lupus erythematosus (SLE) cells is accelerated compared to that in cells from normal individuals. To determine whether estrogen might be involved in regulating the rate of apoptosis in lupus, PBMCs or T cells from women with or without normal menstrual cycles were cultured for 16-20 hr with or without 30 ng/ml estradiol. The rate of apoptosis of the cells was measured, and supernatants of these cultures were tested for various cytokines known to affect apoptosis directly or indirectly. Compared to untreated cultures, estrogen significantly reduced in vitro apoptosis of both patient (P < 0.05, n = 12) and normal (P < 0.001, n = 14) PBMCs if the donors had normal menstrual cycles. Estrogen did not decrease apoptosis of noncycling patient (n = 8) nor of normal (n = 11) cells. Apoptosis of T cells cultured alone was not affected by estrogen. Supernatants from patients' estrogen-treated PBMCs had significantly less TNF-alpha than untreated cultures (P < 0.05, n = 12). TNF-alpha levels from normals' cell cultures were unchanged. Changes in hormone status (hysterectomy or menopause) alter estrogen-sensitive apoptosis, which may be mediated through monocytes. Estrogen-induced decreases in apoptosis combined with decreased TNF-alpha production in the presence of estrogen may allow survival of auto-immune cells in SLE patients.
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PMID:Estrogen decreases in vitro apoptosis of peripheral blood mononuclear cells from women with normal menstrual cycles and decreases TNF-alpha production in SLE but not in normal cultures. 907 49

We have investigated TNF microsatellite polymorphisms in SLE and their association with both HLA class II alleles and disease expression. A total of 91 Caucasoid SLE and 109 matched Caucasoid controls were recruited for this study. TNF microsatellites a, b and d were typed using fluorescent based semi-automated gene scanning. TNF a2, b3 and d2 allele frequencies were significantly increased in the SLE group compared to controls. These alleles were found to be part of an extended HLA-DRB1*0301 haplotype and have previously been associated with high TNF-alpha production. When the SLE group was analyzed according to presentation of certain clinical features, photosensitivity and Raynaud's phenomenon, the frequency of these alleles (TNF a2, b3 and d2) were also significantly increased. No significant increase in the allele frequencies of TNF a2, b3 and d2 was demonstrated in the group of patients with renal involvement. These data suggest that TNF microsatellite alleles are not independent of HLA associations in SLE and may be important in the expression of certain clinical features in SLE.
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PMID:TNF microsatellite a2, b3 and d2 alleles are associated with systemic lupus erythematosus. 909 28

TNFa, TNFb and TNFc microsatellites were analyzed in 102 SLE patients recruited from a defined area in Southern Sweden. Furthermore we studied 27 SLE patients belonging to 10 multiplex families in which a majority of the members were living within the same area in Southern Sweden. As a control population 98 healthy blood donors from the same region was used. The TNFa2 allele was found more often in the SLE patients (48%) than in the normal controls (33%) (P < 0.01). A low frequency of the TNFa4 allele (10%) vs 16% in controls was observed. The family study showed that the TNFabc haplotype 2-3-1 was more common in SLE associated haplotypes than in non-SLE haplotypes (P < 0.001). The 2-3-1 haplotype was associated with the extended haplotype MHC haplotype [HLA-B8,SC01,DR17]. The results suggest that TNF haplotypes do not constitute special markers of susceptibility to SLE but reflect the increased frequencies of specific intact haplotypes already known to be associated with the disease.
Lupus 1996 Dec
PMID:TNF microsatellites in systemic lupus erythematosus-a high frequency of the TNFabc 2-3-1 haplotype in multicase SLE families. 911 7

We have previously shown in inbred strains of mice which naturally develop systemic lupus erythematosus that kidney C3, C2, C4 and factor B gene expression increases coincidently with the occurrence of glomerulonephritis, suggesting that local tissue complement gene expression could contribute to the pathogenesis of immune complex injury. In this study, we investigated the synthesis of complement proteins in glomerular epithelial cells (GECs) and its regulation. Using biosynthetic labelling, immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, we demonstrated that GECs synthesized C1r, C1s, C1 inhibitor, C3, C2 and factor B. Interferon-gamma induced increases in the synthesis of all these proteins. Both factor B and C3 proteins were increased following addition of either IL-1beta, IL-6 or TNF-alpha to GEC cultures; however, these cytokines did not increase either C2, C1r, C1s or C1-inhibitor biosynthesis. Lipopolysaccharide affected the biosynthesis of these proteins in a similar way. A semiquantitative analysis of the mRNA expression of some of these proteins by reverse-transcriptase polymerase chain reaction showed that these cytokine effects were pretranslational as there was enhancement of factor B mRNA expression by IL-1, TNF-alpha, IFN-gamma, IL-6 and endotoxin, but only IFN-gamma enhanced C1-inhibitor and C4 mRNA expression. These results may be of significance in the immunopathogenesis of glomerulonephritis, where it is likely that local complement production in GECs is independently regulated by cytokines, derived from resident glomerular mesangial cells or infiltrating monocyte/macrophages and T cells.
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PMID:Differential cytokine regulation of complement proteins in human glomerular epithelial cells. 922 27

It has recently been found that in systemic lupus erythematosus (SLE), a multisystem inflammatory disorder characterized by autoantibody production and decreased cellular immune response, increased spontaneous production of IL-10 occurs. The immunomodulator AS101 (ammonium trichloro(dioxoethylene-0,0')tellurate) was previously shown to significantly decrease IL-10 levels in cancer patients and in murine models. This study shows that AS101 inhibits the development of SLE-related autoimmune pathological manifestations. AS101 decreased the spontaneous IL-10 production by mononuclear cells from SLE patients in vitro. In vivo, systemic injection of AS101 to SCID mice transplanted with mononuclear cells from SLE patients significantly decreased serum human IL-10 levels. There was also a decrease in all serum human Ig isotypes, in anti-dsDNA, and in anti-Sm Igs. In the New Zealand Black/New Zealand White/F1 model, AS101 significantly increased serum TNF-alpha and IFN-gamma while decreasing IL-10 levels; these changes were accompanied by a rapid decrease in anti-dsDNA and anti-ssDNA Igs. More importantly, continuous treatment of New Zealand Black/New Zealand White/F1 mice with AS101 for 6 mo led to the development of proteinuria in 30% of the treated mice compared with 100% in PBS-treated mice (p < 0.001). AS101 treatment reduced the level of immmune complex deposition in the glomeruli, prevented glomerular hypercellularity and mesangial expansion and led to a much smaller mean glomerular volume in treated mice (185 +/- 6 vs 428 +/- 47.103 microm3; p < 0.01). We suggest that treatment with a nontoxic immunomodulator such as AS101, previously used in phase II trials on cancer patients, may be an effective therapeutic approach for controlling SLE.
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PMID:Delay in the onset of systemic lupus erythematosus following treatment with the immunomodulator AS101: association with IL-10 inhibition and increase in TNF-alpha levels. 930 Jun 85

Low TNF production and its association with TNF gene restriction fragment length polymorphism (RFLP) was demonstrated in (NZW/NZB) F1 mice. However, little is known about the significance of TNF production in association with TNF gene polymorphism in human SLE. This study was designed to evaluate the role of TNF production of peripheral blood mononuclear cells (PBMC) and its association with TNFB gene polymorphism in SLE, particularly lupus nephritis. TNFB gene polymorphism was defined by PCR-NcoI RFLP. TNF productions of phytohemagglutinin (PHA)-stimulated PBMC and T cells were examined by bioassay using L929 cell line and ELISA. The PBMC stimulated by PHA from patients with SLE (n = 60) tended to secrete less amounts of TNF by bioassay (1032 +/- 184 pg/ml vs 1524 +/- 224 pg/ml, P = 0.094), and TNF-beta by ELISA (P = 0.0082) than that from normal controls (n = 38). The low TNF-alpha producer was more frequent in nephritis than non-nephritis (34.4% vs 7.1% respectively, P < 0.01). TNF-beta also revealed similar results (53.1% vs 21.4%, P < 0.05). In SLE, mean production of TNF-beta was decreased in TNFB*2 homozygote (n = 18) than that in TNFB*1 homozygote (n = 9) (1126.3 +/- 145 pg/ml) vs 642 +/- 118.4 pg/ml, respectively, P = 0.021), whereas TNF-alpha production showed little difference between the two groups (710.1 +/- 56.4 vs 542.4 +/- 71.1 pg/ml, respectively, P = 0.149). Our results demonstrate that decreased TNF production of PBMC, which was significantly associated with TNFB*2 homozygosity, could be an important predisposing factor of lupus nephritis in Koreans.
Lupus 1997
PMID:Decreased tumour necrosis factor-beta production in TNFB*2 homozygote: an important predisposing factor of lupus nephritis in Koreans. 930 64

Anti-murine IL-1 alpha, IL-6 antibodies were intra-peritoneally injected to the lupus-like NZB/W F1 mice of 4 months with the dosage of 10 micrograms per day for three days and then per month for three months. The mice were killed at the age of 11 months. The results showed that the treatment of the dosage could not absolutely prevent lupus nephritis--it could alleviate proteinuria, obviously reduce the levels of serum IL-1 alpha and inhibit the secretion of IL-1 alpha by celiac macrophage. As to the level of IL-6 and TNF-alpha no significant change was observed.
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PMID:Immunoregulation of lupus-like NZB/W F1 mice by anti-murine IL-1 alpha, IL-6 antibodies. 938 83


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