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)

Two models of murine graft-versus-host disease (GVHD) were studied with respect to autoantibody production and development of systemic lupus erythematosus (SLE) like disease. One model was induced by injection of (B10.A(4R) x B10.A(2R]F1 mice with parental (B10.A(4R] spleen and lymph node cells (groups I GVHD), the other by injection of (DBA/2 x C57/B16)F1 mice with DBA/2 cells (group II GVHD). Group I GVHD mice remained in a seemingly healthy condition and did not show any proteinuria, in spite of high titres of anti-nuclear antibodies including antibodies to dsDNA, anti-Sm and anti-ribosomal P protein antibodies. Measured levels of these autoantibodies as well as their isotypes were comparable with those found in MRL/lpr and NZB/W mice. Group II GVHD mice developed SLE-like disease signs, including severe proteinuria. At 4 months after induction of the GVHD, almost 50% of these mice had died. At the time nephritis was present, group II mice also produced anti-dsDNA and anti-nuclear antibodies of other (unknown) specificities, but no anti-Sm or anti-P. Furthermore, the incidence of these antibodies was lower than observed in group I GVHD, MRL/lpr or NZB/W mice. It is concluded that (high avidity) anti-dsDNA as well as anti-Sm and anti-P may be present in the circulation without giving rise to the development of nephritis.
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PMID:Fine specificities of anti-nuclear antibodies in murine models of graft-versus-host disease. 237 20

The present studies dealt with the pathogenesis of renal involvement in murine chronic graft-versus-host disease, which is a model for human systemic lupus erythematosus. The disease was induced in (C57BL10xDBA/2)F1 hybrids by injection of DBA/2 lymphocytes. The animals developed systemic disease accompanied by deposition of autoantibodies in the glomeruli and a lupus type of nephritis. Antibodies were eluted from glomeruli isolated during various stages of the disease by magnetic extraction from iron-perfused kidneys. For assessment of the specificity of the antibodies, we used indirect immunofluorescence, an enzyme-linked immunosorbent assay, and immunoblotting. In glomeruli from week 4, autoantibodies were found to be directed against several antigens, among which were the glomerular basement membrane component laminin and the glomerular enzyme dipeptidyl peptidase IV, whereas week 8 glomeruli also showed antibodies directed against nuclear antigens. Both laminin and dipeptidyl peptidase IV are known nephritogenic antigens occurring in renal tubular epithelial brush border preparations. Antibodies eluted from isolated glomeruli of diseased animals bound in a granular pattern along the glomerular capillary wall after in vivo transfer. Anti-renal tubular epithelial antibodies in the sera of diseased animals were affinity purified and injected into naive mice, which induced immune complex glomerulonephritis and proteinuria, thus confirming the nephritogenic role of these autoantibodies in this model.
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PMID:Characterization and in vivo transfer of nephritogenic autoantibodies directed against dipeptidyl peptidase IV and laminin in experimental lupus nephritis. 239 30

IgG-anti-keratin intermediate filament autoantibodies occur in low titers in all normal human sera. These same antibodies are present in high titers in the sera of patients who have diseases in which cells containing keratin intermediate filaments (KIF) have been damaged, such as systemic lupus erythematosus, graft-versus-host disease, and cutaneous tumors. Since some human autoantibodies are thought to function in part as opsonins promoting the removal of insoluble cellular proteins after tissue injury, we investigated the influence of IgG-anti-KIF autoantibodies on the phagocytosis of insoluble KIF aggregates by human monocytes and polymorphonuclear neutrophils (PMN). Keratin intermediate filaments assembled in vitro were reconstituted into dense spherical KIF aggregates 0.3-2.5 microns in diameter by dialysis against phosphate-buffered saline. Immunoelectron microscopy revealed that, as expected, human IgG-anti-KIF autoantibodies bound to the KIF aggregates. Human monocytes or PMN were incubated either with nonopsonized KIF aggregates or with KIF aggregates that had been reacted with IgG-anti-KIF autoantibodies. The uptake of KIF aggregates was visualized by indirect immunofluorescence, immunoperoxidase staining, and immunoelectron microscopy. Monocytes rapidly and efficiently bound and phagocytosed KIF aggregates that had been coated with IgG-anti-KIF autoantibodies. Nonopsonized KIF aggregates, in contrast, were taken up much less efficiently. Differences were most marked at 4 degrees C for 60 min with phagocytosis of opsonized KIF aggregates by 23 +/- 8% of monocytes in contrast to phagocytosis by only 0.2 +/- 3% monocytes when nonopsonized KIF aggregates were used. Similar results occurred at 37 degrees C for 5 min with phagocytosis by 38 +/- 28% vs 1.8 +/- 0.4% of monocytes of opsonized and nonopsonized KIF aggregates, respectively. A high percentage of PMN also phagocytosed opsonized KIF aggregates, whereas nonopsonized KIF aggregates were ingested less avidly. These data indicate that the opsonization of extracellular KIF aggregates by IgG-anti-KIF autoantibodies plays an important role in promoting the phagocytosis of KIF aggregates. The subsequent phagocytosis represents a rapid and very effective mechanism for the removal of insoluble KIF following keratinocyte cell death.
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PMID:Phagocytosis of keratin filament aggregates following opsonization with IgG-anti-keratin filament autoantibodies. 243 55

The effect of a number of drugs commonly used to treat the more severe exacerbations of the autoimmune disease systemic lupus erythematosus (SLE) in humans has been investigated in the murine chronic graft-versus-host (GVH) induced model of lupus. This was undertaken in order to determine the value of this model for the investigation of immunomodulant drugs, with particular regard to the reproducibility of disease induction and methods of monitoring disease progression. The drugs were azathioprine, cyclophosphamide, cyclosporin A and dexamethasone. All of these, except for azathioprine, reduced disease severity, assessed as the development of lupus nephritis. Anti-ssDNA autoantibodies were also reduced in titre in the dexamethasone-treated group. Overall, these findings, combined with the reproducible induction of disease seen in this model, support the use of chronic GVH disease as a model for SLE and show that the induced disease can be ameliorated by drugs effective in the treatment of SLE in humans.
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PMID:Murine chronic graft-versus-host disease as a model of systemic lupus erythematosus: effect of immunosuppressive drugs on disease development. 261 55

The inoculation of B6D2F1 mice with T lymphocytes from the C57BL/6 parental strain induces an "immunosuppressive" graft-vs-host reaction (B6 GVH), whereas inoculation of T cells from the other, DBA/2 parental strain induces an "immunostimulatory" GVH reaction and a lupus-like disease (DBA GVH). The present study compares cytotoxic T lymphocyte (CTL) function in the spleens of these GVH mice as well as differences in the donor inoculum that could account for these different types of GVH. We observed that the B6 GVH induces an immunodeficiency that encompasses CTL precursors (and possibly T helper cells) and results in suppressor cells that abrogate responses to both trinitrophenyl (TNP)-modified self and third party alloantigens. In contrast, the DBA GVH induces only a T helper cell immunodeficiency and results in suppressor cells selective for class II restricted L3T4+ T helper cells. Chimeric T cells were detected in both types of GVH. In the B6 GVH both L3T4+ and Lyt-2+ donor cells were observed, although Lyt-2+ cells predominated. In the DBA GVH, donor T cells were almost exclusively of the L3T4+ phenotype. The lack of appreciable donor Lyt-2+ cells in the DBA GVH can be explained by a defect in the DBA donor inoculum manifested by a naturally occurring two-fold reduction in Lyt-2+ cell numbers as well as a nine-fold reduction in CTL precursors with anti-F1 specificity. T cells in the DBA inoculum, therefore, are predominantly L3T4+. A similar defect induced in B6 donor cells by anti-Lyt2 antibody and complement not only converted the suppressive GVH to a stimulatory GVH, as measured by anti-DNA antibodies, but also resulted in a T cell immune deficiency characteristic of the DBA GVH, i.e., a selective loss of the TNP-self CTL response. Thus the presence or absence of adequate numbers of functioning Lyt-2+ cells in the donor inoculum is correlated with the development of either a suppressive or stimulatory GVH, respectively. That donor Lyt-2+ cells mediate a suppressive GVH through cytolytic mechanisms is evidenced by greater than 70% reduction in B6 GVH spleen cell numbers and readily demonstrable anti-F1 CTL activity by these spleen cells despite an inability to generate anti-allogeneic or anti-TNP self CTL activity even in the presence of added T helper factors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of cytotoxic T lymphocytes in the prevention of lupus-like disease occurring in a murine model of graft-vs-host disease. 295 40

The graft-versus-host reaction (GVHR) in both mice and humans can lead to the development of a broad spectrum of clinical and pathological symptoms. These symptoms are strikingly similar to those of a number of diseases of proven or presumed immunological origin, such as systemic lupus erythematosus (SLE), other collagen vascular diseases, lymphoproliferative disease, and aplastic anemia. The purpose of our investigation was to describe the immunological and pathological events that take place in the course of graft-versus-host disease (GVHD) and to gain insight into the cellular mechanisms underlying these events. To this end, a model was employed in which nonirradiated F1 mice were used as recipients of parental lymphoid cells. By pathological manifestations, 2 basic forms of GVHD can be distinguished in such non-irradiated F1 recipients: One is acute GVHD which is often lethal. It is characterized by a variety of suppressive (hypoplastic) pathological symptoms, including a severe hypoplasia of the lymphohemopoietic system accompanied by aplastic anemia and hypogammaglobulinemia. The other basic form is characterized by stimulatory symptoms, such as persistent lymphoid hyperplasia, formation of autoantibodies, and development of pathological symptoms reminiscent of SLE and other collagen vascular diseases. The suppressive pathological graft-versus-host (GVH) symptoms are caused by T suppressor/killer (TS/K) cells of the donor which react towards allogeneic class-I-structures of the F1 recipient's major histocompatibility complex (MHC). The stimulatory pathological GVH symptoms, by contrast, are caused by donor T helper (TH) cells which react toward the recipient's allogeneic class-II-MHC structures. The possible implications of these observations for the pathogenesis of a number of GVH-like diseases in humans are discussed. The hypothesis is advanced that some of these GVH-like conditions, which arise either e causa ignota or after exposure to certain viruses or drugs, are caused by T lymphocytes reacting against self-MHC structures on lymphohemopoietic cells that were rendered "foreign". By analogy to GVHD, it is conceivable that the development of either stimulatory or suppressive GVH-like symptoms in individuals exposed to a given virus or sensitizing drug depends not on the etiologic agent per se, but on whether the predominant response is made by the individual's TH or TS@K cells. This, in turn, might depend on whether the agent becomes immunogenic in combination with class-II or class-I alloantigens.
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PMID:Pathogenesis of graft-versus-host reactions (GVHR) and GVH-like diseases. 315 4

Systemic lupus erythematosus-like graft-versus-host (GVH) disease was induced in 10-week-old male (C57BL/10 X DBA/2) F1 mice by the intravenous injection of spleen and thymus cells (2:1) from 10-week-old male DBA/2 mice. GVH mice were bled at regular intervals 1 month after injection. Antibody to nuclear antigens (ANA) were detected by immunofluorescence using HEp-2 cells as substrate, and antibody to histones and DNA were detected by enzyme-linked immunosorbent assay (ELISA). The titer and frequency of ANA were found to relate directly to the number of donor cells injected. In order to determine the spectrum of ANA in GVH disease, mice were reinjected with optimum cell numbers (120 X 10(6], and splenocytes from two mice with high titer ANA were fused to mouse myeloma cell line P3/X63Ag8.653. Hybridomas were analyzed for ANA by immunofluorescence and ELISA. Sixty-eight clones were found which secreted ANA. Of these, 59% produced antibody to double-stranded DNA, single-stranded DNA, and/or histones and the remainder gave a variety of nuclear immunofluorescence patterns including speckled, homogeneous, nuclear matrix, and nucleolar. This study indicates that GVH disease provides an excellent source of splenocytes for the production of ANA-producing hybridomas as well as a model for the study of autoimmunity.
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PMID:Monoclonal autoantibodies to nuclear antigens from murine graft-versus-host disease. 349 80

(C57BL/6 X DBA/2)F1 mice undergoing the graft-vs-host reaction (GVHR) produce autoantibodies after the injection of DBA/2 lymphoid cells. The anti-nuclear antibodies, including anti-poly (ADP-ribose) and anti-extractable nuclear antigens (ENA), in the sera of the autoimmune GVH F1 mice were investigated. Antibodies to double-stranded DNA, single-stranded DNA and ENA were predominantly IgG. In contrast, the autoantibodies to poly(ADP-ribose) were both IgG and IgM, although the former was predominant. These autoantibodies induced by the GVHR showed similar cross-reactivities with a number of nucleic acids to the monoclonal and some serum antinuclear antibodies derived from mice or humans with systemic lupus erythematosus (SLE). These results support the idea that GVH F1 mice are a good model of human SLE.
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PMID:Specificity of anti-nuclear antibodies induced in F1 mice undergoing the graft-vs-host reaction: isotypes and cross-reactivities. 349 93

Highly purified and cloned preparations of interleukin-1 (IL-1) were found to antagonize the capacity of erythropoietin (Epo) to stimulate the proliferation of mouse spleen and bone marrow erythroid precursor cells (EPC) in culture. Cloned murine IL-1 and purified and cloned human IL-1 alpha and IL-1 beta were approximately equipotent in this assay. IL-1 inhibited the proliferation response of EPC even when added as long as 17 h after Epo, suggesting that IL-1 does not affect binding of Epo to receptors or biochemical events following shortly thereafter. Indomethacin did not influence the inhibitory effect of IL-1 on Epo-induced proliferation, and PGE2 had no demonstrable effect on the process. Tumor-necrosis factor-alpha and interferons beta 1, and gamma did not affect Epo-induced proliferation. It is suggested that IL-1 mediated antagonism of the effects of Epo on erythroid precursors is a factor in the pathogenesis of many types of hypoplastic anaemia, including those associated with infections, rheumatoid arthritis and systemic lupus erythematosus, giant-cell arteritis, graft-versus-host disease and disorders associated with lymphocyte-mediated suppression of erythropoiesis.
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PMID:Inhibition by interleukin-1 of the action of erythropoietin on erythroid precursors and its possible role in the pathogenesis of hypoplastic anaemias. 349 70

This review covers significant developments in the understanding of the biochemistry and clinical pharmacology of Interleukin-2 (IL-2) that were achieved from 1984 through September 1986. These include developments in the molecular biology of IL-2 and its receptors. Human IL-2 was cloned and sequenced by Taniguchi et al. in 1983. The gene for human IL-2 is located on the long arm of chromosome 4. The secondary structure of the gene is predominantly alpha helix. The mature gene product is a 133 amino acid glycoprotein with a molecular weight of 15,420 Daltons. The IL-2 receptor was revealed to be a glycoprotein of 272 amino acids. The mature receptor has a molecular weight of 55,000 Daltons. A more precise understanding of the mechanism of action IL-2, in particular its role in the induction of the IL-2 receptor, and aspects of the control of IL-2 production was also achieved. Metabolic and morphologic studies have revealed that activation of the T-cell antigen receptor renders the cells responsive to IL-2, but does not move them through the cell cycle. Rather, it appears that IL-2 stimulates G1 progression to S phase ie. blastic transformation. During this progression the cellular proto-oncogene c-myb is induced transiently to 6 to 7 times basal levels. The role of IL-2 as a growth factor for several subsets of T cells has been confirmed, and a new role as a growth factor for B cells was defined. Most importantly, IL-2 was shown to be directly mitogenic for and to expand subpopulations of peripheral blood cells, termed lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes (TIL). A number of pathologies of IL-2 production or activity have been defined, including Hodgkin's disease, graft versus host disease, systemic lupus erythematosus, lepromatous leprosy, acquired immune deficiency syndrome, and adult T cell leukemia. Murine and human in vivo studies reviewed here have revealed significant parameters of the therapeutic potential as well as the toxicity of this growth factor. Finally, the modulation of IL-2 receptors on human PBL's by thymosin fraction 5 and thymosin alpha 1 suggests that it might be possible to up-regulate IL-2 receptor expression in certain disease states and thus increase the efficacy of IL-2.
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PMID:Recent advances in the understanding of the biochemistry and clinical pharmacology of interleukin-2. 354 63


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