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)

It is generally accepted that the interaction between CD40 and its ligand (CD154) plays a decisive role in contact-dependent help for T and B cells. In CD154-deficient MRL/Mp-Fas(lpr) (MRL/lpr) mice, however, high titres of IgG2a-type autoantibodies against small nuclear ribonucleoproteins (snRNPs) are observed. We successfully isolated two CD154-deficient MRL/lpr Th1 lines, which could provide B cell help for anti-snRNP antibody production. The proliferative responses of the Th1 cell lines were MHC class II (I-Ek)-restricted. Although syngeneic B cell proliferation was induced by Th1 lines in both a contact-dependent and -independent manner, the soluble form of TNF-alpha (sTNF-alpha) was not involved in contact-independent B cell proliferation. On the other hand, both anti-TNF-alpha and TNF-receptor 2 (TNF-R2, p75) monoclonal antibody (MoAb) blocked contact-dependent B cell proliferation, suggesting that the transmembrane form of TNF-alpha (mTNF-alpha)-TNF-R2 co-stimulation participates in B cell activation. Similarly, anti-TNF-alpha and TNF-R2 MoAb inhibited anti-snRNP antibody production in vitro, but anti-CD154 or TNF-R1 MoAb did not. These results indicate that the interaction of mTNF-alpha on activated Th1 cells with TNF-R2 on B cells may be involved in the autoimmunity seen in MRL mice, and that the blockade of CD40-CD154 co-stimulation may not always be able to suppress some Th1-related manifestations of lupus.
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PMID:The transmembrane form of TNF-alpha drives autoantibody production in the absence of CD154: studies using MRL/Mp-Fas(lpr) mice. 1239 Mar 9

The systemic lupus erythematosus is a significant therapeutic challenge: Multiorgan involvement and a variable disease course, characterized by clinical exacerbations and remissions, make difficult to predict the outcome. Few products have been specifically developed for this affection, and most accepted therapies have not been tested in randomized controlled trials of systemic lupus erythematosus. A variety of biological agents under investigation as potential treatments for systemic lupus erythematosus are designed to interfere with specific immunologic responses, hopefully avoiding generalized immunosuppression. Agents, which interfere with T cell-B cell collaboration, such as CTLA-4-Ig and anti-CD154 ligand monoclonal antibodies, may result in long-term therapeutic benefit. Products designed to decrease production of anti-dsDNA antibodies or inhibit complement activation, may prevent immune complex deposition and ameliorate organ-specific manifestations, such as renal disease. More aggressive interventions include gene therapy and stem cell transplantation.
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PMID:[New prospects for the treatment of systemic lupus erythematosus]. 1256 49

Systemic lupus erythematosus is a multigenic disorder of unknown etiology. To investigate the roles that specific genes play in lupus, we have examined the disease profiles in mice with single-gene deletions. In total, some 17 genes have been studied. Absence of certain genes, such as CD40L, CD28, or Igh6, abrogated induction of autoimmunity. Other genes, such as Igh5, IL-4, or ICAM-1, had little effect on the development of disease. Intermediate effects were observed in IL-6-deficient mice, while absence of beta2-microglobulin resulted in loss of hypergammaglobulinemia and IgG1 autoantibodies, but produced little change in anti-chromatin antibodies or glomerular deposits. The most interesting observations were obtained with genes related to the expression or function of interferon-gamma (IFN-gamma). Reductions in IFN-gamma levels in murine lupus are associated with reductions in both autoantibody levels and immune-complex- mediated pathology. Genes involved in up-regulation of IFN-gamma expression, such as IL-12, STAT-4, or ICE, did not significantly influence autoimmunity, whereas absence of IFN-gamma or IFN-gamma receptor led to greatly reduced autoantibody response and immunopathology. Absence of IRF-1, a gene ex-pressed in response to IFN-gamma, resulted in selective retention of anti-chromatin antibodies but little glomerular pathology. These studies suggest that the presence of a baseline level of IFN-gamma, rather than increased expression, is important for autoimmunity. Furthermore, as the IRF-1 knockout demonstrates, specific defects in signaling pathways and gene expression subsequent to IFN-gamma/IFN-gamma receptor interaction may influence only certain disease parameters. It has not escaped our attention that IFN-gamma influences the expression and function of other immunologically relevant genes, such as IL-4, IL-6, and beta2-microglobulin. Thus, these genes may be part of the downstream events following IFN-gamma/IFN-gamma receptor interaction that promote the development of autoimmunity.
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PMID:Using single-gene deletions to identify checkpoints in the progression of systemic autoimmunity. 1272 44

Systemic lupus erythematosus (SLE) is a CD4(+) T cell-dependent, immune complex-mediated, autoimmune disease that primarily affects women of childbearing age. Generation of high-titer affinity-matured IgG autoantibodies, specific for double-stranded DNA and other nuclear antigens, coincides with disease progression. Current forms of treatment of SLE including glucocorticosteroids are often inadequate and induce severe side effects. Immunological approaches for treating SLE in mice using anti-CD4 mAb's or CTLA4-Ig and anti-CD154 mAb's have proven to be effective. However, like steroid treatment, these regimens induce global immunosuppression, and their withdrawal allows for disease progression. In this report we show that lupus-prone NZB x NZW F(1) mice given three injections of anti-CD137 (4-1BB) mAb's between 26 and 35 weeks of age reversed acute disease, blocked chronic disease, and extended the mice's lifespan from 10 months to more than 2 years. Autoantibody production in recipients was rapidly suppressed without inducing immunosuppression. Successful treatment could be traced to the fact that NZB x NZW F(1) mice, regardless of their age or disease status, could not maintain pathogenic IgG autoantibody production in the absence of continuous CD4(+) T cell help. Our data support the hypothesis that CD137-mediated signaling anergized CD4(+) T cells during priming at the DC interface.
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PMID:CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice. 1275 Apr

Systemic lupus erythematosus (SLE) is an autoimmune disease manifested by multi-organ involvement and elevated titers of anti-DNA antibodies. Current therapies for SLE are broadspectrum, and include steroids and immunosuppressive cytotoxic agents that are counterbalanced by the toxicity and side effects of the medications. One of the goals 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 under investigation, which may be beneficial, are manipulation of second-signal stimulation of the immune response (anti-CD40L), manipulation of cytokines (monoclonal anti-IL-10), inducing tolerance by administration of blocking peptides (LJP394), and the manipulation of idiotypes (IVIg). In this article, we also discuss modalities that are steroid-sparing (MTX), and selective immunosuppression (stem-cell restoration and MMF). We review the ongoing literature from 2000-2002, utilizing the MEDLINE search. Controlled trials, open trials, and trials in phase I and II have been included, and anecdotal reports were excluded. The major advances have been with mycophenolate mofetil (MMF) and LJP 394.
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PMID:Novel Approaches to Therapy for SLE. 1279 65

CD154 (CD40-ligand) has a wide variety of pleiotropic effects throughout the immune system and is critical to both cellular and humoral immunity. Cell surface and soluble CD154 are primarily expressed by activated CD4 T cells. Expression of CD154 is tightly regulated in a time-dependent manner, and, like most T cell-derived cytokines and other members of the tumor necrosis factor (TNF) superfamily, CD154 is largely regulated at the level of gene transcription. Recently, dysregulated expression of CD154 has been noted in a number of autoimmune disorders, including systemic lupus erythematosus (SLE). In addition, abnormal expression of CD154 has been hypothesized to contribute to a wider array of diseases, from atherosclerosis to Alzheimer's disease. Until recently, very little was known about the transcriptional regulation of CD154. We are exploring CD154 regulation in primary human CD4 T cells in hopes of understanding the cis- and trans-regulatory elements that control its expression in the cells that normally express CD154. Ultimately, we hope to be able to correct abnormal expression of CD154 in various disease states and to help design gene therapy vectors for treating CD154-deficient individuals with hyper-IgM syndrome.
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PMID:CD154 transcriptional regulation in primary human CD4 T cells. 1285 68

Systemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease characterized by the production of pathogenic autoantibodies. A new study demonstrates that passive antibody specific for the TNF family member, CD154, ameliorates disease by reducing levels of self-reactive antibody in the serum. This study demonstrates a substantial potential for anti-CD154 antibody in the treatment of humoral autoimmunity.
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PMID:Therapeutic CD154 antibody for lupus: promise for the future? 1461 52

To determine the role of CD154-CD40 interactions in the B cell overactivity exhibited by patients with active systemic lupus erythematosus (SLE), CD19+ peripheral B cells were examined before and after treatment with humanized anti-CD154 mAb (BG9588, 5c8). Before treatment, SLE patients manifested activated B cells that expressed CD154, CD69, CD38, CD5, and CD27. Cells expressing CD38, CD5, or CD27 disappeared from the periphery during treatment with anti-CD154 mAb, and cells expressing CD69 and CD154 disappeared from the periphery during the post-treatment period. Before treatment, active-SLE patients had circulating CD38 (bright) Ig-secreting cells that were not found in normal individuals. Disappearance of this plasma cell subset during treatment was associated with decreases in anti-double-stranded DNA (anti-dsDNA) Ab levels, proteinuria, and SLE disease activity index. Consistent with this finding, peripheral B cells cultured in vitro spontaneously proliferated and secreted Ig in a manner that was inhibited by anti-CD154 mAb. Finally, the CD38(+/++)IgD(+), CD38(+++), and CD38(+)IgD(-) B cell subsets present in the peripheral blood also disappeared following treatment with humanized anti-CD154. Together, these results indicate that patients with active lupus nephritis exhibit abnormalities in the peripheral B cell compartment that are consistent with intensive germinal center activity, are driven via CD154-CD40 interactions, and may reflect or contribute to the propensity of these patients to produce autoantibodies.
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PMID:Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions. 1461 48

Abnormalities in lymphocyte signaling cascades are thought to play an important role in the development of autoimmune disease. However, the large amount of cellular material needed for standard biochemical assessment of signaling status has made it difficult to evaluate putative abnormalities completely using primary lymphocytes. The development of technology to employ intracellular staining and flow cytometry to assess the signaling status of individual cells has now made it possible to delineate the perturbations that are present in lymphocytes from patients with autoimmune disease. As an example, human B cells from the Ramos B cell line and the periphery of systemic lupus erythematosus (SLE) patients or normal nonautoimmune controls were assessed for activation of the NF-kappaB and mitogen activated protein kinase (MAPK) signaling cascades by intracellular multiparameter flow cytometric analysis and biochemical Western blotting. In combination with fluorochrome conjugated antibodies specific for surface proteins that define B cell subsets, antibodies that recognize activated, or phosphorylated inhibitors of kappaB (IkappaB) as well as the extracellular regulated kinase (ERK), jun N-terminal kinase (JNK) or p38 MAPKs were used to stain fixed and permeabilized human B cells and analyze them flow cytometrically. Examination of the known signaling pathways following engagement of CD40 on human B cells confirmed that intracellular flow cytometry and Western blotting equivalently assay CD154-induced phosphorylation and degradation of IkappaB proteins as well as phosphorylation of the MAPKs ERK, JNK and p38. In addition, B cells from the periphery of SLE patients had a more activated status immediately ex vivo as assessed by intracellular flow cytometric analysis of phosphorylated ERK, JNK and p38 when compared with B cells from the periphery of normal, nonautoimmune individuals. Together, these results indicate that multiparameter intracellular flow cytometric analysis of signaling pathways, such as the NF-kappaB and MAPK cascades, can be used routinely to assess the activation status of a small number of cells and thus delineate abnormalities in signaling molecules expressed in primary lymphocytes from patients with autoimmune disease.
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PMID:Flow cytometric assessment of the signaling status of human B lymphocytes from normal and autoimmune individuals. 1497 30

The autoimmune response is executed via cognate interactions between effector immune cells and antigen presenting cells. Cognate interactions provide the immune effectors with specific signals generated through the antigen receptor as well as with second, non-specific signals, generated from the interaction of pairs of cell-surface molecules (costimulatory molecules) present on their plasma membrane. Disruption of this second, non-specific costimulatory signal results in the interruption of the productive (auto)immune response, leading to anergy, a state of immune unresponsiveness. The CD28:B7 families of molecules and the CD40:CD40L pair of molecules are considered as critical costimulatory elements. Disruption of the CD28:B7 interaction using a genetically engineered soluble form of the inhibitory molecule CTLA4 in vitro, as well as in experimental models of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), led to the inhibition of the autoimmune response. Similarly, promising data stem from the use of an anti-CD40L monoclonal antibody (mAb) in murine SLE. While such treatments prevent the development of autoimmunity in animal models, this preventive approach is inapplicable to human diseases. However, the rational bench-to-bedside approach led investigators to clinical trials of CTLA4-Ig and of two different humanized anti-human CD40L mAbs in patients with RA and SLE, respectively. Initial experience with the use of CTLA4-Ig in patients with RA is encouraging, since in one short-term trial the construct was well-tolerated and produced clinically meaningful improvement of the disease in a significant proportion of those treated. Surprisingly, the anti-CD40L mAb treatment approach in human lupus was not fruitful, since short-term administration of the anti-CD40L mAb ruplizumab in lupus nephritis was correlated with life-threatening prothrombotic activity despite initial encouraging data in the serology and renal function of the patients. Also, IDEC-131 anti-CD40L mAb treatment did not prove to be clinically effective in human SLE, despite being well tolerated. Precise tailoring of the administration schemes for these novel therapeutic modalities is awaited.Finally, conceptually different approaches to block costimulation by inhibiting the induced expression of costimulatory molecules or the transmission of their specific intracytoplasmic signal have already produced encouraging preliminary results.
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PMID:Costimulation blockade in the treatment of rheumatic diseases. 1504 25


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