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)

It has been previously reported that the production of interleukin-6 (IL-6) is often enhanced in systemic lupus erythematosus (SLE). The authors examined the secretion of IL-6, tumour necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor, IL-1 alpha and IL-4 by B cells and monocytes from lupus patients and compared this to the production in normal controls and in rheumatoid arthritis patients. IL-6 production was increased an average of 3.4-fold compared to that in normal subjects and 8.4-fold compared to rheumatoid arthritis patients. In SLE, a strongly positive correlation was found between the levels of IL-6 and TNF-alpha (R = 0.8987, P = 0.002). Since production of both IL-6 and TNF-alpha is regulated by IL-10, the enhancement of the production of these cytokines could reflect a defect in either IL-10 production or responsiveness. However, spontaneous production of IL-10 was enhanced in cultures of B cells and monocytes from lupus patients, compared to normal controls, the levels being increased 3.1- to 6-fold for monocytes and B cells, respectively. The finding of increased secretion of these cytokines implies an abnormality in IL-10-mediated suppression in SLE. To assess this possibility, the authors examined recombinant human IL-10-mediated suppression of IL-6 production by monocytes and B cells from lupus patients, compared to normal controls, and found that whereas IL-10 caused a concentration-dependent suppression of IL-6 production in normal B cells and monocytes, this suppression was deficient in B cells and monocytes from lupus patients. In SLE, it therefore appears that there may be an intrinsic defect in IL-10-induced suppression of cytokine synthesis. This could explain the increased levels of IL-10 and IL-6 found in this condition, and may also be responsible for the characteristic polyclonal B-cell activation that is seen.
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PMID:Interleukin-10 response abnormalities in systemic lupus erythematosus. 935 Feb 93

T cells with T cell receptor (TCR) transgenes that recognized CD1 on syngeneic B cells stimulated B cells to secrete immunoglobulins in vitro. The CD4+, CD8+, or CD4-CD8- T cells from the spleen of the TCR transgenic BALB/c donors induced lupus with anti-double stranded DNA antibodies, proteinuria, and immune complex glomerulonephritis in irradiated BALB/c nude mice reconstituted with nude bone marrow. Injection of purified CD4-CD8- T cells from the marrow of transgenic donors prevented the induction of lupus by the transgenic T cells. Transgenic T cells that induced lupus secreted large amounts of interferon (IFN)-gamma and little interleukin (IL)-4, and those that prevented lupus secreted large amounts of IL-4 and little IFN-gamma or IL-10.
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PMID:Subsets of transgenic T cells that recognize CD1 induce or prevent murine lupus: role of cytokines. 946 3

Polyclonal B-cell activation is the central theme in the production of autoantibodies and possible activation of autoreactive T cells in both human and murine lupus. The abnormal expansion of CD5+ B cells in murine lupus has been suggested, in particular, to be one of the most characteristic findings in these mice. Activated B cells can be separated from the B cells of resting stage by the difference in cell density. The aim of this study was to investigate the characteristics of different densities of the spleen cells separated by gradient density. Furthermore, the ability of anti-DNA antibody secretion in each percoll gradient fraction of B cells was also analysed. The results showed: a higher percentage of CD5+ B cells, which corresponded to the activated B-cell population, in percoll gradient 1 and 2 fractions; that splenic B cells of NZB/W F1 mice had proliferative response to interleukin (IL)-4 or IL-5 but not to IL-10 or interferon-gamma (IFN-gamma); and that B cells isolated by percoll gradient produced anti-DNA antibody after stimulation with lipopolysaccharide (LPS) plus IL-5 and IFN-gamma, but not IL-4 and IL-10. These data suggest that B cells at different stages of activation express differential characteristics and functions.
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PMID:Phenotypic and functional analysis of activated B cells of autoimmune NZB x NZW F1 mice. 949 86

We investigated whether macrophages (Mphi) from young, lupus-prone MRL+/+ and NZB/W F1 mice expressed common defects in immunoregulatory cytokine production. Endotoxin-activated Mphi from both strains, obtained well before disease signs, had a markedly reduced capacity to maintain IL-1 production compared with Mphi from normal strains (BALB/c, A/J, and C57BL/6). Mphi from lupus-prone mice showed similar defects in IL-6 and TNF-alpha production, which preceded the IL-1 defect. In fact, defective TNF-alpha production appeared to be responsible for aberrant expression of the other cytokines because this defect was the first to be expressed, and treatment with exogenous TNF-alpha reduced the extent of defective IL-1 and IL-6. These "proinflammatory" cytokine defects appeared to be selective because the anti-inflammatory cytokine IL-10 was not expressed aberrantly in the lupus-prone strains. For this reason, and because anti-IL-10 mAb treatment did not correct defective proinflammatory cytokine production, IL-10 did not appear to be responsible for these defects. IFN-gamma was able to normalize TNF-alpha production in Mphi from lupus-prone mice, demonstrating a stimulus-specific induction of the proinflammatory defects. These studies also revealed that Mphi from the three normal strains studied here maintain a precise inverse relationship between levels of TNF-alpha and IL-10, a relationship not seen in Mphi from lupus-prone strains. These findings reveal shared elements of cytokine dysregulation in the two principal animal models of multigenic lupus, and suggest that the study of Mphi (and perhaps other cells of the innate immune system) may provide valuable insights into intrinsic functional defects associated with systemic autoimmunity.
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PMID:Aberrant cytokine expression and autocrine regulation characterize macrophages from young MRL+/+ and NZB/W F1 lupus-prone mice. 954 4

The objective of the submitted study was to evaluate the role of the serum level of the soluble form of the vascular adhesive molecule-1(VCAM-1) in systemic lupus erythematosus (SLE) and to evaluate the possible relation to selected clinical and laboratory indicators of activity of the disease and cytokine serum levels. The analyzed group comprised 20 women, median age 37 years (range 18-65 years). Elevated VACM-1 serum levels were detected in 18 subjects (90%). Statistical analysis (Pearson's test, p < 0.05) revealed a significant relationship between serum levels of VCAM-1 and the index of clinical activity of SLE evaluated by the ECLAM system (European Consensus Lupus Activity Measurement), values of the C3 complement component, the level of antibodies against dsDNA and serum levels of IL-10. No significant correlation was found with levels of the soluble receptor IL-2 (sIL-2R) and the C4 complement component in serum. From the investigation ensues that investigation of serum levels of the adhesive molecule of the VCAM-1 type is a promising method which makes early diagnosis of exacerbation of the disease possible. However, for evaluation of its real asset in clinical practice a more widely conceived longitudinal investigation is needed.
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PMID:[Vascular intercellular adhesive molecule-1 (VCAM-1)--a new indicator of activity in systemic lupus erythematosus?]. 960 54

We investigated the effects of IL-12 on immunoglobulin (Ig) production in vitro in murine chronic graft-vs. -host disease (cGVHD), a lupus-like model of overt B cell activation induced by allogeneic stimulation. Addition of IL-12 to cGVHD splenocytes strongly inhibited total Ig (Igkappa), IgM and IgG1 production. Although IL-12 down-regulated IL-4, IL-5, IL-9 and IL-10 production, its inhibitory activity on Ig production could not be ascribed to down-regulation of these cytokines, as addition of saturating doses of IL-4, IL-5 and/or IL-9 did not reverse the inhibitory activity of IL-12. Interestingly, IL-12 was also found to suppress the stimulating effect of IL-4 and IL-5 on Ig synthesis by cGVHD splenocytes. Several lines of evidence indicated that the inhibitory activity exerted by IL-12 on Ig production was mediated by IFN-gamma. First, IFN-gamma was produced in large amounts upon IL-12 stimulation. Secondly, it displayed a potent inhibitory activity on Ig production. Thirdly, Ig production was also inhibited by IL-18, a recently cloned IFN-gamma-inducing cytokine. Finally, the inhibitory activity of IL-12 was blocked by anti-IFN-gamma monoclonal antibody. We also investigated whether IL-12 down-regulated Ig production by purified cGVHD B cells. We found that IL-12 had only a marginal inhibitory activity on highly purified B cell populations isolated from cGVHD splenocytes and stimulated with IL-4 and IL-5, and that IL-18 was inactive in this respect. However, when the two cytokines were combined, a striking synergy was unmasked not only for IgG1 inhibition but also for IFN-gamma production by these B cell populations. Taken together, our results demonstrate that IL-12 inhibits in vitro Ig production by activated splenocytes through IFN-gamma production and that it synergizes with IL-18 on activated B cells to inhibit Ig production, through up-regulation of IFN-gamma production by B cells.
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PMID:Inhibition of in vitro immunoglobulin production by IL-12 in murine chronic graft-vs.-host disease: synergism with IL-18. 964 83

The onset of lupus-like disease in NZB/NZW F1 mice was correlated with the expression of IL-10 at 4 m of age, and with a sequential enhanced expression of IFN-gamma and IL-6 between 6 to 8 m of age. The expression of IFN-gamma and IL-6 was associated with exacerbation of disease symptom, production of anti-DNA antibody, and increase in total serum IgG1. Exogenous dehydroepiandrosterone (DHEA) given in animal diet significantly prolonged survival, and delayed formation of autoantibody of NZB/NZW F1 mice as compared to mice fed on control diet. The effect of DHEA paralleled a delay in the expression of IL-10 and IL-6 and an earlier detection of IL-12 transcripts. Moreover, DHEA-fed mice had higher serum IgG2a level than control diet-fed mice. Collectively, DHEA may modify the activation of distinct subset of T helper cells in NZB/NZW F1 mice at different phases of disease progression.
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PMID:Exogenous dehydroepiandrosterone modified the expression of T helper-related cytokines in NZB/NZW F1 mice. 973 89

We have demonstrated that macrophages (Mphi) from young, prediseased, lupus-prone MRL/++ and New Zealand Black/White F1 mice display defective production of TNF-alpha, IL-1, and IL-6, but normal production of IL-10. In an attempt to determine the potential functional implications of this phenotype for autoimmunity, we demonstrate here that endotoxin-activated Mphi from these lupus-prone mice showed dramatically reduced expression of IL-12, a cytokine essential for Th1 responses that may be defective during lupus. IL-12 production was also reduced by Mphi from the control BALB/c strain, compatible with the concept that a genetically programmed deficit in IL-12 levels may underlie the IL-4-dominated BALB/c response to infection by the parasite Leishmania major. Although both IL-12 and TNF-alpha expression defects by Mphi from lupus-prone strains are expressed rapidly after activation, treatment with each cytokine demonstrated that only TNF-alpha contributes to the subsequent dysregulation of Mphi IL-1 and IL-6 expression in these strains, and that the reduced autocrine activity of defective IL-12 or TNF-alpha levels was not causal to each other. Although the intrinsic defect in IL-12 expression by lupus-prone and BALB/c Mphi may lead to defective Th1 responses, these Mphi responded to the Th1-derived cytokine, IFN-gamma, in a normal fashion suggesting a defective role in the induction, rather than the propagation, of Th1 responses in these mice. Our finding of a conserved intrinsic defect in IL-12 production by Mphi from the two principal mouse models of multigenic lupus provides insight into how excessive humoral responses may develop, and perhaps be prevented, in systemic autoimmune disease.
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PMID:Intrinsic defects in macrophage IL-12 production associated with immune dysfunction in the MRL/++ and New Zealand Black/White F1 lupus-prone mice and the Leishmania major-susceptible BALB/c strain. 986 20

Although cumulative evidence suggests that a genetic predisposition plays a major role in development of systemic lupus erythematosus (SLE) and/or lupus nephritis (LN), the susceptibility genes are mostly unknown. The difficulty in identifying susceptibility genes is due in part to multiple genes with variable genetic effects and the diverse genetic backgrounds of human populations. In human SLE, genes of early components of complements as well as many polymorphic genes (including the MHC class II and class III, FcgammaR, mannose-binding protein, IL-6, Bcl-2, and IL-10 genes) have been associated with SLE or LN by population-based case-control or within-case studies. The contribution of some of these disease-associated genes to the presence or absence of clinical manifestations has been further tested in mice with targeted disruption of the specific candidate gene. In addition to SLE susceptibility genes, there may be a separate set of nephropathy susceptibility genes predisposing to LN as suggested by the familial clustering of end-stage renal disease in African-Americans with LN. The availability of densely mapped genetic markers spanning the entire genome has enabled the identification of chromosomal regions linked to disease susceptibility genes without prior knowledge of the gene function. Our group has used known murine lupus susceptibility loci as a guide, and conducted linkage analysis of genetic markers located within a specific, possibly syntenic human chromosomal region. Evidence for linkage of a chromosome 1q41-42 region was observed in SLE-affected sib pairs from multiple ethnic groups. More recently, several groups have reported results of genome scans of SLE-affected sib pairs or pedigrees. These exciting recent developments in delineating the genetic basis of SLE or LN are summarized in this review.
Lupus 1998
PMID:Genetic susceptibility to lupus nephritis. 988 94

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies to nucleoprotein antigens, including double-stranded DNA (dsDNA). The deposition of IgG dsDNA immune complexes in glomeruli is thought to be crucial for disease pathogenesis and complement activation. rhDNase catalyzes the hydrolysis of extracellular DNA and has been shown to delay the development of dsDNA antibodies, reduce proteinuria, and delay mortality in a lupus-prone murine model. We conducted a 40d, phase Ib, randomized, double-masked, placebo-controlled trial to determine the safety and pharmacokinetics of rhDNase, and to measure any changes in markers of disease activity in 17 patients with lupus nephritis. Patients were assigned to receive either: (1) 25 microg/kg rhDNase (n = 8); (2) 125 microg/kg rhDNase (n=6); or (3) placebo (n = 3) initial single intravenous (IV) dose followed by 10 subcutaneous (SC) doses. Skin biopsies performed on nine patients pre- and post-treatment were studied for immune complex deposition by immunofluorescence. Serum cytokine levels (sIL2-R, IL-6, IL-10, and TNF-alpha) were analyzed by ELISA. Cytokine secretion and antibody production were measured by ELISPOT analysis and ELISA. Serum hydrolytic activity of rhDNase was achieved after IV administration at 25 and 125 microg/kg, but not after SC administration at either dose. A t 1/2 of 3-4h was estimated from serum concentration profiles following IV administration. Serum dsDNA antibodies were unchanged (mean values: 33 IU/mL vs 39 IU/mL [pre- and post-treatment] for the 25 microg/kg group, and 74 IU/mL vs 74 IU/mL for the 125 microg/kg group, and 14 IU/mL vs 20 IU/mL for the placebo group). Complement levels (C3 and C4) and circulating immune complexes did not change appreciably during the treatment period for any of the groups. Serum cytokine profiles by ELISA revealed no changes in sIL-2 receptor, IL-6, IL-10, or TNF-alpha. There was no change in the number of cells secreting either Th1 or Th2 specific cytokines, nor in the number of cells secreting dsDNA antibodies. Neutralizing antibodies to rhDNase were not detected in serum at any time during the study. Immune complex deposition was unchanged in pre- and post-treatment in skin biopsies in both dose groups. rhDnase was well tolerated without significant adverse events following administration, and treatment was not associated with the development of neutralizing antibodies to rhDNase. Serum rhDNase concentrations capable of hydrolytic activity of rhDNase were achieved for a few hours following IV, but not SC administration. Serum markers of disease activity were unchanged during the study period.
Lupus 1999
PMID:Recombinant human Dnase I (rhDNase) in patients with lupus nephritis. 1002 1


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