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)

Blockade of the interactions between CD28/CTLA-4 and their ligands, CD80 (B7, B7.1)/CD86 (B70, B7.2), seems an attractive means to induce antigen-specific peripheral tolerance in organ transplantation and autoimmune disease. Recently, diversities between CD80 and CD86 in expression, regulation, and function have been reported in certain cell populations and murine experimental disease models. To investigate the possible differential role of CD80 and CD86 in the development of lupus, we treated lupus-prone NZB/W F1 mice with specific monoclonal antibodies (mAb) against CD80, CD86, or both. The treatment with a combination of anti-CD80 and CD86 mAb before the onset of lupus completely prevented autoantibody production and nephritis, and prolonged survival. Interestingly, we found that anti-CD86 mAb alone, but not anti-CD80 mAb, efficiently inhibited autoantibody production. Subclass study on IgG anti-double-stranded (ds) DNA antibody revealed that the treatment with anti-CD86 mAb almost completely inhibited both IgG1 and IgG2b, but not IgG2a production. The incomplete reduction of IgG2a anti-dsDNA antibody by anti-CD86 mAb was compensated by the addition of anti-CD80 mAb. A significant reduction of mRNA for interleukin (IL)-2, interferon-gamma, IL-4 and IL-6 was observed in mice treated with a combination of anti-CD80 and CD86 mAb or anti-CD86 mAb alone. Treatment with both mAb after the onset of lupus resulted in a significantly prolonged survival with reduction of autoantibody production. These results suggest that CD86 plays a more critical role in autoantibody production, and CD86, but not CD80, contributes to Th2-mediated Ig production. However, the blockade of both CD80 and CD86 are required for preventing the development and progression of lupus.
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PMID:Preferential dependence of autoantibody production in murine lupus on CD86 costimulatory molecule. 748 44

Defective T cell functions, including IL-2 production and proliferation, have been shown in SLE patients. After T cell stimulation (first signal), a costimulatory signal (second signal) is required to achieve complete T cell activation. Main costimulatory signals are provided to T cells by B7 antigens (CD80 and CD86, expressed on antigen-presenting cells (APC)) upon interaction with its receptor, the CD28 molecule expressed on T cells. The aim of this study was to investigate the role of CD28/B7 interactions in the impaired T cell responses of SLE patients. We show that stimulation of T cells with phytohaemagglutinin (PHA) in the presence, but not in the absence, of anti-CD28 MoAb or B7+ cells results in tyrosine phosphorylation of specific substrates, transcription of mRNA and production of IL-2 that is indistinguishable in SLE patients and healthy controls. Moreover, proliferation of costimulated T cells from SLE and controls was specifically abrogated by blocking the CD28/B7 interactions by means of addition to the culture of the CTLA4-Ig fusion protein. However, in most patients activated APC failed to up-regulate B7 molecules, giving rise to ineffective costimulatory signalling to T cells. These results indicate that the CD28/B7 costimulatory pathway is defective in SLE patients.
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PMID:Defective B7 expression on antigen-presenting cells underlying T cell activation abnormalities in systemic lupus erythematosus (SLE) patients. 860 37

The specificity of T cell help for B cell activation and differentiation is maintained by the brief expression on the T cell surface, following T cell receptor-mediated triggering, of CD40 ligand (CD40L). Interaction of T helper (Th) cell CD40L with B cell CD40 induces B cell activation, cell surface expression of activation antigens, proliferation, and initiation of immunoglobulin isotype switch. We predicted that in patients with systemic lupus erythematosus (SLE), in whom Th cell-dependent production of autoantibodies results in immune complex-mediated tissue damage, CD40L expression might be augmented, prolonged, or abnormally regulated. Baseline expression of CD40L was increased in some SLE patients studied, when compared with control subjects. While Th cells from normal subjects (n = 14) and rheumatic disease control patients (n = 9) showed maximal expression of CD40L, after in vitro activation with phorbol myristate acetate (PMA) and ionomycin, at 6 h of culture with diminished levels observed at 24 and 48 h, Th cells from SLE patients (n = 19) maintained high level cell surface expression of CD40L through 24 and 48 h of culture. The prolonged expression of CD40L was functionally significant, as 24 h-activated SLE T cells, when cocultured with target B cells, induced greater B cell surface CD80 (B7-1) expression than did 24 h-activated normal T cells. These results document impaired regulation of CD40L expression in SLE T cells and identify an important potential target for therapy in this systemic autoimmune disease.
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PMID:Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. 869 75

Studies reported during the past year have added new knowledge to our understanding of cellular abnormalities in systemic lupus erythematosus: 1) Antigen-specific and "pathogenic" T cells display a limited T cell receptor repertoire in lupus. 2) The ratio of interleukin-10 to interferon gamma-secreting cells in the peripheral blood of patients with lupus is increased in patients with active disease. 3) CD3-mediated increases in free intracytoplasmic calcium occur specifically in lupus T cells and lines; this finding provides additional evidence that cell-signaling events are defective in patients with lupus. 4) Aberrant expression of adhesion molecules on the surface membrane of leukocytes and endothelial cells was shown, a finding with important mechanistic and therapeutic implications. 5) Lupus antigen-presenting cells fail to upregulate the expression of B7-1 (CD80) in response to interferon gamma; defective expression of B7-1 is responsible for the decreased response of lupus cells to recall antigens.
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PMID:Lymphocytes, cytokines, inflammation, and immune trafficking. 894 41

The CD28/CTLA4-B7-family plays an important role in T-cell costimulation and is crucial for IL-2 production and tolerance induction. The costimulatory molecule B7-BB1 (CD80) is expressed on activated antigen presenting cells, but its expression on peripheral blood mononuclear cells is very low. Here we report a patient with untreated SLE whose peripheral blood antigen presenting cells expressed increased amounts of B7-BB1.
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PMID:Elevated in vivo expression of the costimulatory molecule B7-BB1 (CD80) on antigen presenting cells from a patient with SLE. 897 70

We screened peripheral blood mononuclear cells from 13 SLE patients, all having quiescent disease at the time of analysis, 12 allergy patients, and 21 normal subjects for the expression of CD80 (B7-1) and CD86 (B7-2, B70) on small (resting) and large (activated) subsets of CD19+ B cells. The percentage of CD86+ cells was significantly higher in all B cell subsets in the SLE patients compared to either normal controls or allergy patients. No differences in the mean percentage CD86+ stained B cells (CD19+) were found when comparing the allergy patients and the normal controls. The percentage of CD80+ cells in the large activated B cell (CD19+) subset of the SLE patient population was significantly higher than in the comparable subset from the normal controls and the allergy patients. Comparison of the small resting B cell subset did not reveal a significant difference in CD80 expression between the normal controls, the allergy patients, and the SLE patients. Our findings suggest that the B7 family of molecules, and CD86 in particular, may reflect immunologic dysregulation in patients with autoimmune disease and may reflect a state facilitating heightened B cell activity and hypergammaglobulinemia that occur in active SLE.
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PMID:Analysis of CD80 and CD86 expression on peripheral blood B lymphocytes reveals increased expression of CD86 in lupus patients. 917 7

Studies reported during the past year have added new knowledge to our understanding of the pathogenesis of systemic lupus erythematosus. A study of sibpairs with lupus revealed a strong linkage of a region located at chromosome 1q41-42 that crossed ethnic barriers. B-cell receptor-initiated signaling events, such as tyrosine protein phosphorylation and intracellular calcium concentrations, were found to be increased in patients with lupus in a disease- and clinical activity-independent manner. T cells from patients with lupus express increased amounts of the CD40 ligand, which is functional because it helps B cells to produce anti-DNA antibodies and express more CD80 (B7-1) on their surface. Only occasionally do lupus patients display structural defects of either Fas antigen or ligand molecules, and although spontaneous apoptosis is increased in lupus cells (as well as in other systemic autoimmune disorders), the activation-induced T-cell death is defective.
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PMID:Lymphocytes, cytokines, inflammation, and immune trafficking. 930 92

A large array of heterogeneous aberrations of the immune system have been described in systemic lupus erythematosus (SLE). Since the function and the fate of the immune system cells are governed principally by the biochemical events that follow ligation of specialized cell-surface receptors, we will review in this article recent developments in our understanding of abnormalities in the biochemistry of signals generated either by the antigen-receptor complex or by systems of costimulatory cell-surface molecules, like the CD28/CTLA4:CD80/CD86 and the CD40:CD40L pairs found on the surface membrane of lupus immune cells.
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PMID:Immune cell signaling aberrations in human lupus. 972 47

Patients with systemic lupus erythematosus (SLE) were recently shown to be defective in costimulatory molecule CD80 (B7-1) expression on antigen-presenting cells. This study was undertaken to further investigate the expression and cytokine regulation of both CD80 and CD86 (B7-2) on monocytes from patients with SLE. Freshly isolated and in vitro cytokine-stimulated peripheral blood mononuclear cells from 13 patients with SLE and 10 healthy subjects were analysed, cytometrically with dual-fluorescence staining, to detect expression of CD80 and CD86 in the CD14+ monocyte population. The results showed that, as in normal individuals, an overwhelming majority (95.62+/-3.54%) of monocytes from patients with SLE expressed the CD86 molecule, but only a few monocytes (5.54+/-4.36%) had detectable CD80 expression. The effects of interleukin-10 (IL-10) on the expression of CD80 and CD86 on monocytes from patients with SLE and normal controls were similar. IL-10 down-regulated the expression of CD86 while it slightly enhanced that of CD80. Interferon-gamma (IFN-gamma) increased both CD80 and CD86 expression on monocytes from both SLE patients and normal groups, albeit less significantly in the former than in the latter, i.e. CD80: 142.84+/-65.99% versus 226.08+/-78.90%, P<0.05; and CD86: 72.55+/-74.23% versus 153.99+/-94.14%, P<0.05, when expressed as percentage modulation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) showed a capacity for up-regulation of CD80 and CD86 expression on monocytes, of a magnitude that was similar both in patients with SLE and in normal subjects. We concluded that CD80 and CD86 were differentially expressed and modulated on monocytes and the defective IFN-gamma-induced up-regulation of CD80 and CD86 expression on SLE monocytes might be a factor in the pathogenesis of SLE.
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PMID:Differential expression and modulation of costimulatory molecules CD80 and CD86 on monocytes from patients with systemic lupus erythematosus. 1002 62

CD80 and CD86 were detected in high amounts on circulating T cells in the peripheral blood of some patients with systemic lupus erythematosus (SLE), using flow cytometry and monoclonal antibodies. Patients with other connective tissue diseases did not have a high percentage of T cells expressing CD80 or CD86 in their peripheral blood. CD80 was expressed mainly on CD4 T cells, whereas CD86 was expressed on CD8 T cells, and these two populations were associated with particular clinical features. These two molecules were expressed on different T-cell populations and might have different roles in the generation and regulation of immune responses. Since high expression of CD86 on T cells was detected much earlier than the appearance of clinical features and a high titer of anti-DNA antibody, it may be a useful parameter for predicting the flare of SLE.
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PMID:Expression of CD80 and CD86 on peripheral blood T lymphocytes in patients with systemic lupus erythematosus. 1008 Jan 5


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