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 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

The onset of clinical disease in autoimmune MRL-lpr/lpr mice is preceded by a switch from predominantly IgM production to IgG production. Previous studies have shown that IgG autoantibodies play a central role in the development of life-threatening glomerulonephritis in this strain. Delaying or preventing the switch from IgM to IgG production might therefore be of therapeutic benefit. We previously documented similarities in the B cell repertoire expressed by young MRL-lpr/lpr mice and normal mice treated with the polyclonal activator LPS. Recent in vivo studies indicate that cross-linking membrane IgM or IgD can suppress LPS-dependent IgG production in normal animals. These observations led us to examine whether membrane cross-linking could also lower serum IgG levels in MRL-lpr/lpr mice. Lupus-prone animals were treated with multivalent anti-IgD conjugated to high m.w. dextran. This anti-IgD dextran conjugate was previously shown to reduce IgG production in LPS-stimulated normal animals. Treatment of young lupus-prone MRL-lpr/lpr mice resulted in a significant reduction in the total number of B cells secreting IgG and lower serum titers of IgG anti-DNA and IgG anti-histone autoantibodies. Anti-IgD dextran treatment also delayed the development of glomerulonephritis and improved survival. Thus, anti-IgD dextran interfered with autoantibody-dependent disease progression, perhaps by inhibiting the switch from IgM to IgG autoantibody production.
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PMID:Treatment with dextran-conjugated anti-IgD delays the development of autoimmunity in MRL-lpr/lpr mice. 751 19

Dogs can develop systemic lupus erythematosus syndromes that are clinically similar to those seen in humans. In contrast, previous observations suggest differences in their autoantibody reactivity patterns against histones and DNA which are components of the nucleosome in chromatin. The objective of this study was to assess comprehensively the levels of autoantibodies against histone, DNA and nucleosome antigens in a population of lupus dogs. The specificities of antibodies in lupus and control dog sera were determined using IgM- and IgG-specific reagents in an ELISA against a variety of chromatin antigens. When compared with control sera, IgG antibodies to individual histones H1, H2A, H3 and H4 were significantly higher in the lupus group. In contrast, we did not detect IgG antibodies specific for H2B, H2A-H2B, DNA, H2A-H2B-DNA or nucleosome in lupus dogs. There was no significant increase in any of the IgM specificities tested. Therefore, the reactivity pattern to nucleosome antigens in canine lupus is restricted to IgG antibodies against individual histones H1, H2A, H3 and H4. This stands in contrast with human and murine lupus, where autoantibodies are directed against a wide variety of nucleosomal determinants, suggesting that unique mechanisms lead to the expansion of anti-histone antibody clones in canine lupus. The high incidence of glomerulonephritis in dog lupus suggests that anti-DNA antibodies are not required for the development of this complication, whereas IgG anti-histone antibodies may be relevant to its pathogenesis.
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PMID:Autoantibodies to histone, DNA and nucleosome antigens in canine systemic lupus erythematosus. 752 50

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

Heparan sulphate-reactive antibodies in lupus sera have been suggested to be anti-DNA-DNA/histone immune complexes and to be associated with lupus nephritis. In this study, 23 anti-DNA-positive lupus sera including 13 active nephritis sera were tested for the presence of circulating anti-DNA-DNA/histone immune complexes by solid phase heparan sulphate-ELISA. Because of high background binding to protamine chloride-linked heparan sulphate plates, poly-L-lysine (PLL) was used as a linker and the remaining active sites of PLL were blocked with poly-L-glutamic acid. The ELISA was capable of detecting small amounts of anti-DNA IgG-DNA/histone immune complexes formed in vitro. However, only three active nephritis sera of the 23 sera tested showed significant binding to heparan sulphate plates. This binding was found to be non-specific, the result of high background binding of IgG to PLL. Anti-heparan sulphate ELISA using positively charged linkers detects non-specific binding when lupus sera are tested. Specific assays need to be developed for DNA/histone-related immune complexes present in lupus sera.
Lupus 1995 Feb
PMID:Heparan sulphate-ELISA gives false positive results for anti-DNA-DNA/histone immune complexes in sera of patients with SLE. 753 23

When measured serially by Farr assay at a frequency of approximately once a month, changes in levels of anti-dsDNA appear to be a good predictor of clinical disease activity. Although the role of antibodies to the RNA component of snRNP awaits further studies, measurement of anti-UsnRNP antibody levels seems to be of limited value in monitoring lupus patients in clinical practice. The same holds for antibodies to SSA (Ro) and anti-histone antibodies. More recently described antibodies to C1q are probably useful in the follow-up of SLE patients suspected of proliferative renal involvement. The best alternative to measuring levels of the antibodies mentioned before is probably serial analysis of activation of the complement cascade. Levels of complement factors like C3, C4 and, functionally, CH50 remain a useful parameter for monitoring disease activity in SLE, although fluctuations in anti-dsDNA as measured by Farr assay seem superior with respect to sensitivity and specificity for an ensuing relapse. Despite the problems in sampling, measuring levels of activated split products of complement factors like C3a, C3d or C5a may prove to be a valuable tool in the follow-up of lupus patients. The involvement of the endothelial surface is illustrated by rising sVCAM-1 levels prior to relapses in SLE. Although one could expect that subsequent inflammation should be reflected by increased levels of inflammatory molecules like CRP and IL-6, the use of these molecules as predictors of lupus activity seems limited. Interferon-alpha as a direct reflector of the effector phase seems, however, rather promising in this respect and awaits longitudinal studies to analyse the possible relation with clinical disease activity and other serological parameters.
Lupus 1995 Apr
PMID:Serological markers of disease activity in systemic lupus erythematosus. 779 29

A 58 year old woman developed systemic symptoms, interstitial lung disease, splenomegaly, leukopenia and anti-histone and anti-nuclear antibodies (ANA), while treated with hydralazine for hypertension. Five months after presentation she was admitted with high fever, skin rash and atypical lymphocytosis due to acute cytomegalovirus (CMV) infection. Worsening leukopenia and increased ANA were found, and high titres of anti-DNA antibodies, anti-cardiolipin antibodies and rheumatoid factors appeared. Hydralazine was stopped and the patient gradually became asymptomatic. All autoantibodies spontaneously disappeared (over 16 weeks), and the white cell count and spleen size became normal. The patient was found to be a slow acetylator and to have both HLA-DR4 and selective IgA deficiency. Thus, a multifactorial genetic susceptibility to develop drug-induced lupus was brought out in stages first by hydralazine and then by CMV, yet all manifestations and autoantibodies resolved spontaneously, demonstrating the complex interplay of varied environmental factors with a genetic predisposition in the pathogenesis of autoimmunity.
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PMID:Effect of acute cytomegalovirus infection on drug-induced SLE. 783 Nov 73

The production of potentially pathogenic anti-DNA autoantibodies in SLE is driven by special, autoimmune T helper (Th) cells. Herein, we sequenced the T cell receptor (TCR) alpha and beta chain genes expressed by 42 autoimmune Th lines from lupus patients that were mostly CD4+ and represented the strongest inducers of such autoantibodies. These autoimmune TCRs displayed a recurrent motif of highly charged residues in their CDR3 loops that were contributed by N-nucleotide additions and also positioned there by the recombination process. Furthermore, Th lines from four of the five patients showed a marked increase in the usage of the V alpha 8 gene family. Several independent Th lines expressed identical TCR alpha and/or beta chain sequences indicating again antigenic selection. 10 of these Th lines could be tested further for antigenic specificity. 4 of the 10 pathogenic anti-DNA autoantibody-inducing Th lines responded to the non-histone chromosomal protein HMG and two responded to nucleosomal histone proteins; all presented by HLA-DR molecules. Another Th line responded to purified DNA more than nucleosomes. Thus, these autoimmune Th cells of lupus patients respond to charged epitopes in various DNA-binding nucleoproteins that are probably processed and presented by the anti-DNA B cells they selectively help.
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PMID:Structure and specificity of T cell receptors expressed by potentially pathogenic anti-DNA autoantibody-inducing T cells in human lupus. 786 Jul 35

To clarify the pathogenesis of lupus nephritis, we developed an assay that defines a glomerular binding activity (GBA) in both murine and human lupus sera highly correlated with nephritis. In the current study, we used a cross-adsorption strategy to establish that the GBA in MRL lpr serum binds to the glomerular basement membrane (GBM). We subsequently observed that this binding to the GBM was competitively inhibited by either exogenous DNA or histone, abrogated by pretreatment of the GBM with DNAse, and restored after DNase treatment with DNA/histone in a synergistic fashion. GBM binding was also completely inhibited by pretreatment of GBM with collagenase but not heparatinase. The effect of collagenase was not reversed by the subsequent addition of DNA, but was restored by the sequential re-addition of type IV collagen and DNA. By using purified basement membrane components, we found that MRL lpr serum bound avidly to DNA coated on type I collagen but less well (or not at all) to DNA coated on type IV collagen, laminin, or fibronectin. Histone pretreatment of type IV collagen before DNA addition, however, synergistically enhanced binding in a fashion similar to that seen with native GBM. Thus, the GBA in MRL lpr serum seems to be comprised of autoantibodies that bind to histones and/or DNA that adhere to type IV collagen within the GBM. These data support the planted Ag hypothesis as the principal pathogenic mechanism in lupus nephritis and suggest that multiple autoantibodies may contribute to this disorder.
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PMID:Glomerular binding activity in MRL lpr serum consists of antibodies that bind to a DNA/histone/type IV collagen complex. 786 8

We report evidence for a strong selection event directing the outgrowth of autoreactive B cells in spontaneous murine lupus. The event occurred shortly following the induction of the somatic hypermutation process. This conclusion is derived from extensive sequence analyses of VH and VL loci expressed by hybridomas representing two large histone-specific clones (lineages) from an autoimmune (NZB x SWR)F1 mouse. To obtain unambiguous somatic mutational information, we devised a strategy to amplify and sequence the JH and JK clusters that flank expressed V genes. Somatic mutations in V flanking sequences of the two autoreactive clones revealed that in one clone the pattern was relatively simple: the frequency of mutation was low, and only one somatic mutation was shared by all clone members. Members of the second large histone-specific clone contained many somatic mutations in combinations that indicated numerous rounds of selection. Importantly, however, as observed with the first clone, one observed somatic mutation was shared by all clone members. Since, for each clone, all members shared only one visible mutation over extensive sequence tracts, we conclude that the autoreactive clones were derived from single precursors that had just begun to mutate their V genes. The data indicate that a strong selection event had occurred shortly after the initial acquisition of somatic mutation(s) in precursors to each clone, at a stage of development corresponding to that of the germinal center B cell approximately 1 week post immunization.
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PMID:An early post-mutational selection event directs expansion of autoreactive B cells in murine lupus. 787 64


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