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)

Novel data have emerged which attempt to characterize the biochemical abnormalities that are exhibited by lupus immune cells. Lupus lymphocytes display abnormal antigen-receptor-mediated signaling, consisting of increased Ca2+ mobilization and increased protein tyrosyl phosphorylation that are independent of disease activity. Abnormalities in the expression and function of co-stimulatory molecules (B7-CD28 and CD40-CD40L) have been established. Transcription of cytokine genes and the methylation of DNA which affects multiple genes are also abnormal. Finally, aberrations of the apoptosis of lupus immune cells are contributors to the pathogenesis of the disease.
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PMID:Immune cell biochemical abnormalities in systemic lupus erythematosus. 944 27

A 24-year-old woman had suffered from recurrent bacterial infections and clinical manifestations of systemic lupus erythematosus (SLE). Laboratory findings disclosed an elevated level of serum IgM, markedly decreased IgG, IgA, IgD and IgE levels, and low levels of serum complement. Both the CD40 and CD40 ligands appeared to be normally expressed. Assays of in vitro immunoglobulin production by lymphocytes showed that IgM was produced normally and that IgE but not IgG or IgA production was rescued by signaling through CD40 on B cells. The proliferative response of lymphocytes to phobol ester was markedly decreased, suggesting some impairment of signal transduction in the patient's lymphocytes.
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PMID:Non-X-linked hyper-IgM syndrome with systemic lupus erythematosus. 954 71

New treatments for autoimmune renal disease are required, and a developing knowledge of its underlying immunopathogenesis has identified sites where immunotherapy is likely to be effective. Experience with intravenous immunoglobulin and lymphocyte depletion by monoclonal antibodies in systemic vasculitis and systemic lupus erythematosus is awaiting confirmation by randomized trials. Treatments at or near clinical testing include monoclonal antibody blockade of leucocyte-endothelial interactions and CD40 mediated B-cell activation, and immunoablation with autologous stem-cell transplantation for more severe multisystem autoimmune disease.
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PMID:Immunotherapy for autoimmune and inflammatory renal diseases. 961 63

Human hybridomas that secrete monoclonal antibodies (MAbs) in a stable manner are technically difficult to obtain. The problems limiting their production are the low numbers of sensitized B cells in peripheral blood, the limited choice of techniques for B cell immortalization, the limited number of suitable human myeloma or lymphoblastoid fusion partners, and the inability to immunize humans with most antigens. In order to circumvent these problems, we have compared the efficiency of different methods for production of B cell lines secreting human MAbs against the nuclear antigens dsDNA, ssDNA, and Sm/RNP from patients with the autoimmune disease systemic lupus erythematosus (SLE). We have tested various combinations of the following procedures: (1) EBV infection for immortalization of activated B lymphocytes, (2) activation of human resting B lymphocytes by anti-CD40, and (3) direct fusion of lymphocytes with a myeloma cell line using PBL or splenocytes from SLE patients. The methodological aspects of this investigation include optimization of the CD40 system and the generation of human hybridomas specific for nuclear antigens by fusion between sensitized lymphocytes and the human/mouse heteromyeloma cell line CBF7. The most efficient method for producing stable, IgG autoantibody-secreting human hybridomas was fusion of lymphocytes with cell line CBF7; human spleen was the best source of lymphocytes.
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PMID:A comparison of three methods for production of human hybridomas secreting autoantibodies. 970 33

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

Abnormalities in the regulation of both cell-mediated and humoral immunity have been implicated in the pathophysiology of systemic lupus erythematosus (SLE). Cognate contact-dependent T-B cell interactions involving CD154 (CD40 ligand) on activated T cells and CD40 on B lymphocytes have a critical role in antibody production. Abnormal CD154 expression on lymphocytes may play a role in the production of potentially pathogenic autoantibodies and defects in self-tolerance mechanisms may be important. Failure of intrathymic or peripheral deletion of autoreactive T cells may also result in an autoimmune phenotype. Elevated levels of CD3(+)CD4(-)/8(-) (double negative) T cells (DNT) in the peripheral blood are a surrogate marker for defects of this type. The expression of CD154 on T and B cells was evaluated and levels of double negative T cells in the peripheral blood were assessed by two and three colour flow cytometric analyses. We studied peripheral blood lymphocytes in 48 patients with SLE. Twenty-five normal subjects and 12 patients with rheumatoid arthritis (RA) were studied as disease controls. T cells in 22/48 (45%) lupus patients expressed CD154 between 20-80% (median=52%). In normal controls and RA patients 8-18% T cells were CD154(+). Twelve patients (30%) had elevated expression of CD154 (20-50%) on B cells. In the control RA patients, less than 15% T cells were CD154(+). Twelve of 48 SLE patients had elevated numbers of DNT cells (18-27%). The control subjects had DNT cell numbers <10. These observations suggest that defects in either the intrathymic or peripheral deletion of potentially pathogenic T lymphocytes may play a role in the pathogenesis of SLE. The high expression of CD154 on both T and B cells may also be important in mediating the production of potentially harmful autoantibodies.
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PMID:Peripheral blood lymphocytes in SLE--hyperexpression of CD154 on T and B lymphocytes and increased number of double negative T cells. 980 31

A significant number of T cells and macrophages infiltrate the kidneys of patients with lupus nephritis. Chemotactic factors, especially monocyte chemoattractant factor-1 (MCP-1) and adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), cooperatively facilitate recruitment of mononuclear cells into inflamed tissue. Increased expression of class II MHC molecules and CD40 on renal tubular epithelial cells coupled with upregulation of CD40 ligand (CD40L) and interleukin-2 receptor on infiltrating T cells suggest ongoing cellular immune responses. Recent studies employing knockout mice suggest that the T(H)-1 cytokine interferon-gamma is an important cytokine in amplifying the local immune response of lupus nephritis. Infiltrating mononuclear cells exert their effects on resident renal cells through secretion of soluble factors and/or direct cell to cell contact. These interactions, among others, involve molecules such as CD40/CD40L and adhesion molecules. Studies to better define these molecules are in progress and may provide additional targets for therapeutic intervention. Thus, while autoantibody production and complement activation are the major players in initiating the inflammatory response in lupus nephritis, cellular immune mechanisms mediated through infiltrating mononuclear cells have an important role in its amplification and the progression of renal injury.
Lupus 1998
PMID:Cellular interactions in the pathogenesis of lupus nephritis: the role of T cells and macrophages in the amplification of the inflammatory process in the kidney. 988 96

We found that the plasma of patients with active systemic lupus erythematosus (SLE) could induce a human B-cell line (Ramos) to express high levels of immune accessory molecules that are commonly found on blood B cells of patients with active SLE. The ability of SLE plasma to induce such phenotypic changes could be abrogated by neutralizing antibodies specific for the CD40 ligand (CD154) but not by antibodies to TNF-alpha. Immunoprecipitation studies with anti-CD154 identified a 20-kDa protein in the plasma of SLE patients with active disease, but not in plasma of normal donors, indicating that such plasma contained soluble CD154 (sCD154). Using a quantitative ELISA method, we found that the plasma of patients with active disease had levels of sCD154 that were significantly higher than those found in plasma of normal donors. Levels of CD154 transcripts in SLE blood lymphocytes correlated with the relative concentrations of sCD154 found in SLE plasma. Furthermore, plasma levels of sCD154 correlated with the titers of anti-double-stranded DNA autoantibody and with clinical disease activity. These studies indicate that sCD154 of patients with SLE may act as a functional ligand for CD40 that is associated with SLE disease activity.
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PMID:The soluble CD40 ligand sCD154 in systemic lupus erythematosus. 1051 Mar 35

Male, but not female, BXSB mice develop severe lupus associated with multiple immune system defects. It was recently shown that one immunological abnormality found in male BXSB mice encompasses B cell expression of CD40 ligand (CD40L) by an expanded population of large B cells. The present study was undertaken to determine how the CD40L-expressing large B cells in male BXSB mice compared with size-matched B cells from female mice in terms of their ability to secrete antibody. It was shown that the large B cells from female mice, similar to the small B cells from either male or female mice, required CD40 signalling, immunoglobulin cross-linking and cytokines for optimal antibody synthesis. In contrast, large B cells from male BXSB mice produced high levels of antibody when stimulated with only two of the three signals, and made significantly more total IgM and IgG, and anti-ssDNA antibody than size-matched B cells from female mice when stimulated with IL-4/IL-5 alone, IL-4/IL-5 plus low levels of anti-IgD-dextran, or IL-4/IL-5 plus anti-CD40 MoAb. The ability of the large B cells from male mice to produce antibody under suboptimal stimulatory conditions correlated with their expression of CD40L, and was inhibited by CD40-immunoglobulin. Taken together, these findings suggested that large CD40L-expressing B cells from male BXSB mice may be able to bypass a need for CD40 signalling from T cells, thus contributing to autoimmune disease by promoting antibody production in the absence of cognate T cell help.
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PMID:Antibody production in autoimmune BXSB mice. I. CD40L-expressing B cells need fewer signals for polyclonal antibody synthesis. 1054 Jan 72

Since the mechanism mediating the beneficial effect of intravenous cyclophosphamide (IVCY) in systemic lupus erythematosus (SLE) is unknown, we investigated lymphocyte subsets and markers of activated lymphocytes in patients received IVCY, and compared the results with the effect of steroid pulse. In 55 patients with SLE, 34 patients receiving IVCY [21 cases (61.8%) were responsive] and 25 patients received steroid pulse [21 cases (84.0%) were responsive] (four patients who were resistant to steroid pulse therapy were transferred to IVCY). When the lymphocyte subsets and markers of activated lymphocytes were compared in the responsive and unresponsive group of IVCY, soluble CD4 levels and the ratio of HLA-DP-positive T cells were significantly higher in the unresponsive group. Further, the changes of these markers and costimulatory molecules [LFA-1 (CD11a), ICAM-1 (CD54), CD40 and CD40-ligand (CD154)] were also examined in the responsive patients. The ratio of HLA-DP-positive T cells did not change in the IVCY-responsive group, while it decreased in the steroid pulse therapy-responsive group. The ratio of CD11a on T cells increased and CD54 on B cells decreased in the IVCY-responsive group. The ratio of CD154 on T cells increased in the steroid pulse-responsive group, while it decreased in the IVCY-responsive group. These results suggest that the effect of IVCY is different to that of steroid pulse therapy and mainly related to B cell activation, and that these markers may contribute to predict the responsiveness of IVCY.
Lupus 2000
PMID:Effect of intravenous cyclophosphamide in systemic lupus erythematosus: relation to lymphocyte subsets and activation markers. 1098 57


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