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)

Cognate interactions between major histocompatibility complex class II antigen (Ag)-reactive CD4+ T helper (Th) and Ag-presenting B cells induce first the activation of B cells and their subsequent differentiation into Ig-secreting cells (IgSC). The Th cell-associated homodimeric glycoprotein CD28 has been implicated as an important regulator of Th activation. Recently, B cell-associated early activation Ag B7 has been identified as a ligand for the CD28 molecule. In this study, we have examined using monoclonal antibodies (mAb) the roles of CD28 and B7 molecules during the Th-B cell cognate interactions leading to the differentiation of B7+ B cells. Anti-CD28 mAb 9.3 specifically inhibited proliferative responses of CD4+ T cells to both allogeneic B cells and soluble Ag-presenting autologous non-T cells. In addition, anti-CD28 mAb 9.3 inhibited Th-induced differentiation of alloantigen-presenting B cells into ISC. Similar inhibition of both Ag-induced Th activation and B cell differentiation into ISC was observed using mAb BB1 which recognizes a B cell-associated molecule B7. In contrast, non-cognate Th-independent exogenous interleukin 6-induced differentiation of B7+ B cells into ISC was not inhibited by mAb to either molecule. These results clearly demonstrate the involvement of CD28 on Th and its ligand B7 on B cells during cognate Th-B interactions leading to the differentiation of B cells. Furthermore, these results also suggest the development of new mAb-based therapeutic approaches for exaggerated B cell activation associated with certain autoimmune diseases such as systemic lupus erythematosus.
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PMID:Direct helper T cell-induced B cell differentiation involves interaction between T cell antigen CD28 and B cell activation antigen B7. 164 70

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.
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PMID:Preferential dependence of autoantibody production in murine lupus on CD86 costimulatory molecule. 748 44

Successful T cell activation via the T cell receptor (TCR)/CD3 complex requires at least one contact-dependent second signal delivered by costimulatory molecules, including the B7/BB1 molecule, that are present on antigen-presenting cells (APC). SLE is characterized by multiple complex lymphocyte abnormalities of undefined molecular origin. It is currently unclear whether an intrinsic defect of T cell or an underlying APC dysfunction is responsible for defective in vitro proliferation of T cells from patients with SLE. We planned the present experiments to ask whether the TCR/CD3-mediated and B7/BB1-costimulated T cell proliferation is normal in these patients. We used enriched T cell populations that were stimulated with an anti-CD3 MoAb in the presence of controlled quantities of functional B7/BB1 antigen. Freshly isolated T cells from 17 SLE patients (10 and seven patients with either active or inactive disease, respectively) and 11 normal individuals were cocultured with irradiated B7/BB1-transfected P815 cells or parental P815 cells in the presence of OKT3 MoAb at optimal and suboptimal concentrations for 2.5-7 days. Normal or SLE T cells responded similarly to stimulation via anti-CD3, in the absence of B7/BB1 antigen. A several-fold increase in T cell proliferation in the presence of B7/BB1 antigen was observed. Proliferation was inhibited in the presence of anti-B7/BB1 MoAb, but not with control MoAbs. Interestingly, dose-response curves and time kinetics of B7/BB1 costimulation were similar in T cells from patients with either active or inactive SLE at the time of study, and normal individuals. In addition, no differences in the IL-2 receptor release by T cells cultured under these conditions were observed between SLE patients and normal individuals. These results demonstrate that CD28 signalling is not intrinsically impaired in patients with SLE; further studies to investigate whether abnormal B7/BB1 expression is involved in the autoimmune process are needed.
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PMID:B7/BB1 provides an important costimulatory signal for CD3-mediated T lymphocyte proliferation in patients with systemic lupus erythematosus (SLE). 751 10

The interaction of B7-related molecules on antigen-presenting cells with CD28 or CTLA-4 antigens on T cells provides a second signal for T cell activation. Selection inhibition of the B7-CD28 or B7-CTLA-4 interactions produces antigen-specific T cell unresponsiveness in vitro and suppresses immune function in vivo. To determine whether selective inhibition of the B7-CD28 or B7-CTLA-4 interactions could suppress spontaneous autoimmune disease, a B7-binding protein was generated by genetic fusion of the extracellular domain of murine CTLA-4 to the Fc portion of a mouse immunoglobulin G2a monoclonal antibody (muCTLA4Ig). In lupus-prone NZB/NZW filial generation (F1) mice, treatment with muCTLA4Ig blocked autoantibody production and prolonged life, even when treatment was delayed until the most advanced stage of clinical illness. These findings suggest a possible role for human CTLA4Ig in the treatment of autoimmune diseases in humans.
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PMID:Treatment of murine lupus with CTLA4Ig. 752 Jun 4

CD28 is a 44-kDa glycoprotein that contributes to T cell activation and proliferation. To elucidate the functional role of CD28 in T cell proliferation and IL-2 production in SLE, we studied its effects in cells from untreated patients with active (n = 10) or inactive disease (n = 10) as compared with normal subjects. Mean percentages of CD4+ CD28+ and CD8+ CD28+ T cells were decreased in SLE patients (P < 0.01). SLE patients had significantly decreased absolute CD8+ CD28+ T cells. To investigate whether CD28 antibody affects T cell proliferation, we stimulated peripheral blood T cells from SLE patients and normal controls with anti-CD28, anti-CD3 and/or Interleukin-2 (IL-2) during 3 days of culture. We found that T cells from SLE patients had significantly higher responses to CD28 than did cells from normal controls. This effect was higher in cells from patients with active disease than in those with inactive disease. Conversely, IL-2 had no significant effect on the proliferative response of SLE T cells. However, when it was used for co-stimulating with anti-CD28, there was an increase in the secretion of IL-2 which was greater in the cells of patients with active disease. Thus, on average, there was an 81% increase in the production of IL-2 in T cells from patients with active SLE, 48% in those from patients with inactive disease and 40% in T cells from healthy controls, as compared with the production in response to stimulus by anti-CD3 or with anti-CD3 and anti-CD28. Lymphocytes from patients with active disease showed increased gene expression of CD28 when compared with normal subjects. These data suggest that CD28 might play a central role in the defective immune response observed in SLE patients.
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PMID:Effect of CD28 antibody on T cells from patients with systemic lupus erythematosus. 788 34

Defective T cell functions, including IL-2 production and proliferation, have been shown in SLE patients. After T cell stimulation (first signal), a costimulatory signal (second signal) is required to achieve complete T cell activation. Main costimulatory signals are provided to T cells by B7 antigens (CD80 and CD86, expressed on antigen-presenting cells (APC)) upon interaction with its receptor, the CD28 molecule expressed on T cells. The aim of this study was to investigate the role of CD28/B7 interactions in the impaired T cell responses of SLE patients. We show that stimulation of T cells with phytohaemagglutinin (PHA) in the presence, but not in the absence, of anti-CD28 MoAb or B7+ cells results in tyrosine phosphorylation of specific substrates, transcription of mRNA and production of IL-2 that is indistinguishable in SLE patients and healthy controls. Moreover, proliferation of costimulated T cells from SLE and controls was specifically abrogated by blocking the CD28/B7 interactions by means of addition to the culture of the CTLA4-Ig fusion protein. However, in most patients activated APC failed to up-regulate B7 molecules, giving rise to ineffective costimulatory signalling to T cells. These results indicate that the CD28/B7 costimulatory pathway is defective in SLE patients.
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PMID:Defective B7 expression on antigen-presenting cells underlying T cell activation abnormalities in systemic lupus erythematosus (SLE) patients. 860 37

The role of costimulation was examined in an in vivo model of alloantigen-driven Th1 or Th2 cytokine responses, the parent-into-F1 model of acute or chronic graft-vs-host disease (GVHD), respectively. The soluble fusion protein, murine CTLA4Ig, which blocks engagement of CD28 by its natural ligand B7-1 and B7-2, was administered either early, at the time of GVHD induction, or delayed, after the establishment of Th1 or Th2 effector responses (day 7). Early administration of CTLA4Ig prevented the development of both acute and chronic GVHD by preventing the activation of donor T cells, i.e., by blocking characteristic Th1 or Th2 cytokine production and blocking memory marker up-regulation on donor T cells. Delayed CTLA4Ig administration was unable to alter acute GVHD but did reverse chronic GVHD as evidenced by normalization of serum autoantibody levels, normal host B cell numbers and MHC class II expression, reduced donor T cell expression of CD40 ligand, and reduced numbers of donor CD4+ memory T cells. The percentage of donor memory cells was not altered by delayed CTLA4Ig. We conclude that in this model, alloantigen-driven Th1 or Th2 responses are equally susceptible to costimulatory blockade at the onset of disease; however, once effector mechanisms become established, only Th2-driven responses have a requirement for further costimulation for the continued expansion of CD4+ T cells. These data suggest that humoral, lupus-like autoimmunity requires continuous T cell help for B cells, and agents that interrupt this process may be beneficial.
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PMID:Differential effect of CTLA4Ig on murine graft-versus-host disease (GVHD) development: CTLA4Ig prevents both acute and chronic GVHD development but reverses only chronic GVHD. 889 65

CD28 on T cells provides a potent costimulatory signal for T cell activation. Down-regulation of CD28 on peripheral T cells has been reported in certain clinical conditions, but full studies on the mechanism and biological significance have not been performed. Our extensive phenotype analysis of peripheral blood lymphocytes (PBL) from SLE patients revealed that the absolute number of CD28+ T cells of both CD4 and CD8 phenotypes was selectively decreased, while that of CD28- T cells was maintained. CD28+ T cells from SLE patients exhibited mostly normal proliferative responses to both CD28-dependent and -independent stimulations. In contrast, CD28- T cells were hyporesponsive to anti-CD3 stimulation in both SLE and normal controls. These results implied that the selective decrease of CD28+ T cells in SLE does not result from a hyporesponsiveness of CD28+ T cells. To investigate the reason for the selective loss of CD28+ T cells, we determined the appearance of apoptotic cells in culture with or without anti-CD3 stimulation. Apoptotic cells defined by merocyanine (MC)540 were gradually increased from 12 h to 24 h. Anti-CD3-induced apoptosis of CD28+ T cells was significantly accelerated in SLE, whereas apoptosis of CD28- T cells was hardly detected in both SLE and normal controls. Comparative analysis between CD28+ and CD28- T cells on CD95 (Fas) and Bcl-2 expression, which are related to activation-induced cell death (AICD), did not show a major difference, although CTLA4, which has been demonstrated to transmit an apoptosis-inducing signal, was expressed only on CD28+ T cells. Our results suggest that CD28-mediated costimulation influences T cell susceptibility to AICD and may be involved in T cell lymphopenia in SLE.
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PMID:Preferential elimination of CD28+ T cells in systemic lupus erythematosus (SLE) and the relation with activation-induced apoptosis. 891 66

The CD28/CTLA4-B7-family plays an important role in T-cell costimulation and is crucial for IL-2 production and tolerance induction. The costimulatory molecule B7-BB1 (CD80) is expressed on activated antigen presenting cells, but its expression on peripheral blood mononuclear cells is very low. Here we report a patient with untreated SLE whose peripheral blood antigen presenting cells expressed increased amounts of B7-BB1.
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PMID:Elevated in vivo expression of the costimulatory molecule B7-BB1 (CD80) on antigen presenting cells from a patient with SLE. 897 70

MRL/Mp-lpr/lpr (lpr) mice develop autoantibodies, vasculitis, and glomerulonephritis, which are similar to human systemic lupus erythematosus, and acquire a generalized, nonmalignant, lymphoproliferative disorder. CD4- CD8- CD3+ TCR alphabeta+ (double-negative, DN) T cells accumulate in spleen and lymph nodes, and become a major T cell population in vivo. These DN T cells, however, are refractory to various stimuli, including CD3, IL-2, CD28, PMA, and PHA. Recently, the lpr gene mutation has been identified as a mutant gene for Fas, resulting in expression defects of Fas Ag. It is still unclear, however, what kinds of mechanisms cause the dysfunction of lpr DN T cells. To elucidate the pathogenic mechanisms in abnormal DN T cells, biochemical analyses were conducted for the expression and tyrosine phosphorylation of the vav proto-oncogene product (Vav) in DN T cells from lpr mice. We demonstrated that Vav, a 95-kDa cytoplasmic protein, from lpr mice was constitutively tyrosine phosphorylated several times higher than in control +/+ mice, while expression of Vav protein in lpr and +/+ mice was equal. Additionally, in contrast with +/+ T cells, tyrosine phosphorylation of Vav, which normally increases within a minute of stimulation via TCR, did not increase in lpr DN T cells following PHA or Ab activation. Taken together with the suggested roles of Vav in multiple receptor-mediated signal transductions, our findings suggest that the functional abnormalities of lpr DN T cells may be related to Vav abnormal tyrosine phosphorylation, which could lead to impaired signaling between surface receptors and G proteins in this cell population.
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PMID:Constitutive tyrosine phosphorylation of the vav proto-oncogene product in MRL/Mp-lpr/lpr mice. 905 37


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