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)

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

Systemic lupus erythematosus (SLE) is envisioned to arise from hyperactivate helper T-cells that cause polyclonal B-cell secretion of pathogenic autoantibodies and formation of immune complexes which deposit in sites such as the kidney. The most widely used immunosuppressive drugs, notably corticosteroids and cyclophosphamide, are often criticized as being nonspecific. In fact, these agents may be effective in SLE and lupus nephritis because broad, rather than highly selective, effects are required to control the aberrant immune system. Nonetheless, these agents are not uniformly effective and are associated with substantial toxicities. The lack of universal efficacy raises the specter that lupus is a heterogeneous disorder with different etiopathogenesis in different subsets of patients (as in lupus-prone mice). Therapeutic prospects for the upcoming millennium include new forms and combinations of chemotherapeutic agents (mycophenolate and adenosine analogues), attempts to achieve immunological reconstitution using near-ablative chemotherapy (with or without bone marrow or stem cell rescue), monoclonal antibodies, and other inhibitors of T-cell costimulatory pathways (e.g., anti-CD154 and/or CTLA4-Ig). The prospect for gene therapy has already been realized in some animal models of SLE. In human SLE, the feasibility of gene therapy will depend on further definition of lupus-promoting genes and availability of methods to establish stable expression of potentially corrective genes.
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PMID:New prospects for treatment of lupus nephritis. 1065 Dec 16

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

Lupus nephritis is often well developed at the time of diagnosis. High-dose corticosteroids are universally accepted as the initial approach to the control of severe inflammation in the kidney. Long-term disease control and the minimization of iatrogenic risk usually require adjunctive therapies that target the more fundamental immunoregulatory disturbances of lymphoid cells. Of the available cytotoxic drugs, cyclophosphamide is currently among the most effective, although it cannot be considered ideal in terms of efficacy or toxicity. New prospects for the treatment of proliferative lupus nephritis include novel immunosuppressive agents (e.g. mycophenolate, cyclosporine, fludarabine), combination chemotherapy (e.g. cyclophosphamide plus fludarabine), and sequential chemotherapy (e.g. cyclophosphamide-azathioprine), immunological reconstitution using intensive cytoreductive chemotherapy (with or without stem cell rescue), co-stimulatory molecule inhibition (e.g. humanized anti-CD154 monoclonal antibody, CTLA4-Ig). Gene therapy remains an attractive prospect, but its feasibility clearly depends on the further definition of lupus-promoting genes and the availability of methods to establish stable expression of disease-corrective genes in the appropriate lymphoid cells.
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PMID:Progress in the treatment of proliferative lupus nephritis. 1075 14

Current therapies for systemic lupus erythematosus (SLE) are targeted at immunosuppression and at reducing inflammation. The current therapies are broad-spectrum and include steroids and cytotoxic agents that are counterbalanced by toxicity and side effects of the medications. Methotrexate can be utilized to reduce steroid requirements in mild to moderate SLE. Manipulation of the hormonal axis includes DHEA and bromocriptine. Mycophenolate mofetil is an immunosuppressive agent that is being investigated for SLE renal disease. Autologous stem cell transplantation or high-dose cyclophosphamide may be an option for severe refractory SLE. The aim of the future is to target therapies by altering specific known mechanisms of inflammation and autoimmunity. Although the inciting antigen is still unknown in SLE, it may be possible to alter the regulation of the immune response by targeted molecular therapy. Methods to do so would include manipulation of idiotypes, manipulation of second signal stimulation of the immune response, manipulation of cytokines, and the induction of tolerance by administration of blocking peptides. IVIg is an immunomodulator that has been successful in the treatment of SLE. Targeted molecular therapy is undergoing phase I trials with monoclonal anti-CD40L, a signaling inhibitor. Anti-CTLA4Ig, another signaling blocker, is presently being investigated for psoriasis, but may be a potential therapy for SLE. Finally, therapies may include the administration of peptides to induce tolerance.
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PMID:Novel approaches to therapy for systemic lupus erythematosus. 1085 17

Male BXSB mice, unlike female BXSB mice, develop an early-onset, lupus-like disease characterized by high levels of anti-nuclear antibodies (Abs) and total Ig. It has recently been shown that the male BXSB mice contain an expanded population of large B cells which are hyperresponsive to stimulation by anti-CD40 mAb. The present study was undertaken to determine whether their potential for extra CD40 signaling enabled the B cells from male BXSB mice to hyper-respond to CD40L-expressing CD4+ T cells. In contrast to expectations, large B cells from male BXSB mice did not interact with CD4+ T cells in a positive manner; cultures of B cells from antigen (Ag)-primed male BXSB mice, unlike cultures of B cells from Ag-primed female mice, generated few antibody forming cells (AFC) following interaction with activated CD4+T cells. In addition, B cells from male BXSB mice, unlike B cells from female BXSB mice, failed to upregulate MHC class II molecules following interaction with activated CD4+ T cells. Subsequent experiments revealed that the inability of the B cells from the male mice to upregulate MHC class II molecules in response to T cell-mediated activation resided primarily in the population of large B cells. Large B cells from male BXSB mice were also defective in their ability to proliferate following stimulation with activated CD4+ T cells. Taken together, these findings demonstrated that similar to B cells in lupus patients, large B cells from male BXSB mice could function in a hyporesponsive manner, and that this hyporesponsiveness related to the inability of the B cells to interact in a positive manner with CD4+T cells.
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PMID:B cells from autoimmune BXSB mice are hyporesponsive to signals provided by CD4+ T cells. 1093 11

Systemic lupus erythematosus (SLE) is a disease of relatively low prevalence with a wide range of clinical manifestations. Due in part to these two facts, there is little new evidence on the treatment of lupus. In fact, randomised controlled studies and prospective series are few and usually involve a small number of patients. Despite this, some therapies have shown to be beneficial within the last five years, while others emerge as possibilities in the near future. Among the former, antimalarials appear to be the treatment of choice for maintaining mild to moderate disease in remission. Methotrexate may be an alternative to other corticosteroid-sparing drugs, especially in patients with active arthritis and skin disease. Cyclosporin can be of use in proteinuric nephritis, although the incidence of hypertension with this drug is high. Thalidomide is useful for refractory skin lesions, but the efficacy of lower, less toxic doses is still to be studied. Immunoglobulins should probably be limited to selected patients with manifestations such as thrombocytopoenia. Experience is more limited with cladribine, fludarabine, tacrolimus, danazol and pentoxifylline. New therapies for severe SLE include mycophenolate mofetil, a potent immunosuppressive drug with a reasonable safety profile and immunoablative therapy with or without stem cell transplantation, in highly resistant cases or those with a poor prognosis. Other recently developed molecules, including anti-CD40L monoclonal antibodies (mAbs), are still under investigation.
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PMID:Therapy of systemic lupus erythematosus: new agents and new evidence. 1106 Jul 62

To identify intrinsic defects in lupus, we studied short-term, CD4(+) T cell lines that were established from 16 lupus patients (active or inactive) and 15 normal subjects by stimulating once with anti-CD3, anti-CD28, and IL-2. After resting, the pure CD4(+) T cells were exposed to anergy-inducing stimulation with plate-bound anti-CD3 mAb in the absence of APC. Lupus T cells showed prolonged high level expression of CD40 ligand (CD40L, CD154) even in the face of anergy protocol, which shut down CD40L expression in normal T cells. The sustained CD40L expression in lupus T cells did not correlate with memory status or Th deviation, and was relatively independent of IL-2 or other autocrine or paracrine signals via CD28 or CTLA-4. Cyclosporin A could block CD40L expression by lupus T cells when added early during the anti-CD3 stimulation period, but only partially when added later, indicating that another mechanism regulates the prolonged hyperexpression of CD40L besides the Ca(2+) --> calcineurin-dependent NF-AT pathway. When exposed to the anergy protocol, lupus T cells, in marked contrast to normal T cells, did not phosphorylate Cbl/Cbl-b but continued to express strongly phosphorylated extracellular signal-regulated kinase (ERK); U0126, a specific inhibitor of mitogen-activated protein kinase kinase --> ERK, could block both the early and the prolonged hyperexpression of CD40L. Thus, pathways regulating the activities of Cbl and one particular mitogen-activated protein kinase, ERK, are involved in the prolonged hyperexpression of CD40L in lupus T cells.
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PMID:Regulatory defects in Cbl and mitogen-activated protein kinase (extracellular signal-related kinase) pathways cause persistent hyperexpression of CD40 ligand in human lupus T cells. 1108 8

CD154 is an activation-induced CD4+ T cell surface molecule that interacts with CD40 on antigen-presenting cells (APC) and upregulates the key costimulatory molecules, CD80 and CD86. Bidirectional intercellular signaling mediated by CD40 ligation and CD80/CD86 interactions with counter-receptors on T cells play central roles in regulating the survival and outgrowth of pathogenic autoreactive T cells and B cells in systemic lupus erythematosus (SLE). CD40 is also expressed on a variety of other cells, including endothelial cells and renal tubule epithelial cells. CD154 activation of APCs, endothelial cells, and renal tubular epithelial cells have proinflammatory or procoagulant effects that may contribute to the pathogenesis of lupus. This review will focus on the immunobiology of CD154-CD40 interactions and the costimulatory functions of CD80 and CD86. The experimental evidence suggesting roles for these molecules in the immunopathogenesis of SLE will be reviewed.
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PMID:T cells in the pathogenesis of systemic lupus erythematosus: potential roles of CD154-CD40 interactions and costimulatory molecules. 1112 36

In systemic lupus erythematosus (SLE), T helper cells exhibit increased and prolonged expression of cell-surface CD40 ligand (CD154), spontaneously overproduce interleukin-10 (IL-10), but underproduce interferon-gamma (IFN-gamma). We tested the hypothesis that the imbalance of these gene products reflects skewed expression of CD154, IL-10, and IFN-gamma genes. Here, we demonstrate that the histone deacetylase inhibitor, trichostatin A, significantly down-regulated CD154 and IL-10 and up-regulated IFN-gamma gene expression in SLE T cells. This reversal corrected the aberrant expression of these gene products, thereby enhancing IFN-gamma production and inhibiting IL-10 and CD154 expression. That trichostatin A can simultaneously reverse the skewed expression of multiple genes implicated in the immunopathogenesis of SLE suggests that this pharmacologic agent may be a candidate for the treatment of this autoimmune disease.
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PMID:Trichostatin A reverses skewed expression of CD154, interleukin-10, and interferon-gamma gene and protein expression in lupus T cells. 1122 90


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