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)

SK&F 105685 (N,N-Dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine+ ++ dihydrochloride) is a novel azaspirane with beneficial activity in animal models of autoimmune diseases such as adjuvant-induced arthritis and experimental autoimmune encephalomyelitis in the Lewis rat and lupus-like disease in the MRL mouse. The effect of SK&F 105685 on the proliferation of rat lymphoid cells was examined in vitro. The compound inhibited the proliferative response of spleen, thymus and lymph node cells to the mitogen concanavalin A (Con A) in a dose-dependent manner but had little or no effect on the mitogenic response of peripheral blood lymphocytes. Although less potent than cyclosporin A, SK&F 105685 was able to inhibit the proliferation of spleen cells stimulated with PMA and ionomycin or the mitogens phytohemagglutinin (PHA), Con A and pokeweed mitogen (PWM). Relatively early event(s) in cell proliferation were affected by SK&F 105685 since delaying addition of the drug by 24 to 48 hours after Con A stimulation of rat spleen cells resulted in reduced levels of suppression. The mode of action of SK&F 105685 appeared to differ from that of cyclosporin A or rapamycin. Unlike cyclosporin A, SK&F 105685 did not affect IL-2 production by Con A-stimulated spleen cells or the IL-2-producing Jurkat cell line, but, like rapamycin, the compound significantly reduced the IL-2-induced proliferation of rat ConA blasts. These results suggest that inhibition of lymphocyte proliferation by SK&F 105685 may require the activity of an intermediate effector cell(s) present in susceptible populations such as cells from the spleen, thymus, lymph nodes and Con A blast preparations but absent or present in low numbers in resistant populations such as peripheral blood cells. Indomethacin and NG-monomethyl-L-arginine (NGMMA), a competitive inhibitor of nitric oxide synthase, were both unable to relieve SK&F 105685-induced suppression of splenic Con A responses thereby ruling out a role for the production of prostaglandins or nitric oxide by macrophages as an intermediate in drug-mediated suppression. In summary, SK&F 105685 was unable to inhibit lymphoproliferative responses by a mechanism distinct from that of cyclosporin A or rapamycin and which appears to involve regulation of cellular interactions rather than a direct effect on responding lymphocytes.
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PMID:Inhibition of lymphoproliferative responses by SK&F 105685, a novel anti-arthritic agent. 166 43

Interferon-gamma activates both in vitro and in vivo macrophage functions. Injection of rat recombinant interferon-gamma (rR-IFN-gamma) induced the expression of interleukin-2 receptors (IL-2R) by peritoneal macrophages from normal BALB/c and MRL-+/+ mice. Moreover, rR-IFN-gamma stimulated in a dose-dependent manner the oxidative burst of cells as revealed by luminol-dependent chemiluminescene (LDCL). Resident peritoneal macrophages from MRL-lpr/lpr (mice that develop a systemic lupus-like syndrome) showed a higher PMA-triggered LDCL response. This enhanced activity was accompanied by an increase in IL-2R expression (30% vs. less than 1%). The "activated" macrophages from rR-IFN-gamma-treated normal mice as well as MRL-lpr/lpr mice did not respond to the addition of recombinant interleukin-2 (rHu-IL-2) by an increase in LDCL. However, rHu-IL-2 triggering became efficient when cells enriched in IL-2R-bearing macrophages were preincubated overnight with rHu-IL-2R. This response may point out a functional role for IL-2R and provide a role for IL-2 in certain macrophage functions.
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PMID:Role of interferon-gamma on the in vivo expression of functional interleukin-2 receptors by murine macrophages. 193 95

We have studied the ability of isolated T cell subpopulations from the autoimmune mouse MRL/MPJ/lpr/lpr (lpr) to proliferate and to undergo changes in cytokine gene transcription in vitro, in the presence or absence of cytokines. The lpr mouse develops lupus-like symptoms and massive lymphadenopathy due to accumulation of abnormal CD4-/CD8- T lymphocytes, which are unusual in coexpressing Thy1 and B220. FACS-purified B220+/Thy1+ lpr lymph node cells showed little proliferative response to cytokines, even in the presence of PMA, and failed to proliferate in response to stimulation through the CD3/TcR complex. Polymerase chain reaction was used to examine the presence of cytokine gene transcripts in B220-/Thy1+ and B220+/Thy1+ ("abnormal") T cells, before and after in vitro culture. The high level of transcripts of IFN-gamma and TNF-alpha genes observed in freshly isolated B220+/Thy1+ cells decreased after 10 hr of in vitro culture, while levels of TNF-beta, IL-6 and TGF-beta transcripts were maintained. These results suggest that a positive stimulus for IFN-gamma and TNF-alpha gene transcription by lpr B220+/Thy1+ cells may exist in vivo but is removed upon purification of this abnormal T cell subset.
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PMID:Abnormal T cells from lpr mice down-regulate transcription of interferon-gamma and tumor necrosis factor-alpha in vitro. 213 61

CD4+ cells are thought to play a significant role in the development of lupus-like disease in a variety of autoimmune disease-prone mouse strains. In one such strain, BXSB/MpJScR, male mice develop severe lupus-like symptoms early in life but females do not. In this study, splenic CD4+ cells from male and female BXSB mice were evaluated for age-related changes in: 1) membrane expression of CD4+ cell subset markers (1, 2, and 4 mo) and activation Ags (4 mo) and 2) the capacity to proliferate and produce cytokines (4 mo) in response to polyclonal stimuli. CD4+ cells from females of all age groups and from younger males were predominantly CD44lo, CD45RBhi, MEL-14hi, and 3G11hi (phenotypes associated with naive T cells). In contrast, 4-mo-old males were predominantly CD44hi, CD45RBlo, MEL-14lo, and 3G11lo (phenotypes associated with activated/memory T cells). Furthermore, an increased constitutive expression of the activation Ags RL388, IL-2R, and TfR was observed in CD4+ cells of 4-mo-old male BXSB mice in comparison with age-matched females. In 3-day cultures, purified CD4+ cells from 4-mo-old males proliferated significantly less than cells from age-matched females in response to plate-bound anti-CD3 epsilon (2C11i). The reduced proliferation was restored in large part by PMA and ionomycin. CD4+ cells from older males generally produced increased amounts of IFN-gamma and IL-4 and significantly less IL-2 than age-matched females in response to either stimulus (IL-2 mRNA was also decreased in response to 2C11i). Taken together, these studies suggest that profound phenotypic and functional changes occur with age in the CD4+ cells of male BXSB mice that are indicative of an activated state.
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PMID:Maturational changes in CD4+ cell subsets and lymphokine production in BXSB mice. 751 69

Several immuno-regulatory abnormalities have been described in SLE patients. T cell dysfunction in SLE includes defective in vitro proliferative responses to several stimuli, reduced IL-2 production and a poor helper function. It has been widely proposed that this defective T cell immunoregulatory function has a key role in the hyperactivity of B cells and auto-antibody production in SLE. However, it has not been elucidated whether or not this cell dysfunction is intrinsic to lymphocytes or is due to other factors such as anti-lymphocyte auto-antibodies. In this study we have evaluated some important early cell activation events in T and non-T lymphocytes from patients with systemic lupus erythematosus (SLE). Peripheral blood lymphocytes from SLE patients and controls were isolated. The intracellular pH (pHi), cytosolic calcium (Ca2+i) and CD69 expression were determined by spectrofluorometry and flow cytometry. Modifications of these parameters in response to protein kinase C (PKC) activators, mitogenic lectins and calcium ionophores were also studied. We found a significant reduction in the increase of pHi in response to PKC activators (PMA) in SLE cells. In addition, the induction of CD69 expression by PMA was significantly lower in T cells from SLE patients. By contrast, freshly isolated non-stimulated SLE cells exhibited a significantly higher pHi, as well as an increased baseline expression of the early cell activation antigen CD69. On the other hand, the increase in Ca2+i in response to a Ca2+ ionophore (4Br-A23187) or thapsigargin in Ca(2+)-free solutions, was smaller in SLE lymphocytes. We concluded that T cells from SLE patients exhibit abnormalities in several key early cell activation events (pHi, Ca2+i and CD69 expression). These abnormalities could have an important role in the T cell dysfunction observed in SLE. The presence of T cells with a preactivated phenotype in the peripheral blood of SLE patients, could be a reflection of the ongoing autoimmune phenomena that is occurring in these patients.
Lupus 1997
PMID:Abnormalities in CD69 expression, cytosolic pH and Ca2+ during activation of lymphocytes from patients with systemic lupus erythematosus. 911 19

CTLA-4 is a cell surface molecule expressed on activated T cells that is suggested to deliver a negative signal for T cell activation. Since CTLA-4 might be a negative regulator of autoimmune diseases, we investigated its expression on T cells from 20 patients with systemic lupus erythematosus (SLE) by flow cytometric analysis and RT-PCR. We found that although CTLA-4 mRNA was readily detected in all patients and controls, only a very minor subset of T cells expressed detectable surface CTLA-4 molecules in both groups. But patients with SLE had significantly increased percentages of CTLA-4-positive T cells compared with normal controls, implying at least that there was no apparent defective expression of CTLA-4 molecule in human lupus. The kinetics of CTLA-4 expression on T cells stimulated in vitro with PMA plus ionomycin were similar in normal controls and patients with SLE. The expression of CTLA-4 molecules after stimulation increased gradually and peaked at 72 hr. However, the induction of CTLA-4 expression on patients' T cells appeared to be weaker than that of normal individuals. Whether this reflects impaired downregulation by CTLA-4 molecules in SLE patients needs to be clarified further.
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PMID:Expression of CTLA-4 molecule in peripheral blood T lymphocytes from patients with systemic lupus erythematosus. 985 83

Numerous cellular and biochemical abnormalities in immune regulation have been described in patients with systemic lupus erythematosus (SLE), including surface Ag receptor-initiated signaling events and lymphokine production. Because NF-kappa B contributes to the transcription of numerous inflammatory genes and has been shown to be a molecular target of antiinflammatory drugs, we sought to characterize the functional role of the NF-kappa B protein complex in lupus T cells. Freshly isolated T cells from lupus patients, rheumatoid arthritis (RA) patients, and normal individuals were activated physiologically via the TCR with anti-CD3 and anti-CD28 Abs to assess proximal membrane signaling, and with PMA and a calcium ionophore (A23187) to bypass membrane-mediated signaling events. We measured the NF-kappa B binding activity in nuclear extracts by gel shift analysis. When compared with normal cells, the activation of NF-kappa B activity in SLE patients was significantly decreased in SLE, but not in RA, patients. NF-kappa B binding activity was absent in several SLE patients who were not receiving any medication, including corticosteroids. Also, NF-kappa B activity remained absent in follow-up studies. In supershift experiments using specific Abs, we showed that, in the group of SLE patients who displayed undetectable NF-kappa B activity, p65 complexes were not formed. Finally, immunoblot analysis of nuclear extracts showed decreased or absent p65 protein levels. As p65 complexes are transcriptionally active in comparison to the p50 homodimer, this novel finding may provide insight on the origin of abnormal cytokine or other gene transcription in SLE patients.
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PMID:Abnormal NF-kappa B activity in T lymphocytes from patients with systemic lupus erythematosus is associated with decreased p65-RelA protein expression. 1041 75

We have shown that estrogen receptor (ERalpha, ERbeta) transcripts are expressed in SLE and normal T cells. In this study, T cell nuclear extracts from female lupus patients and normal donors were tested for biologically active ER proteins capable of binding to the human estrogen response element (hERE) by electrophoretic mobility shift assays. When peripheral blood T cells were stimulated with 17beta-estradiol (E2), PMA and ionomycin, two major retarded bands in T cell nuclear extracts exhibited a migration pattern similar to slow migrating protein-ERE complexes in human breast cancer cell extracts. T cells cultured only with E2 did not have these complexes. The formation of the complexes was inhibited by competition with the hERE cold oligonucleotide and partially with anti-ERalpha antibodies. There was no notable difference in the migration pattern of ERE-binding proteins between the SLE and normal T cell extracts. Together, these results suggest that activated human T cells, whether lupus-derived or normal-derived, contain biologically active ERalpha proteins. Other factors may be responsible for differential sensitivity of lupus T cells to estrogen.
Lupus 2001
PMID:In vitro-activated human lupus T cells express normal estrogen receptor proteins which bind to the estrogen response element. 1123 23

CD80 and CD86, expressed on the antigen-presenting cells (APCs) provide costimulatory signals for T lymphocytes. Recently, defective expression of CD80 has been reported in systemic lupus erythematosus (SLE) although its mechanism is unclear. Here, expression of the B7 antigens induced by interferon-gamma, interleukin-4 or granulocyte-macrophage stimulating-factor (GM-CSF) along the differentiation process of APCs was investigated. In contrast to CD86, expression of CD80 on the CD14+ cells induced by GM-CSF was reduced in SLE. GM-CSF receptor (GM-CSFR) was down-regulated by GM-CSF or phorbol 12-myristate 13-acetate in both of the normal controls and SLE patients, while this change was more remarkable in the latter. In the presence of 1-(5-isoquinolinsulfonyl)-2-methylpiperazine, an inhibitor of protein kinase C, the PMA-induced down-regulation of GM-CSFR was reversed in the normal controls but not in SLE. These data suggest that dysregulation of the GM-CSFR might be associated with the defective expression of CD80, leading to dysfunction of the APCs in SLE.
Lupus 2002
PMID:Dysregulation of the granulocyte-macrophage colony-stimulating factor receptor is one of the causes of defective expression of CD80 antigen in systemic lupus erythematosus. 1209 May 68

Recent studies indicate that normal B cells can be primed to differentiate into two distinct cytokine-secreting effector subsets, Be1 and Be2. The aim of this study was to analyse, for the first time, Be1 and Be2 cells at the single cell level in SLE patients using the recently developed technique of flow cytometry for intracellular cytokines. Peripheral blood mononuclear cells (PBMC) from SLE patients and age- and sex-matched normal controls were cultured for 24 h in the presence or absence of phorbal myristate acetate and ionomycin (PMA/I) or lipopolysaccharide (LPS). The production of type I (IFN-gamma, IL-2) and type 2 (IL-4, IL-5, IL-6, IL-10, IL-13) cytokines by B cells (and IL-10 production by fractionated CD5+ and CD5- B cells) was investigated using an intracellular cytokine staining technique and flow cytometry. In the absence of PMA/I stimulation, the percentage of B cells from SLE patients was significantly lower than those of normal subjects and significantly more SLE B cells spontaneously produced IL-10 than controls. Moreover, CD5+ B cells from SLE patients were enriched for cells with signs of previous in vivo activation and for high levels of IL-10 production. A significant positive correlation was observed between the percentage of IL-10- and IL-6-producing PMA/I-stimulated B cells in SLE patients, but not in controls. There were no significant differences in the production of other cytokines by B cells of SLE patients and normal subjects. In conclusion, a general alteration of type 1 and type 2 cytokine production by B cells is not observed in SLE patients. The role of B cell cytokines in the pathogenesis of SLE appears to be exerted by elevated secretion of in vivo IL-10, which may play an important role in the immune dysregulation observed in SLE patients. Moreover, the cross regulation of IL-10 and IL-6 is disrupted in SLE patients.
Lupus 2003
PMID:Assessment of Be1 and Be2 cells in systemic lupus erythematosus indicates elevated interleukin-10 producing CD5+ B cells. 1276 98


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