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)

MRL/1 mice develop a severe form of systemic lupus erythematosus and spontaneously produce high levels of autoantibodies to DNA. Spleen cells from these animals were used as fusion partners to prepare hybridomas that produce autoantibodies to DNA. Since exogenous immunization was not employed, the hybridoma antibodies were derived from populations of B cells that spontaneously produced autoantibodies. Each hybridoma autoantibody had a distinctive binding specificity with S-DNA, N-DNA, or oligonucleotides.
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PMID:Hybridoma autoantibodies to DNA. 735 89

Trichloroethene (TCE) has been implicated in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE) and scleroderma in humans. However, experimental studies have not been conducted to establish the role of TCE in causing autoimmunity and/or SLE. To clarify the role of TCE in autoimmune responses, subchronic studies were carried out in female autoimmune prone mice (MRL +/+). Three groups of mice (5 weeks old) received intraperitoneal injections of 10 mmol/kg of TCE, 0.2 mmol/kg of dichloroacetyl chloride (DCAC) (one of the metabolites of TCE with strong acylating property), or an equal volume (100 microliters) of corn oil alone (controls). Animals were dosed every 4th day for 6 weeks and euthanized 24 hr following the last dose. Sera and major tissues were collected and analyzed. Spleen weights in the TCE and DCAC groups increased 36% with a similar pattern of change in the spleen-to-body weight ratios. Serum IgG in the TCE and DCAC groups increased 45 and 322%, respectively. Using specific ELISA assays for mice, autoimmune antibodies were detected in the sera of TCE- and DCAC-treated mice in the following patterns: for anti-nuclear antibodies; controls, 0/4; TCE, 4/4; DCAC, 3/5; for anti-ssDNA antibodies; controls, 0/4; TCE, 2/4; DCAC, 5/5; for anti-cardiolipin antibodies; controls, 0/4; TCE, 0/4; DCAC, 3/5. An ELISA developed for the measurement of DCAC-specific antibodies using conjugated DCAC-albumin as an antigen showed the following pattern: for controls, 0/4; TCE, 0/4; DCAC, 5/5. These results suggest that TCE and its metabolite, DCAC, induce and/or accelerate autoimmune responses in female MRL +/+ mice. The greater responses induced by DCAC at a dose 50 times lower than TCE suggests that this metabolite may be important in the mechanisms leading to TCE-induced autoimmunity.
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PMID:Trichloroethene-induced autoimmune response in female MRL +/+ mice. 767 50

F1 hybrid New Zealand Black (NZB) x New Zealand White (NZM) (NZB/NZW) mice spontaneously develop an autoimmune disease analogous to systemic lupus erythematosus (SLE). Testosterone experts a powerful suppressive effect on this disorder in adult NZB/NZW mice. A series of experiments was designed to determine if disease would also be suppressed by exposing fetal NZB/NZW mice to increased testosterone. A model was developed in which NZB dams carrying NZB/NZW fetuses were treated with testosterone in a dose adequate to masculinize the external genitalia in female fetuses. NZB/NZW mice that were derived from testosterone-treated dams and control NZB/NZW offspring were followed in a longevity study and had serial assays to assess development of SLE. Additional experiments were carried out to measure lymphocyte subsets and responses to mitogens. Results were compared with F1 hybrid offspring of C57BL/6 dams crossed with DBA/2 males, which are not autoimmune and do not develop SLE. Spleen cells from these groups were tested for Thy 1.2, CD4, CD8, and IgM receptors, and for responses to the mitogens Concanavalin A (ConA) and lipopolysaccharide. Control male NZB/NZW fetuses had unexpectedly high serum estradiol, which decreased significantly with maternal testosterone treatment. The testosterone-exposed male NZB/NZW fetuses developed into adults that lived longer than male NZB/NZW controls. Testosterone treatment of the dam was associated with elevated terminal anti-DNA levels but did not alter markers of renal diseases in adult NZB/NZW mice of either sex. Testosterone-exposed NZB/NZW females had altered T-lymphocyte subsets and testosterone-exposed males had increased response to ConA compared to controls. In male NZB/NZW fetuses whose mothers were administered testosterone, the naturally high level of circulating estradiol observed in untreated male fetuses was decreased significantly. This decrease was associated with an increase in longevity. This unique observation has important implications for fetal exposure to endocrine disruptors in the environment.
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PMID:Effects of altered prenatal hormonal environment on expression of autoimmune disease in NZB/NZW mice. 888 4

To gain a better understanding of inherent gender-related effects on autoimmunity, cytokine genes were examined in female and male New Zealand Black X New Zealand White (B/W) mice, which are a murine model of systemic lupus erythematosus (SLE). In preliminary studies, semiquantitative reverse transcriptase-polymerase chain reaction analysis showed a trend for B/W spleen cell interferon gamma (IFN-gamma) mRNA in B/W female spleen cells to exceed that of males. This difference was obliterated following concanavalin A (Con A) stimulation. Spleen cells from B/W mice of both sexes were then examined at 6, 18, and 27 weeks of age, and results were compared with matched groups of nonautoimmune DBA/2 mice. Pooled splenocytes from all 12 groups of animals were compared simultaneously for expression of mRNA specific for IFN-gamma, interleukin 4 (IL-4) and interleukin 6 (IL-6). Strain was a potent influence on cytokine transcripts. In unstimulated splenocytes from female and male B/W mice, there was a notable trend for IFN-gamma and IL-6 mRNA expression to exceed transcripts from nonautoimmune DBA/2 mice. When comparisons were carried out by gender, a highly significant increase of IFN-gamma transcripts was apparent in B/W females compared to B/W males at the age of 27 weeks. Following Con A incubation, strain and gender differences were eliminated. IL-4 transcript expression was similar in all pools of cells, and age was not an important factor in expression of any transcript. This study represents the first examination of multiple cytokine transcripts in lymphoid cells from B/W mice. In this hormone-sensitive model of SLE, strain and gender determined in vivo expression of IFN-gamma and IL-6 mRNA.
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PMID:Cytokine mRNA expression in the B/W mouse model of systemic lupus erythematosus--analyses of strain, gender, and age effects. 928 84

Bacterial DNA triggers B-cell proliferation and induces immunoglobulin secretion. Chromatin-IgG complexes activate autoreactive B cells by co-engaging B-cell receptor (BCR) and TLR-9, thus suggesting a role for innate signaling in systemic autoimmunity. Spleen cells from lupus prone Palmerston North (PN) mice produce several fold less IL-12p40 than controls in response to CpG-oligodeoxynucleotides (ODNs). Here we show that B cells are primarily responsible for this abnormality. The removal of B cells from PN cultures markedly increased IL-12p40. Moreover, the addition of purified B cells back to PN splenocyte cultures resulted in a B-cell number dependent/ IL-10-mediated suppression of IL-12p40. The B cells were the major source of IL-10. In response to CpG, B cells from several lupus strains produced twice as a much IL-10 as controls, but failed to produce IL-10 when stimulated through BCR or CD40. PN and control mice expressed IL-10R similarly, and the difference in IL-10 secretion remained when anti-IL-10R blocking antibodies were used. IFN-gamma and IL-4 regulated CpG-induced IL-10 secretion in opposite directions. The abnormal IL-10 response in lupus mice was derived from B cells with the marginal zone phenotype, and could be downregulated with inhibitory ODNs. We hypothesize that TLR-9 activated lupus B cells can modulate T-cell mediated inflammatory responses through IL-10 production. Therefore, B cells may contribute to the lupus pathogenesis in many different ways: as antigen-presenting cells for self antigens, as effector cells for autoantibody production, and as IL-10 secreting regulatory cells.
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PMID:TLR-9 activation of marginal zone B cells in lupus mice regulates immunity through increased IL-10 production. 1574 55

Although multiple studies suggest a potential role for angiotensin II in inflammation, most were performed either in vitro or in animals with non-immune-complex-mediated diseases. Extrapolation of these findings to humans, particularly patients with lupus, which involves multiple immunoregulatory pathways, is unclear. In autoimmune-prone MRL/lpr mice, angiotensin-converting-enzyme (ACE) inhibition improved survival although to a lesser degree than cyclophosphamide and diminished the glomerular histopathologic damage, proteinuria, lymphoid hyperplasia, dermatitis, and hypergammaglobulinemia, with a reduction in TGF-beta1 and beta 2 expression in the kidneys and renal chemokine mRNA expression. Spleen levels of IL-4 and IL-10 were also reduced. Uncontrolled studies in patients with treatment-refractory lupus nephritis showed a significant reduction in proteinuria with ACE-inhibitors and Angiotensin receptor blockers treatment. The 'masking' effect of ACE-inhibitors should be taken into consideration, as an exacerbation of lupus nephritis may be missed when estimated by the magnitude of proteinuria, which is decreased by these treatments. No single ACE genotype was consistently associated with subsets of SLE patients. In retrospective analyses, ACE-inhibitor use predicted a favourable outcome in 94 cases of pauci-immune vasculitis. The attenuating effect of angiotensin II inhibitors on the progression of chronic renal disease is well recognized. The data on the role of this intervention in lupus is limited.
Lupus 2006
PMID:The renin-angiotensin system in lupus: physiology, genes and practice, in animals and humans. 1683 Aug 77

Chronic graft-vs-host (cGVH) disease is induced in nonautoimmune mice by the transfer of alloreactive T cells that recognize foreign MHC class II. It closely resembles systemic lupus erythematosus, with antinuclear Abs and immune-mediated nephritis. Recent work has implicated TLRs, particularly TLR9, in the recognition of certain autoantigens in vitro and in vivo. To explore further the role of TLR9 in systemic autoimmunity, we induced cGVH disease in C57BL/6 (B6) mice lacking TLR9, including B6 mice expressing the anti-DNA-encoding IgH transgenes 3H9 or 56R (B6.3H9.TLR9(-/-), B6.56R.TLR9(-/-)). We found that cGVH disease caused breakdown of B cell tolerance to chromatin and DNA in TLR9(-/-) recipients of alloreactive cells, yet that nephritis was less severe and that some autoantibody titers were lower compared with B6-cGVH controls. Spleen lymphocyte analysis showed that cGVH disease strikingly depleted marginal zone B cells in B6 mice, but did not influence T cell subsets in either B6 or B6-TLR9(-/-) hosts. B6.56R.TLR9(-/-) mice had less spontaneous production of autoantibodies than B6.56R mice, but there were no significant differences between B6.56R and B6.56R.TLR9(-/-) postinduction of cGVH disease. Taken together, these results suggested that TLR9 may worsen some aspects of systemic autoimmunity while alleviating others.
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PMID:Modulation of autoimmunity by TLR9 in the chronic graft-vs-host model of systemic lupus erythematosus. 1708 64

We sought to determine if the histone deacetylase inhibitor (HDI), trichostatin A (TSA), would alter systemic lupus erythematosus (SLE) in NZB/W mice. Fourteen to sixteen-week-old female NZB/W F1 mice were given TSA (1.0mg/kg body weight (BW)) intraperitonealy (i.p.) daily, TSA (1.0mg/kg BW) i.p.+anti-CD25 (250mg/mouse) i.p. every third day, only anti-CD25 (250mg/mouse) i.p., DMSO or isotype IgG. Disease progression was assessed as they aged. Mice were sacrificed at 26 or 38 weeks of age, tissues collected and evaluated. At 36 weeks, TSA-treated animals had decreased anti-double stranded DNA (dsDNA) autoantibodies and decreased protein excretion compared to controls. Spleen size and the percentage of CD4+CD69+ cells were decreased, with an increase in CD4+CD25+ T cells in the TSA-treated mice. Real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis of T cells showed a decrease in IL-6 production but an increase in TGF-beta1 and Foxp3 in the TSA-treated animals. Kidney analysis showed a decrease in IgG and C3 deposition, decrease in pathologic glomerular disease and renal MCP-1, MMP-9, and IL-6 mRNA expression. Anti-CD25-treated mice euthanized at 26 weeks of age showed decreased Foxp3+CD4+CD25+ T cells compared to TSA-treated mice. These data suggest TSA administration modulates lupus-like disease, in part, by increasing T regulatory cells.
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PMID:The histone deacetylase inhibitor trichostatin A upregulates regulatory T cells and modulates autoimmunity in NZB/W F1 mice. 1865 65

Female B6.MRLc1(82-100) congenic mice develop more severe autoimmune glomerulonephritis (AGN) than males. We assessed the effects of gonadectomy on the pathogenesis of AGN in these mice. One-month-old male and female mice were divided into sham-operated group (SG) and gonadectomized group (GG), and the pathological changes were investigated at 8 months. SG females showed higher spleen and thymus weights, serum total IgG and autoantibody levels, glomerular damage scores and percent IgG- and CD3-positive glomeruli as compared with SG males. Gonadectomy showed more remarkable effects in males than in females. Spleen and thymus weights, urinary albumin excretion, glomerular damage scores, percent IgG- and CD3-positive glomeruli, and CD3-positive areas in the spleen were significantly higher in GG males than in SG males. CD3-positive cells were observed in both the thymic cortex and medulla in all animals except SG males. The expression ratio of active Fc gamma receptor (Fcgr) 3 to inhibitory Fcgr2b in the kidneys, which we have previously demonstrated to have a great impact on pathogenesis in B6.MRLc1(82-100), was significantly higher in GG males than in SG males. These results suggested that the differences in the pathogenesis of AGN are primarily because of the inhibitory roles of the male sex hormones.
Lupus 2009 May
PMID:Onset of autoimmune glomerulonephritis derived from the telomeric region of MRL-chromosome 1 is associated with the male sex hormone in mice. 1939 50

Multiple genetic factors contribute to the clinical variability of spontaneous systemic lupus erythematosus (SLE) but their role in drug-induced SLE remain largely unknown. Hydrocarbon oil-induced SLE depends on mesothelial cell apoptosis and Toll-like receptor (TLR)-7-mediated induction of type I interferons. Hence, we hypothesized that TIR8/SIGIRR, an endogenous TLR inhibitor, prevents oil-induced SLE. Sigirr-deficient dendritic cells expressed higher TLR7 mRNA levels and TLR7 activation resulted in increased IL-12 production in vitro. In vivo, lack of SIGIRR increased surface CD40 expression on spleen CD11c(+) dendritic cells and MX-1, TNF, IL-12, BAFF and BCL-2 mRNA expression 6 months after pristane injection. Spleen cell counts of CD4(-)/CD8(-) 'autoreactive' T cells and B220(+) B cells were also increased in Sigirr(-/-) mice. Serum autoantibody analysis revealed that Sigirr deficiency specifically enhanced the production of rheumatoid factor (from 4 months of age) and anti-snRNP IgG (from 5 months of age), while anti-Smith IgG or anti-dsDNA IgG were independent of the Sigirr genotype. This effect was sufficient to significantly aggravate lupus nephritis in Sigirr-deficient mice. Structure model prediction identified the BB loop of SIGIRR's intracellular TIR domain to interact with TLR7 and MyD88. BB loop deletion was sufficient to completely abrogate SIGIRR's inhibitory effect on TLR7 signalling. Thus, TIR8/SIGIRR protects from hydrocarbon oil-induced lupus by suppressing the TLR7-mediated activation of dendritic cells, via its intracellular BB loop.
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PMID:Lack of SIGIRR/TIR8 aggravates hydrocarbon oil-induced lupus nephritis. 2011 71


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