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)

Lobenzarit (CCA) is a novel disease modifying anti-rheumatic drug. Although CCA has been shown to prevent the development of the autoimmune disorders in NZB/W F1 mice and in MRL/l mice, the precise mechanism of its action has not yet been clarified. The current study examined the effect of CCA on the in vitro production of anti-DNA antibody, a hallmark of the autoimmune disorders. In vitro anti-DNA antibody production was induced from highly purified B cells of normal human individuals by stimulation with Staphylococcus aureus and CD4+ T cells or with immobilized anti-CD3 activated CD4+ T cells. CCA suppressed the production of anti-DNA antibody as well as IgM at pharmacologically obtainable concentrations (10-50 micrograms/ml). CCA did not inhibit the initial stages of B cell activation in either culture system, but rather suppressed the maturation of previously activated B cells. Although CCA suppressed IL2 production by immobilized anti-CD3 activated CD4+ T cells, its suppressive effects on B cells were not overcome by the addition of IL2 or factors generated from mitogen activated T cells (TF). CCA did not suppress IL6 production by immobilized anti-CD3 activated CD4+ T cells nor that by B cells activated with SA+ IL2. These results indicate that CCA suppresses the production of anti-DNA antibody by directly inhibiting activated B cells. The data therefore suggest the possible efficacy of CCA in suppressing the function of activated B cells in human SLE patients.
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PMID:Regulation of in vitro anti-DNA antibody production by a novel disease modifying anti-rheumatic drug, Lobenzarit. 135 78

Different characteristics of peritoneal macrophages have been studied, to assess the role of macrophages in the pathogenesis of MRL-lpr/lpr mice which develop a lupus-like syndrome. Resident peritoneal macrophages from MRL-lpr/lpr mice (greater than 10 weeks old) displayed characteristics of activation, while thioglycollate-elicited or resident macrophages from normal mice (Balb/c or MRL-+/+) did not. In addition to Ia antigens, macrophages spontaneously expressed Interleukin-2 receptors (IL2-R) whereas resident macrophages from normal mice did not. Injection of recombinant human Interleukin-2 (rHu-IL2) by the i.p. route to normal mice did not modify the cellular composition of the resident peritoneal population. On the contrary, rHu-IL2 treatment of MRL-lpr/lpr mice induced an enhancement in cell number in the peritoneal cavity. At the same time, macrophages harvested from treated MRL-lpr/lpr mice showed enhanced chemiluminescence triggered by phorbol-12-myristate-13-acetate (PMA) whereas peritoneal macrophages from treated normal mice did not. These results indicate that MRL-lpr/lpr peritoneal macrophages display features of selective 'activation' and suggest that the expression of IL2-R could be involved in the pathogenesis of inflammatory disorders seen in MRL-lpr/lpr autoimmunity.
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PMID:Effect of in vivo injection of recombinant human interleukin-2 on peritoneal macrophages from MRL-lpr/lpr mice. 307 62

To characterize B cell hyperactivity in systemic lupus erythematosus (SLE) patients we studied the early events of B cell activation in 14 patients and controls. We measured B cell proliferation induced by three interleukin (IL) preparations (20-kDa B cell growth factor, BCGF, recombinant IL2 and 50-kDa BCGF) in the absence and in the presence of an anti-mu antibody (Ab). SLE B cells exhibited a markedly enhanced proliferative response to the 50-kDa BCGF in the absence of an anti-mu Ab, while responding normally in the presence of a first signal. This pattern of hyperactivity was observed in 11 out of 14 patients tested, and was absent in control patients. In contrast, SLE B cells behaved like normal B cells for the response to the other two IL tested, and to the anti-mu Ab alone. It should be pointed out that SLE B cells responded normally to recombinant IL2 whereas T cells from the same patients exhibited a decreased response to this IL. The selectively enhanced responsiveness of SLE B cells to the 50-kDa BCGF suggests that the events leading to B cell hyperactivity in this disease affect the early stages of B cell activation.
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PMID:B cell hyperactivity in systemic lupus erythematosus: selectively enhanced responsiveness to a high molecular weight B cell growth factor. 309 24

T cell growth is principally regulated by the lymphokine interleukin 2 (IL 2). Following induction of IL 2 receptors, immunologically normal cells proliferate and will continue to do so until the level of IL2 becomes limiting. Spleen cells from autoimmune-prone mice and peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE), however, are severely deficient in their capacity to both produce and respond to IL 2 following a challenge with mitogenic lectins. These observations have suggested the possibility that IL 2 may not function as a T cell growth factor in the autoimmune milieu. In order to determine the requirements for T lymphocyte proliferation in autoimmunity, MRL-lpr/lpr mice were studied. Spleen cells from this murine model of lupus exhibit profound defects in IL 2 activity in vitro. Yet, paradoxically, massive expansion of the T cell pool occurs in vivo. While spleen cells from such mice were, indeed, unable to produce IL 2 or to proliferate when stimulated with concanavalin A (Con A), the combination of Con A plus the comitogen phorbol myristate acetate (PMA) engendered substantial IL 2 production and normal cellular proliferation. Since numerous lymphokines are produced when cells are cultured with Con A + PMA, it remained to be shown that IL 2 was, in fact, the responsible growth factor. We found that culturing lpr spleen cells with an anti-IL 2 receptor antibody abrogated the mitogenicity of Con A + PMA; that on stimulation with Con A + PMA, MRL-lpr/lpr T cells expressed IL 2 receptors, and that addition of recombinant IL 2 to the receptor positive population resulted in marked proliferation. Furthermore, by two-color flow cytometric analysis it was demonstrated that T cells which bear the phenotype of those which undergo clonal expansion in the lpr were capable of expressing IL 2 receptors. Thus, IL 2 can be utilized as a growth factor, in vitro, by autoimmune as well as normal T cells. The etiology of the Con A unresponsiveness of MRL-lpr/lpr cells remained to be clarified. We observed that, in contrast to the refractoriness of fresh cells, lymph node cells which had been cultured for several days in the absence of antigenic stimulation were capable of expressing IL 2 receptors and of proliferating on exposure to Con A. Using flow cytometry it was found that selective expansion of a subset of phenotypically "normal" lymphocytes had not occurred.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Signals required for activation and growth of autoimmune T lymphocytes. 608 44

MRL/MP-lpr/lpr (MRL/lpr) mice develop a lupus-like autoimmune disease and a massive generalized lymphadenopathy associated with proliferation of nonmalignant Thy-1+ Lyt-1+ cells. The mechanism(s) leading to outgrowth of these cells is unknown. We report here that Thy-1+, Lyt-1+, Lyt2- lymphocytes from spleens of MRL/lpr mice, but not from several strains of normal mice, spontaneously secrete IL3. The presence of IL3 is shown by: (a) the ability of the supernatants from unstimulated spleen cells of MRL/lpr (MRL/lpr SUP) to support growth of IL3 but not IL2 addicted cells and (b) the growth-promoting activity in MRL/lpr SUP was absorbed with IL3-dependent cells but not with IL2-dependent cells. Spontaneous release of IL3 was detected in supernatants from spleen cells of 6-week-old MRL/lpr mice and the titers of IL3 activity increased with age. Nylon wool-enriched cells from spleens of MRL/lpr mice proliferated in response to purified IL3 and IL3 secreted by MRL/lpr T cells, in a manner similar to nylon wool-passed cells from normal mice. The cells responding to both sources of IL3 were Thy-1+, Lyt-1+, Lyt-2-. Thus, Thy-1+, Lyt-1+,2- cells from spleen of MRL/lpr mice spontaneously secrete IL3 and respond normally to this lymphokine. Four Thy-1+, Lyt-1+,2- cell lines derived from unstimulated spleen cells of MRL/lpr mice were established in culture with IL3. These IL3-sensitive T cell lines help syngeneic and H-2 compatible normal small "resting" B cells to mature into plasma cells secreting predominantly IgG1, IgG2 and IgA. Taken together, these data and previous findings that T cells from MRL/lpr mice have an impaired production of and response to IL2, strongly suggest that abnormal production of IL3 may account for the outgrowth of Thy-1+, Lyt-1+,2- cells in the MRL/lpr mouse. Finally, a mechanism linking abnormal production of IL3 and B cell hyperactivity in these animals is proposed.
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PMID:Spontaneous production of interleukin 3 by T lymphocytes from autoimmune MRL/MP-lpr/lpr mice. 643 Jul 8

Microbial superantigens (SAg), by virtue of their binding to TCR V beta elements and to class II MHC molecules on accessory cells, trigger T cell proliferation in a dose-dependent fashion. In contrast, SAg-induced T cell-dependent B cell differentiation occurs only at SAg concentrations that are orders of magnitude lower that those required for optimal mitogenesis (low-dose SAg). At optimal mitogenic doses (high-dose SAg), SAg-driven B cell differentiation does not ensue. In this report, we demonstrate that this dichotomy in SAg-driven B cell differentiation is due to the active inhibition of B cell differentiation by high-dose SAg. Such inhibition is not reversed by feeding cultures with fresh medium, with conditioned media, or with IL2 +/- IL4, and impaired B cell differentiation is observed in cultures containing purified T cells or CD4+ T cells + B cells, as well as in PBMC cultures. Although preincubation of either T cells or B cells with high-dose SAg impairs subsequent SAg-induced B cell differentiation, high-dose SAg is not toxic per se, since high-dose SAg does promote vigorous B cell differentiation in cultures of mitomycin C-treated T cells + B cells and does not inhibit T cell-independent B cell differentiation. No correlation exists between SAg-induced B cell surface expression of CTLA4 ligand and generation of Ig-secreting cells, but the dose of SAg does correlate with T cell-mediated SAg-dependent cytolysis of transformed B cell targets or autologous nontransformed activated B cell targets. B cell recovery from cultures stimulated with high-dose SAg is lower than that from cultures stimulated with low-dose SAg, whereas B cell apoptosis is greater in the former cultures than that in the latter cultures. T cells stimulated with high-dose SAg do not inhibit differentiation of activated B cells in the absence of physical contact between the T cells and the target B cells, supporting the notion of direct killing of activated B cells by T cells. The ability of low doses of SAg to promote B cell differentiation without generating biologically meaningful cytolytic activity and the ability of higher doses of SAg to modulate Ig production may have important pathogenetic and therapeutic ramifications for certain autoimmune disorders, such as systemic lupus erythematosus.
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PMID:Differential human T cell-dependent B cell differentiation induced by staphylococcal superantigens (SAg). Regulatory role for SAg-dependent B cell cytolysis. 763 37

In autoimmune diseases striking abnormalities of T and B cell activation and of cytokine production are present. In 14 patients with autoimmune hemolytic anemia (AIHA), idiopathic or in the course of: lymphoma, B hepatitis, carcinoma, drug therapy (alpha-methyldopa), systemic lupus erythematosus (SLE), and not yet submitted to immunosuppressive therapy, the PBL proliferative response to PHA and the IL1 alpha, IL2, IL4 and IL2R serum levels have been valued. While the stimulation index of PBL was strongly reduced in 10 cases (64 +/- 56 vs 138 +/- 45 in the control group), IL1 alpha, IL2 and IL2R were greatly increased in all the patients, and IL4 in 5 (IL1 alpha :199 +/- 268 pg/ml in patients vs 0.30 +/- 0.2 in controls; IL2:716 +/- 311 pg/ml vs 16 +/- 4; IL4:29 +/- 13 pg/ml vs 13 +/- 7; IL2R:1233 +/- 471 U/ml vs 256 +/- 114). Cytokine serum levels were not related with the associated disease, with the CD4+ and CD8+ cells absolute number or with PBL blastogenic in vitro response. The high serum levels of cytokines and IL2R suggest that in AIHA there exist a CD4+ lymphocyte hyperactivation (the low proliferative response of PBL might imply a temporary functional exhaustion of T lymphocytes) as in the other autoimmune diseases.
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PMID:High cytokine serum levels in patients with autoimmune hemolytic anemia (AIHA). 785 62

Despite an extensive literature dealing with IL2-induced cytolytic activity, noncytotoxicity-related effects of IL2 on peripheral blood mononuclear cells (PBMC) or T cell function have received less attention. We have focused on the effects of irradiated, IL2-activated PBMC (PBMC*rIL2) on anti-CD3- and formalin-fixed heat-killed Staphylococcus aureus-induced polyclonal B cell differentiation in secondary cultures. PBMC*rIL2 act directly on B cells and cross major histocompatibility complex barriers to augment polyclonal B cell differentiation as measured by plaque-forming cell (PFC) generation. These effects are preferentially mediated by T (both CD4+ and CD8+) cells, and physical contact between effector PBMC*rIL2 and target B cells is not absolutely required for enhanced PFC generation. PBMC*rIL2 must be present for the initial 24 hr of the secondary cultures, indicating that some soluble B cell differentiation factor rapidly released by PBMC*rIL2 mediates the PFC-enhancing effect. Of IL2, IL4, IL5, IL6, IL10, IFN-gamma, and TNF-alpha, only IFN-gamma mRNA is appreciably and reproducibly increased in irradiated, IL2-activated T cells (T cells*rIL2). Nevertheless, exogenous rIFN-gamma cannot mimic and anti-IFN antibodies cannot block the PFC-enhancing effects of T cells*rIL2, indicating that some unidentified soluble factor(s) apart from or in addition to IFN-gamma is involved. IL2-induced effects on T cell noncytolytic function may help explain certain observed immune anomalies in IL2-treated patients, and a better understanding of the IL2-induced effects on T cell noncytolytic function may have ramifications for autoimmune diseases such as SLE.
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PMID:Enhancing effects of interleukin 2-treated peripheral blood mononuclear cells on subsequent B cell differentiation. 806 23

T lymphocytes from subjects with active systemic lupus erythematosus (SLE) exhibit reduced cAMP-inducible, protein kinase A (PKA)-dependent phosphorylation of several intracellular substrates compared with healthy and disease controls. To ascertain whether the persistent T cell activation observed during active SLE can result in impaired PKA-dependent protein phosphorylation, normal T cells were activated in vitro by monoclonal anti-CD3-epsilon antibody and recombinant IL1-alpha (rIL1-alpha) for 24 hr. T cell activation, verified by IL2 mRNA, IL2 receptor-alpha (IL2R-alpha) mRNA, and IL2R-beta mRNA expression, did not diminish cAMP-inducible, PKA-dependent protein phosphorylation. We also tested the hypothesis that circulating factors present in active SLE serum can decrease cAMP-inducible total PKA phosphotransferase activity and PKA-dependent protein phosphorylation in normal T lymphocytes. T cells cultured for 24 hr in medium supplemented with 10% active SLE sera (from subjects who exhibited the defect of PKA-dependent protein phosphorylation) exhibited similar total PKA phosphotransferase activity and substrate phosphorylation as cells cultured in normal AB serum. Moreover, the addition of interferon-alpha (IFN-alpha) and/or immune complexes (IC) did not diminish either total PKA activity or PKA-dependent substrate phosphorylation. Lastly, we found that the defect of PKA-dependent protein phosphorylation in active SLE T cells could not be reversed by culturing the cells in culture medium supplemented with 10% AB serum for 24 hr. In conclusion, (a) deficient cAMP-inducible, PKA-dependent phosphorylation in SLE T cells is not reversible by culturing cells in vitro; (b) there is no evidence to support the concept that serum factors, including IC and IFN-alpha, can induce a defect of PKA-dependent protein phosphorylation in normal T cells.
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PMID:The effect of circulating serum factors from patients with systemic lupus erythematosus on protein kinase A (PKA) activity and PKA-dependent protein phosphorylation in T lymphocytes. 838 27

A large body of clinical experience on the adverse consequences of cytokine administration has accumulated since the last decade. Side-effects reported after the therapeutic use of cytokines has provided evidence that activation of the immune response may sometimes have deleterious consequences. Several effects appeared as a direct consequence of the immune activation induced by cytokines, e.g. flu-like reactions, vascular leak syndrome. Cytokine-induced exacerbation of underlying diseases or immune dysregulation were other complications of growing concern. Interferon-alpha (IFN-alpha) treatment has now been clearly linked with the exacerbation or the occurrence of several types of autoantibodies or autoimmune diseases (thyroiditis, systemic lupus erythematosus, hematologic disorders, insulin-dependent diabetes mellitus) or diseases involving altered cell-mediated immune functions (inflammatory dermatologic diseases, nephritis, pneumonitis, colitis). By contrast immunological side-effects of IFN-beta and IFN-gamma have been seldom reported. However, the extent of clinical experience with both of these cytokines is still very limited. Interleukin-2 (IL-2) has also been implicated in various conditions that may involve immunopathological processes (thyroid disorders, rheumatoid arthritis, dermatological diseases, interstitial nephritis). Growth factors have been more specifically linked with the development or the exacerbation of dermatological inflammatory diseases through neutrophils, monocytes/macrophages or eosinophils activation (e.g. cutaneous vasculitis and generalized cutaneous eruption, Sweet's syndrome, bullous eruption, psoriasis). Exacerbation of autoimmune thyroiditis was described with granulocyte-macrophage colony-stimulating factor (GM-CSF) only. The immunogenicity of cytokines is also of great relevance and the occurrence of antibodies binding IFN-alpha and IFN-beta, IL2 and GM-CSF have been reported. While the clinical significance of non-neutralizing antibodies is not clearly established, an absence of response or reversal of clinical efficacy has been described in patients developing neutralizing antibodies. Finally, several isolated reports have recently suggested that IFN-alpha treatment may be associated with several immunosuppressive effects while IL-2 is clinically associated with an increased incidence of infectious complications.
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PMID:Immune-mediated side-effects of cytokines in humans. 863 83


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