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)

Cultured human keratinocytes were lysed by activated PBMC in a 4-h 51Cr release assay. PBMC were activated by incubation with 50 U/ml of rIL-2 for 4 days. The cytotoxic precursors were found to be NKH1+ and included both CD2+ and CD2- phenotypes. This cytotoxicity was not genetically restricted, as cells killed both allogeneic and autologous keratinocytes without priming. Cytotoxicity was blocked by pre-incubation of effector cells with mAb against LFA-1 alpha-(TS1/22) and beta-chains (TS1/18), but not by antibodies directed against CD4, CD8, or leukocyte common Ag (T200) suggesting that LFA-1 is an important interactive molecule in this cytotoxicity. IFN-gamma is reported to upregulate ICAM-1, the ligand for LFA-1. Pre-treatment of target keratinocytes with IFN-gamma was also found to greatly increase the sensitivity of keratinocytes to lysis. This increased sensitivity to lysis was blocked by anti-LFA-1 and anti-ICAM-1, but not by anti-DR (L243), and thus was not the result of increased DR expression. Such treated targets were lysed at low levels (15 to 18%) by an Ag-specific CD8+ cytotoxic clone as well as a T cell line derived from a skin lesion of allergic contact dermatitis. In contrast, control keratinocytes were only sensitive to IL-2-activated PBMC as described above. The above findings may be relevant to a variety of conditions in which epidermal damage is associated with lymphocytic infiltrate. These conditions include graft-vs-host disease, erythema multiforme, and lupus erythematosus. DR+ keratinocytes, which may be a marker for IFN-gamma are also found in the above conditions. It is suggested that epidermal pathology may be mediated by non-specific cytotoxicity induced in the course of an immune response.
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PMID:Non-specifically activated human peripheral blood mononuclear cells are cytotoxic for human keratinocytes in vitro. 246 92

Intravenous cyclophosphamide therapy of severe systemic lupus is associated with reduction in the numbers of circulating T and B lymphocytes, suppression of T11 (CD2) receptor-mediated responses, and suppression of autoantibody production. In clinical trials, intravenous cyclophosphamide plus moderate-to low-dose daily oral prednisone appears to reduce the rate of progression of irreversible renal injury in patients who have active nephritis and definite but limited chronic changes in biopsy specimens. It may also be effective in other forms of severe lupus, although controlled trials are lacking. It may be the treatment of choice in severe lupus characterized by ongoing antibody or immune-complex mediated tissue injury.
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PMID:Intravenous cyclophosphamide therapy of severe SLE. 267 32

Severe systemic lupus erythematosus affecting the kidney or central nervous system may lead to organ failure or death despite treatment with high doses of corticosteroids. To evaluate the clinical and immunologic effects of intravenous cyclophosphamide in this setting, we treated nine patients with monthly intravenous infusions of cyclophosphamide for six months. A comparison of characteristics at entry and follow-up revealed improvements (by paired t-test) in creatinine clearance (66 vs. 96 ml per minute, P less than 0.001); 24-hour urinary protein level (4.11 vs. 0.90 g, P less than 0.05), Farr anti-DNA titer (43 vs. 8.5 percent, P less than 0.01); complement components C3 (894 vs. 1150 mg per liter, P less than 0.05), C4 (154 vs. 222 mg per liter, P less than 0.05), and total complement activity (CH50) (88.7 vs. 113.4 IU, P less than 0.05); and Westergren erythrocyte sedimentation rate (60.2 vs. 34.4 mm per hour, P less than 0.0005). Other manifestations of lupus improved markedly in most cases, despite a reduction in the mean daily dose of prednisone, from 45 mg at entry to 17 mg at follow-up (P less than 0.01). The numbers of lymphocytes positive for T3, T4, T8, and B1 declined progressively during treatment. At follow-up, persistent decreases were observed in the T-lymphocyte subsets, whereas the absolute number of B lymphocytes had returned to levels near base line. T-cell proliferative responses at follow-up were not significantly different from entry values, except that the response to mitogenic anti-T11 (CD2) antibodies was decreased (P less than 0.01). Our data indicate that monthly intravenous administration of cyclophosphamide was associated with a substantial amelioration of severe systemic lupus, in conjunction with discrete changes in T-lymphocyte markers and T-cell function. This was a preliminary, uncontrolled study, but the results warrant further investigation of this form of treatment.
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PMID:Clinical and immunologic effects of monthly administration of intravenous cyclophosphamide in severe systemic lupus erythematosus. 325 86

The purpose of this paper is to establish whether there is increased lymphocyte adhesion molecule density in systemic lupus erythematosus (SLE), which could alter the migration pathways and activation thresholds of lymphocytes and thus contribute to the pathogenesis of the disease. We analysed the CD11a, CD29 and CD2 bound antibody molecule (bam) density on the CD4+ and CD8+ CAMhigh (primed) lymphocytes of 28 SLE patients (8 active and 20 inactive by BILAG), using reproducible flow cytometric measurements, standardized with fluorescent beads and antibodies of known fluorescein: protein ratios. In a second patient cohort (17 patients), we investigated whether CD29 density on CD8+ cells correlated with measures of humoral (serum IgG) or cellular (urine neopterin) activation. In the first cohort, 36% of patients had elevated CD29 (beta 1 integrin) density on CD8+ cells. In the second cohort, CD29 density on CD8+ cells was found to be closely associated with total plasma IgG (r = 0.71, P = 0.001), but not with urine neopterin, disease activity (BILAG) or drug treatment. We conclude that CD29 on CD8+ cells is associated with B cell activation in SLE.
Lupus 1997
PMID:Correlation between CD29 density on CD8+ lymphocytes and serum IgG in systemic lupus erythematosus. 917 23

Transforming growth factor beta (TGF-beta) comprises of a family of proteins with pleiotropic signaling properties and potent immunoregulatory effects. In SLE we recently reported that lymphocyte production of the total and active forms of TGF-beta1 was decreased. Here we asked whether these defects correlate with disease activity and/or severity. TGF-beta1 production by blood lymphocytes from 17 prospectively studied SLE patients was compared with 10 rheumatoid arthritis (RA) patients and 23 matched healthy controls. The RA levels of active TGF-beta1 were lower than controls, but were not deceased to the extent found in SLE. Levels of constitutive and anti-CD2 stimulated active TGF-beta1 detected in picomolar amounts were markedly reduced in six untreated patients hospitalized with recent onset, very active and severe SLE and similarly reduced in 11 patients with treated, less active disease. By contrast, decreased production of total TGF-beta1 inversely correlated with disease activity. These studies suggest, therefore, that although impaired lymphocyte secretion of the latent precursor of TGF-beta1 may result as a consequence of disease activity, a decreased capacity to convert the precursor molecule to its active form may pre-date disease onset. Insufficient exposure of T cells to picomolar concentrations of TGF-beta1 at the time they are activated can result in impaired down-regulation of Ig synthesis. Therefore, decreased lymphocyte production of active TGF-beta1 in SLE could be an immunologic defect which contributes to the B cell hyperactivity characteristic of this disease.
Lupus 1999
PMID:The relationship between defects in lymphocyte production of transforming growth factor-beta1 in systemic lupus erythematosus and disease activity or severity. 1019 99

We have recently reported that transforming growth factor-beta (TGF-beta) co-stimulates interleukin-2 (IL-2) activated CD8+ T cells to down-regulate antibody production. In SLE, lymphocyte production of both IL-2 and TGF-beta is decreased. Here we report that a brief treatment of PBMC from SLE patients with IL-2 and TGF-beta can result in marked inhibition of spontaneous polyclonal IgG and autoantibody production. Peripheral blood mononuclear cells (PBMC) from 12 patients with active SLE were exposed to IL-2 with or without TGF-beta for three days, washed and cultured for seven more days. The mean decrease in IgG secretion was 79%. The strongest inhibitory effect was observed in cases with the most marked B cell hyperactivity. Spontaneous production of anti-nucleoprotein (NP) antibodies was observed in four cases and cytokine treatment of PBMC decreased autoantibody production by 50-96%. IL-2 inhibited Ig production by either TGF-beta-dependent or independent mechanisms in individual patients. In a study of anti-CD2 stimulated IgG production in a patient with active SLE, we documented that IL-2 and TGF-beta reversed the enhancing effects of CD8+ T cells on IgG production and induced suppressive activity instead. These results raise the possibility that cytokine-mediated down-regulation of B cell hyperactivity in SLE may have therapeutic potential.
Lupus 1999
PMID:Cytokine-mediated down-regulation of B cell activity in SLE: effects of interleukin-2 and transforming growth factor-beta. 1019 2

Previous studies suggest that the forkhead transcription factor Foxj1 inhibits spontaneous autoimmunity in part by antagonizing NF-kappaB activation. To test this hypothesis, we ectopically expressed Foxj1 in the T cells of lupus-prone MRL/lpr mice by backcrossing a CD2-Foxj1 transgene against the MRL/lpr background. Strikingly, CD2-Foxj1-MRL/lpr animals showed a significant reduction in lymphadenopathy, pathogenic autoantibodies, and end-organ disease-but surprisingly, reversion of autoimmunity was not attributable to modulation of NF-kappaB. Instead, CD2-Foxj1 transgenic mice exhibited a peripheral T cell lymphopenia, associated with an accumulation of mature single-positive thymocytes. Transgenic thymocytes demonstrated unimpaired lymphoid organ entry in adoptive transfer studies but demonstrated impaired thymic exodus in response to CCL19, apparently independent of CCR7, S1P1, and NF-kappaB. These findings confirm the importance of Foxj1 in the regulation of T cell tolerance but furthermore suggest a novel and specific role for Foxj1 in regulating thymic egress.
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PMID:Cutting edge: Foxj1 protects against autoimmunity and inhibits thymocyte egress. 1633 15

The evolutionary origin of genetic diversity in the SLAM/CD2 gene cluster, implicated in autoimmune lupus susceptibility in mice, was investigated by sequence analysis of exons from six members of the cluster in 48 wild mouse samples derived from the global mouse population. A total of 80 coding region SNPs were identified among the six genes analyzed, indicating that this gene cluster is highly polymorphic in natural mouse populations. Phylogenetic analyses of these allelic sequences revealed clustering of alleles derived from multiple Mus species and subspecies, indicating alleles at several SLAM/CD2 loci were present in ancestral Mus populations prior to speciation and have persisted as polymorphisms for more than 1 million years. Analyses of nonsynonymous/synonymous ratios using likelihood codon substitution models identified several segments in Cd229, Cd48 and Cd84 that were impacted by positive diversifying selective pressures. These findings support the interpretation that selection favoring the generation and retention of functional polymorphisms has played a role in the evolutionary origin of genetic polymorphisms that are predisposing to autoimmunity.
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PMID:Prevalence and evolutionary origins of autoimmune susceptibility alleles in natural mouse populations. 1809 11

B6.Sle1b mice, which contain the Sle1b gene interval derived from lupus prone NZM2410 mice on a C57BL/6 background, present with gender-biased, highly penetrant anti-nuclear antibody (ANA) production. To obtain some insight into the possible induction mechanism of autoantibodies in these mice we compared antigen-specific T dependent (TD) and T independent (TI-II) responses between B6.Sle1b and B6 mice before the development of high ANA titers. Our results show that B6.Sle1b mice mount enhanced responses to a TI-II antigen. Additionally, the memory T cell response generated by a TD antigen also increased. This enhancement correlates with the greater ability of B cells from B6.Sle1b mice to present antigen to T cells. The SLAM Associated Protein (SAP) is critical for signaling of many of the molecules encoded by the SLAM/CD2 gene cluster, candidates for mediating the Sle1b phenotype; therefore, we also investigated the effect of sap deletion in these strains on the TD and TI-II responses as well as on ANA production. The results of these studies of responses to non-self-antigens provide further insight into the mechanism by which responses to self-antigens might be initiated in the context of specific genetic alterations.
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PMID:Antigen-specific responses and ANA production in B6.Sle1b mice: a role for SAP. 1884 19

Systemic lupus erythematosus (SLE) is an autoimmune disease induced by the combinations of environmental and genetic factors. Recently, mice in which the early growth response 2 (EGR2) gene, a zinc-finger transcription factor, is conditionally knocked out in CD2(+) T cells have been shown to develop a lupus-like autoimmune disease. Here, we evaluated if polymorphisms in the EGR2 gene influence SLE susceptibility in humans. We first analyzed the effect of SNPs in the EGR2 region on EGR2 expression, and a significant positive correlation with expression was identified in an SNP located at the 5' flanking region of EGR2 (rs10761670, R=0.23, P=0.00072). We then performed a case-control association study using three sets of SLE cohorts by genotyping 14 tag SNPs in the EGR2 gene region. A peak of association with SLE susceptibility was observed for rs10761670 [Pooled: OR = 1.23 (95% CI 1.10-1.37), P=0.00023). This SNP was also associated with susceptibility to rheumatoid arthritis (RA) [OR = 1.15 (95% CI 1.05-1.26), P = 0.0019), suggesting that EGR2 is a common risk factor for SLE and RA. Among the SNPs in complete linkage disequilibrium with rs10761670 (r(2) = 1.0), two SNPs (rs1412554 and rs1509957) affected the binding of transcription factors and transcriptional activity in vitro, suggesting that they may be candidates of causal regulatory variants in this region. Therefore, EGR2 is a genetic risk factor for SLE, in which increased gene expression may contribute to SLE pathogenesis.
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PMID:Regulatory polymorphisms in EGR2 are associated with susceptibility to systemic lupus erythematosus. 2019 24


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