Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We and others recently reported tumor necrosis factor (TNF) and apoptosis ligand-related leukocyte-expressed ligand 1 (TALL-1) as a novel member of the TNF ligand family that is functionally involved in B cell proliferation. Transgenic mice overexpressing TALL-1 have severe B cell hyperplasia and lupus-like autoimmune disease. Here, we describe expression cloning of a cell surface receptor for TALL-1 from a human Burkitt's lymphoma RAJI cell library. The cloned receptor is identical to the previously reported TNF receptor (TNFR) homologue transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI). Murine TACI was subsequently isolated from the mouse B lymphoma A20 cells. Human and murine TACI share 54% identity overall. Human TACI exhibits high binding affinities to both human and murine TALL-1. Soluble TACI extracellular domain protein specifically blocks TALL-1-mediated B cell proliferation without affecting CD40- or lipopolysaccharide-mediated B cell proliferation in vitro. In addition, when injected into mice, soluble TACI inhibits antibody production to both T cell-dependent and -independent antigens. By yeast two-hybrid screening of a B cell library with TACI intracellular domain, we identified that, like many other TNFR family members, TACI intracellular domain interacts with TNFR-associated factor (TRAF)2, 5, and 6. Correspondingly, TACI activation in a B cell line results in nuclear factor kappaB and c-Jun NH(2)-terminal kinase activation. The identification and characterization of the receptor for TALL-1 provides useful information for the development of a treatment for B cell-mediated autoimmune diseases such as systemic lupus erythematosus.
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PMID:TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation. 1088 May 35

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

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

The CD154/CD40 pathway is required for the development and progression of disease in a variety of autoimmune model systems. We have demonstrated previously that long-term anti-CD154 treatment of nephritic (SWRxNZB)F1 mice prolonged survival and preserved kidney function. Herein we ask if long-term treatment is required and further characterize the protective effect on renal pathology by examining alpha-smooth muscle actin, collagen and TGF-beta1 expression in renal tissue. The effects of anti-CD154 on brain and heart inflammation are also examined. Three dosing strategies of anti-CD154 mAb were compared in SNF1 mice that exhibited moderate or severe nephritis: (1) weekly for 6 weeks; (2) monthly; (3) weekly for 6-12 weeks followed by monthly dosing. Proteinuria, serum anti-DNA, anti-CD154 pharmacokinetics and serum soluble CD154 analyses were performed. Anti-CD154 treatment of moderate disease increased survival across all regimens, although weekly followed by monthly maintenance dosing proved most efficacious. This regime also inhibited renal alpha-smooth muscle actin and collagen deposition. Only the most aggressive anti-CD154 treatment protocol increased survival in severely nephritic mice. Long-term anti-CD154 treatment significantly inhibits key mediators of kidney fibrosis and is required to maximize survival and renal function. Potential reasons for differential therapeutic efficacy in moderately vs severely nephritic mice are discussed.
Lupus 2001
PMID:Long-term anti-CD154 dosing in nephritic mice is required to maintain survival and inhibit mediators of renal fibrosis. 1124 13

Humanized anti-CD154 antibody, IDEC-131, had a slightly, but reproducibly, better binding affinity for CD154 (Kd = 5.6 nM), compared to the parent antibody 24-31 (Kd = 8.5 nM). Otherwise it was indistinguishable from the murine parent antibody in its ability to bind to CD154, block CD154 binding to CD40 and inhibit T cell-dependent B cell differentiation. The latter activity was independent of FcR binding as the Fab'1 fragment of IDEC-131 had an equivalent biological activity to that of the whole antibody. IDEC-131 blocked soluble CD154 from inducing proliferation of purified B cells, and blocked T cell dependent anti-tetanus toxoid specific antibody production by human B cells in vitro. IDEC-131, gamma1, kappa, had strong Fc gammaRI, Fc gammaRII and C1q binding, but was unable to induce complement dependent (CDC) or antibody dependent cell-cytotoxicity (ADCC) of activated peripheral blood T cells, which express relatively low levels of CD154. IDEC-131 antibody inhibited both primary and secondary antibody responses to ovalbumin in cynomolgus monkeys at a dose of 5 mg/kg. In non-immunized animals, treatment with IDEC-131 at 50 mg/kg weekly for 13 weeks induced no change in any of the measured lymphocyte subsets, including B cells, CD4+ and CD8+ T cells. Similarly, a safety study in chimpanzees showed no discernible safety related issues at 20 mg/kg, including B and T cell subsets. These results show that the humanized anti-CD154 antibody, IDEC-131, has retained the affinity and functional activity of its murine parent antibody, is unlikely to deplete CD154 positive lymphocytes in humans, and is safe and effective in blocking antibody production in monkeys. Based on its safety and efficacy profile, IDEC-131 is being developed for therapy of systemic lupus erythematosus.
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PMID:A humanized anti-human CD154 monoclonal antibody blocks CD154-CD40 mediated human B cell activation. 1136 Sep 29

Autoimmunity results from a failure in central and/or peripheral tolerance; however, the events that initiate and maintain this dysfunction remain unclear. To better understand the mediators involved in autoimmunity, we investigated the cellular mechanisms maintaining disease in the (SWR x NZB)F(1) (SNF(1)) mouse model of systemic lupus erythematosus. Previously, we have shown that autoimmunity in this model is dependent on CD40-CD154 interactions. Herein, our studies reveal that the severity of disease in SNF(1) mice correlates with a marked increase in the frequency of apoptotic splenocytes, including a higher proportion of apoptotic dendritic cells (DC) in vivo. In addition, we demonstrate a significant disease-related increase in the absolute number of splenic CD11c(high) DC. The increased DC number appears to be attributable to DC proliferation and enhanced migration to the spleen, most likely induced by elevated splenic expression of secondary lymphoid chemokine. Importantly, these imbalances in apoptosis, secondary lymphoid chemokine expression, and DC homeostasis were reduced or normalized by anti-CD154 treatment. Thus, our data demonstrate CD154-dependent regulation of apoptosis and DC homeostasis in mice with lupus-like autoimmune disease. We suggest that these mechanisms comprise an autostimulatory loop, maintaining the cascade of autoimmunity by DC presentation of self-Ags derived from apoptotic cells and CD154-mediated costimulation.
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PMID:Apoptosis and altered dendritic cell homeostasis in lupus nephritis are limited by anti-CD154 treatment. 1146 99

Production of pathogenic autoantibodies in systemic lupus erythematosus (SLE) requires T cell help, along with ligation of the B cell surface immunoglobulin receptor by antigen. It is likely that macrophages, dendritic cells, and endothelial cells are also activated by interactions with T cells and contribute to lupus pathology. CD40 ligand (CD40L, CD154), a member of the tumor necrosis factor family of cell surface molecules, mediates these contact dependent signals delivered by CD4 + T helper cells to CD40 + target cells. Recent data from SLE patients and murine lupus models have demonstrated prolonged expression of CD40L on lupus T cells and its capacity to mediate excessive B cell activation. This review summarizes the current information regarding transcriptional and post-transcriptional regulation of CD40L expression in normal and SLE T cells. More complete characterization of the mechanisms that regulate the magnitude and duration of CD40L expression should suggest new approaches to modulate this promising therapeutic target.
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PMID:Regulation of CD40 ligand expression in systemic lupus erythematosus. 1160 89

Monocyte derived macrophages (Mphi) and dendritic cells (DC) play critical roles at the interface between innate and adaptive immunity. Both types of cells can effectively phagocytose exogenous antigens, whereas only DC can process and present them efficiently to antigen-specific T lymphocytes. The hormone PRL is also produced by immune cells and is regarded as a key component of the neuroendocrine--immune loop and a local regulator of lymphocyte response. Its main feature is cooperation with cytokines and hemopoietins. Triggering of monocyte PRL receptors with physiological-to-supraphysiological concentrations of PRL up-regulates the GM-CSF receptors, resulting in synergistic PRL-GM-CSF induced maturation of immature (i)DC. Further incubation induces increased antigen-presenting activity at the highest PRL concentrations studied (200 ng/ml). IFN-gamma, release by allogeneic lymphocytes is dependent on T cell-triggered IL-12 release by PRL-preincubated iDC. This, in turn, may be secondary to increased DC expression of CD40 or IFN-gamma. The permissive action of high PRL concentrations in the antigen presenting process may be of significance in initiation of the response against major histocompatibility complex (MHC)-presented self-antigens and may explain the association of hyperprolactinemia with autoimmune diseases.
Lupus 2001
PMID:Effect of prolactin on the antigen presenting function of monocyte-derived dendritic cells. 1172 99

Understanding the regulation of B lymphocytes specific for self-Ags targeted in human and murine systemic lupus erythematosus, such as the ribonucleoprotein Smith Ag (Sm), is crucial to understanding the etiology of this autoimmune disease. To address the role of B cell receptor affinity in the regulation of anti-Sm B cells, we generated low-affinity anti-Sm transgenic mice by combining the anti-Sm 2-12H transgene with a V(kappa)8 transgene. In contrast to 2-12H transgenic mice, in which anti-Sm B cells are predominantly splenic transitional, and peritoneal B-1, low-affinity anti-Sm B cells are long-lived B-2 cells and are found in the spleen, lymph nodes, and peritoneum. However, they are unresponsive to LPS in vitro, indicating that they are anergic, although they do not down-regulate IgM and are not excluded from follicles even in the presence of nonautoreactive B cells. Thus, low-affinity anti-Sm B cells appear to have a partial form of anergy. Interestingly, these cells have elevated levels of MHC class II and CD95, but not CD40, CD80, or CD86, suggesting that they are poised to undergo deletion rather than activation upon T cell encounter. These data identify anergy as a mechanism involved in anti-Sm B cell regulation.
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PMID:Low-affinity anti-Smith antigen B cells are regulated by anergy as opposed to developmental arrest or differentiation to B-1. 1175 41

Idiopathic or immune thrombocytopenic purpura (ITP) is characterized by antibody-mediated destruction of platelets. The etiology is unknown. We postulated that increased autoantibody production in ITP might be attributable to either increased or prolonged expression of CD40 ligand (CD40L, CD154) in T or B lymphocytes, as has been previously observed in systemic lupus erythematosus (SLE). In addition, we hypothesized that ITP is characterized by increased levels of interleukin 4 (IL-4), a prototypic Th2 cytokine which, along with CD40 ligation, is required for B cell differentiation and production of several IgG subclasses. Cell surface CD154 expression was measured in freshly-isolated and in vitro-activated peripheral blood lymphocytes of sixteen ITP patients and eight healthy volunteers. Plasma levels of IL-4 and the prototypic Th1 cytokine interferon-gamma (IFNgamma) were determined. We observed that CD154 expression in unstimulated and in vitro-activated lymphocytes did not differ between ITP patients and healthy controls. Plasma levels of the Th2 cytokine IL-4 were significantly higher in the ITP patients. These studies indicate that overexpression of CD154 in lymphocytes is unlikely to be a primary pathophysiological defect in most patients with ITP. The data support that in addition to cell membrane antigens such as CD154, soluble cytokines such as IL-4 should be considered as potential targets for therapy in this disease.
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PMID:Functional properties of lymphocytes in idiopathic thrombocytopenic purpura. 1175 3


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