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)

BALB/c mice injected at birth with semi-allogeneic F1 spleen cells become tolerant to alloantigens as shown by their CTL unresponsiveness to the corresponding alloantigen and the persistence of donor F1 cells into the BALB/c host. Moreover, these mice develop a transient systemic lupus erythematosis-like autoimmune syndrome characterized by splenomegaly, glomerulonephritis, thrombocytopenia and abnormal serological findings, such as several autoantibodies and IgG1 hypergammaglobulinemia. Recent studies done in our laboratory have shown that donor F1 B cells persisting in the host are responsible for the production of autoantibodies and must be activated in vivo by the host CD4+ T lymphocytes in a MHC class II-restricted fashion. In the present work, we have focused our attention on the ability of splenic CD4+ T cells recovered at different periods from BALB/c mice injected at birth with (CBA/Ca x BALB.Ighb) F1 spleen cells to interact with and activate F1 semi-allogeneic spleen cells in vitro. We show that (i) only CD4+ T cells from 2- and 3-week-old tolerant BALB/c mice preferentially produce IL-4 and IL-5 in response to a F1 semi-allogeneic in vitro stimulation, (ii) CD4+ T cells purified from 3-week-old tolerant BALB/c mice are able to induce in vitro IgG and IgM production by F1 B cells. Taken together, these results strongly suggest that host CD4+ T cells, belonging to the TH2 subset progressively lose their reactivity towards the F1 semi-allogeneic persistent B cells, reaching a state of unresponsiveness that correlates with the disappearance of serum autoantibodies and autoimmune pathology.
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PMID:Characterization of host CD4+ T lymphocytes in mice neonatally tolerized to alloantigens. 810 95

This study was designed to investigate the mechanisms by which marine lipids rich in long chain omega-3 fatty acids inhibit autoimmune disease and prolong the survival rate in female (NZB/NZW) F1 (B/W) mice, an animal model for human SLE. Nutritionally adequate semipurified diets containing at 10% either corn oil (CO) or fish oil (FO) were fed from 1 mo of age and were monitored for proteinuria and survival. Proteinuria was detected earlier and became progressively severe in CO-fed mice. The average life span was significantly shortened by the CO diet (266.7 days +/- 12.5), whereas FO extended the survival significantly (402.1 days +/- 26.1; p < 0.001). A cross-sectional study at 6.5 mo of age revealed an increased proliferative response to T cell mitogens including bacterial superantigens and decreased serum anti-dsDNA Ab titers in the FO group compared with the CO group. Furthermore, splenocytes from the FO group when stimulated with Con A had higher IL-2 and lower IL-4 production similar to that of young (3.5 mo) mice. Flow cytometric analyses of splenocytes revealed lower Ig+, higher lymphocyte endothelial cell adhesion molecule-1, and lower Pgp-1+ cells within CD4+ and CD8+ subsets in FO-fed mice. Also, elevated IL-2 and IL-4 and significantly higher TGF-beta 1 and lower c-myc and c-ras mRNA expression and higher TGF-beta 1 and significantly lower c-Myc and c-Ha-Ras proteins were detected in spleens of FO-fed mice. Fatty acid analysis revealed significantly higher linoleic (18:2 omega-6) and arachidonic (20:4 omega-6) acid levels in splenocytes of the CO-fed group and higher eicosapentaenoic (20:5 omega-3) and docosahexanoic (22:6 omega-3) acid levels in the FO-fed group, indicating that changes in membrane fatty acid composition may contribute to the altered immune function and gene expression during the development of murine SLE.
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PMID:Increased TGF-beta and decreased oncogene expression by omega-3 fatty acids in the spleen delays onset of autoimmune disease in B/W mice. 820 22

The murine autosomal recessive gene, lpr, induces a progressive lymphadenopathy and lupus-like autoimmune syndrome characterized by the accumulation of immature, dull Thy 1.2+, TCR+, L3T4-/Lyt 2- (double-negative, DN) T cells in peripheral lymphoid organs. Previous studies demonstrated that the thymic microenvironment is required for the generation of the abnormal, peripheral DN T cells, while a more recent report linked the lpr gene defect with a failure of thymocytes to express a functional form of the Fas antigen, which mediates apoptosis. Thus, the lpr gene defect apparently prevents lpr thymocytes from responding to the ordered sequence of differentiation and proliferation signals involved in normal thymocyte maturation and selection. We compared the responses of thymocytes from C57BL/6 +/+ (normal) and congenic C57BL/6 lpr/lpr (lpr) mice to a thymic stromal cell product which down-regulates DNA synthesis in vitro. The results indicate that (a) thymic stromal cells from lpr mice produce a factor that can down-regulate DNA synthesis as efficiently as that from normal mice, even at an age when massive lymphadenopathy is present, (b) mitogen-stimulated thymocytes of normal, but not lpr, mice are sensitive to the inhibitory factor, (c) normal DN thymocytes are the cellular target of the inhibitory factor, which acts at some postmembrane receptor-ligand binding event during mitogen-stimulated proliferation, and (d) IL-4-dependent DN thymocyte proliferation seems to be the main target of the inhibitory factor.
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PMID:Double-negative (L3T4-, Lyt2-) thymocytes of autoimmune lpr/lpr mice are resistant to down-regulation of DNA synthesis by a thymic stromal cell product. 837 81

Somatic gene therapy is an interesting approach for the delivery of cytokines for prolonged periods. The present experiments show that direct injections into mouse skeletal muscle of cDNA expression vectors encoding interleukin 2 (IL-2), IL-4, or type beta 1 transforming growth factor (TGF-beta 1) induce biological effects characteristic of these cytokines in vivo. Mice injected intramuscularly with a vector encoding IL-2 had enhanced humoral and cellular immune responses to an exogenous antigen, transferrin, that was delivered at a separate site. These IL-2 effects were abolished by coadministration of a vector directing synthesis of TGF-beta 1. The TGF-beta 1 vector by itself depressed the anti-transferrin antibody response and caused an 8-fold increase in plasma TGF-beta 1 activity. The TGF-beta 1 plasmid injection did not cause muscle infiltration with monocytes or neutrophils and there was no evidence for fibrotic changes. Muscle injection with a cDNA encoding IL-4 selectively increased IgG1 levels but did not alter the cellular immune response to transferrin. In lupus-prone mice (MRL/lpr/lpr), injection with IL-2 expression vectors increased and TGF-beta 1 vectors decreased auto-antibodies to chromatin. These results demonstrate that intramuscular injection of cytokine genes, in the absence of infectious viral vectors, can regulate humoral and cellular immune responses in vivo.
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PMID:Systemic immunological effects of cytokine genes injected into skeletal muscle. 850 93

Systemic lupus erythematosus (SLE) is an autoimmune disease with a clear imbalance in the network made up of different cytokines. However this statement has been derived from studies which have focused on the analysis of some specific cytokines and few have simultaneously analyzed those cytokines that could be involved in the pathogenesis of SLE. Therefore, we decided to analyze interleukin IL-1b, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor-a (TNF-a) and gamma interferon (IFN-g) gene expression in peripheral blood mononuclear cells from 17 women with SLE and 10 normal females by a coupled reverse transcriptase-polymerase chain reaction technique. High gene expression of IL-4, IL-6, IL-10 and TNF-a was found in SLE patients as compared to normal subjects. The expression of IL-1b, IL-2 and IFN-g genes was low or undetectable. The resulting high level of cytokines with strong effect on proliferation and differentiation of B lymphocytes in SLE could be responsible for the characteristic B cell hyperactivity and autoantibody production seen in SLE.
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PMID:High levels of TH2 cytokine gene expression in systemic lupus erythematosus. 852 28

As has been reported previously, models of chronic graft-versus-host (GvH) and systemic lupus erythematosus (SLE)-like diseases are characterized by high IgE and IgG1 immunoglobulin (Ig) levels in the serum. An IL-4 induced pathological expansion of Th2 helper cells has been described for both disease models. Due to the immunopharmacological profile of soluble recombinant interleukin-4 receptor (IL-4-R) to bind specifically the corresponding ligand IL-4 and thereby to modulate biological activity upon exogenous administration in various autoimmune disease models, we investigated the immunoregulatory activity of IL-4-R and anti-IL-4 monoclonal antibody (MAb) 11B11 on the development of SLE-like disease in MRL/lpr autoimmune mice and on chronic GvH reaction in BDF1 hybrid mice. Sensitized GvH-BDF1 hybrid mice and SLE in MRL/lpr autoimmune mice were treated in vivo with the IL-4 antagonists to alter the pattern of serum Ig production and to modulate the disease process. These animals were followed for proteinuria, autoantibody production (anti-dsDNA), serum IgE, IgG1 and IgG2a levels, and the survival was monitored. Treatment of these diseased animals resulted in an improved survival rate, lowered the percentage of animals with lymphadenopathy and hepatosplenomegaly, reduced the levels of autoantibodies and inhibited proteinuria of the developing glomerulonephritis in both mouse strains, even in the established diseases. In both models the increase in total IgE and IgG1 levels in serum was strongly inhibited by the IL-4 antagonists, even under therapeutic conditions. But there was no inhibitory activity observed on the IgG2a serum levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of the immunoglobulin dysregulation in GvH- and SLE-like diseases by the murine IL-4 receptor (IL-4-R). 854 94

To investigate the respective roles of Th1 and Th2 cells in the pathogenesis of lupus-like autoimmune disease, we have analyzed the spontaneous and antigen-induced productions of IgG1 vs IgG2a and IgG3 subclasses in relation to the mRNA expression of INF-gamma (Th1 cytokine promoting IgG2a and IgG3 production), IL-4 (Th2 cytokine promoting IgG1 production), and IL-10 (Th2 cytokine) in CD4+ T cells from lupus-prone MRL mice. For this purpose, two paired sets of MRL mice were chosen for the comparison of these parameters: (a) MRL-lpr/lpr (lpr for lymphoproliferation) and its recently described substrain with a prolonged survival, termed MRL-lpr/lpr.ll (ll for long lived) and (b) MRL male mice bearing the Yaa (Y-linked autoimmune acceleration) gene (MRL.Yaa) with an accelerated disease and their male counterparts lacking the Yaa gene. We demonstrate herein that the accelerated development of lupus-like autoimmune disease in MRL-lpr/lpr and MRL.Yaa mice, as compared with MRL-lpr/lpr.ll and MRL-+/+ mice, respectively, was correlated with an enhanced expression of IFN-gamma vs IL-4 and IL-10 mRNA in CD4+ T cells, which paralleled with an increase of spontaneous and foreign T cell-dependent antigen-induced productions of IgG2a and IgG3 vs IgG1 antibodies. These data suggest that an imbalance towards Th1 predominance may play a significant role in the acceleration of lupus-like autoimmune disease in MRL mice.
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PMID:Imbalance towards Th1 predominance is associated with acceleration of lupus-like autoimmune syndrome in MRL mice. 860 23

Systemic lupus erythematosus (SLE) manifested with multiple autoantibodies production and glomerulonephritis, is the best example of systemic autoimmune diseases. To further elucidate the role of cytokines and the potential involvement of natural killer cells (NK cells) in the pathogenesis of lupus, phenotypic analysis of peripheral blood mononuclear cells (PBMC), NK cells cytotoxicity and cytokines production pattern of SLE patients and normal controls were examined. In addition, the effect of a variety of cytokines on anti-dsDNA antibodies production was also investigated. Our results showed that: (a) there was an increased percentage of memory T cells and decreased percentage of NK cells in SLE patients when compared to normal controls (p < 0.05); (b) a decreased production of cytokines like gamma-IFN in mitogen-stimulated PBMCs was also noted in SLE patients; (c) cytolytic activity of NK cells was markedly reduced in SLE patients (p < 0.05); (d) spontaneous secretion of IgG anti-dsDNA antibodies by B cells isolated from SLE patients could be inhibited by gamma-IFN, but not by IL-2, IL-4 and IL-5. These data suggested that decreased functions of NK cells and related type 1 T helper cells be closely related to the immune dysregulation and autoantibodies production in SLE.
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PMID:Phenotypic and functional analysis of natural killer cells in systemic lupus erythematosus patients. 860 62

Neonatal exposure to antigen is believed to result in T cell clonal inactivation or deletion. Here we report that, contrary to this notion, neonatal injection of BALB/c mice with a hen egg lysozyme peptide 106-116 in putative "tolergenic" doses induced a T cell proliferative and an immunoglobulin G (IgG) antibody (Ab) response of both T helper cell 1 (Th1)- (IgG2a, IgG2b, and IgG 3) and Th2-dependent (IgG1) isotopes. Upon subsequent challenge with the peptide in complete Freund's adjuvant in adult life, although this neonatal regimen suppressed proliferation and the production of Th1 cytokines (interleukin[IL]-2 and interferon gamma), Th2 cytokine (IL-5, IL-4, and IL-10) secretion was increased, and the serum levels of Th1- and Th2-dependent isotypes of peptide-specific Ab remained elevated. The in vitro proliferative unresponsiveness in Th1 cells could be reversed by Abs to Th2 cytokines (IL-4 and IL-10). Thus, neonatal treatment with a peptide antigen induces T cell priming including production of IgG Abs of both Th1- and Th2-dependent isotypes. Upon subsequent peptide exposure, the peptide-specific T cell responses undergo an effective class switch in the direction of Th2, resulting in T cell proliferative unresponsiveness. Accordingly, this shift towards increased Ab production to autoantigen could be deleterious in individuals prone to antibody-mediated diseases. Indeed, neonatal treatment with a self-autoantigenic peptide from an anti-DNA monoclonal Ab (A6H 58-69) significantly increased the IgG anti-double-stranded DNA Ab levels in lupus-prone NZB/NZW F1 mice, despite suppressing peptide-specific T cell proliferation. This adverse clinical response is in sharp contrast to the beneficial outcome of neonatal treatment with autoantigens in Th1-mediated autoimmune diseases, such as autoimmune encephalomyelitis, as reported by others. A Th1 to Th2 immune deviation can explain the discordant biological responses after the presumed induction of neonatal tolerance in autoantibody- vs. Th-1 mediated autoimmune diseases.
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PMID:Neonatal peptide exposure can prime T cells and, upon subsequent immunization, induce their immune deviation: implications for antibody vs. T cell-mediated autoimmunity. 866 87

Nitric oxide (NO) is a critical mediator of a variety of biological functions. A range of micro-organisms, including viruses, bacteria, protozoa and helminths, is sensitive to NO produced by macrophages activated with gamma-interferon (IFN-gamma) and lipopolysaccharide. In contrast, NO is involved in a number of important immunopathologies, including diabetes, graft-vs-host reaction, rheumatoid arthritis, systemic lupus erythematosus, experimental autoimmune encephalomyelitis and multiple sclerosis. Thus, it is crucial that the synthesis of NO is under tight regulation. This is achieved, in part, through the opposing cytokines produced by T helper 1 (Th1) and Th2 cells. Th1 cells produce IFN-gamma, which is the most powerful inducer of inducible NO synthase (iNOS). In contrast, interleukin 4 is produced by Th2 cells and inhibits the induction of iNOS at the level of transcription. Furthermore, NO is also produced by Th1 cells, whose proliferation can be inhibited by high concentrations of NO. Thus, apart from being a mediator of Th1/Th2 interaction, NO may also be an important self-regulatory molecule that prevents the over-expansion of Th1 cells which are implicated in a range of severe immunopathologies.
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PMID:Nitric oxide in infectious and autoimmune diseases. 872 41


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