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)

Perforin is one of the important cytolytic factors in cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. In this study, the authors examined perforin mRNA levels in the kidney, spleen, liver, lung, heart, and brain of NZB/W F1 lupus mice and NZW mice. Perforin mRNA levels in the kidney, spleen, liver, and lung of NZB/W F1 mice increased significantly with age, whereas those in the heart and brain of NZB/W F1 mice showed little change between 2 and 10 months of age. In all tissues examined in NZW, control mice perforin mRNA levels showed little change during the experimental period. In addition, the authors examined the effect of methylprednisolone (MPSL) on perforin gene expression in the tissues of NZB/W F1 mice. MPSL ameliorated the increase in perforin mRNA levels in the kidney, spleen, liver, and lung of NZB/W F1 mice. These findings suggest that perforin may contribute to tissue injuries in autoimmune lupus mice and that MPSL may be effective in lupus partly by decreasing perforin expression.
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PMID:Perforin mRNA expression in the inflamed tissues of NZB/W F1 lupus mice decreases with methylprednisolone treatment. 192 97

Mutations in the Fas receptor or its ligand (FasL) lead to lupus-like systemic autoimmune diseases in mice and in some humans. To determine whether a significant number of patients with systemic lupus erythematosus (SLE) have impaired FasL function, we compared T cell effector function by superantigen-activated CD4+ T cell lines or by anti-CD3- and IL-2-generated cytotoxic T cells. No differences were observed between SLE and normal control superantigen-derived CD4+ T cells in either the ability of these cells to up-regulate Fas expression or to induce apoptosis of the Fas-sensitive target B cells. When anti-CD3/IL-2-activated T cells were examined, SLE T cells had a modest reduction (-8%) in T cell cytotoxicity compared with normal controls, but the reduction was similar to the rheumatoid arthritis disease controls. A modest reduction in cytotoxicity was evident in both the Fas and perforin/granzyme pathways as determined by testing Fas-positive and -negative targets as well as by selective blockade of the perforin/granzyme pathway with concanamycin. These results indicate that no specific defects in FasL function are evident in the majority of SLE patients under the in vitro conditions tested. The proportional reduction in FasL and perforin/granzyme function in SLE and rheumatoid arthritis patients following anti-CD3/IL-2 stimulation most likely reflects subtle differences in activation in patient-derived vs normal control T cells.
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PMID:Fas ligand expression and function in systemic lupus erythematosus. 937 65

The roles of cytolytic regulatory mechanisms in the immune system of lupus-prone mice were examined in perforin-deficient animals bearing functional or defective (lpr) Fas Ag (CD95). Perforin-deficient Fas+ animals developed accelerated autoimmunity, characterized by increased hypergammaglobulinemia, autoantibody production, and immune deposit-related end-organ disease compared with perforin-intact counterparts. In comparison, perforin-deficient lpr animals had accelerated mortality compared with perforin-intact lpr mice, associated with the abnormal accumulation of CD3+CD4-CD8- alphabeta T cells in conjunction with unaltered hypergammaglobulinemia, autoantibody production, and immune complex renal disease. These results indicate that cytolytic lymphoid regulation plays critical roles in the immune homeostasis of lupus-prone animals, and identify perforin-mediated cytotoxicity as a specific mechanism in the regulation of systemic autoimmunity.
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PMID:Perforin protects against autoimmunity in lupus-prone mice. 955 99

Inhibiting DNA methylation in CD4+ T cells causes aberrant gene expression and autoreactive monocyte/macrophage killing in vitro, and the hypomethylated cells cause a lupus-like disease in animal models. Similar decreases in T cell DNA methylation occur in idiopathic lupus, potentially contributing to disease pathogenesis. The genes affected by DNA hypomethylation are largely unknown. Using DNA methylation inhibitors and oligonucleotide arrays we have identified perforin as a methylation-sensitive gene. Our group has also reported that DNA methylation inhibitors increase CD4+ T cell perforin by demethylating a conserved methylation-sensitive region that is hypomethylated in primary CD8+ cells, which express perforin, but is largely methylated in primary CD4+ cells, which do not. As lupus T cells also have hypomethylated DNA and promiscuously kill autologous monocytes/macrophages, we hypothesized that perforin may be similarly overexpressed in lupus T cells and contribute to the monocyte killing. We report that CD4+ T cells from patients with active, but not inactive, lupus overexpress perforin, and that overexpression is related to demethylation of the same sequences suppressing perforin transcription in primary CD4+ T cells and demethylated by DNA methylation inhibitors. Further, the perforin inhibitor concanamycin A blocks autologous monocyte killing by CD4+ lupus T cells, suggesting that the perforin is functional. We conclude that demethylation of specific regulatory elements contributes to perforin overexpression in CD4+ lupus T cells. Our results also suggest that aberrant perforin expression in CD4+ lupus T cells may contribute to monocyte killing.
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PMID:Demethylation of promoter regulatory elements contributes to perforin overexpression in CD4+ lupus T cells. 1500 68

T cells play an essential role in driving humoral autoimmunity in lupus. Molecules such as TRAIL exhibit strong T cell modulatory effects and are up-regulated in lupus, raising the possibility that they may influence disease severity. To address this possibility, we examined the role of TRAIL expression on pathogenic T cells in an induced model of murine lupus, the parent-into-F(1) (P-->F(1)) model of chronic graft-vs-host disease (GVHD), using wild-type or TRAIL-deficient donor T cells. Results were compared with mice undergoing suppressive acute GVHD. Although chronic GVHD mice exhibited less donor T cell TRAIL up-regulation and IFN-alpha-inducible gene expression than acute GVHD mice, donor CD4(+) T cell TRAIL expression in chronic GVHD was essential for sustaining effector CD4(+) Th cell numbers, for sustaining help to B cells, and for more severe lupus-like renal disease development. Conversely, TRAIL expression on donor CD8(+) T cells had a milder, but significant down-regulatory effect on CTL effector function, affecting the perforin/granzyme pathway and not the Fas ligand pathway. These results indicate that, in this model, T cell-expressed TRAIL exacerbates lupus by the following: 1) positively regulating CD4(+) Th cell numbers, thereby sustaining T cell help for B cells, and 2) to a lesser degree by negatively regulating perforin-mediated CD8(+) CTL killing that could potentially eliminate activated autoreactive B cells.
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PMID:T cell TRAIL promotes murine lupus by sustaining effector CD4 Th cell numbers and by inhibiting CD8 CTL activity. 1733 97

Kikuchi-Fujimoto disease (KFD), first described independently by Kikuchi and Fujimoto in 1972, is a subacute necrotizing lymphadenitis of unknown cause. Although most frequent in young Asian women, KFD has a worldwide distribution. Clinically, KFD is characterized by lymphadenitis of one or more lymph nodes, predominantly in the posterior cervical region, fever, and leukopenia in up to 50% of cases. Extranodal manifestations can occur, especially skin lesions and aseptic meningitides. Diagnosis is usually confirmed by analysis of samples from an excisional biopsy of the affected nodes. Histologically, the lesions affect the cortical and paracortical areas of the node. Characteristic features include focal necrosis predominantly in the paracortical region with abundant karyorrhectic debris and atypical mononuclear cells around the necrotic zone (crescent-shaped histiocytes, plasmacytoid monocytes, and small lymphocytes and immunoblasts, mostly CD3(+)/CD8(+)), most often with an intact lymph node capsule, an absence of neutrophils, and a paucity of plasma cells. KFD has been classified into three histological subtypes and is thought to progress from the proliferative type (> 50%) to the necrotizing type (30%) and finally resolve into the xanthomatous type (< 20%). Differential diagnoses should include malignant lymphoma, infectious diseases such as toxoplasmatic lymphadenitis, tuberculous lymphadenitis and cat scratch disease, and systemic lupus erythematosus (SLE). The cause of KFD is unknown: a viral infection has been suggested, but not demonstrated, possibly involving human herpes virus 8 or Epstein-Barr virus. Apoptotic cell death plays a role: proliferating CD8(+) T-lymphocytes act as both killers and victims in the apoptotic process via Fas and perforin pathways. The course is usually benign with resolution in a few months with the use of antiinflammatory drugs. Regular follow-up is required because SLE may develop several years after the onset of Kikuchi-Fujimoto disease.
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PMID:[Subacute necrotizing lymphadenitis or Kikuchi-Fujimoto disease]. 1761 Oct 68

Perforin had been demonstrated to play important roles in the pathology of systemic lupus erythematosus (SLE), which was a potential target of clinical treatment of SLE. CD134 was a member of the tumor necrosis factor receptor family, which had been demonstrated to inhibit expression of perforin mRNA. The aim of the present study was to determine the effects of CD134 monoclonal antibody (MAb) on expression and hemolysis activities of perforin and its mechanisms. Effects of CD134 MAb on hemolysis activities of perforin were measured by rabbit red blood cells. Effects of CD134 MAb on expression of perforin in peripheral blood mononuclear cells (PBMCs) were determined by reverse transcription-polymerase chain reaction (RT-PCR) method and flow cytometry. Then, expression of NF-kappaB P65 was detected by Western blot. The results showed that CD134 MAb could inhibit hemolysis activities and expression of perforin through decreasing expression of NF-kappaB P65. The inhibition effects were positively correlated to the SLE disease activity index (SLEDAI) and 24-hour protein-uria of SLE patients in active state. CD134 MAb is suggested to be a potential treatment for SLE patients.
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PMID:Effects of CD134 monoclonal antibody on hemolysis activities and expression of perforin in peripheral blood mononuclear cells of systemic lupus erythematosus patients. 1772 80

CD4(+) T cells from patients with systemic lupus erythematosus (SLE) exhibit increased expression of various proteins contributing to defective function of CD4(+) T cells. We evaluated the transcript and protein levels of perforin (PRF1) in CD4(+) T cells from SLE patients (n = 41) and healthy individuals (n = 34). The CD4(+) T cells were obtained by a positive biomagnetic separation system. The amounts of mRNA were determined by reverse transcription and real-time quantitative PCR. The protein levels in the CD4(+) T cells were evaluated by Western blotting analysis. We observed significantly higher levels of PRF1 protein (p = 0.013) in SLE CD4(+) T cells than in controls. There was no significant increase in PRF1 transcript levels (p = 0.908) in CD4(+) T cells from SLE patients as compared to healthy individuals. Moreover, we did not observe a correlation between PRF1 transcript and protein levels in SLE CD4(+) T cells and disease activity expressed by the SLEDAI scale. We confirmed previous observations that demonstrated higher levels of PRF1 protein in CD4(+) T cells from SLE patients. However, we did not find a correlation between PRF1 transcripts and proteins in CD4(+) T cells and SLE disease activity.
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PMID:Perforin level in CD4+ T cells from patients with systemic lupus erythematosus. 2004 50

Perforin is a membrane-disrupting protein that allows the entry of granzymes into a target cell inducing degradation of target substances in the cytoplasm and nucleus thus leading to programmed cell death or apoptosis. CD134 was originally described as an activation antigen found on activated T cells. In this work Flowcytometry was used to evaluate the expression of perforin and CD134, as a costimulatory molecule on T cells, in patients with Systemic Lupus Erythematosus (SLE) to elucidate their role in the pathogenesis of SLE and disease severity. The study was conducted on 15 patients with SLE, 6 patients out of the 15 patients were suffering from lupus nephritis, 10 healthy subjects were included as controls. The results revealed that absolute number of circulating CD3+ lymphocytes in the patients was significantly lower than the controls (P = 0.013). The percentage of CD8+ CD3+ T cells was significantly increased in the SLE group when compared to that of CD4+ CD3+ T cells in same group (P = 0.001) Perforin expression on both CD4+ and CD8+ cells was significantly increased in patients compared to controls. (P = 0.002 & P = 0.001, respectively). In addition, a significant increase was observed in the percent of pf+CD8+CD3+ in the patient group compared to that of pf+CD4+CD3+ in the same group (P = 0.001). There was a significant increase in the expression of CD134 on CD4+ and CD8+ cells (P = 0.001 & P = 0.001 respectively). Also, in the same group of patients a significant increase was detected in the frequency of CD134+CD4+CD3+ T cells compared to that of CD134+CD8+CD3+ T cells (P = 0.032). A significant positive correlation was detected in the patient group between CD134 and perforin expression on both CD4+ and CD8+ T cells (p = 0.045, r = 0.523). Moreover, CD134+CD4+CD3+ was also correlated positively with urinary proteinuria (P = 0.023, r = 0.524). Our data suggest the role of Perforin + cytotoxic T lymphocytes and CD134+ cells in the pathogenesis of autoimmunity of SLE. Thus, inhibition of perforin could be beneficial for SLE patients. Targeting pf and CD134 could be a new therapeutic approach in patients with SLE.
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PMID:Flowcytometric study of expression of perforin and CD134 in patients with systemic lupus erythematosus. 2030 96

Global disease activity measurement in systemic lupus erythematosus (SLE) patients is important for the clinical estimation and adjustment of therapy. By contrast, immune system activation plays a significant role in disease pathogenesis, with CD4+ lymphocytes acting as central cells in the immune response. We investigated which scale better correlates with immunologic changes in the blood of SLE patients, the SLE Disease Activity Index (SLEDAI) or the Systemic Lupus Activity Measure (SLAM) scale. Samples of peripheral blood were obtained from 45 SLE patients with different disease activity as assessed by the SLEDAI and the SLAM scales on the same day. We assessed the percentage of CD4+ T cells with activation-associated receptors: CD69, CD25int, CD95, HLA-DR, and CD4+ T cells with killing properties containing perforin and granzyme B. Our results indicated that the percentage of CD4+CD69+ and CD4+CD25(int) cells did not correlate with either the SLEDAI or the SLAM scale. Significant and positive correlations were observed between percentages of CD4+CD95+ and CD4+HLA-DR+ lymphocytes and SLE activity, but only when activity was measured using the SLAM scale, not with the SLEDAI scale. The percentage of CD4+perforin+ and CD4+granzyme B+ cells also strongly correlated with disease activity measured only with the SLAM scale. We conclude that the SLAM scale better reflects changes of immune system activity in SLE patients compared with the SLEDAI scale.
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PMID:Two systemic lupus erythematosus (SLE) global disease activity indexes--the SLE Disease Activity Index and the Systemic Lupus Activity Measure--demonstrate different correlations with activation of peripheral blood CD4+ T cells. 2190 46


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