Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Blockade of the interactions between CD28/CTLA-4 and their ligands, CD80 (B7, B7.1)/CD86 (B70, B7.2), seems an attractive means to induce antigen-specific peripheral tolerance in organ transplantation and autoimmune disease. Recently, diversities between CD80 and CD86 in expression, regulation, and function have been reported in certain cell populations and murine experimental disease models. To investigate the possible differential role of CD80 and CD86 in the development of lupus, we treated lupus-prone NZB/W F1 mice with specific monoclonal antibodies (mAb) against CD80, CD86, or both. The treatment with a combination of anti-CD80 and CD86 mAb before the onset of lupus completely prevented autoantibody production and nephritis, and prolonged survival. Interestingly, we found that anti-CD86 mAb alone, but not anti-CD80 mAb, efficiently inhibited autoantibody production. Subclass study on IgG anti-double-stranded (ds) DNA antibody revealed that the treatment with anti-CD86 mAb almost completely inhibited both IgG1 and IgG2b, but not IgG2a production. The incomplete reduction of IgG2a anti-dsDNA antibody by anti-CD86 mAb was compensated by the addition of anti-CD80 mAb. A significant reduction of mRNA for interleukin (IL)-2, interferon-gamma, IL-4 and IL-6 was observed in mice treated with a combination of anti-CD80 and CD86 mAb or anti-CD86 mAb alone. Treatment with both mAb after the onset of lupus resulted in a significantly prolonged survival with reduction of autoantibody production. These results suggest that CD86 plays a more critical role in autoantibody production, and CD86, but not CD80, contributes to Th2-mediated Ig production. However, the blockade of both CD80 and CD86 are required for preventing the development and progression of lupus.
 ...
PMID:Preferential dependence of autoantibody production in murine lupus on CD86 costimulatory molecule. 748 44

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.
 ...
PMID:Immune cell signaling aberrations in human lupus. 972 47

Systemic lupus erythematosus is characterized by the presence of high titers of autoantibodies reacting with various components of the U1 small nuclear ribonucleoprotein particle (snRNP). It has been suggested that these antibodies are produced by an antigen-driven mechanism under the dependence of antigen-specific T cells. To investigate the role of T cell help in this process, we sought, with 20 overlapping peptides, the Th epitopes on the U1-70K snRNP in unprimed H-2(k) MRL / lpr lupus mice and immunized CBA normal mice. The peptide 131 - 151 was recognized by both IgG autoantibodies and CD4(+) T cells from 7 - 9-week-old MRL / lpr mice. In this test, antigen-presenting cells (APC) from MRL / lpr mice were required; APC from naive CBA mice failed to stimulate CD4(+) cells from MRL / lpr mice. The potential role of MRL / lpr B cells as APC, the expression of MHC class II molecules at their surface and their activation state (expression of CD69, CD80 / B7-1 and CD86 / B7-2 molecules) were studied. Peptide 131 - 151 bound both I-A(k) and I-E(k) class II molecules and favored an IL-2-positive T cell response but not IFN-gamma, IL-6 and IL-10 secretion. Segment 131 - 151 is localized within the RNP80 motif and contains residues that are highly conserved in many nuclear, nucleolar and cytoplasmic RNA binding proteins.
 ...
PMID:B and T cell immune response to small nuclear ribonucleoprotein particles in lupus mice: autoreactive CD4(+) T cells recognize a T cell epitope located within the RNP80 motif of the 70K protein. 1094 Sep 10

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.
 ...
PMID:T cells in the pathogenesis of systemic lupus erythematosus: potential roles of CD154-CD40 interactions and costimulatory molecules. 1112 36

CD80 and CD86, expressed on the antigen-presenting cells (APCs) provide costimulatory signals for T lymphocytes. Recently, defective expression of CD80 has been reported in systemic lupus erythematosus (SLE) although its mechanism is unclear. Here, expression of the B7 antigens induced by interferon-gamma, interleukin-4 or granulocyte-macrophage stimulating-factor (GM-CSF) along the differentiation process of APCs was investigated. In contrast to CD86, expression of CD80 on the CD14+ cells induced by GM-CSF was reduced in SLE. GM-CSF receptor (GM-CSFR) was down-regulated by GM-CSF or phorbol 12-myristate 13-acetate in both of the normal controls and SLE patients, while this change was more remarkable in the latter. In the presence of 1-(5-isoquinolinsulfonyl)-2-methylpiperazine, an inhibitor of protein kinase C, the PMA-induced down-regulation of GM-CSFR was reversed in the normal controls but not in SLE. These data suggest that dysregulation of the GM-CSFR might be associated with the defective expression of CD80, leading to dysfunction of the APCs in SLE.
Lupus 2002
PMID:Dysregulation of the granulocyte-macrophage colony-stimulating factor receptor is one of the causes of defective expression of CD80 antigen in systemic lupus erythematosus. 1209 May 68

An objective was to determine the frequency of GM-CSF secreting peripheral blood mononuclear cells (PBMC) in patients with active systemic lupus erythematosus (SLE) and their relation to other cytokine secreting PBMC, activation markers on lymphocytes/monocytes, clinical manifestations and anti-dsDNA antibodies. A second objective was to further investigate the influence of immunoadsorption (IA) therapy on these parameters. The number of GM-CSF, interleukin-1beta (IL-1beta), IL-6, interferon-gamma (INF-gamma) or tumour necrosis factor-alpha (TNF-alpha) secreting PBMC was assessed by ELISPOT assay in 10 patients with active SLE. Further, the expression of activation markers on lymphocytes and monocytes was determined by flow cytometry. Three courses of IA were performed in the patients. Seventeen healthy, age- and sex-matched volunteers served as controls. GM-CSF secreting PBMC were significantly increased whereas INF-gamma secreting cells were decreased in SLE patients. The expression of CD71 (transferrin receptor) on CD4+ T-cells and of the costimulatory molecule CD86 on B-lymphocytes was significantly increased in SLE patients. GM-CSF secreting PBMC and CD4+/CD71+ T-cells correlated with anti-dsDNA antibody titres and decreased towards levels of controls during IA. Disease activity and anti-dsDNA autoantibody titres were significantly reduced after the treatment. Our results demonstrate significant alterations of cellular and humoral immunity in SLE patients. The impaired immunity can be modulated by IA. Thus IA may prove an immunomodulatory therapeutic option in addition to the mere depletion of anti-dsDNA autoantibodies.
Lupus 2004
PMID:Increased frequency of GM-CSF secreting PBMC in patients with active systemic lupus erythematosus can be reduced by immunoadsorption. 1517 62

Costimulatory and adhesion molecules are known to play a major role in the pathogenesis of systemic lupus erythematosus. Since fish oil and calorie restriction have been reported to attenuate the development of disease in lupus prone (NZBxNZW)F1 mice, the objective of this study was to assess the expression of these key inflammatory molecules in these mice fed diets differing in n-6 and n-3 fatty acid content and fed either food restricted or ad libitum. Age-associated increases in the expression of CD28, ICAM-1, and PGP-1 molecules that are involved in the recruitment of inflamed lymphocytes into the kidney were attenuated in mice restricted in food intake. The increase in costimulatory (CD80 and CD86) and adhesion (ICAM-1, PGP-1, LFA-1, and Mac-1) in peripheral blood mononuclear cells was also attenuated by food restriction and to a lesser extent by fish oil alone. Interestingly, amelioration of lupus (laminin expression and proteinuria) correlated with the above beneficial effects and could be seen even in 24-month-old mice. In summary, food restriction and fish oil delay the onset of lupus disease and increase life span in B/W mice by prolonging the maintenance of a youthful immune phenotype.
 ...
PMID:Age associated alterations in costimulatory and adhesion molecule expression in lupus-prone mice are attenuated by food restriction with n-6 and n-3 fatty acids. 1535 6

Costimulation between T cells and APC is required for productive immune responses. A number of receptor/ligand pairs have been shown to mediate costimulation, including CD28/B7 molecules (CD80 and CD86), CD40/CD40 ligand (CD40L, CD154), and LFA-1 (CD18)/ICAM-1 (CD54). T-B cell costimulation also plays a significant role in autoimmune diseases such as systemic lupus erythematosus. Murine HgCl2-induced autoimmunity (mHgIA) is a T cell-dependent systemic autoimmune disease that shares a number of common pathogenic mechanisms with idiopathic lupus. In this report, the significance of costimulation in mHgIA is examined by attempting to induce disease in mice deficient in either CD40L, CD28, or ICAM-1. Unlike absence of ICAM-1, homozygous deficiencies in either CD40L or CD28 significantly reduced the development of mHgIA. CD40L displayed a gene dosage effect as heterozygous mice also showed reduction of autoantibody responses and immunopathology. Markers of T cell activation such as CD44 and CTLA-4 were associated with disease expression in wild-type and ICAM-1-deficient mice but not in CD40L- or CD28-deficient mice. Absence of CTLA-4 expression in CD40L-/- mice suggests that signaling via both CD28 and CD40L is important for T cell activation and subsequent autoimmunity in mHgIA. Attempts to circumvent the absence of CD40L by increasing CD28 signaling via agonistic Ab failed to elicit CTLA-4 expression. These findings indicate that breaking of self-tolerance in mHgIA requires signaling via both the CD28/B7 and CD40/CD40L pathways.
 ...
PMID:Costimulation requirements of induced murine systemic autoimmune disease. 1549 42

Systemic lupus erythematosus is a multisystem autoimmune disease characterized by a wide range of immunological abnormalities that underlie the loss of tolerance. In this study we show that administration of atorvastatin to lupus-prone NZB/W F(1) mice resulted in a significant reduction in serum IgG anti-dsDNA Abs and decreased proteinuria. Histologically, the treatment was associated with reduced glomerular Ig deposition and less glomerular injury. Disease improvement was paralleled by decreased expression of MHC class II on monocytes and B lymphocytes and reduced expression of CD80 and CD86 on B lymphocytes. Consequent upon this inhibition of Ag presentation, T cell proliferation was strongly impaired by atorvastatin in vitro and in vivo. A significant decrease in MHC class II expression was also observed in the target organ of lupus disease (i.e., the glomerulus). Serum cholesterol in atorvastatin-treated lupus mice fell to the level found in young NZB/W mice before disease onset. This is the first demonstration that atorvastatin can delay the progression of a spontaneous autoimmune disease and may specifically benefit patients with systemic lupus erythematosus.
 ...
PMID:Atorvastatin inhibits autoreactive B cell activation and delays lupus development in New Zealand black/white F1 mice. 1558 92

Several types of CpG-oligodeoxynucleotides (ODN) have been recently characterized. In mice, type A(D) CpG-ODNs primarily stimulate macrophages and dendritic cells, but fail to stimulate B cells. On the contrary, type B(K) CpG-ODNs are excellent B cell activators. Type C CpG-ODNs combine features of both types A(D) and B(K) CpG-ODNs. Despite cell type preferences, all CpG-ODNs require the presence of TLR9 for activation. In this study, we show that a subset of B cells from lupus mice responds to type A(D) CpG-ODN stimulation vigorously and directly with increased CD25 and CD86 expression and IL-10 secretion. Furthermore, these CpG-ODNs induce high surface IgM expression and promote 50- to 100-fold higher IgM and IgG3 secretion in lupus B cells than in controls. This response is similar to that seen with bacterial DNA stimulation of B cells. Type A(D)-responsive cells are enriched within lupus B cells with the marginal zone (MZ) phenotype. These cells are at least twice more numerous in lupus mice than in controls. The ability of lupus B cells to respond to type A(D) CpG-ODN stimulation is not due to differential TLR9 expression. Therefore, type A(D) CpG-ODNs may contribute to the lupus pathogenesis by inducing MZ-B cell activation, costimulatory molecule expression, and polyclonal Ig secretion. Through increased IL-10 secretion, MZ-B cells may also modify the activity of other cell types, particularly dendritic cells and macrophages.
 ...
PMID:Activation of marginal zone B cells from lupus mice with type A(D) CpG-oligodeoxynucleotides. 1569 80


1 2 3 4 5 Next >>