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 investigated the role of gp39-CD40 interaction in the development of glomerulonephritis in lupus mice. In contrast to normal mice, lupus mice had much higher percentages of intensely gp39+ T cells in their spleens even at the preautoimmune age of 1 mo, and the further increase in gp39 expression by anti-CD3 Ab stimulation was markedly greater in lupus T cells. The pathogenic autoantibody-inducing ability of Th clones and splenic Th cells from lupus mice could be blocked in vitro by anti-gp39 Ab. Acceleration of lupus nephritis by the transfer of pathogenic autoantibody-inducing Th clones in vivo could also be completely blocked by anti-gp39 Ab. Surprisingly, a brief treatment of lupus mice with anti-gp39 Ab had a sustained beneficial effect on their spontaneous disease long after the Ab had been cleared from their systems. Only three injections of anti-gp39 Ab given to prenephritic lupus mice at 3 mo of age markedly delayed and reduced the incidence of lupus nephritis up to 12 mo of age by which time almost all the control mice had developed severe glomerulonephritis. Remarkably, pathogenic Th cells were left intact in these anti-gp39-treated mice but their B cells could not produce pathogenic autoantibodies even 9 mo after the therapy. Our studies suggest that blocking the interaction between gp39 on pathogenic Th cells and CD40 on lupus B cells at a crucial window of time delays the expansion autoimmune memory B cells resulting in long-term therapeutic benefits.
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PMID:Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. 752 4

We investigated the role of the costimulatory molecules, CD40 and its ligand CD40L, in the pathogenesis of human SLE. In comparison to normal subjects or patients in remission, PBMC from active lupus patients had a 21-fold increase in the frequency of CD40L-expressing, CD4+T cells. However, the expression of CD40L induced in either lupus or normal T cells by mitogenic stimulation could be down-regulated equally well by CD40 molecules on autologous B cells. Active lupus patients also had a 22-fold increase in percentage of CD8+ T cells expressing CD40L, consistent with their unusual helper activity in SLE. Surprisingly, patients with active lupus had a 20.5-fold increase in B cells that spontaneously expressed high levels of CD40L, as strongly as their T cells. Although lupus patients in remission had low levels of CD40L+ cells in the range of normal subjects, mitogen-induced upregulation of CD40L expression in the T and B cells was markedly greater than normal, suggesting an intrinsic defect. A mAb to CD40L blocked significantly the ability of lymphocytes from lupus patients with active and established disease to produce the pathogenic variety of antinuclear autoantibodies in vitro, bolstering the possibility of anti-CD40L immunotherapy for lupus. Future studies on the hyperexpression of CD40L could elucidate a regulatory defect in the pathogenic T and B cells of lupus.
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PMID:Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. 862 96

Systemic lupus erythematosus is characterized by polyclonal B cell activation, the production of autoantibodies, and often by renal disease. Previous studies demonstrated that unfractionated B cells from several strains of mice with lupus hyperproliferate in culture when stimulated with lipopolysaccharide (LPS) or anti-IgM. We wished to further examine proliferation of resting B cells from the BXSB mouse model of lupus and mice with the Yaa allele, when activated with a number of stimuli. Our work demonstrates that: (1) resting B cells from mice containing the Yaa allele hyperproliferated compared to that seen with B cells from mice lacking the Yaa allele, (2) this hyperproliferation occurred whether cells were stimulated with phorbol myristate acetate/ionomycin, LPS, anti-IgM, or CD40L cross-linking, (3) this hyperproliferation is specific to B and not T cells. Taken together these data suggest that one mechanism by which the Yaa allele contributes to the accelerated onset of lupus in BXSB male mice is through its influence on B cell activation.
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PMID:Hyperproliferation of BXSB B cells is linked to the Yaa allele. 890 45

To explore the mechanisms by which alpha beta T cells and gamma delta T cells regulate systemic autoimmunity, lupus-prone mice were rendered deficient in CD40 ligand and/or alpha beta T cells by intercrossing CD40L -/- and TCR-alpha -/- knockouts, generating CD40L-intact or -deficient (CD40L+ or CD40L-), alpha beta T cell-intact or -deficient (alpha beta+ or alpha beta-) MRL-lpr/lpr animals. As expected, CD40L+ alpha beta+ mice developed high titer autoantibodies along with severe renal and cutaneous disease. CD40L+ alpha beta- animals developed lower levels of autoantibodies, accompanied by less severe or delayed renal and cutaneous disease. CD40L- alpha beta+ mice developed even lower titers of autoantibodies and less severe renal disease yet developed cutaneous lesions indistinguishable from those of CD40L+ alpha beta+ disease. Most surprisingly, CD40L- alpha beta- animals developed higher levels of some autoantibodies than did CD40L- alpha beta+ mice and developed renal disease similar in severity to CD40L+ alpha beta- counterparts; however, they failed to develop skin disease. Thus, disruption of CD40L and alpha beta T cells provides a novel dissection of the physiology and pathology of murine lupus; while these data confirm previous findings demonstrating a role for CD40L-dependent, alpha beta T cell-dependent mechanisms in autoantibody production and renal disease in murine lupus, they also: 1) establish that alpha beta T cells may drive autoimmune skin disease by a CD40L-independent mechanism; 2) identify a role for CD40L in non-alpha beta T cell-dependent autoantibody production and autoimmune skin disease; and 3) suggest a role for alpha beta T cells in the down-regulation of autoimmunity driven by other T cells. Thus, both alpha beta and non-alpha beta T cells, such as gamma delta T cells, regulate systemic autoimmunity by CD40L-dependent and -independent mechanisms.
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PMID:alpha beta T cell regulation and CD40 ligand dependence in murine systemic autoimmunity. 903 98

A major advance in understanding the basic mechanism driving the pathogenic autoimmune response in SLE has been the identification of nucleosome as a primary immunogen. The production of pathogenic antinuclear antibodies in SLE is mediated by a MHC class II restricted, cognate interaction between select populations of autoimmune T helper cells and autoimmune B cells that recognize epitopes in the different molecular components of the nucleosome particle: a form of intermolecular-intrastructural help. In the SNF1 model, we have localized the critical peptide autoepitopes for lupus nephritis-inducing Th cells in the core histones of nucleosomes, at amino acid positions 10-33 of H-2B and 16-39 and 71-94 of H4. Remarkabely, the nephritogenic epitopes are located in the regions of histones that are also targeted by lupus B cells, as well as the sites where the histones contact DNA in the nucleosome, indicating that they are specially protected during antigen processing. Identification of the peptide epitopes is a basic step toward defining how the pathogenic Th cells emerge in lupus. In addition, we found that the pathogenic Th cells and B cells of lupus have a regulatory defect in the expression of CD40 ligand (CD40L or gp39), which results in abnormal costimulatory signals that sustain the production of pathogenic autoantibodies. Specific immunotherapy that blocks the pathogenic T and B cell interaction in lupus can be designed based on the knowledge of these disease mechanisms.
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PMID:T cells of lupus and molecular targets for immunotherapy. 904 81

Murine lupus in NZB/NZW F1 (B/W) mice can be retarded by sustained administration of CTLA4Ig and by brief treatment early in life with mAb that block CD40/gp39 interactions. We sought to determine whether brief therapy with CTLA4Ig could provide sustained benefit in B/W mice and whether a synergistic effect could be derived by blockade of both the B7/CD28 and the CD40/gp39 pathways. We found that a short course of CTLA4Ig at the onset of disease produced only short-term benefit. However, when CTLA4Ig was combined with anti-gp39, there was long-lasting inhibition of autoantibody production and renal disease. Ten months after the 2-wk course of therapy, 70% of these mice were alive, compared with only 18% and 0% of those that received only anti-gp39 or CTLA4Ig, respectively. These findings demonstrate that brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways can produce benefit that lasts long after treatment has been discontinued.
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PMID:Long-term inhibition of murine lupus by brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways. 931 5

The phage display approach has proven to be a major step forward in studies on the human autoimmune repertoire. However, it remains doubtful whether the heavy and light chains of the antibodies obtained from these libraries resemble original in vivo pairings. Here we describe a novel, simple method for the immortalization of the variable heavy and light chain regions originating from individual, nonboosted, autoantigen-specific human B cells. Our method is based on the clonal expansion of B cells in which cell-cell interactions (CD40-CD40L) as well as soluble factors were shown to be essential. This B cell culture system combined with a selection on antigen (the U1A protein, a frequent autoantigenic target in patients with systemic lupus erythematosus) and single cell sorting resulted in the isolation of U1A-specific human B cells and the subsequent expression of an U1A-specific single chain variable fragment (scFv). Our method circumvents laborious plating and screening and has the advantage that original heavy/light chain pairings can be isolated. Due to the high growth efficiency of single cultured B cells (50-70% outgrowth) even rare B cell activities can be studied using this system.
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PMID:A new method for the analysis and production of monoclonal antibody fragments originating from single human B cells. 932 87

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 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


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