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)

PD-1 is an immunoglobulin superfamily member bearing an immunoreceptor tyrosine-based inhibitory motif, and disruption of the PD-1 gene results in the development of lupus-like autoimmune diseases. In this study, we examined effects of the PD-1 deficiency on the thymocyte differentiation at the clonal level using T cell receptor (TCR)-beta (Vbeta8) and TCR-alpha/beta (H-Y and 2C) transgenic mice. In these TCR transgenic lines, PD-1 expression in the thymus was variably augmented, but as in the normal mice, confined largely to the CD4(-)CD8(-) thymocytes. The transgenic mice crossed with PD-1(-/)- mice in the neutral genetic backgrounds exhibited selective increase in the CD4(+)CD8(+) (DP) population with little effect on other thymocytes subsets. Similarly, the absence of PD-1 facilitated expansion of DP thymocytes in recombination activating gene (RAG)-2(-/)- mice by anti-CD3epsilon antibody injection. On the other hand, H-Y or 2C transgenic PD-1(-/)- mice with the positively selecting background showed significantly reduced efficiency for the generation of CD8(+) single positive cells bearing the transgenic TCR-alpha/beta in spite of the increased DP population. These results collectively indicate that PD-1 negatively regulates the beta selection and modulates the positive selection, and suggest that PD-1 deficiency may lead to the significant alteration of mature T cell repertoire.
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PMID:Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. 1070 69

We previously showed that dietary fish oil (FO) and energy restriction (R) have beneficial anti-inflammatory properties in the peripheral blood and spleens of (NZB x NZW)F1 (B/W) lupus-prone mice. Furthermore, unsaturated fatty acids also were shown in the past to influence mesenteric lymph node (MLN) lymphocyte function in healthy young rats. The MLN play a pivotal role in mediating food allergy. To date, the effect of R on intestinal immunity is not well understood; therefore we determined the effect of diet on MLN lymphocyte function. Mice were given either free access to a 5 g/100 g corn oil (CO) or fish oil (FO) diet or the same corn oil (CR) or fish oil (FR) diets restricted to 60% of the intake of the control group. At the age of 4 (young) and 8 (old) mo, MLN lymphocytes were isolated and B- (CD19(+)) and T-lymphocyte subsets (CD4(+) and CD8(+)) were determined by flow cytometry. Additional MLN lymphocytes were placed in culture with or without concanavalin A and culture supernatants collected after 72 h for cytokine and immunoglobulin (Ig) quantitation by ELISA. Aging significantly (P < 0.05) decreased both CD4(+) and CD8(+) T-lymphocytes. Spontaneous and activation-induced interleukin-4 (IL-4), IL-10, and interferon-gamma secretion were greater while IL-2 was lower in CO-fed old mice compared to CO-fed young mice. In contrast, CR or FO alone partially blunted the age-dependent alterations in T-lymphocyte ratios including cytokine and Ig secretion, whereas the FR diet significantly (P < 0.005) normalized the accelerated aging effects on these immune variables. We show for the first time that FR is a far more potent anti-inflammatory therapy than either CR or FO alone in modulating MLN lymphocyte function.
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PMID:Dietary (n-6) and (n-3) fatty acids and energy restriction modulate mesenteric lymph node lymphocyte function in autoimmune-prone (NZB x NZW)F1 mice. 1086 32

Systemic lupus erythematosus (SLE) is characterized by immune abnormalities explained by the overproduction of Th(2)cytokines such as autoantibody production and polyclonal B cell activation. We examined the effect of administering a DNA plasmid encoding IL-12 on the lupus-like disease of MRL/MP-lpr/lpr (MRL/lpr) mice. Treatments were delivered intramuscularly every 4 weeks, starting at 4 weeks of age. This intervention significantly inhibited the accumulation of CD4(-)CD8(-)T cells, and reduced lymphadenopathy and splenomegaly. A significant decrease in serum IgG anti-DNA autoantibody titers was observed, and plasmid IL-12 therapy was also associated with a reduction in the proteinuria and glomerulonephritis characteristic of this disease. Serum IFN-gamma level was increased by inoculating IL-12 encoding plasmid, suggesting that the cytokine balance was skewed towards Th(1). The clinical implications of this suppression of autoimmune disease are also discussed.
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PMID:IL-12-encoding plasmid has a beneficial effect on spontaneous autoimmune disease in MRL/MP-lpr/lpr mice. 1088 Feb 49

Mouse mammary tumor virus transmitted by FM mice (FM-MMTV) encodes a superantigen (SAg) characterized by strong reactivity with TCR Vbeta8.2 element and broad spectrum of Vbeta reactivity. To investigate what effects the expression in vivo of FM-MMTV SAg exhibits on the course of the disease in a lupus-prone model, MRL/MpJ-Fas(lprcg)/Fas(lprcg) (MRL-lpr9cg) mice, neonatally FM-MMTV-infected MRL-lprcg(MMTV) and uninfected MRL-lpr(cg) mice were compared for various disease parameters. In MRL-lprcg(MMTV), survival was significantly prolonged, glomerulonephritis, proteinuria, and lymphadenopathy were clearly ameliorated, and the production of serum immunoglobulin G (IgG), complement-activating IgG2a, and cryogenic IgG3 autoantibodies, which are thought to be pathogenic to kidneys, and circulating immune complexes (IC), and glomerular IC deposition were significantly suppressed. FM-MMTV infection deleted Vbeta8.2+ cells by about 90% and Vbeta14+ cells less efficiently in all of the CD4+, CD8+, and B220+ CD4- CD8- or double-negative (DN) T-cell populations, and Vbeta8.1+ cells in the CD4+ population but not in the others. Similar deletion profiles of CD8+ and DN T cells support that DN T cells are derived from the CD8 lineage. The results imply that the specific regulation of the immune system with viral SAg has a potential for development of an attractive immunomodulatory therapy of autoimmune diseases.
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PMID:Alleviation of renal disease and lymphadenopathy in MRL-Fasp(lrcg)/Fas(lprcg) (MR-lpr(cg)) mice neonatally infected with mouse mammary tumor virus encoding superantigen strongly reactive with TCR Vbeta8.2 element. 1101 95

T cells play a critical role in both the immunological and clinical manifestations of systemic autoimmune diseases such as systemic lupus erythematosus (SLE). Although in normal mice multiple T cell epitopes have been characterized in several self-proteins, there is little information on the fine specificity of autoreactive T cells in lupus model mice and humans. In SLE-prone mice and humans, the only Th cell epitopes identified at the molecular level in self-antigens concern histones and nucleosomes, and the 70-kD U1-snRNP protein. T cell characterization in certain autoimmune mice such as MRL lpr/lpr and NZB/NZW mice has been largely impaired by their hyporesponsiveness in response to mitogen and minimal IL-2 secretion. In addition, MRL lpr/lpr mice also develop lymphadenopathy characterized by the progressive accumulation of functionally immature CD4(-) CD8(-) T cells. It is therefore important to optimize the methods used to measure T cell proliferation and cytokine production ex vivo in order to identify minimal activation in the presence of appropriate antigen. The protocol described in this article has been used for identifying in young MRL lpr/lpr and NZB/NZW mice a CD4(+) T cell epitope in the murine 70-kD U1-RNP protein.
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PMID:Laboratory protocols for the identification of Th cell epitopes on self-antigens in mice with systemic autoimmune diseases. 1103 32

In this report we summarize evidence to support a model for the development of Graves' disease. The model suggests that Graves' disease is initiated by an insult to the thyrocyte in an individual with a normal immune system. The insult, infectious or otherwise, causes double strand DNA or RNA to enter the cytoplasm of the cell. This causes abnormal expression of major histocompatibility (MHC) class I as a dominant feature, but also aberrant expression of MHC class II, as well as changes in genes or gene products needed for the thyrocyte to become an antigen presenting cell (APC). These include increased expression of proteasome processing proteins (LMP2), transporters of antigen peptides (TAP), invariant chain (Ii), HLA-DM, and the co-stimulatory molecule, B7, as well as STAT and NF-kappaB activation. A critical factor in these changes is the loss of normal negative regulation of MHC class I, class II, and thyrotropin receptor (TSHR) gene expression, which is necessary to maintain self-tolerance during the normal changes in gene expression involved in hormonally-increased growth and function of the cell. Self-tolerance to the TSHR is maintained in normals because there is a population of CD8- cells which normally suppresses a population of CD4+ cells that can interact with the TSHR if thyrocytes become APCs. This is a host self-defense mechanism that we hypothesize leads to autoimmune disease in persons, for example, with a specific viral infection, a genetic predisposition, or even, possibly, a TSHR polymorphism. The model is suggested to be important to explain the development of other autoimmune diseases including systemic lupus or diabetes.
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PMID:Graves' disease: a host defense mechanism gone awry. 1112 19

MRL lpr/lpr mice spontaneously develop a severe autoimmune lupus syndrome characterized by strong autoantibody production and massive lymphoproliferation, in which IFN-gamma plays a major pathogenic effect. The role of the IFN-gamma-inducing cytokine IL-18 in the autoimmune syndrome of lpr/lpr mice has been investigated. In response to IL-18, lymph node cells of lpr/lpr mice produce significant amounts of IFN-gamma and proliferate more potently as compared with cells from +/+ mice. Cells likely responsible for such hyperresponsiveness to IL-18 include NK cells and the CD4(+)/CD8(+) self-reactive T lymphocytes characteristically present in lymph nodes of lpr/lpr mice. Analysis of the expression of IL-18R complex revealed that mRNA for the IL-18R alpha-chain is constitutively expressed at similar level both in +/+ and lpr/lpr lymphocytes. In contrast, the expression of the accessory receptor chain IL-18R beta is low in unstimulated +/+ cells but significantly high in lpr/lpr cells. Thus, the abnormally high expression of the IL-18R chain IL-18R beta could be one of the causes of the hyperresponsiveness of lpr/lpr cells to IL-18 at the basis of consequent enhancement of IFN-gamma production and development of IFN-gamma-dependent autoimmune pathology.
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PMID:Lymphocytes from autoimmune MRL lpr/lpr mice are hyperresponsive to IL-18 and overexpress the IL-18 receptor accessory chain. 1123 17

When mutations that inactivate molecules that function in the immune system have been crossed to murine lupus strains, the result has generally been a uniform up-regulation or down-regulation of autoimmune disease in the end organs. In the current work we report an interesting dissociation of target organ disease in beta(2)-microglobulin (beta(2)m)-deficient MRL-Fas(lpr) (MRL/lpr) mice: lupus skin lesions are accelerated, whereas nephritis is ameliorated. beta(2)m deficiency affects the expression of classical and nonclassical MHC molecules and thus prevents the normal development of CD8- as well as CD1-dependent NK1(+) T cells. To further define the mechanism by which beta(2)m deficiency accelerates skin disease, we studied CD1-deficient MRL/lpr mice. These mice do not have accelerated skin disease, excluding a CD1 or NK1(+) T cell-dependent mechanism of beta(2)m deficiency. The data indicate that the regulation of systemic disease is not solely governed by regulation of initial activation of autoreactive lymphocytes in secondary lymphoid tissue, as this is equally relevant to renal and skin diseases. Rather, regulation of autoimmunity can also occur at the target organ level, explaining the divergence of disease in skin and kidney in beta(2)m-deficient mice.
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PMID:Deficiency in beta(2)-microglobulin, but not CD1, accelerates spontaneous lupus skin disease while inhibiting nephritis in MRL-Fas(lpr) nice: an example of disease regulation at the organ level. 1150 49

The neonatal Ab and TCR repertoires are much less diverse, and also very different from, the adult repertoires due to the delayed onset of terminal deoxynucleotidyl transferase (TdT) expression in ontogeny. TdT adds nontemplated N nucleotides to the junctions of Igs and TCRs, and thus its absence removes one of the major components of junctional diversity in complementarity-determining region 3 (CDR3). We have generated TdT-deficient MRL/lpr, Fas-deficient (MRL-Fas(lpr)) mice, and show that they have an increased lifespan, decreased incidence of skin lesions, and much lower serum levels of anti-dsDNA, anti-chromatin, and IgM rheumatoid factors. The generalized hypergammaglobulinemia characteristic of MRL-Fas(lpr) mice is also greatly reduced, as is the percentage of CD4(-)CD8(-)B220(+) (double-negative) T cells. IgG deposits in the kidney are significantly reduced, although evidence of renal disease is present in many mice at 6 mo. CDR3 regions of both IgH and TCR from peripheral lymphocytes of MRL-Fas(lpr) mice are shorter in the absence of TdT, and there is a paucity of arginines in the IgH CDR3 regions of the MRL-Fas(lpr) TdT(-/-) mice. Because the amelioration of symptoms is so widespread, it is likely that the absence of N regions has more of an affect than merely decreasing the precursor frequency of anti-dsDNA B cells. Hence, either the T or B cell repertoires, or more likely both, require N region diversity to produce the full spectrum of autoimmune lupus disease.
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PMID:Terminal deoxynucleotidyl transferase deficiency decreases autoimmune disease in MRL-Fas(lpr) mice. 1154 42

Genetic dissection of lupus pathogenesis in the NZM2410 strain has recently revealed that Sle1 is a potent locus that triggers the formation of IgG anti-histone/DNA antibodies, when expressed on the B6 background as a congenic interval. B6.lpr mice, in contrast, exhibit distinctly different cellular and serological phenotypes. Both strains, however, do not usually exhibit pathogenic autoantibodies, or succumb to lupus nephritis. In this study, we show that the epistatic interaction of Sle1 (in particular, Sle1/Sle1) with FAS(lpr) leads to massive lymphosplenomegaly (with elevated numbers of activated CD4 T cells, CD4(-)CD8(-) double negative (DN) T cells, and B1a cells), high levels of IgG and IgM antinuclear (including anti-ssDNA, anti-dsDNA, and anti-histone/DNA), and antiglomerular autoantibodies, histological, and clinical evidence of glomerulonephritis, and >80% mortality by 5-6 mo of age. Whereas FAS(lpr) functions as a recessive gene, Sle1 exhibits a gene dosage effect. These studies indicate that Sle1 and FAS(lpr) must be impacting alternate pathways leading to lymphoproliferative autoimmunity.
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PMID:Genetic dissection of SLE: SLE1 and FAS impact alternate pathways leading to lymphoproliferative autoimmunity. 1216 57


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