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)

The murine MRL/lpr model of lupus nephritis is characterized by a systemic autoimmune syndrome closely resembling the human disease. The lpr mutation represents a defect in the expression of the apoptosis-signaling Fas antigen gene which causes accelerated autoimmune disease in MRL/ lpr mice and a milder, non-lethal autoimmune syndrome in C57BL6-lpr/lpr mice. The role of cytokines in autoimmune pathogenesis and its relationship with the lpr mutation remains poorly understood. In this study we utilized a RNase protection assay to quantitatively and simultaneously examine the expression of 10 different cytokine genes, namely IL-1 alpha, II-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IFN-gamma, TNF-alpha, and TNF-beta in kidney, spleen, liver, and lymph nodes obtained from pre-diseased and diseased lupus-prone MRL/lpr, pre-diseased MRL/+2 and C57BL/6-lpr mice, as well as healthy non-autoimmune C57BL/6 and Balb/c mice. Diseased MRL/lpr mice demonstrated marked and predominant IL-1 beta gene upregulation in kidneys, liver, lymph nodes and spleen. Increased message for both TNF-alpha and IFN-gamma genes was also observed in lymph nodes, and less consistently, in the spleen, and kidneys derived from diseased MRL/lpr mice as compared to pre-diseased MRL/+2 or normal nonautoimmune control mice. Furthermore, a modest increase in the expression of both IL-1 beta and IFN-gamma message was observed in lymphoid organs of pre-diseased MRL/lpr and C57BL/6-lpr mice compared with MRL/+2 and C57BL/6 controls, respectively. Increased IL-1 beta gene expression was associated with the presence of the lpr mutation, was observed during the prediseased stage, and increased during active disease in both male and female mice. In summary, these results demonstrate that generalized up-regulation of IL-1 beta gene expression, in concert with a more limited up-regulation of both TNF-alpha and IFN-gamma expression, are prominent features of the autoimmune syndrome in the MRL/lpr model of SLE and may contribute to the disease-accelerating effect of the lpr mutation.
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PMID:Cytokine gene expression in the MRL/lpr model of lupus nephritis. 880 76

Autoantigen-reactive T cells might play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Autoantigen-reactive T cell clones were generated from spleens of NZB x NZW F1 (BWF1) and normal control BALB/c mice with interleukin-2 (IL-2), a procedure that selects for in vivo activated antigen-reactive T cells. The antigen-specificity of the T cell clones was tested by using a panel of candidate autoantigens. The T cell clones from BWF1 mice but not those from BALB/c mice proliferated against heparan sulfate, the major glycosaminoglycan of glomerular basement membrane. None of the clones proliferated against dsDNA or cardiolipin. All the heparan sulfate-reactive T cell clones had the ability to selectively augment the production of IgG anti-dsDNA autoantibodies. When cultured with either heparan sulfate or Concanavalin A, the T cell clones produced high levels of IL-4 and IL-5 with no detectable IL-2 or IFN-gamma. In contrast, T cell clones derived from BALB/c mice augmented the production of total polyclonal IgG but not the production of anti-dsDNA antibodies. These studies indicate the existence of heparan sulfate-reactive T cells in BWF1 mice. Characterization of heparan sulfate-reactive T cells that could selectively augment anti-dsDNA production will permit the design of targeted and antigen-specific therapy.
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PMID:Isolation and functional characterization of IL-2 responsive T cell clones from NZB x NZW F1 mice. 893 77

Accelerated apoptosis and improper expression of cytokine genes have been considered as important defects of lymphocytes for the development of systemic lupus erythematosus (SLE). This study was undertaken to test the possible contribution of serum factors obtained from SLE patients to these abnormalities. Molt-4 and Jurkat cells constantly exhibited a slower growth rate as well as more dead cells in culture with SLE sera tested than controls, although the cell cycle progression was apparently unaffected. Increased apoptosis was demonstrable among SLE sera-cultured cells by ELISA for apoptosis-specific DNA fragments and terminal deoxynucleotidyl transferase (TdT) in situ death analysis. Different levels of Fas, Fas-L, and Bcl-2 gene products were not detected between SLE sera-treated cells and the controls. The transcripts of interleukin-10 (IL-10) and interferon-gamma (IFN-gamma) genes of these two T cell lines were evidently increased in the presence of SLE sera, while IL-2 and IL-4 were unaffected. Elevated expression of IL-5 was also found in Molt-4 cells. By contrast, SLE sera reduced the transcripts of IL-6 gene in Jurkat cells. The effects of SLE sera were independent of corticosteroid medication. These results suggest that serum abnormalities may also play a role in T cell dysfunction.
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PMID:Induction of apoptosis and cytokine gene expression in T-cell lines by sera of patients with systemic lupus erythematosus. 901 May 6

Development of either Th1 or Th2 cell subsets has profound immunologic consequences, either pathogenic or protective, in several autoimmune diseases. However, it remains unclear which subset of Th cells plays a more critical role in lupus. In this study, we examined IL-4 and IL-12, which play decisive roles in the development of Th2 and Th1, respectively, in the IgG autoantibody production and development of lupus nephritis in NZB/W (B/W) F1 mice. Transfer of either IL-4- or IL-12-stimulated splenocytes from 5-mo-old B/W F1 mice into B/W F1 mice of the same age enhanced the production of IgG anti-dsDNA Ab. Consistently, administration of mAb against either IL-4 or IL-12 before the onset of lupus could inhibit the production of IgG anti-dsDNA Ab. However, only anti-IL-4 mAb was effective in preventing the onset of lupus nephritis. This discrepancy appeared to be explained by the differential effect on the production of IgG3-type autoantibody and TNF production. Interestingly, when combined, anti-IL-12 mAb abrogated the beneficial effect of anti-IL-4 mAb. These results indicate that both Th2 and Th1 contribute to the IgG autoantibody production, and IL-4 and IL-12 play key roles in the complexity of cytokine regulation in the pathogenesis of autoimmunity in lupus, but the former is more critical.
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PMID:Roles of IL-4 and IL-12 in the development of lupus in NZB/W F1 mice. 901 93

We studied 16 patients affected by autoimmune hemolytic anaemia (AIHA), both idiopathic and associated with other diseases (B and T lymphoma, B hepatitis, gastric carcinoma, systemic lupus erythematosus) or alpha-methyldopa therapy, in order to value T- and B-cell activation. We determined the count of T- and B-cell subsets in peripheral blood, the proliferative response of peripheral blood lymphocytes (PBL) to phytohemagglutinin (PHA) and to pokeweed mitogen (PWM), the percentage of CD25+ cells in culture and interleukin (IL)-1alpha, IL-2, IL-4, tumor necrosis factor (TNF)alpha and soluble IL-2 receptor (sIL-2R) levels in sera and in culture. Except for an increase in CD4+ and CD8+ T cell number in a case of AIHA associated with a T lymphoma and an increase in the percentage of CD5+ and PCA1+ B cells in two cases of AIHA associated with B lymphoma and with SLE, no further data showed a relationship with the disease possibly associated with AIHA, so both idiopathic and secondary AIHA cases were analyzed together. CD4+ T cells were reduced in number in 9 cases, while CD8+ T cells were reduced in 6 cases. The percentage of CD5+ B cells was increased in 5 cases. The percentage of PCA1+ cells was increased in all cases (mean +/- sd: 18 +/- 22 vs 0,2 +/- 1 in controls). The average PBL proliferative response to PHA was reduced (S.I. 71 +/- 55 vs 138 +/- 45 in controls) as well as that to PWM (S.I. 27 +/- 21 vs 75 +/- 24 in controls), despite IL-2 high levels, in all cases, in both sera (mean +/- sd: 648 +/- 351 pg/ml vs 16 +/- 4 pg/ml in controls) and culture supernatants (mean +/- sd: 1045 +/- 677 pg/ml vs 195 +/- 51 pg/ml in controls). In PHA stimulated cultures the percentage of CD25+ cells was reduced (mean +/- sd: 37 +/- 18 vs 63 +/- 14 in controls), sIL-2R levels were like controls in 7 cases. In sera sIL-2R levels were increased in all cases (mean +/- sd: 1256 +/- 465 U/ml vs 256 +/- 114 U/ml in controls), IL-1alpha was increased in all cases too, while IL-4 levels were increased only in 7 cases. Linear regression analysis generally showed a low relationship between S.I. and IL-2, IL-4 and sIL-2R levels in supernatants of PHA stimulated culture as well as between S.I. and the percentage of CD25+ cells. Taken together these data suggest a state of B- and T-cell hyperactivation in AIHA. The low PBL proliferative response in vitro, explained in previous studies as a temporary functional exhaustion, might be itself a sign of the complete lymphocyte activation occurring in vivo in AIHA.
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PMID:Lymphocyte activation and cytokine production in autoimmune hemolytic anaemia (AIHA). 902 Apr 7

In an attempt to elucidate the role of oestrogens in systemic lupus erythematosus (SLE) we investigated the effects of treatment with an oestrogen antagonist-tamoxifen and a monoclonal anti-oestradiol (anti-E2) antibody on mice in which experimental systemic lupus erythematosus (SLE) was induced by a human monoclonal anti-DNA antibody bearing the 16/6 idiotype (16/6 Id). Thus, groups of BALB/c female mice were immunized with the 16/6 Id and 3 weeks following the booster injection, when antibody titres were elevated in the injected mice, treatment protocols with anti-oestradiol or tamoxifen were initiated. Control groups that were not immunized with the 16/6 Id but were similarly treated with the above agents were included in the study. The treatment with the above agents had no effect on the total autoantibody titres; however, a decrease in the immunoglobulin G (IgG)2a/IgG1 ratio of the anti-DNA antibodies was determined in the 16/6 Id immunized and treated mice. Further both the anti-oestradiol and tamoxifen had beneficial effects on the clinical manifestations (white blood cell counts, levels of protein in the urine and immune complex deposits in the kidneys) of the 16/6 Id immunized and treated mice. We have previously observed a significant elevation in interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha) secretion in mice with experimental SLE and a reduction in IL-2, IL-4 and interferon-gamma (INF-gamma) levels as compared with the levels detected in healthy controls. Treatment with either the anti-oestradiol antibody or with tamoxifen restored the levels of all the above cytokines to the normal levels observed in the control mice. These findings suggest that cytokine modulation may be the basis for the therapeutic effects of both anti-oestrogens in experimental SLE.
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PMID:The beneficial effects of treatment with tamoxifen and anti-oestradiol antibody on experimental systemic lupus erythematosus are associated with cytokine modulations. 903 19

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

Eicosapentaenoic acid and docosahexaenoic acid (EPA and DHA respectively) can suppress the production of interleukin-1 (IL-1), IL-2 and TNF (tumor necrosis factor) but not of IL-4 by human lymphocytes in vitro. In addition, the concentrations of EPA and DHA were also found to be low in the plasma phospholipid fraction of patients with SLE. In a limited clinical study performed by us earlier, it was observed that oral supplementation of EPA/DHA to patients with SLE can induce clinical remission without any side-effects. Since oxygen free radicals are known to be involved in the pathobiology of SLE, we estimated the plasma concentrations of lipid peroxides, nitric oxide, and anti-oxidants such as catalase, superoxide dismutase (SOD), glutathione peroxidase and vitamin E in these patients both before and after the induction of remission following EPA/DHA administration. These results showed that the levels of lipid peroxides are elevated and those of nitric oxide, SOD and glutathione peroxidase are decreased in SLE prior to EPA/DHA supplementation. Following EPA/DHA administration the concentrations of lipid peroxides, and those of nitric oxide, SOD and glutathione peroxidase reverted to near normal levels. These results suggest that oxidant stress, nitric oxide, and anti-oxidants play a significant role in SLE and that EPA/DHA can modulate oxidant stress and nitric oxide synthesis and may have a regulator role in the synthesis of anti-oxidant enzymes such as SOD and glutathione peroxidase. From the results of this study, we would like to suggest that measurement of lipid peroxides, nitric oxide and anti-oxidants can be used as markers to predict prognosis in patients with SLE.
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PMID:Oxidant stress, anti-oxidants and essential fatty acids in systemic lupus erythematosus. 908 97

It has been established that CD4+ T cells play an essential role in the development of systemic lupus erythematosus (SLE). Since CD4+ T cells differentiate upon activation into two defined subsets, TH1 and TH2, differing in their capacities of cytokine production with distinct immunopathological consequences, it becomes important to understand the respective roles of TH subsets in the pathogenesis of SLE. Our analysis on 4 different substrains of autoimmune-prone MRL mice revealed that the progression of SLE in these mice is correlated with an enhanced expression of interferon-gamma (a TH1 type cytokine regulating the production of IgG2a and IgG3) vs interleukin-4 (IL-4; a TH2 type cytokine regulating the production of IgG1), in parallel with an increased production of IgG2a and IgG3 autoantibodies over IgG1. In addition, studies on lupus-prone mice expressing an IL-4 transgene have shown that the constitutive expression of IL-4, biasing autoimmune responses towards a TH2 phenotype, inhibits the development of lupus nephritis. These results suggest that the development and progression of murine lupus is determined by the type of TH responses (either acceleration by TH1 responses or protection by TH2 responses) inducing the generation of more or less pathogenic autoantibodies. In fact, murine IgG3 has been shown to be extremely nephritogenic, generating "wire-loop" lupus-like glomerular lesions, because of their cryoglobulin activity associated with a unique physicochemical property of IgG3 constant region. Our results underline the importance in the pathogenesis of SLE of the qualitative aspects of autoantibody responses controlled by subpopulations of TH cells.
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PMID:T helper cell subsets in the pathogenesis of systemic lupus erythematosus. 909 56

The systemic autoimmune syndrome of MRL/Mp-lpr/lpr (MRL/lpr) mice consists of severe pan-isotype hypergammaglobulinemia, autoantibody production, lymphadenopathy, and immune complex-associated end-organ disease. Its pathogenesis has been largely attributed to helper alphabeta T cells that may require critical cytokines to propagate pathogenic autoantibody production. To investigate the roles of prototypical Th1 and Th2 cytokines in the pathogenesis of murine lupus, IFN-gamma -/- and IL-4 -/- lupus-prone mice were generated by backcrossing cytokine knockout animals against MRL/lpr breeders. IFN-gamma -/- animals produced significantly reduced titers of IgG2a and IgG2b serum immunoglobulins as well as autoantibodies, but maintained comparable levels of IgG1 and IgE in comparison to cytokine-intact controls; in contrast, IL-4 -/- animals produced significantly less IgG1 and IgE serum immunoglobulins, but maintained comparable levels of IgG2a and IgG2b as well as autoantibodies in comparison to controls. Both IFN-gamma -/- and IL-4 -/- mice, however, developed significantly reduced lymphadenopathy and end-organ disease. These results suggest that IFN-gamma and IL-4 play opposing but dispensable roles in the development of lupus-associated hypergammaglobulinemia and autoantibody production; however, they both play prominent roles in the pathogenesis of murine lupus-associated tissue injury, as well as in lpr-induced lymphadenopathy.
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PMID:Roles of interferon-gamma and interleukin-4 in murine lupus. 910 38


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