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 pathogenesis of systemic lupus erythematosus is thought to be primarily under genetic control, with environmental factors playing a secondary role. However, it has been shown recently that intraperitoneal injection of pristane (2,6,10,14-tetramethylpentadecane) induces autoantibodies typical of lupus in BALB/c mice, a strain not usually considered to be genetically susceptible to the disease. In this study, the induction of autoimmune disease by pristane was investigated. BALB/c mice receiving pristane were tested for autoantibody production and histopathological evidence of glomerulonephritis. Six of 11 mice developed IgM anti-single-stranded DNA antibodies shortly after receiving pristane and 4 developed IgM anti-histone antibodies, but anti-double-stranded DNA antibodies were absent. IgG anti-DNA and anti-histone antibodies were absent. In contrast, the lupus-associated anti-nuclear ribonucleoprotein/Sm and anti-Su autoantibodies produced by these mice were predominantly IgG. In addition to autoantibodies, most of the mice developed significant proteinuria. Light microscopy of the kidney showed segmental or diffuse proliferative glomerulonephritis. Electron microscopy showed subepithelial and mesangial immune-complex deposits and epithelial foot process effacement. Immunofluorescence revealed striking glomerular deposition of IgM, IgG, and C3 with a mesangial or mesangiocapillary distribution. Thus, pristane induces immune-complex glomerulonephritis in association with autoantibodies typical of lupus in BALB/c mice. These data support the idea that lupus is produced by an interplay of genetic and environmental factors and that unlike the MRL or (NZB x W)F1 mouse models, in which genetic susceptibility factors are of primary importance, environmental factors are of considerable importance in the autoimmune disease of pristane-treated BALB/c mice.
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PMID:Anti-nuclear antibody production and immune-complex glomerulonephritis in BALB/c mice treated with pristane. 747 13

Pristane induces a lupus-like syndrome characterized by autoantibody production and glomerulonephritis in nonautoimmune strains of mice. Although it has been suggested that this syndrome results from nonspecific immune activation, there is little evidence so far that B cells are activated nonspecifically by pristane or that this promotes autoimmunity. In this study, we examined whether polyclonal hypergammaglobulinemia occurs in pristane-induced lupus, and its relationship to the production of anti-DNA, nRNP/Sm, and Su autoantibodies. In conventionally housed mice, there was a marked increase in total IgM and IgG3 2 weeks after i.p. pristane injection, followed by increased IgG1, IgG2a, and IgG2b levels. IgM levels were higher in pristane-treated specific pathogen-free (SPF) mice than in conventionally housed mice, whereas IgG and IgA levels were reduced. Pristane induced anti-nRNP/Sm and Su autoantibodies in SPF mice, but their onset was delayed and levels were lower than those in conventionally housed mice. There was no consistent relationship between total IgG1, 2a, and 2b hypergammaglobulinemia and production of anti-nRNP/Sm and Su autoantibodies. Moreover, the total Ig levels were similar in the anti-nRNP/Sm-positive and -negative groups. In contrast, production of IgM anti-ssDNA antibodies paralleled IgM hypergammaglobulinemia in some, but not all, mice. These studies indicate that pristane-induced lupus is associated with marked hypergammaglobulinemia, the magnitude of which is influenced by the microbial environment. However, anti-nRNP/Sm and Su autoantibody production is at least partly independent of polyclonal B cell activation. The data strongly suggest that pristane-induced lupus is not exclusively the consequence of nonspecific immune stimulation. They also point to the importance of microbial stimulation in the development of hypergammaglobulinemia in this inducible lupus model.
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PMID:Influence of microbial stimulation on hypergammaglobulinemia and autoantibody production in pristane-induced lupus. 955 60

Pristane induces a lupus-like syndrome in nonautoimmune mice characterized by the development of glomerulonephritis and lupus-associated autoantibodies. This is accompanied by overproduction of interleukin (IL)-6, a cytokine linked with autoimmune phenomena. The goal of this study was to evaluate the role of IL-6 in autoantibody production in pristane-induced lupus. BALB/cAn IL-6-deficient (-/-) and -intact (+/+) mice were treated with pristane or phosphate-buffered saline, and autoantibody production was evaluated. Pristane induced high levels of immunoglobulin (Ig)G anti-single-stranded DNA, -double-stranded (ds)DNA, and -chromatin antibodies in IL-6(+/+), but not IL-6(-/-) mice by enzyme-linked immunosorbent assay. High titer IgG anti-dsDNA antibodies also were detected in sera from +/+, but not -/-, mice by Crithidia luciliae kinetoplast staining. The onset of IgG anti-dsDNA antibody production in +/+ mice occurred >5 mo after pristane treatment, well after the onset of nephritis, suggesting that these antibodies are not directly responsible for inducing renal disease. In contrast to anti-DNA, the frequencies of anti-nRNP/Sm and anti-Su antibodies were similar in pristane-treated IL-6(-/-) and IL-6(+/+) mice. However, levels were higher in the +/+ group. These results suggest that IgG anti-DNA and chromatin antibodies in pristane-treated mice are strictly IL-6 dependent, whereas induction of anti-nRNP/Sm and Su autoantibodies is IL-6 independent. The IL-6 dependence of anti-DNA, but not anti-nRNP/Sm, may have implications for understanding the patterns of autoantibody production in lupus. Anti-DNA antibodies are produced transiently, mainly during periods of disease activity, whereas anti-nRNP/Sm antibody levels are relatively insensitive to disease activity. This may reflect the differential IL-6 dependence of the two responses.
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PMID:Interleukin 6 dependence of anti-DNA antibody production: evidence for two pathways of autoantibody formation in pristane-induced lupus. 973 Sep

Intraperitoneal injection of pristane induces a lupus-like disease in BALB/c and other non-autoimmune mice characterized by autoantibody production and the development of immune complex disease closely resembling lupus nephritis. Two subsets of autoantibodies are induced by pristane: IgG anti-DNA DNA and -chromatin autoantibodies are strongly IL-6-dependent, whereas IgG anti-nRNP/Sm and -Su antibodies are not. The present studies were carried out to examine the role of T cells in establishing this dichotomy between the production of anti-nRNP/Sm/Su versus anti-DNA/chromatin autoantibodies. Autoantibody production and renal disease were evaluated in athymic (nude) mice treated with pristane. BALB/c nu/nu mice spontaneously developed IgM and IgG anti-single-stranded (ss)DNA and -chromatin, but not anti-nRNP/Sm or -Su, autoantibodies. Pristane treatment increased the levels of IgG anti-chromatin antibodies in nu/nu mice, but did not induce production of anti-nRNP/Sm or -Su antibodies. In contrast, BALB/c nu/+ and +/+ control mice did not spontaneously produce autoantibodies, whereas anti-nRNP/Sm and -Su autoantibodies were induced by pristane in approx. 50% of nu/+ and +/+ mice and anti-DNA/chromatin antibodies at lower frequencies. Nude mice spontaneously developed mild renal lesions that were marginally affected by pristane, but were generally milder than the lesions developing in pristane-treated nu/+ and +/+ mice. The data provide further evidence that two distinct pathways with different cytokine and T cell requirements are involved in autoantibody formation in pristane-induced lupus. This dichotomy may be relevant to understanding differences in the regulation of anti-DNA versus anti-nRNP/Sm autoantibodies in systemic lupus erythematosus, as well as the association of anti-DNA, but not anti-nRNP/Sm, with lupus nephritis.
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PMID:Disparate T cell requirements of two subsets of lupus-specific autoantibodies in pristane-treated mice. 1019 32

Systemic lupus erythematosus (SLE) is a systemic autoimmune syndrome defined by clinical and serologic features, including arthritis, glomerulonephritis, and certain autoantibodies such as anti-nuclear ribonucleoprotein (nRNP)/Smith antigen (Sm), DNA, and ribosomal P. Although lupus is considered primarily a genetic disorder, we recently demonstrated the induction of a syndrome strikingly similar to spontaneous lupus in many nonautoimmune strains of mice exposed to the isoprenoid alkane pristane (2,6,10,14-tetramethylpentadecane), a component of mineral oil. Intraperitoneal injection of pristane leads to the formation of lipogranulomas consisting of phagocytic cells that have engulfed the oil and collections of lymphocytes. Subsequently, pristane-treated BALB/c and SJL mice develop autoantibodies characteristic of SLE, including anti-nRNP/Sm, antiribosomal P, anti-Su, antichromatin, anti-single-stranded DNA, and anti-double-stranded DNA. This is accompanied by a severe glomerulonephritis with immune complex deposition, mesangial or mesangiocapillary proliferation, and proteinuria. All inbred mice examined appear to be susceptible to this novel form of chemically induced lupus. Pristane-induced lupus is the only inducible model of autoimmunity associated with the clinical syndrome as well as with the characteristic serologic abnormalities of SLE. Defining the immunopathogenesis of pristane-induced lupus in mice may provide insight into the causes of spontaneous (idiopathic) lupus and also may lead to information concerning possible risks associated with the ingestion or inhalation of mineral oil and exposure to hydrocarbons in the environment.
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PMID:Immunopathogenesis of environmentally induced lupus in mice. 1050 37

Mutations of Fas (lpr) or Fas ligand (gld) cause a limited lupus-like syndrome in B6 mice by interfering with the deletion of autoreactive B and/or T cells. A more generalized lupus syndrome reminiscent of that of MRL mice can be induced in nonautoimmune strains by pristane, which causes a nonspecific inflammatory response in the peritoneal cavity. We hypothesized that, as in MRL mice, the lpr and gld mutations might accelerate lupus in pristane-treated mice. Pristane-treated B6 mice developed anti-nRNP/Sm, Su, and ribosomal P Abs, but little anti-ssDNA or chromatin. In contrast, B6/lpr and B6/gld mice spontaneously developed anti-ssDNA/chromatin Abs, but not anti-nRNP/Sm/Su/ribosomal P. Unexpectedly, B6/lpr and B6/gld mice were highly resistant to the induction by pristane of IgM anti-ssDNA (2 wk) and IgG anti-nRNP/Sm/Su/ribosomal P autoantibodies (6 mo), suggesting that intact Fas signaling is necessary. Interestingly, pristane did not enhance IgG chromatin Ab production in B6/lpr or B6/gld mice, suggesting that it did not influence the production of autoantibodies that develop spontaneously in the setting of Fas deficiency. Pristane treatment also decreased lymphoproliferation in B6/lpr mice. Increased production of IL-12 was associated consistently with the production of anti-nRNP/Sm/Su/ribosomal P as well as anti-DNA/chromatin. In contrast, production of anti-DNA/chromatin Abs was associated with IL-6 overproduction in pristane-treated mice, but not in lpr mice. The data strongly support the idea that different subsets of autoantibodies are regulated differentially by cytokine stimulation and/or Fas signaling.
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PMID:Fas and Fas ligand mutations inhibit autoantibody production in pristane-induced lupus. 1087 81

Although mineral oils are generally considered nontoxic and have a long history of use in humans, the mineral oil Bayol F (incomplete Freund's adjuvant, IFA) and certain mineral oil components (squalene and n-hexadecane) induce lupus-related anti-nRNP/Sm or -Su autoantibodies in nonautoimmune mice. In the present study, we investigated whether medicinal mineral oils can induce other types of autoantibodies and whether structural features of hydrocarbons influence autoantibody specificity. Female 3-month-old BALB/c (16-45/group) mice each received an i.p. injection of pristane (C19), squalene (C30), IFA, three medicinal mineral oils (MO-F, MO-HT, MO-S), or PBS. Sera were tested for autoantibodies and immunoglobulin levels. Hydrocarbons were analyzed by gas chromatography/mass spectrometry. IFA contained mainly C15-C25 hydrocarbons, whereas MO-HT and MO-S contained C20-C40, and MO-F contained C15-C40. Pristane and n-hexadecane were found in IFA (0.17% and 0.10% w/v, respectively) and MOs (0.0026-0.027%). At 3 months, pristane and IFA induced mainly IgG2a, squalene IgG1, and MOs IgG3 and IgM in sera. Anti-cytoplasmic antibodies were common in mice treated with MO-F, as well as those treated with pristane, squalene, and IFA. Anti-ssDNA and -chromatin antibodies were higher in MO-F and MO-S than in untreated/PBS, squalene-, or IFA-treated mice, suggesting that there is variability in the induction of anti-nRNP/Sm versus -chromatin/DNA antibodies. The preferential induction of anti-chromatin/ssDNA antibodies without anti-nRNP/Sm/Su by MO-S and MO-F is consistent with the idea that different types of autoantibodies are regulated differently. Induction of autoantibodies by mineral oils considered nontoxic also may have pathogenetic implications in human autoimmune diseases.
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PMID:Distinctive patterns of autoimmune response induced by different types of mineral oil. 1471 49

The metabolism of radioiodinated mouse IgG was studied in mice with lupus-like syndrome before and after the onset of the disease. Before the onset of the disease, the pharmacokinetic parameters of IgG in MLR-1pr and Pristane-primed Balb/c mice were within the normal range of values. After the onset of the disease a considerable increase in the catabolic rate of IgG was recorded abbreviating its half life to less than one third of the normal value. The increased catabolism of IgG could not be related to the concentration--catabolism effect or to the presence of rheumatoid factor and autoantibody or to the IgG loss through the kidney and gastrointestinal tract. The hypercatabolism of IgG was explained by disease-induced impairment of the function of the receptor FcRn, which regulates the homeostasis of IgG.
Lupus 2005
PMID:Hypercatabolism of IgG in mice with lupus-like syndrome. 1603 10

Intraperitoneal injection of the hydrocarbon oil pristane into normal mice leads to a lupus-like autoimmune syndrome. Although advances in defining the roles of cellular and humoral mediators involved in this syndrome have been made, the mechanisms that initiate a break in tolerance leading to autoimmunity remain unknown. We describe in this study that pristane induces apoptosis both in vivo and in vitro. Pristane arrests cell growth and induces cell death by apoptosis via the mitochondrial pathway of caspase activation in a dose-dependent manner. Nuclear autoantigens created by pristane-induced apoptosis of lymphoid cells within the peritoneal cavity in the setting of a profoundly altered cytokine milieu may be the initiating event in the development of autoimmunity in this syndrome. These findings suggest that apoptosis may be a critical initial event in the pathogenesis of pristane-induced lupus and are of potential relevance for human systemic lupus erythematosus.
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PMID:Induction of apoptosis by the hydrocarbon oil pristane: implications for pristane-induced lupus. 1617 26

Increased type I interferon (IFN-I) production and IFN-stimulated gene (ISG) expression are linked to the pathogenesis of systemic lupus erythematosus (SLE). Although the mechanisms responsible for dysregulated IFN-I production in SLE remain unclear, autoantibody-mediated uptake of endogenous nucleic acids is thought to play a role. 2,6,10,14-tetramethylpentadecane (TMPD; also known as pristane) induces a lupus-like disease in mice characterized by immune complex nephritis with autoantibodies to DNA and ribonucleoproteins. We recently reported that TMPD also causes increased ISG expression and that the development of the lupus is completely dependent on IFN-I signaling (Nacionales, D.C., K.M. Kelly-Scumpia, P.Y. Lee, J.S. Weinstein, R. Lyons, E. Sobel, M. Satoh, and W.H. Reeves. 2007. Arthritis Rheum. 56:3770-3783). We show that TMPD elicits IFN-I production, monocyte recruitment, and autoantibody production exclusively through a Toll-like receptor (TLR) 7- and myeloid differentiation factor 88 (MyD88)-dependent pathway. In vitro studies revealed that TMPD augments the effect of TLR7 ligands but does not directly activate TLR7 itself. The effects of TMPD were amplified by the Y-linked autoimmune acceleration cluster, which carries a duplication of the TLR7 gene. In contrast, deficiency of Fcgamma receptors (FcgammaRs) did not affect the production of IFN-I. Collectively, the data demonstrate that TMPD-stimulated IFN-I production requires TLR7/MyD88 signaling and is independent of autoantibody-mediated uptake of ribonucleoproteins by FcgammaRs.
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PMID:TLR7-dependent and FcgammaR-independent production of type I interferon in experimental mouse lupus. 1904 36


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