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

The systemic autoimmune syndrome of MRL/Mp-lpr/lpr (MRL/lpr) mice consists of severe pan-isotype hypergammaglobulinemia, autoantibody production, lymphadenopathy, and immune complex-associated end-organ disease. Its pathogenesis has been largely attributed to helper alphabeta T cells that may require critical cytokines to propagate pathogenic autoantibody production. To investigate the roles of prototypical Th1 and Th2 cytokines in the pathogenesis of murine lupus, IFN-gamma -/- and IL-4 -/- lupus-prone mice were generated by backcrossing cytokine knockout animals against MRL/lpr breeders. IFN-gamma -/- animals produced significantly reduced titers of IgG2a and IgG2b serum immunoglobulins as well as autoantibodies, but maintained comparable levels of IgG1 and IgE in comparison to cytokine-intact controls; in contrast, IL-4 -/- animals produced significantly less IgG1 and IgE serum immunoglobulins, but maintained comparable levels of IgG2a and IgG2b as well as autoantibodies in comparison to controls. Both IFN-gamma -/- and IL-4 -/- mice, however, developed significantly reduced lymphadenopathy and end-organ disease. These results suggest that IFN-gamma and IL-4 play opposing but dispensable roles in the development of lupus-associated hypergammaglobulinemia and autoantibody production; however, they both play prominent roles in the pathogenesis of murine lupus-associated tissue injury, as well as in lpr-induced lymphadenopathy.
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PMID:Roles of interferon-gamma and interleukin-4 in murine lupus. 910 38

Therapeutic treatment with procainamide is occasionally associated with the development of drug-induced lupus. This syndrome has become the prototype for an aseptic systemic autoimmune disease caused by a known environmental agent, but the underlying mechanisms remain puzzling. We explored the possibility that lupus-inducing drugs affect processes involved in T cell tolerance to self-Ag. An in vitro model of anergy using established T cell clones was used to determine whether procainamide or one of its metabolites could prevent development of T cell nonresponsiveness to cognate Ag. Addition of procainamide-hydroxylamine, but not procainamide or its further oxidation products during anergy induction by CD3 engagement, caused a dose-dependent recovery of the capacity of T cells to proliferate and secrete IFN-gamma upon subsequent Ag challenge. Resistance to anergy induction required 2 h of exposure to procainamide-hydroxylamine, and this state remained for 8 h, suggesting that uptake of the drug caused a reversible interference in signaling pathways involved in establishing anergy. We suggest that prevention of anergy induction by procainamide-hydroxylamine may also take place in vivo during establishment of T cell tolerance to self-Ag, thereby allowing the production of autoreactive T cells.
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PMID:A metabolite of the lupus-inducing drug procainamide prevents anergy induction in T cell clones. 912 12

We established a colony of MHC class I deleted (knockout) NZB mice, which lack the beta2 microglobulin gene (NZB.beta2m-/-), to characterize the contribution of MHC class I to the thymic microenvironment abnormalities, autoantibody production and lupus-like disease of NZB mice. Using an extensive panel of well characterized monoclonal antibodies defining thymic epithelial and other stromal elements, we demonstrated that deletion of MHC class I molecules does not change the thymic abnormalities, including the presence of a cortical epithelial cell free region, ectopic expression of medullary epithelial antigens, and the irregular shape of the medullary epithelial network of NZB mice. Moreover, the decreased staining of MTS 33(+) cells, a marker of premature thymocyte maturation, was also seen in NZB.beta2m-/-. However, although NZB.beta2m-/- mice had approximately the same levels of IgM and IgG anti-ss and dsDNA antibodies when compared to control NZB mice, there were significant alterations in the incidence and onset of anti-erythrocyte antibody levels. NZB.beta2m-/- had a lower incidence and a delayed onset of anti-erythrocyte autoantibody production compared to that seen in NZB mice. We also compared constitutive and PHA-P-driven levels of IFN-gamma, IL-4, IL-6, and IL-12 in cells from NZB, NZB.beta-/-2, and control C57BL/6 mice. Mitogen stimulated cells showed a decreased IFN-gamma, and a marked increase in IL-6 and IL-12 in NZB and NZB.beta2m-/- mice.
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PMID:Autoantibody production and cytokine profiles of MHC class I (beta2-microglobulin) gene deleted New Zealand black (NZB) mice. 928 91

Congenic MRL-lpr mice homozygous and heterozygous for the IFN-gamma gene disruption were created to assess the role of this pleotropic cytokine on the lymphoaccumulation and lupus-like disease of Fas-defective mice. Early death was prevented, and glomerulonephritis severely reduced in IFN-gamma-/- mice. Hypergammaglobulinemia was maintained with a switch from IgG2a to IgG1 predominance, but the dramatic decrease in levels of the dominant IgG2a anti-dsDNA autoantibodies was not associated with a compensatory increase in TH2-associated IgG subclasses. Remarkably, early death and glomerulonephritis were also prevented in IFN-gamma+/- mice, although autoantibody levels and glomerular immune deposits were equivalent to IFN-gamma+/+ lpr mice, indicating the importance of additional locally-exerted disease-promoting effects of IFN-gamma. IFN-gamma-/- mice exhibited reduced lymphadenopathy concomitant to a decrease in DN B220(+) T cells. In vivo BrdU labeling showed reduced proliferation of DN B220(+) cells in IFN-gamma-/- vs. IFN-gamma+/+ lpr mice, while enhanced proliferation of all other T cell subsets was unaffected. Macrophages of IFN-gamma-/-lpr mice expressed markedly decreased levels of MHC class I and II molecules compared with controls. Moreover, the heightened expression of MHC class II molecules on proximal tubules of IFN-gamma+/+ lpr mice was significantly reduced in both IFN-gamma-/- and IFN-gamma+/- mice. The data indicate that IFN-gamma hyperproduction is required for lupus development, presumably by increasing MHC expression and autoantigen presentation to otherwise quiescent nontolerant anti-self T cells, and also by promoting local immune and inflammatory processes.
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PMID:Interferon-gamma is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice. 943 8

T cells with T cell receptor (TCR) transgenes that recognized CD1 on syngeneic B cells stimulated B cells to secrete immunoglobulins in vitro. The CD4+, CD8+, or CD4-CD8- T cells from the spleen of the TCR transgenic BALB/c donors induced lupus with anti-double stranded DNA antibodies, proteinuria, and immune complex glomerulonephritis in irradiated BALB/c nude mice reconstituted with nude bone marrow. Injection of purified CD4-CD8- T cells from the marrow of transgenic donors prevented the induction of lupus by the transgenic T cells. Transgenic T cells that induced lupus secreted large amounts of interferon (IFN)-gamma and little interleukin (IL)-4, and those that prevented lupus secreted large amounts of IL-4 and little IFN-gamma or IL-10.
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PMID:Subsets of transgenic T cells that recognize CD1 induce or prevent murine lupus: role of cytokines. 946 3

We investigated whether macrophages (Mphi) from young, lupus-prone MRL+/+ and NZB/W F1 mice expressed common defects in immunoregulatory cytokine production. Endotoxin-activated Mphi from both strains, obtained well before disease signs, had a markedly reduced capacity to maintain IL-1 production compared with Mphi from normal strains (BALB/c, A/J, and C57BL/6). Mphi from lupus-prone mice showed similar defects in IL-6 and TNF-alpha production, which preceded the IL-1 defect. In fact, defective TNF-alpha production appeared to be responsible for aberrant expression of the other cytokines because this defect was the first to be expressed, and treatment with exogenous TNF-alpha reduced the extent of defective IL-1 and IL-6. These "proinflammatory" cytokine defects appeared to be selective because the anti-inflammatory cytokine IL-10 was not expressed aberrantly in the lupus-prone strains. For this reason, and because anti-IL-10 mAb treatment did not correct defective proinflammatory cytokine production, IL-10 did not appear to be responsible for these defects. IFN-gamma was able to normalize TNF-alpha production in Mphi from lupus-prone mice, demonstrating a stimulus-specific induction of the proinflammatory defects. These studies also revealed that Mphi from the three normal strains studied here maintain a precise inverse relationship between levels of TNF-alpha and IL-10, a relationship not seen in Mphi from lupus-prone strains. These findings reveal shared elements of cytokine dysregulation in the two principal animal models of multigenic lupus, and suggest that the study of Mphi (and perhaps other cells of the innate immune system) may provide valuable insights into intrinsic functional defects associated with systemic autoimmunity.
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PMID:Aberrant cytokine expression and autocrine regulation characterize macrophages from young MRL+/+ and NZB/W F1 lupus-prone mice. 954 4

We investigated the effects of IL-12 on immunoglobulin (Ig) production in vitro in murine chronic graft-vs. -host disease (cGVHD), a lupus-like model of overt B cell activation induced by allogeneic stimulation. Addition of IL-12 to cGVHD splenocytes strongly inhibited total Ig (Igkappa), IgM and IgG1 production. Although IL-12 down-regulated IL-4, IL-5, IL-9 and IL-10 production, its inhibitory activity on Ig production could not be ascribed to down-regulation of these cytokines, as addition of saturating doses of IL-4, IL-5 and/or IL-9 did not reverse the inhibitory activity of IL-12. Interestingly, IL-12 was also found to suppress the stimulating effect of IL-4 and IL-5 on Ig synthesis by cGVHD splenocytes. Several lines of evidence indicated that the inhibitory activity exerted by IL-12 on Ig production was mediated by IFN-gamma. First, IFN-gamma was produced in large amounts upon IL-12 stimulation. Secondly, it displayed a potent inhibitory activity on Ig production. Thirdly, Ig production was also inhibited by IL-18, a recently cloned IFN-gamma-inducing cytokine. Finally, the inhibitory activity of IL-12 was blocked by anti-IFN-gamma monoclonal antibody. We also investigated whether IL-12 down-regulated Ig production by purified cGVHD B cells. We found that IL-12 had only a marginal inhibitory activity on highly purified B cell populations isolated from cGVHD splenocytes and stimulated with IL-4 and IL-5, and that IL-18 was inactive in this respect. However, when the two cytokines were combined, a striking synergy was unmasked not only for IgG1 inhibition but also for IFN-gamma production by these B cell populations. Taken together, our results demonstrate that IL-12 inhibits in vitro Ig production by activated splenocytes through IFN-gamma production and that it synergizes with IL-18 on activated B cells to inhibit Ig production, through up-regulation of IFN-gamma production by B cells.
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PMID:Inhibition of in vitro immunoglobulin production by IL-12 in murine chronic graft-vs.-host disease: synergism with IL-18. 964 83

The onset of lupus-like disease in NZB/NZW F1 mice was correlated with the expression of IL-10 at 4 m of age, and with a sequential enhanced expression of IFN-gamma and IL-6 between 6 to 8 m of age. The expression of IFN-gamma and IL-6 was associated with exacerbation of disease symptom, production of anti-DNA antibody, and increase in total serum IgG1. Exogenous dehydroepiandrosterone (DHEA) given in animal diet significantly prolonged survival, and delayed formation of autoantibody of NZB/NZW F1 mice as compared to mice fed on control diet. The effect of DHEA paralleled a delay in the expression of IL-10 and IL-6 and an earlier detection of IL-12 transcripts. Moreover, DHEA-fed mice had higher serum IgG2a level than control diet-fed mice. Collectively, DHEA may modify the activation of distinct subset of T helper cells in NZB/NZW F1 mice at different phases of disease progression.
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PMID:Exogenous dehydroepiandrosterone modified the expression of T helper-related cytokines in NZB/NZW F1 mice. 973 89

Microbial DNA has multiple immune effects including the capacity to induce polyclonal B cell activation and cytokine production in normal mice. We recently described the accelerated induction of anti-DNA Abs in NZB/NZW mice immunized with Escherichia coli (EC) dsDNA; paradoxically these mice developed less renal disease than unimmunized mice or mice immunized with calf thymus DNA. We postulated that alterations in cytokine production induced by bacterial DNA may play a key role in renal protection. To determine the effect of bacterial DNA on cytokine production in NZB/NZW mice, we measured the serum cytokine levels, cell culture supernatant cytokine levels, and number of cytokine-producing splenocytes in NZB/NZW mice injected with EC DNA, calf thymus DNA, or an immune active oligonucleotide. There was a 10- to 25-fold increase in the number of cells secreting IFN-gamma compared with IL-4 in mice immunized with EC DNA. IL-12-secreting cells were also increased by bacterial DNA immunization. In parallel with the increase in IFN-gamma secreting cells, there was a significant rise in serum IFN-gamma levels in mice receiving EC DNA. These results indicate that EC DNA modulates systemic cytokine levels in NZB/NZW mice, selectively increasing IL-12 and IFN-gamma while decreasing IL-4 production. The cytokine response of NZB/NZW mice to bacterial DNA may be of significance in disease pathogenesis and relevant to the treatment of lupus-like disease.
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PMID:Effects of bacterial DNA on cytokine production by (NZB/NZW)F1 mice. 978 Jan 54

The objective of this study was to assess the impact of murine recombinant IFN-gamma and anti-IFN-gamma monoclonal antibody on the BALB/c mice experimental model of lupus. BALB/c female mice were immunized with a human anti-DNA antibody that carries the 16/6 idiotype. These mice were divided into several therapeutic groups according to different treatment strategies; injection with mouse recombinant IFN-gamma, anti-IFN-gamma mAb, phosphate-buffered saline (PBS), irrelevant mouse IgG and control groups that were neither treated nor immunized with the human anti-DNA antibody. The administration of IFN-gamma, intensified the degree of clinical, histological and serological parameters in this model of BALB/c murine lupus. This immunomanipulation decreased the mice longevity. All the laboratory parameters reflected acceleration of the disease in the IFN-gamma treated group as an elevated sedimentation rate, decreased white blood cell count and the development of massive proteinuria. One month after the boost injection, all the mice that were immunized with the anti-DNA antibody, developed high titers of autoantibodies; however, following an additional month, their levels declined in the IFN-gamma treated group. These findings were in concordance with an increased glomerular deposition of immune complexes in the IFN-gamma treated mice. IFN-gamma upregulated the levels of IL-4 and increased the number of IL-4 and IL-6 secreting splenocytes. In conclusion IFN-gamma administration can aggravate the clinical and laboratory outcome of 16/6 id induced lupus in BALB/c mice.
Lupus 1998
PMID:Immunomodulation of murine experimental SLE-like disease by interferon-gamma. 979 46


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