Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The T cell-associated antigen CD5 has been shown to play an important role in the regulation of T cell activation. Monoclonal antibodies directed against CD5 upregulate helper function, and induce interleukin 2 (IL2) production by mature T cells as well as thymocytes. CD5 is also expressed on subsets of B cells associated with autoantibody production, and CD5+ B cells are present in increased numbers in patients with rheumatoid arthritis and systemic lupus erythematosis. More recently CD5 has been found to be present on human B lymphocytes following in vitro activation with phorbol myristate acetate. To date a similar functional role for CD5 has not to date been demonstrated for B cells. In this study we have shown that structurally similar CD5 molecules are present on activated B cells and T cells. In addition, CD5 on both stimulated B cells and T cells is phosphorylated, which may be important in the function of CD5 following activation. CD5 protein or mRNA was not detected on unstimulated splenic B cells depleted of any CD5+ cells. To investigate the control of CD5 expression, we examined a series of cytokines either alone or in combination for their effect on the induction of CD5. CD5 expression was specifically inhibited by IL4 but not by the other cytokines tested. This inhibition was very specific as IL4 did not inhibit the expression of other B cell activation antigens including CD25, B5, T9 and CD23 as well as the pan-B cell antigen CD20. The addition of other cytokines did not increase or reverse the inhibition of CD5 expression by IL4. This inhibition was demonstrated by immunofluorescence and flow cytometric analysis. Immunoprecipitation studies of 125I-labeled activated B cells demonstrated that there was a decrease in cell surface CD5 protein, and not simply inhibition of expression of a particular epitope. Northern blot analysis demonstrated that the expression of CD5 mRNA was markedly inhibited in the presence of IL4, whereas the induction of the protooncogene c-myb was unaffected. This suggests that IL4 inhibits CD5 protein expression on activated B cells by reducing the amount of CD5 mRNA transcription or increasing the degradation of CD5 mRNA. The role of the T cell-derived lymphokine IL4 in regulating CD5 expression may be important in the disease states characterized by increased numbers of CD5+ B cells.
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PMID:Expression and regulation of CD5 on in vitro activated human B cells. 247 77

Microbial superantigens (SAg), by virtue of their binding to TCR V beta elements and to class II MHC molecules on accessory cells, trigger T cell proliferation in a dose-dependent fashion. In contrast, SAg-induced T cell-dependent B cell differentiation occurs only at SAg concentrations that are orders of magnitude lower that those required for optimal mitogenesis (low-dose SAg). At optimal mitogenic doses (high-dose SAg), SAg-driven B cell differentiation does not ensue. In this report, we demonstrate that this dichotomy in SAg-driven B cell differentiation is due to the active inhibition of B cell differentiation by high-dose SAg. Such inhibition is not reversed by feeding cultures with fresh medium, with conditioned media, or with IL2 +/- IL4, and impaired B cell differentiation is observed in cultures containing purified T cells or CD4+ T cells + B cells, as well as in PBMC cultures. Although preincubation of either T cells or B cells with high-dose SAg impairs subsequent SAg-induced B cell differentiation, high-dose SAg is not toxic per se, since high-dose SAg does promote vigorous B cell differentiation in cultures of mitomycin C-treated T cells + B cells and does not inhibit T cell-independent B cell differentiation. No correlation exists between SAg-induced B cell surface expression of CTLA4 ligand and generation of Ig-secreting cells, but the dose of SAg does correlate with T cell-mediated SAg-dependent cytolysis of transformed B cell targets or autologous nontransformed activated B cell targets. B cell recovery from cultures stimulated with high-dose SAg is lower than that from cultures stimulated with low-dose SAg, whereas B cell apoptosis is greater in the former cultures than that in the latter cultures. T cells stimulated with high-dose SAg do not inhibit differentiation of activated B cells in the absence of physical contact between the T cells and the target B cells, supporting the notion of direct killing of activated B cells by T cells. The ability of low doses of SAg to promote B cell differentiation without generating biologically meaningful cytolytic activity and the ability of higher doses of SAg to modulate Ig production may have important pathogenetic and therapeutic ramifications for certain autoimmune disorders, such as systemic lupus erythematosus.
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PMID:Differential human T cell-dependent B cell differentiation induced by staphylococcal superantigens (SAg). Regulatory role for SAg-dependent B cell cytolysis. 763 37

In autoimmune diseases striking abnormalities of T and B cell activation and of cytokine production are present. In 14 patients with autoimmune hemolytic anemia (AIHA), idiopathic or in the course of: lymphoma, B hepatitis, carcinoma, drug therapy (alpha-methyldopa), systemic lupus erythematosus (SLE), and not yet submitted to immunosuppressive therapy, the PBL proliferative response to PHA and the IL1 alpha, IL2, IL4 and IL2R serum levels have been valued. While the stimulation index of PBL was strongly reduced in 10 cases (64 +/- 56 vs 138 +/- 45 in the control group), IL1 alpha, IL2 and IL2R were greatly increased in all the patients, and IL4 in 5 (IL1 alpha :199 +/- 268 pg/ml in patients vs 0.30 +/- 0.2 in controls; IL2:716 +/- 311 pg/ml vs 16 +/- 4; IL4:29 +/- 13 pg/ml vs 13 +/- 7; IL2R:1233 +/- 471 U/ml vs 256 +/- 114). Cytokine serum levels were not related with the associated disease, with the CD4+ and CD8+ cells absolute number or with PBL blastogenic in vitro response. The high serum levels of cytokines and IL2R suggest that in AIHA there exist a CD4+ lymphocyte hyperactivation (the low proliferative response of PBL might imply a temporary functional exhaustion of T lymphocytes) as in the other autoimmune diseases.
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PMID:High cytokine serum levels in patients with autoimmune hemolytic anemia (AIHA). 785 62

Despite an extensive literature dealing with IL2-induced cytolytic activity, noncytotoxicity-related effects of IL2 on peripheral blood mononuclear cells (PBMC) or T cell function have received less attention. We have focused on the effects of irradiated, IL2-activated PBMC (PBMC*rIL2) on anti-CD3- and formalin-fixed heat-killed Staphylococcus aureus-induced polyclonal B cell differentiation in secondary cultures. PBMC*rIL2 act directly on B cells and cross major histocompatibility complex barriers to augment polyclonal B cell differentiation as measured by plaque-forming cell (PFC) generation. These effects are preferentially mediated by T (both CD4+ and CD8+) cells, and physical contact between effector PBMC*rIL2 and target B cells is not absolutely required for enhanced PFC generation. PBMC*rIL2 must be present for the initial 24 hr of the secondary cultures, indicating that some soluble B cell differentiation factor rapidly released by PBMC*rIL2 mediates the PFC-enhancing effect. Of IL2, IL4, IL5, IL6, IL10, IFN-gamma, and TNF-alpha, only IFN-gamma mRNA is appreciably and reproducibly increased in irradiated, IL2-activated T cells (T cells*rIL2). Nevertheless, exogenous rIFN-gamma cannot mimic and anti-IFN antibodies cannot block the PFC-enhancing effects of T cells*rIL2, indicating that some unidentified soluble factor(s) apart from or in addition to IFN-gamma is involved. IL2-induced effects on T cell noncytolytic function may help explain certain observed immune anomalies in IL2-treated patients, and a better understanding of the IL2-induced effects on T cell noncytolytic function may have ramifications for autoimmune diseases such as SLE.
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PMID:Enhancing effects of interleukin 2-treated peripheral blood mononuclear cells on subsequent B cell differentiation. 806 23

Production of cytokines in unstimulated and mitogen-stimulated cultures were evaluated by ELISPOT in 34 SLE patients with low to moderate disease activity and 23 healthy controls. Significantly reduced production of IFN gamma, IL4 and IL12 and significantly increased production of IL6, IL10 and TNF alpha were found in patients with SLE. Regression analysis revealed that production of all six cytokines tended to decrease with increasing disease activity, but negative correlation with SLEDAI was significant (p < 0.05) only for PHA-stimulated IL4, unstimulated and PHA-stimulated IL10 and SAC-stimulated IL6. Negative correlation of stimulated and unstimulated IL6 and TNF alpha production with anti-DNA antibody levels were also significant.
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PMID:Reduced in vitro production of interferon-gamma, interleukin-4 and interleukin-12 and increased production of interleukin-6, interleukin-10 and tumour necrosis factor-alpha in systemic lupus erythematosus. Weak correlations of cytokine production with disease activity. 1068 Jul 50

Systemic lupus erythematosus (SLE) is a chronic autoimmune rheumatic disease that may affect every organ or system in the body. We have shown previously that the TCR alphabeta+ subpopulation of CD3+ CD4- CD8-, DN T cells is expanded in patients with SLE and that double negative T cells express increased levels of activation markers compared both with healthy people and with patients with rheumatoid arthritis, (RA) as autoimmune controls. The aim of this study was to characterize these cells in terms of their ability to produce IL4, a Th2 cytokine, both spontaneously and after mitogen stimulation. It was found that a higher percentage of TCR alphabeta+ double negative T cells from patients with SLE contained IL4 constitutively than did the same population of cells from healthy people or from those with RA. After mitogen stimulation, there was no significant difference in the amount of IL4 produced by each of the three groups. Further study of patients producing high levels of IL4 (about one third of the patients) indicated that they had a lower percentage of alphabeta+ T cells in the double negative compartment than did patients with fewer IL4 containing cells.
Lupus 2002
PMID:Characterization of CD3+ CD4- CD8- (double negative) T cells in patients with systemic lupus erythematosus: production of IL-4. 1222 Jan 4

We aimed to evaluate the relationship between two polymorphisms of the IL4 gene (-590T/C and intron 3) and systemic lupus erythematosus in Chinese patients in Taiwan. This study included 91 patients with systemic lupus erythematosus (SLE) and 163 unrelated, age matched healthy controls living in the same area. The typing of -590T/C and intron 3 VNTR (variable number of tandem repeats) polymorphisms were performed by PCR-RFLP and PCR, respectively. Allelic frequencies and carriage rates between SLE patients and controls were compared, and the relationship between allelic frequencies and clinical manifestations of SLE was evaluated. The genotype frequencies of IL-4 intron 3 were found to differ significantly between SLE patients with and without discoid rash (chi-square test, P = 0.03 5). The allelic frequency of intron 3 RP1 was significant different in the patients with discoid rash when compared to patients without this clinical feature (OR = 3.70, 95% CI 2.04-6.72, chi2 test, P = 0.029). The RP1/RP1 homozygous carriage was significantly associated with patients with discoid rash when compared to patients without this clinical feature (OR = 6.04, 95% CI 2.81-12.95, P = 0.01). The allelic frequency of -590T was significant different in the patients with discoid rash when compared to patients without this clinical feature (OR = 3.44, 95% CI 1.88-6.31, chi-square test, P=0.04). The T/T homozygous carriage was significantly associated with patients with discoid rash when compared to patients without this clinical feature (OR = 5.41, 95% CI 2.50-11.68, P = 0.02). We describe a novel association between RPI/RPI and T/T homozygous carriage and patients with discoid rash. The role of the intron 3 polymorphism of the IL4 gene in SLE remains unclear and further substantiation based on larger patient samples is needed.
Lupus 2003
PMID:Polymorphisms of the interleukin-4 gene in chinese patients with systemic lupus erythematosus in Taiwan. 1258 22

NKT cells are a subset of regulatory lymphocytes characterized by co-expression of the NK cell receptor-CD161 and an invariant TCR-alpha chain (Valpha14-Jalpha28). They are most abundant in the liver, spleen, and bone marrow. NKT lymphocytes have been implicated in the regulation of autoimmune processes in both mice and humans. Activation of NKT lymphocytes leads to rapid amplification of either IFNgamma or IL4, endowing these cells with the capability to mediate both pro-inflammatory and anti-inflammatory immune responses. Activation of this subset of cells is associated with significant liver damage in the Concanavalin A immune mediated hepatitis model. Administration of CD1d ligand has a protective role in collagen-induced arthritis in mice. Disease amelioration was associated with a shift in the immune balance from a pathological Th1 type response towards a protective Th2 type response. In humans, patients with SLE, scleroderma, diabetes, multiple sclerosis, and rheumatoid arthritis have lower numbers of peripheral NKT cells. NKT lymphocytes promote tumor rejection in experimental models of tumor immunotherapy. In contrast, NKT lymphocyte-related anti-tumor activity is associated with pro-inflammatory Th1-type immune responses. NKT cells were shown to have a role in suppression of hepatocellular carcinoma (HCC) via immune regulation towards tumor derived antigens, and adoptive transfer of dendritic cells pulsed ex vivo with the same antigens. NKT lymphocytes are activated by interaction of their TCR with glycolipids presented by CD1d, a nonpolymorphic, MHC class I-like molecule expressed by antigen presenting cells, and also by hepatocytes. Several possible ligands for NKT cells have recently been suggested including CD1d bound Glucocerebroside. Glucocerebroside (GC, beta-glucosylceramide), a naturally occurring glycolipid, is a metabolic intermediate in the anabolic and catabolic pathways of complex glycosphingolipids. Its synthesis from ceramide is catalyzed by the enzyme glucosylceramide synthase. Inherited deficiency of glucocerebrosidase, a lysosomal hydrolase, results in Gaucher's disease. Patients with Gaucher's disease have altered humoral and cellular immune profiles and increased peripheral blood NKT lymphocytes. CD1d-bound glucocerebroside does not activate NKT cells directly, and may inhibit activation of NKT cells by alpha-GalCer. On the other hand, glucosylceramide-synthase deficiency was shown to lead to defective ligand presentation by CD1d, with secondary inhibition of NKT cell activation. Recent studies have suggested that a number of glycolipids, including GC, have an immune modulatory effect in several immune mediated disorders. The ability to alter NKT lymphocyte function in various settings and the potential application of natural glycolipids for treatment are discussed.
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PMID:Glycolipids as immune modulatory tools. 1710 Jun 36

Systemic Lupus Erythematosus (SLE) is a multisystemic autoimmune disease characterized by the loss of self-tolerance revealing defective immune regulatory mechanisms. ACP1 is a highly polymorphic erythrocyte LMW-PTP isozyme encoded by a gene presenting three alleles (A B C). These alleles determine different fast slow isozyme proportions having distinct cellular localization and biological functions. Several studies demonstrated the involvement of LMW-PTP in the PDGFr, IL4 and insulin dependent cellular signalling regulation. The most relevant phenotypic effects of LMW-PTP over expression are the strong reduction of cell growth rate in response to PDGF stimulation together with up regulation of cell adhesion and chemotaxis. Our aims were the characterization of LMW-PTP genetic polymorphisms and the evaluation of erythrocyte LMW-PTP enzymatic activity in a lupus and a control population group and the determination of genotype phenotype relationship in SLE. The results revealed a predominance of AA (n=8) and AB (n=21) genotypes in SLE which are responsible for the low enzymatic activity forms while in the control group there was a predominance of high enzymatic activity genotypes AB (n=52) and BB (n=36). The difference between the two groups was statistically significant (p=0,04 - chi2 for 4 freedom degrees). The LMW-PTP median enzymatic activity in the SLE group (260.53+/-96.18mmol p-nitrophenolate/gHb/h) was lower than in the control group (339.84+/-113.78mmol p-nitrophenolate/gHb/h) (p<0.001). These results suggest a relevant role for LMW-PTP in the context of SLE namely at cellular proliferation and oxidative stress level.
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PMID:[Genetic polymorphisms of low molecular weight protein tyrosine phosphatase (LMW-PTP): relationship with erythrocyte enzymatic phenotype in patients with Systemic Lupus Erythematosus]. 1860 86

An imbalance between T Helper 1 (T(H)1) and T Helper 2 (T(H)2) cytokine production is important for the pathogenesis of systemic lupus erythematosus (SLE). We aimed to investigate gene-gene associations of T(H)1 and T( H)2 cytokines genes in Chinese patients with SLE. Twenty single nucleotide polymorphisms (SNPs) in eight cytokines genes were genotyped in 110 SLE patients and 138 healthy controls in a case-control association study. The minor allelic frequencies of interleukin4(IL4) -590 T/C, -33 T/C, 9241C/G, and IL10 -592 A/C were significantly increased in SLE patients compared with those in controls (p < 0.05). None of the separate 20 SNPs showed significant association with SLE after Bonferroni correction. An IL4 haplotype -590C/-33C/9241G/14965C was significantly associated with SLE (odds ratio 3.7, 95% confidence interval [CI] 1.5-8.9, p = 0.004, Bonferroni-corrected p = 0.024). A borderline significant three-locus gene-gene interaction among IL4 9241 C/G, IL4 -33 T/C, signal transducer and activator of transcription 6, IL4-induced (STAT6) 2892 C/T was detected by a multifactor dimensionality reduction test (p = 0.051). However, the presence of two at-risk genotypes lead to increased risk of SLE for two-locus interaction using logistic regression method. The risk of SLE increased significantly when a subject has two at-risk genotypes for IL4 -590C and STAT6 2892C (odds ratio, 3.24, 95% CI 1.5-7.0, p = 0.003, Bonferroni-corrected p = 0.009), IL4 -33C and STAT6 2892C (odds ratio 3.06, 95% CI 1.4- 6.7, p = 0.005, Bonferroni-corrected p = 0.015), as well as IL4 9241G and STAT6 2892C (odds ratio 3.34, 95% CI 1.6-7.1, p = 0.002, Bonferroni-corrected p = 0.006). Further, plasma IL-4 concentrations were significantly lower in SLE patients than in healthy controls (1.59 + 3.53 versus 5.67 + 11.28 pg/ml, p = 0.042). These results indicated that IL4 and STAT6 genes might be involved in the etiology of SLE and potentially increased SLE risk through their interaction effect in Chinese patients.
Lupus 2010 Sep
PMID:Interleukin 4 and STAT6 gene polymorphisms are associated with systemic lupus erythematosus in Chinese patients. 2053 May 19


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