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 recently described (Sharon, M. et al., Science 1986. 234:859) interleukin 2 (IL 2)-binding molecule p75 was detected in the CD3+4-8-Tac- "double-negative" cell population selectively expanded in lupus-like autoimmune mice MRL/MP-lpr/lpr using cross-linking studies. Scatchard analysis of the IL 2 binding revealed the existence of approximately 4700 sites per cell with an apparent Kd of 1500 pM. The cell line LD1.T3B, derived from this population, shared surface markers and the p75 presence/p55 absence of IL 2-binding proteins with its in vivo counterpart, displaying around 3100 sites per cell with a Kd of about 1300 pM. Functional studies showed that high doses of IL 2 had an inhibitory effect on the autonomous growth of this cell line in the absence of the development of killer activity. This study provides evidence of the functional abilities of p75, and shows that the use of Tac/p55 surface expression only to evaluate IL 2 receptors and T cell activation can be an oversimplification as well as misleading.
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PMID:Expression of the p75 interleukin 2-binding protein on CD3+4-8-Tac- cells from autoimmune MRL/MP-lpr/lpr mice. 278 6

Two TNF binding proteins have been characterized as soluble fragments of TNF receptors. We measured the plasma concentrations of soluble type A (p75) and type B (p55) TNF receptors in patients with systemic lupus erythematodes (SLE), progressive systemic sclerosis (PSS), and mixed connective tissue disease (MCTD). In SLE and PSS patients plasma concentrations of both types of TNF receptors and in MCTD patients type A TNF receptors were significantly elevated compared to controls. Plasma concentrations of both soluble TNF receptors were highly correlated in SLE, PSS, and MCTD patients, indicating a possible coregulation of both TNF receptors. In contrast, soluble interleukin 2 receptor (sCD 25) plasma concentrations were not correlated and seem to be an independent parameter. The soluble forms of the TNF receptors neutralize TNF in cytotoxicity assays and are functionally active as TNF antagonists. In one patient with SLE, autoantibodies against type A TNF receptors were detected, TNF alpha, and TNF beta did not interfere with the autoantibody binding to the receptor.
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PMID:Evaluation of soluble tumor necrosis factor (TNF) receptors and TNF receptor antibodies in patients with systemic lupus erythematodes, progressive systemic sclerosis, and mixed connective tissue disease. 824 78

We studied neurite regeneration in MRL-lpr/lpr mice, a murine model of systemic lupus erythematosus, using a culture system to investigate the influences of immunological abnormalities on neurons. The regeneration of cultured dorsal root ganglion (DRG) neurons from MRL-lpr/lpr mice was delayed compared with control MRL-+/+ mice. This modification of regeneration was age-dependent. MRL-lpr/lpr mice older than 16 weeks of age exhibited less neurite regeneration than controls but those younger than 6 weeks of age showed equal regeneration. Regeneration was improved by adding nerve growth factor (NGF) to culture medium. Following immunocytochemical staining, we counted the low affinity NGF receptor p75-positive DRG neurons in MRL mice. The percentage of p75-positive neurons in MRL-lpr/lpr mice older than 16 weeks of age was higher than that in MRL-+/+ mice. These neuronal abnormalities were thought not to be directly dependent on the genetic defect of Fas antigen, which is related to apoptosis in MRL-lpr/lpr mice, but to be the result of immunological abnormalities. The present study is the first to demonstrate a modification of neurite regeneration by immunological dysfunction in autoimmune mice.
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PMID:Delayed neurite regeneration and its improvement by nerve growth factor (NGF) in dorsal root ganglia from MRL-lpr/lpr mice in vitro. 916 60

The aim of this study was to determine whether the levels of serum cytokines IL-6 and TNFalpha and of the soluble receptors p55 srTNFalpha, p75 srTNFalpha and srIL-2ac are valuable markers of disease activity in patients with systemic lupus erythematosus (SLE) compared with the established parameters of anti-dsDNA, C3, C4 and CH50. Forty patients with SLE, 19 ambulatory and 21 hospitalised, were included in this study. On the day of blood sampling a clinical examination was performed and SLEDAI and ECLAM disease activity scores were used to assess disease activity. Nineteen patients had inactive disease and 21 patients had active disease. Thirteen patients from the second group developed nephritis. In these patients the blood sampling and disease activity assessment were performed twice (at presentation and 6 months after treatment). Serum levels of cytokines and soluble receptors were measured by ELISA. Serum levels of cytokines and soluble receptors of patients with active disease were significantly higher than in patients with inactive disease (IL-6 p = 0.0004, TNFalpha p = 0.0015, srIL-2c p<0.0001, p55 srTNFalpha p<0.0001, p75 srTNFalpha p<0.0001). Serum soluble receptor levels of patients with inactive disease were higher than those of healthy controls (p55 srTNFalpha p<0.0001, p75 srTNFalpha p = 0.0002, srIL-2alpha p = 0.0012). No significant difference was found for TNFalpha and IL-6 (TNFalpha p=0.015, IL-6 p=0.019). Serum TNFalpha levels and especially srIL-2alpha, p55 srTNFalpha( and p75 srTNFalpha levels correlated strongly with SLEDAI and ECLAM disease activity scores, anti-dsDNA, C3, C4 and CH50 (p<0.0001). Serum soluble receptor (srIL-2alphac, p55 srTNFa, p75 srTNFalpha) levels were higher in patients with nephritis before treatment and decreased significantly 6 months after treatment (p=0.005). The same trend was noticed with SLEDAI and ECLAM disease activity scores (p = 0.005) and anti-dsDNA (p = 0.008). In contrast, no significant differences were observed for C3 and C4 levels before and after treatment, which suggests that soluble receptors of cytokines are more sensitive markers of disease activity than C3 or C4 in predicting improvement. Serum levels of srIL-2alpha, p55 srTNFalpha and p75 srTNFalpha could provide useful information about disease activity in SLE patients, especially in cases where the other markers do not.
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PMID:Serum IL-6, TNFalpha, p55 srTNFalpha, p75srTNFalpha, srIL-2alpha levels and disease activity in systemic lupus erythematosus. 1008 43

The role of pro-inflammatory cytokines in systemic lupus erythematosus (SLE) remains somewhat controversial. Several studies have shown increased production of TNF alpha and IL-6 in patients with SLE. Increased production of IL-6, TNF alpha, and IL-1 soluble receptors have also been reported. This finding is provocative because the soluble receptors have the capacity to act as antagonists. Several other inflammatory disorders are also associated with increased production of soluble TNF alpha receptors suggesting that this may be a general compensatory mechanism designed to down-regulate inflammation. The recent identification of an SLE disease susceptibility locus near the TNFR2 locus (TNFR p75) suggested the hypothesis that genetically driven differences in soluble TNFR2 production could play a role in the genetic susceptibility to SLE. We therefore characterized the frequency of a genetic polymorphism in the 3' untranslated region of the TNFR2 gene in Caucasoid SLE patients and geographically matched controls. No difference in the gene frequency of the two base-pair polymorphism in SLE patients compared to controls was found, nor was there any association with any particular clinical phenotype.
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PMID:A TNFR2 3' flanking region polymorphism in systemic lupus erythematosus. 1119 16

Most disease modifying antirheumatic drugs (DMARD) are discontinued within 5 years because of loss of clinical efficacy or toxicity. As a result, there has been a concerted effort to develop new immunomodulatory agents, particularly biological agents, that block the putative proinflammatory cytokines. Among the agents developed thus far, inhibitors of tumor necrosis factor (TNF) have shown perhaps the greatest promise as therapeutic agents for rheumatoid arthritis (RA). Two TNF-blocking agents, etanercept (Enbrel) and infliximab (Remicade), have been approved in the US and more recently in Europe, for the treatment of patients with RA. The results of randomized placebo controlled trials have shown that both agents significantly decrease the intensity of synovitis and prevent or retard the progression of cartilage destruction, especially when combined with methotrexate. Their side effect profiles appear to be acceptable, although rare cases of lupus-like diseases and of severe infections have been reported. Although the early clinical experience with these agents has been encouraging, their longterm safety and continuing efficacy in the general population with RA, as well as in high risk patient subsets (i.e., patients with malignancies or chronic infections), remain to be determined. In addition, the costs of these newer agents must be justified on clinical grounds. Because of the questions still surrounding these new treatment principles, several consensus conferences have been held in Europe and the US to address the role of the new biologicals in the current RA armamentarium.
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PMID:How do the biologics fit into the current DMARD armamentarium? 1140 55

Genetic factors and immune dysregulation play important roles in the development of systemic lupus erythematosus (SLE). Tumor necrosis factor receptor 2 (TNFR2) is suggested to be involved in the development of SLE because its genetic locus (1p36) encompasses one of the susceptible loci for SLE and its ligand (TNF) is associated with SLE. To investigate the role of TNFR2 in the pathogenesis of SLE, 139 Korean patients were genotyped with SLE, 137 healthy control subjects were genotyped for TNFR2 196 R/M polymorphism in exon 6 with PCR-SSCP, and the clinical characteristics of SLE were analyzed according to the genotypes. The genotype frequencies of 196 R/R, 196 R/M, and 196 M/M were 3.6%, 30.9%, and 65.5% in SLE patients and 4.4%, 26.3%, and 69.3% in healthy controls (p = 0.676). The allelic frequency of 196 R was 19.1% in SLE patients and 17.5% in healthy controls (p = 0.638, odds ratio = 1.109, and the 95% confidence interval = 0.720-1.708). The clinical characteristics were not different according to the genotypes. In conclusion, no skewed distribution of TNFR2 196 R/M polymorphism was found in Korean patients with SLE compared with healthy controls. Further studies in other populations will be needed to elucidate the role of the TNFR2 polymorphism in the development of SLE.
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PMID:Tumor necrosis factor receptor 2 polymorphism in systemic lupus erythematosus: no association with disease. 1160 Feb 23

It is generally accepted that the interaction between CD40 and its ligand (CD154) plays a decisive role in contact-dependent help for T and B cells. In CD154-deficient MRL/Mp-Fas(lpr) (MRL/lpr) mice, however, high titres of IgG2a-type autoantibodies against small nuclear ribonucleoproteins (snRNPs) are observed. We successfully isolated two CD154-deficient MRL/lpr Th1 lines, which could provide B cell help for anti-snRNP antibody production. The proliferative responses of the Th1 cell lines were MHC class II (I-Ek)-restricted. Although syngeneic B cell proliferation was induced by Th1 lines in both a contact-dependent and -independent manner, the soluble form of TNF-alpha (sTNF-alpha) was not involved in contact-independent B cell proliferation. On the other hand, both anti-TNF-alpha and TNF-receptor 2 (TNF-R2, p75) monoclonal antibody (MoAb) blocked contact-dependent B cell proliferation, suggesting that the transmembrane form of TNF-alpha (mTNF-alpha)-TNF-R2 co-stimulation participates in B cell activation. Similarly, anti-TNF-alpha and TNF-R2 MoAb inhibited anti-snRNP antibody production in vitro, but anti-CD154 or TNF-R1 MoAb did not. These results indicate that the interaction of mTNF-alpha on activated Th1 cells with TNF-R2 on B cells may be involved in the autoimmunity seen in MRL mice, and that the blockade of CD40-CD154 co-stimulation may not always be able to suppress some Th1-related manifestations of lupus.
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PMID:The transmembrane form of TNF-alpha drives autoantibody production in the absence of CD154: studies using MRL/Mp-Fas(lpr) mice. 1239 Mar 9

Lupus-prone (MRLxC57BL/6) F(1) mice lacking gammadelta T cells show more severe lupus than their T cell-intact counterparts, suggesting that gammadelta T cells down-modulate murine lupus. To determine the mechanisms for this effect, we assessed the capacity of gammadelta T cell lines derived from spleens of alphabeta T cell-deficient MRL/Mp-Fas(lpr) (MRL/Fas(lpr)) mice to down-regulate anti-dsDNA production generated by CD4(+)alphabeta T helper cell lines and activated B cells from wild-type MRL/Fas(lpr) mice. One line, GD12 (gd TCR(+), CD4(-)CD8(-)), had the capacity to reduce anti-dsDNA production in a contact-dependent manner. GD12 also killed activated MRL/Fas(lpr) (H-2(k)) B cells, with less cytolysis of resting B cells than that generated by in comparison to cytokine-matched gammadelta T cell lines. In addition, GD12 also killed activated B cells derived from C57BL/6-Fas(lpr) (H-2(b)) or beta(2)-microglobulin (beta(2) M)-deficient MRL/Fas(lpr) mice, suggesting cytolysis was neither MHC- nor CD1-restricted. Killing by GD12 was inhibited by anti-TNFalpha and anti-TNF-R1, and partially blocked by anti-gd TCR Fab fragments, but not by anti-FasL, anti-TNF-R2 (p75) or concanamycin A. IL-10 produced by GD12 also partially inhibited alphabeta Th1-dependent but not alphabeta Th2-dependent autoantibody production. These findings prove that we have identtified a gammadelta T cell line that suppresses autoantibody synthesis by alphabeta T-B cell collaboration in vitro.
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PMID:Regulation of T cell-dependent autoantibody production by a gammadelta T cell line derived from lupus-prone mice. 1242 98

Tumour necrosis factor (TNF) is a pro-inflammatory cytokine with a role in the pathogenesis of a number of conditions including rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease. Etanercept (Enbrel; Immunex Corp., Seattle, WA, USA) is a recombinant soluble fusion protein of TNF-alpha type II receptor and IgG which acts by blocking the action of TNF-alpha. It is licensed for use in rheumatoid arthritis and juvenile chronic arthritis. A number of studies report the development of antinuclear and anti-double-stranded DNA antibodies in patients treated with TNF antagonists for rheumatoid arthritis. There are few reports of the development of clinical features of discoid, subacute or systemic lupus erythematosus. We present one of the first reported cases of etenercept-induced systemic lupus erythematosus and review the literature of lupus and TNF antagonists.
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PMID:Etanercept-induced systemic lupus erythematosus. 1461 25


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