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)

Gene variants in mice that have strong, Mendelian effects on autoimmune susceptibility have been one of the most productive entry points for identifying genes and processes regulating human autoimmunity. With the tools now available to map and identify new mouse Mendelian gene variants, the handful of spontaneous mutations accumulated over several decades have all been identified, and the main bottleneck lies in producing new Mendelian immune variants. We outline here a strategy to generate large sets of functional variants in genes controlling lupus and humoral immunity, based upon limited variation of the mouse genome sequence with the chemical mutagen, ENU, combined with a set of sensitive immunological screens.
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PMID:Illuminating autoimmune regulators through controlled variation of the mouse genome sequence. 1518 33

Defining the polymorphisms that contribute to the development of complex genetic disease traits is a challenging, although increasingly tractable problem. Historically, the technical difficulties in conducting association studies across the entire human genome are such that murine models have been used to generate candidate genes for analysis in human complex diseases, such as SLE. In this article we discuss the advantages and disadvantages of this approach and specifically address some assumptions made in the transition from studying one species to another, using lupus as an example. These issues include differences in genetic structure and genetic organisation which are a reflection on the population history. Clearly there are major differences in the histories of the human population and inbred laboratory strains of mice. Both human and murine genomes do exhibit structure at the genetic level. That is to say, they comprise haplotypes which are genomic regions that carry runs of polymorphisms that are not independently inherited. Haplotypes therefore reduce the number of combinations of the polymorphisms in the DNA in that region and facilitate the identification of disease susceptibility genes in both mice and humans. There are now novel means of generating candidate genes in SLE using mutagenesis (with ENU) in mice and identifying mice that generate antinuclear autoimmunity. In addition, murine models still provide a valuable means of exploring the functional consequences of genetic variation. However, advances in technology are such that human geneticists can now screen large fractions of the human genome for disease associations using microchip technologies that provide information on upwards of 100,000 different polymorphisms. These approaches are aimed at identifying haplotypes that carry disease susceptibility mutations and rely less on the generation of candidate genes.
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PMID:Mice, humans and haplotypes--the hunt for disease genes in SLE. 1676 71

Even for complex diseases with high rates of monozygotic twin concordance, disease-associated alleles remain elusive. One explanation is that multiple common genetic variants with weak effects cause these diseases and identification of any single allele requires large cohorts. Conversely, if the allelic spectrum of complex disease is heterogeneous, strong effects of rare variants might be offset by their presence in only a small proportion of the patient population. Lupus (SLE) is a systemic autoimmune disease, with significant monozygotic twin concordance, protean clinical manifestations, and production of high-affinity pathogenic autoantibodies. This complex phenotype and results from genome scans point to multiple molecular defects. Contrary to this expectation, our analysis of ENU-mutagenized mice indicates that homozygous mutations frequently cause anti-nuclear antibodies (ANAs), and can account for a full blown lupus phenotype. The best characterized example is the sanroque strain, which develops high-affinity dsDNA autoantibodies and fails to censor self-reactive germinal centre T cells. Mapping the underlying mutation identified not only a novel gene, Roquin, but also a novel pathogenic pathway for SLE. Identification of such rare variants with strong effects is likely to identify pathogenic pathways that underlie pathology in many patients, lead to interacting molecular partners that also cause pathology, and identify the most effective therapeutic targets.
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PMID:Genetic analysis of systemic autoimmunity. 1753 69

Systemic Lupus erythematosus (SLE) is an autoimmune disease caused, in part, by abnormalities in cells of the immune system including B and T cells. Genetically reducing globally the expression of the ETS transcription factor FLI1 by 50% in two lupus mouse models significantly improves disease measures and survival through an unknown mechanism. In this study we analyze the effects of reducing FLI1 in the MRL/lpr lupus prone model on T cell function. We demonstrate that adoptive transfer of MRL/lpr Fli1(+/+) or Fli1(+/-) T cells and B cells into Rag1-deficient mice results in significantly decreased serum immunoglobulin levels in animals receiving Fli1(+/-) lupus T cells compared to animals receiving Fli1(+/+) lupus T cells regardless of the genotype of co-transferred lupus B cells. Ex vivo analyses of MRL/lpr T cells demonstrated that Fli1(+/-) T cells produce significantly less IL-4 during early and late disease and exhibited significantly decreased TCR-specific activation during early disease compared to Fli1(+/+) T cells. Moreover, the Fli1(+/-) T cells expressed significantly less neuraminidase 1 (Neu1) message and decreased NEU activity during early disease and significantly decreased levels of glycosphingolipids during late disease compared to Fli1(+/+) T cells. FLI1 dose-dependently activated the Neu1 promoter in mouse and human T cell lines. Together, our results suggest reducing FLI1 in lupus decreases the pathogenicity of T cells by decreasing TCR-specific activation and IL-4 production in part through the modulation of glycosphingolipid metabolism. Reducing the expression of FLI1 or targeting the glycosphingolipid metabolic pathway in lupus may serve as a therapeutic approach to treating lupus.
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PMID:Reducing FLI1 levels in the MRL/lpr lupus mouse model impacts T cell function by modulating glycosphingolipid metabolism. 2404 Mar 98

MDA5 is an essential intracellular sensor for several viruses, including picornaviruses, and elicits antiviral interferon (IFN) responses by recognizing viral dsRNAs. MDA5 has been implicated in autoimmunity. However, the mechanisms of how MDA5 contributes to autoimmunity remain unclear. Here we provide direct evidence that dysregulation of MDA5 caused autoimmune disorders. We established a mutant mouse line bearing MDA5 mutation by ENU mutagenesis, which spontaneously developed lupus-like autoimmune symptoms without viral infection. Inflammation was dependent on an adaptor molecule, MAVS indicating the importance of MDA5-signaling. In addition, intercrossing the mutant mice with type I IFN receptor-deficient mice ameliorated clinical manifestations. This MDA5 mutant could activate signaling in the absence of its ligand but was paradoxically defective for ligand- and virus-induced signaling, suggesting that the mutation induces a conformational change in MDA5. These findings provide insight into the association between disorders of the innate immune system and autoimmunity.
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PMID:Autoimmune disorders associated with gain of function of the intracellular sensor MDA5. 2456 Jan 91