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)

The production of B cell-stimulating factors (BSF) by B cells in patients with systemic lupus erythematosus (SLE) was studied in vitro. B cells from SLE patients markedly proliferated and differentiated into Ig-producing cells by in vitro culture without any stimulation. The culture supernatant of these B cells contained BSF activity that stimulated Staphylococcus aureus Cowan I-treated normal B cells to proliferate and differentiate into Ig-producing cells. By a Percoll gradient density centrifugation, BSF-producing cells were enriched in the higher density fraction, but were reduced in the lower density fraction. The BSF also stimulated the proliferation and the differentiation of SLE B cells. By a Percoll gradient density centrifugation, SLE B cells responsive to the BSF were enriched in the higher density fraction, but were reduced in the lower density fraction. The Mr of the BSF was estimated as about 18,000 Da by Sephacryl S-200 column chromatography. The BSF fraction did not possess IL-2 and IFN activity, but possessed IL-1 activity, which stimulated murine thymocyte proliferative responses. The BSF activity was partially, but not completely, absorbed by an anti-IL-1 alpha antibody. Furthermore, the BSF possessed IL-4 activity, which induced not only the proliferative responses of normal B cells stimulated with B cell mitogens, but also the expression of low affinity Fc epsilon R/CD23 on normal B cells. The BSF also possessed IL-6 activity, which induced the proliferative responses of IL-6-dependent hybridoma cells, MH-60 BSF2. Moreover, human rIL-1, rIL-4, and rIL-6 stimulated SLE B cells. These results suggest that SLE B cells spontaneously produce the BSF such as IL-1 alpha, IL-4, and IL-6 and express their receptors on their surface, and the interaction between the BSF and their receptors stimulates SLE B cells to spontaneously proliferate and differentiate into Ig-producing cells as an autocrine mechanism.
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PMID:Production of B cell-stimulating factors by B cells in patients with systemic lupus erythematosus. 326 75

Splenocytes of MRL/l mice, one of the murine lupus strains, were found to produce a factor(s) which potentiates antibody formation. This factor was produced by splenocytes of young MRL/l mice and cell-sorting experiments by flow cytometry indicated that Thy 1.2+ cells were producing the factor. The approximate molecular weight of the factor was found to be 35,000-45,000 daltons and its pI value was between 3.3 and 3.8. It was also demonstrated that this factor is distinct from interferons, interleukins (IL-1, IL-2, IL-3) and B cell differentiation factors.
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PMID:A factor potentiating antibody formation spontaneously produced by splenic T cells of MRL/MP-lpr/lpr mice. 349 82

The autoimmune manifestations of MRL/Mp-lpr/lpr(MRL/l), a murine model of systemic lupus erythematosus (SLE), were alleviated by administering 1 microgram cholera toxin (CT) every 14 days. The beneficial effects were: (i) significant prolongation of survival time, (ii) prevention of lymphadenopathy, (iii) improvement of T cell mitogenic responses and suppression of a B cell mitogenic response, (iv) decrease in serum anti-DNA and anti-Sm antibodies, (v) increase in IL-2 production by stimulation of spleen cells with concanavalin A (Con A). It is possible that CT may be effective for treatment of murine lupus nephritis by modulating polyclonal lymphocyte activation. This type of immunomodulation may pave the way toward treatment of lupus and other autoimmune diseases.
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PMID:Treatment of autoimmune MRL/Mp-lpr/lpr mice with cholera toxin. 350 Aug 17

NK cells may be important in the elimination of cells infected by virus, in the regulation of antibody production, and in tissue destruction. The significance of NK cells in rheumatic disorders is unknown, but NK cells and NK-like cells have been found in the peripheral blood and synovial tissues of patients with autoimmune disease. In particular, defects in NK cell activity have been reported in SLE, RA, PSS and SS. Of these diseases, SLE appears to be the best characterized with obvious abnormalities in NK cell numbers, impaired cytotoxicity of individual NK cells, decreased release of cytotoxic factors, deranged IFN modulation of the NK cell, and associated abnormalities in the IL-2 system. The association of these abnormalities with the underlying disease process is currently under investigation.
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PMID:Natural killer cells in connective tissue disorders. 390 53

Isoprinosine (IPS) is a new anti-viral agent which appears to have immunomodulatory activities which include its ability to enhance the in vitro blastogenic responses of normal lymphocytes to mitogens. The present study compares the effects of IPS on the in vitro immune functions of peripheral blood mononuclear cells (PBMC) from systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients with its effects on PBMC from normal controls. Each mitogen (Con A, PHA or PWM) was used at its optimal concentration with a range of IPS concentrations (0-25 micrograms/ml). PHA-induced blastogenesis by PBMC from all three groups was enhanced by IPS at or above 5 micrograms/ml. The Con A-induced responses of SLE lymphocytes were significantly enhanced over controls by IPS (P less than 0.02 at 5 micrograms/ml) while those of RA lymphocytes were not. IPS had little effect on PWM-induced blastogenesis by RA lymphocytes but did enhance the blastogenic responses of SLE lymphocytes (P less than 0.01 at 5 micrograms/ml). In contrast, the characteristically high immunoglobulin synthesis by SLE lymphocytes was decreased by IPS. The mechanism responsible for these effects is not known but IL-2 production by patient lymphocytes in vitro which was low for both RA (P less than 0.01) and SLE (P less than 0.02) increased significantly (P less than 0.05) when SLE lymphocytes were cultured with IPS. These data identify IPS as an agent for the study of aberrant immune regulation in autoimmune diseases and suggest that it may have potential therapeutic value in SLE.
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PMID:Immunomodulation by isoprinosine: effects on in vitro immune functions of lymphocytes from humans with autoimmune diseases. 619 May 98

Three independent mutations involving the apoptosis-1 (APO-1)/Fas receptor or its putative ligand have led to lupuslike diseases associated with lymphadenopathy in different strains of mice. To determine whether humans with SLE also have a defect in this apotosis pathway, we analyzed the expression of APO-1 on freshly isolated blood mononuclear cells and on lymphocytes activated in vitro using flow cytometry and the monoclonal antibody anti-APO-1. Significantly higher level of APO-1 expression were detected on freshly isolated peripheral B cells and both CD4+ and CD8+ T lymphocyte populations obtained from lupus patients when compared with normal controls (P < 0.001). Almost 90% of the cells that stained positive for APO-1 also expressed the CD29 antigen, suggesting that APO-1 was upregulated after lymphocyte activation in vivo. No defect in APO-1 regulation was detected after activation of SLE T (with anti-CD3) or B (with Staphylococcus aureus Cowan 1) lymphocytes in the presence of IL-2 in vitro. Similarly, the anti-APO-1 antibody induced apoptosis in 74 +/- 5% of activated SLE T cells in vitro compared with 79 +/- 6% of the normal controls (P > 0.05). These results reveal that, while APO-1/Fas may play an important role in the regulation of lymphocyte survival in SLE, no consistent defect in the expression or function of the receptor could be detected in these studies.
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PMID:The apoptosis-1/Fas protein in human systemic lupus erythematosus. 751 Jul 16

CD4+ cells are thought to play a significant role in the development of lupus-like disease in a variety of autoimmune disease-prone mouse strains. In one such strain, BXSB/MpJScR, male mice develop severe lupus-like symptoms early in life but females do not. In this study, splenic CD4+ cells from male and female BXSB mice were evaluated for age-related changes in: 1) membrane expression of CD4+ cell subset markers (1, 2, and 4 mo) and activation Ags (4 mo) and 2) the capacity to proliferate and produce cytokines (4 mo) in response to polyclonal stimuli. CD4+ cells from females of all age groups and from younger males were predominantly CD44lo, CD45RBhi, MEL-14hi, and 3G11hi (phenotypes associated with naive T cells). In contrast, 4-mo-old males were predominantly CD44hi, CD45RBlo, MEL-14lo, and 3G11lo (phenotypes associated with activated/memory T cells). Furthermore, an increased constitutive expression of the activation Ags RL388, IL-2R, and TfR was observed in CD4+ cells of 4-mo-old male BXSB mice in comparison with age-matched females. In 3-day cultures, purified CD4+ cells from 4-mo-old males proliferated significantly less than cells from age-matched females in response to plate-bound anti-CD3 epsilon (2C11i). The reduced proliferation was restored in large part by PMA and ionomycin. CD4+ cells from older males generally produced increased amounts of IFN-gamma and IL-4 and significantly less IL-2 than age-matched females in response to either stimulus (IL-2 mRNA was also decreased in response to 2C11i). Taken together, these studies suggest that profound phenotypic and functional changes occur with age in the CD4+ cells of male BXSB mice that are indicative of an activated state.
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PMID:Maturational changes in CD4+ cell subsets and lymphokine production in BXSB mice. 751 69

Treating activated CD4+ T cells with DNA methyltransferase inhibitors modifies gene expression and induces autoreactivity. Adoptive transfer of viable polyclonal autoreactive cells causes a lupus-like disease, most likely because of one or more effector functions expressed by the autoreactive cells. However, the number of potential effector mechanisms expressed by polyclonal cells is large. To more readily identify responsible mechanisms, we asked if autoimmunity can be induced by using the conalbumin-reactive, cloned Th2 cell line D10.G4.1, treated with 5-azacytidine (5-azaC) or procainamide (Pca). Treated, but not untreated, cells responded to syngeneic APCs without Ag, overexpressed LFA-1, spontaneously lysed syngeneic macrophages, and secreted relatively large amounts of IL-6, small amounts of IL-4, and no detectable IL-2 nor IFN-gamma. Adoptive transfer of treated, but not untreated, cells induced a severe immune complex glomerulonephritis, pulmonary alveolitis, central nervous system abnormalities including fibrinoid necrosis, karyorrhexis, and meningitis, and bile duct proliferation with periportal inflammatory cell infiltration resembling primary biliary cirrhosis. Anti-ssDNA, anti-dsDNA, and anti-histone Abs were also found. These experiments demonstrate that modification of this cloned T cell line with DNA methyltransferase inhibitors is sufficient to cause an autoimmune disease, with features of lupus as well as autoimmune liver disease. The results also raise the possibility that macrophage lysis, IL-6 secretion, and LFA-1 overexpression could contribute to the disease process. This system may be useful in testing the role of these and other pathologic mechanisms in the development of specific autoimmune lesions.
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PMID:Mechanism of drug-induced lupus. I. Cloned Th2 cells modified with DNA methylation inhibitors in vitro cause autoimmunity in vivo. 753 91

Groups of female MRL/MpJ-lpr/lpr mice received either saline or FK506 (tacrolimus; 2 mg/kg intraperitoneally) three times weekly, cyclophosphamide (CY; 20 mg/kg) once monthly, or both drugs from 8 weeks of age. Median survival for untreated and CY-treated mice was 26 weeks, and for FK506- and FK506 + CY-treated groups was > or = 44 weeks. Severity of skin lesions and lymph node hyperplasia was markedly reduced by the drug combination, whereas either drug alone was less effective. FK506 or CY alone delayed the onset of proteinuria, but by 24 weeks all of these animals were positive. In contrast, drug combination reduced the prevalence of proteinuria to < or = 60% throughout the 44 weeks of study. Sequential monitoring of peripheral blood lymphocytes revealed that combination therapy but not monotherapy markedly reduced the proportion of atypical CD3+ B220+ and CD3+CD4-CD8- T cells. Neither FK506 nor CY affected the reduction in IL-2 and IL-4 mRNA levels observed in lymph nodes of diseased animals compared with normals. Although the drug combination also did not affect IL-2 mRNA levels, IL-4 mRNA transcripts were increased six-fold compared with saline-treated controls. IL-10 and interferon-gamma (IFN-gamma) mRNAs were induced by FK506, CY and by the drug combination. Serum levels of anti-dsDNA antibodies were reduced in all treatment groups. These data demonstrate improved efficacy of combined T and B cell-directed immunosuppression in murine lupus, associated with marked inhibition of atypical T cells and selective augmentation of IL-4 within the affected lymphoid tissue.
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PMID:Combined effects of FK506 (tacrolimus) and cyclophosphamide on atypical B220+ T cells, cytokine gene expression and disease activity in MRL/MpJ-lpr/lpr mice. 753 8

Male BXSB mice develop lupus-like disease and die early in life (4 to 5 mo) whereas female mice do not. Others have demonstrated that CD4+ cells from male mice support B cell resistance to tolerance induction to human gamma-globulin (HGG). In this study, male and female mice tolerized at 2 mo of age with deaggregated HGG and subsequently immunized with HGG in comparison with mice immunized only were tested for anti-HGG Ab responses. CD4+ cells from draining lymph nodes of these mice were tested in culture for proliferation and production of cytokine mRNA and protein in response to HGG plus APC. Tolerized male but not female mice produced anti-HGG Abs of both the IgG1 and IgG2a isotypes. HGG-stimulated CD4+ cells from immunized male and female mice that were not tolerized produced IL-2, IL-4, IL-5, IFN-gamma, and TNF-beta mRNA as well as IL-2 and IL-4 protein, whereas tolerized, immunized mice of both sexes failed to proliferate or produce either IL-2 or IL-4 or express any cytokine mRNA in response to HGG in vitro. A resistance in tolerance induction in male mice, as determined by anti-HGG Abs, was also observed at 3 mo of age. Although a resistance to tolerance was also seen in terms of proliferation in the 3-mo-old males, production of IL-2 or IL-4 protein was still not observed. Thus, all T cell subsets identified by cytokine expression profiles were tolerized not only from females but also from males, of which the latter appeared to show some resistance to tolerance induction.
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PMID:In vivo tolerance induction and associated cytokine production by subsets of murine CD4+ T cells. 753 93


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