Browsing by Subject "Lupus Erythematosus, Systemic"
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Item Autoantibodies as diagnostic tools and therapeutic targets in Systemic Lupus Erythematosus(2005-04-21) Reimold, AndreasItem Autoimmune disease(1981-07-16) Lipsky, Peter E.Item The clinical spectrum of lupus skin disease: characterization of a new cutaneous LE subset(1979-02-15) Gilliam, James N.Item Clinical syndromes within the spectrum of lupus erythematosus(1975-05-01) Gilliam, James N.Item Common Alleles of the SLAM/CD2 Family are Associated with Murine Lupus(2005-04-25) Limaye, Nisha; Wakeland, Edward K.The Sle1b locus on telomeric mouse chromosome 1 mediates a break in tolerance to chromatin in the NZM2410 model of the autoimmune disease Systemic Lupus Erythematosus (SLE). B6.Sle1b congenic mice produce anti-nuclear autoantibodies (ANAs), and have elevated activated B and CD4+ T cells, and mild splenomegaly. Fine mapping of Sle1b positioned it within a ~900 kb region between 171.3 and 172.2 Mb. A contig of 100 B6-derived Bacterial Artificial Chromosomes (BACs) was constructed across Sle1b, and sequencing of six BACs that form an overlapping tiling path across it revealed that the interval contains 24 genes, 19 of which are expressed in the spleen, and 14 of which are in B and CD4+ T cells. We carried out extensive candidate gene analyses on the spleen-expressed genes, including sequencing of all the exons and flanking introns in the lupus-resistant B6 and susceptible B6.Sle1b parental strains, as well as Quantitative Real-time PCR on B and CD4+ T cell cDNA to detect any potentially functional polymorphisms between them. These analyses showed that the SLAM/CD2 family of seven immunoregulatory receptors, clustered within the locus, are by far the best candidates to be the Sle1b gene(s). The members of this family play important roles in intercellular interactions, activation, and function, by engaging in homophilic interactions with themselves or with each other, on a wide variety of immune cell types. Sequence analyses of their extracellular ligand-binding immunoglobulin (Ig) domains revealed that the cluster forms two stable, linked haplotypes of alleles in 33 common inbred laboratory strains of mice. The B6-like haplotype is found only in a small set of C57-strains, while the B6.Sle1b-like haplotype is found in all of the remaining, including the autoimmune-prone MRL, NOD, and NZB, as well as non-autoimmune strains like 129, Balb/c, and C3H. Introgression of this common haplotype from 129 onto B6 also potentiates autoimmunity, causing phenotypes similar to those of B6.Sle1b mice, which derive this interval from the NZW parent of NZM2410. Autoimmunity is mediated, not by a rare mutation peculiar to the region from NZW, but instead by common polymorphic variants of this family, in combination with the downstream signaling and effector molecules and pathways present in the B6 genetic background, underlining the importance of epistasis in such complex, multigenic autoimmune phenotypes. An examination of the SLAM/CD2 Ig domains in a large group of wild-outbred and wild-derived inbred strains belonging to different species of Mus, and sub-species of Mus musculus, has shown that the "disease" alleles of this family are also very common in these populations, demonstrating that their prevalence in the lab strains is not simply an artifact of their inbreeding. The genes also show the presence of ancestral or trans-species polymorphisms, indicative of maintenance of these alleles by balancing selection, although we do not yet know what precisely drives it. The small size of the Sle1b susceptibility interval, and the presence of this linked cluster of attractive candidate genes within it, makes it hard to identify which gene or combination of genes within this family is actually responsible for the autoimmunity by any further recombinational analysis. We have instead turned to a BAC-transgenic rescue strategy by which to localize the gene to a single B6-derived BAC, by its ability to complement the ANA-production phenotype and rescue autoimmunity in B6.Sle1b mice. We believe the strategy is feasible because Sle1b has a strong allele dose effect, so that the presence of a B6 allele of the Sle1b gene causes a large drop in penetrance of ANA-production, from about 90% in nine month old B6.Sle1b females, to about 33% in (B6 X B6.Sle1b) F1s. Our data show that none of the non-SLAM/CD2 candidates within the region is able to rescue B6.Sle1b mice, despite being demonstrably expressed from their BAC-transgenes. BACs carrying certain SLItem Donald W. Seldin, M.D., Research Symposium finalist presentations(2020-05-29) Adomako, Emmanuel; Hinkamp, Colin; Liu, Po-Hong (Stuart); McAdams, Meredith; Omar, Wally; Segar, MatthewThis edition of the UT Southwestern Internal Medicine Grand Rounds features presentations by the six Foster Fellows selected as finalists from the Fifth Annual Donald W. Seldin, M.D. Research Symposium, which was held on May 21, 2020. These Foster Fellows presented work that spanned the breadth and depth of scholarly activity across the department, and at the close of Grand Rounds, one will be selected as the 2020 Seldin Scholar, in honor of Dr. Donald W. Seldin. The Grand Rounds presentation also includes additional awards honoring Clinical Vignettes and an award for work in Quality and Education at Parkland Hospital.Item Drug-induced lupus(1983-05-05) Goldings, Eliot A.Item The fine specificity of rheumatic disease associated autoantibodies: an aging clinical immunologist's education in modern cell biology(1988-01-28) Sontheimer, Richard D.Item Haplotype-Specific Effects of the Slam/Cd2 Family on the Immune Response(2007-05-22) Nguyen, Charles Minh; Wakeland, Edward K.The Sle1b susceptibility interval mediates a breach in tolerance to nuclear antigens in the NZM2410 model of systemic lupus erythematosus (SLE). Congenic B6 mice carrying the Sle1b locus produce anti-nuclear autoantibodies (ANAs) but do not develop lupus nephritis as seen in the parental NZM2410 strain. Fine mapping of the Sle1b locus placed it within a 900kb interval between 171.3 and 172.2Mb on chromosome 1. A Bacterial Artificial Chromosome (BACs) contig that spanned the interval was constructed, and a tiling pathway comprised of six BACs was sequenced. Sequence analysis revealed a dense region of 24 expressed genes. Expression studies determined numerous polymorphisms between B6 and the B6.Sle1b congenic and identified a cluster of genes known as the Slam/CD2 family as the primary candidates for Sle1b. These immunoregulatory receptors play a role in intercellular interactions and regulate function in several immune cell lineages. Of the seven family members within the locus, Ly108 appears to be the strongest candidate as B6.Sle1b shows a differential expression in isoforms. Ly108-1 is highly expressed, while Ly108-2 is expressed at much lower level in the congenic when compared to B6. When lymphocytes are stimulated, Ly108-2 is strongly up-regulated in B6, but not B6.Sle1b. Sequence analysis of the extra-cellular immunoglobulin domains of the Slam/CD2 family revealed two stable haplotypes in a panel of 33 common inbred strains of mice. The first haplotype is only found in B6 and other C57- related strains. The more common second haplotype is found in Sle1b and other autoimmune strains such as MRL, NOD, and NZB, as well as non-autoimmune strains such as 129Sv and Balb/c. The presence of this haplotype on B6 mediates autoimmunity as B6 congenics carrying the Sle1b locus from 129Sv also produce ANAs. Signaling studies on both B6.Sle1b and B6.129 reveal an altered pattern of calcium mobilization upon stimulation in T cells. In addition, CD4 T cells from B6.Sle1b demonstrate a reduction in IL-4 expression and secretion upon activation, suggesting that haplotype 2 of the Slam/CD2 family alters the immune response in T cells. Studies to understand the mechanisms by which this haplotype mediates autoimmunity are in progress.Item In Vivo Identification of SLE1B: LY108 Mediates Autoantibody Production(2008-05-12) Chan, Alice; Wakeland, Edward K.In the NZM2410 model of murine lupus, Sle1b mediates anti-nuclear autoantibody (ANA) production. Our goal is to determine the causative gene in the Sle1b locus. Seven members of the SLAM/CD2 family are located within the Sle1b interval, and previous work has shown that structural and expression polymorphisms in lymphocytes distinguish two major SLAM/CD2 haplotypes. To further narrow the interval, we utilized a BAC transgenic rescue approach whereby BACs carrying the lupus-resistant B6 alleles were bred to B6.Sle1b mice to identify the region mediating ANA suppression. One BAC carrying Cd84 and Ly108 suppressed autoantibody production. We then generated BAC transgenic mice carrying the lupus-susceptible (129) and lupus-resistant (B6) alleles of Ly108 on the B6 and B6.Sle1b genetic background, respectively. The B6 allele of Ly108 suppresses ANA production on the lupus-susceptible B6.Sle1b background while the 129 allele induces ANA on the lupus-resistant B6 genome. Taken together, these data identify Ly108 as a causative gene in Sle1b. While Ly108 is needed to mediate the breach in tolerance, we have also identified other SLAM family members as genetic modifiers necessary to recapitulate fully penetrant, high titer ANA production as seen in Sle1b. We found that in vitro stimulation of B6.Sle1b CD4 T cells led to altered cytokine production, such as decreased IL4 production. Interestingly, these phenotypes have also been reported in knockouts of SLAM/CD2 family members as well as in the absence of the SLAM family adaptor, SAP. Our data indicates that the presence of the Sle1b haplotype, derived from either NZM2410 or 129, recapitulates these phenotypes, independent of the absence of these molecules. While recent reports have suggested a role for SAP in ANA development, we find that the breach in tolerance in Sle1b mice is SAP-independent. However, SAP is necessary to potentiate the autoantibody production. ANAs is an important biomarker for autoimmune diseases including, Systemic Lupus Erythematosus (SLE), and potentially identifies an autoimmune-prone state. We have identified genes which contribute to the production of ANAs. Elucidating the pathways these genes dysregulate will provide critical insight into our understanding of tolerance and how tolerance can be breached.Item The kidney in systemic lupus erythematosus(1980-03-27) Jacobson, Harry R.Item The lupus anticoagulant-anticardiolipin antibody syndrome(1988-01-21) Jasin, Hugo E.Item The management of systemic lupus erythematosus: an update(2000-12-21) Taurog, Joel D.Item Molecular Players in Lupus: Leads from Proteomic Screens(2014-05-23) Orme, Jacob Jennings; Yarovinsky, Felix; Davis, Laurie; Eagar, Todd N.; Monson, Nancy L.; Farrar, J. David; Mohan, Chandra; Satterthwaite, Anne B.Systemic Lupus Erythematosus is a multifactorial systemic autoimmune disorder marked by anti-nuclear antibodies (ANA), rashes and photosensitivity, joint inflammation, nephritis, and other clinical criteria. SLE develops through the breakdown of three major checkpoints: adaptive immune tolerance, peripheral innate responsiveness, and end-organ inflammation. Adaptive immune dysfunction produces autoantibodies leading to immune complex formation and deposition in the skin, joints, and kidneys. Innate immunity plays an important role in determining disease severity and progression. Molecular markers in patient blood and urine improve diagnosis and treatment of SLE. Proteomic screens identify such markers and provide important clues about disease pathogenesis. We have discovered that soluble Axl receptor tyrosine kinase, the Wnt/β-catenin pathway-related factors, and rare fibrinogen alpha chain variant A-α-E are elevated in the serum of patients with SLE. Here I explore these factors and their contributions to disease. I find that Axl tyrosine kinase is sheared from the surface of lupus-prone and SLE CD19+ and CD11b+/CD14+ leukocytes by proteases ADAM10 and TACE (ADAM17) to abrogate macrophage anti-inflammatory signaling through Twist. I further find that β-catenin is dysregulated in SLE but the deletion of β-catenin in lupus-prone macrophages does not appreciably change disease course. Lastly, I find that fibrinogen alpha chain isoform Aα-E may be associated with aPL-negative thrombotic complications in SLE.Item Narrowing of the SLES1 Internal Reveals Complex Epistatic Interactions in the Suppression of Autoimmunity(2010-05-14) Belobrajdic, Katherine Ann; Wakeland, Edward K.Sle1 is a potent susceptibility locus for spontaneous systemic autoimmunity derived from the NZM2410 mouse strain. The NZW-derived suppressive modifier locus, Sles1, specifically prevents the spontaneous loss in tolerance mediated by the B6.Sle1 congenic. Sles1 had previously been fine-mapped to a remarkably gene-rich region on murine chromosome 17 containing nearly 70 genes. A series of mouse strains were constructed with a variety of suppressive and non-suppressive variants of Sles1 on the B6.Sle1 genomic background which have revealed multiple layers of epistatic gene interactions within the Sles1 interval. Phenotyping of a truncated recombinant interval mapped the Sles1 phenotype to an approximately 638 KB segment, which combined with genomic and expression analysis, suggested Btnl2 and the H2 genes are strong candidates for Sles1. Finally, further characterization of the Sles1 interval has revealed an allele-specific and tissue-specific reduction of major histocompatibility complex (MHC) Class II molecules on the surface of B cells, as well as a possible role for follicular helper T cells in the development of Sle1-mediated autoimmunity. Understanding how Sles1 and other modifiers suppress systemic autoimmunity will reveal important insights for developing therapeutic strategies for systemic lupus eythematosus (SLE).Item [News](1980-10-15) Rutherford, SusanItem [News](1983-10-17) Rutherford, SusanItem NZB/BINJ and NZW/LACJ Embryonic Chimeras Develop Strong Autoimmunity Dependent on NZB/BINJ T Cells(2018-09-25) Hankins, Julia Dee; Satterthwaite, Anne B.; Beutler, Bruce; Monson, Nancy L.; Theofilopoulos, ArgyriosThe NZB/NZW F1 hybrid develops systemic lupus erythematosus (SLE), displaying features of human disease including spontaneous anti-nuclear antibodies, glomerulonephritis, earlier and more penetrant expression of disease in females, and polygenic etiology. The autoimmunity that develops in these mice must result from epistatic interactions between NZB and NZW alleles at specific loci in the hybrid mice. However, the causative alleles and pathways have remained elusive. In the present study we sought to determine whether incompatibility between cells of the two parental strains causes autoimmunity. We generated chimeras (here designated NZB;NZW) by injecting embryonic stem cells from NZB/BINJ (NZB) mice into NZW/LacJ (NZW) blastocysts. These chimeras developed an accelerated form of autoimmunity characterized by the presence of autoantibodies 3 months earlier, and at titers 10-fold greater, than the NZB/NZW F1 hybrids. The chimeras also developed mild glomerulonephritis and severe lymphadenopathy and splenomegaly. The observed cellular incompatibility was specific for the NZB;NZW combination (not observed in NZB;C57BL/6J or NZW;C57BL/6J), and occurred despite the fact that each parental type does not develop SLE features in a non-chimeric environment. Within each chimera, an expansion of activated T cells from the NZB strain and a predominance of B cells from NZW were observed. Furthermore, the expanded NZB T cells correlated with autoimmunity, and removing these T cells in NZB(Cd3e-/-);NZW chimeras prevented disease. Thus, NZB and NZW cells are inherently incompatible with one another, though compatible with C57BL/6J cells. Pathogenic intercellular transactions cause this strong autoimmunity in chimeric mice, dependent upon the presence of NZB T cells.Item Pathogenic and Protective Potential of B Cell Dysregulation in Systemic Lupus Erythematosus(2014-07-25) Mayeux, Jessica; Stüve, Olaf; Satterthwaite, Anne B.; Mohan, Chandra; Monson, Nancy L.; Davis, LaurieSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to nuclear antigens. Hyperactive B cells are present in SLE patients and murine models of lupus, many of which have defects in inhibitors of B cell receptor (BCR) signaling or plasma cell differentiation. Autoantibodies against a wide range of self antigens contribute to the pathogenesis of SLE and are used to diagnose SLE, determine prognosis, and predict specific disease manifestations. Autoantibodies form immune complexes which deposit in the kidney and joints, resulting in glomerulonephritis and arthritis, respectively. Autoantibodies against antigens in the CNS can cause Neuropsychiatric SLE manifestations, such as psychosis, memory loss, seizures, strokes, and mood disorders. Human SLE patients and murine models of lupus are used here to identify novel autoantibodies in SLE and to better understand the mechanisms by which autoantibodies accumulate in SLE. Protein arrays can be used to identify autoantibodies and autoantigens that are targeted in SLE patients. Using this approach, we identified Stress Induced Phosphoprotein 1 (STIP1) as an autoantigen in a subset of SLE patients. Those patients with elevated levels of anti-STIP1 IgG autoantibodies in their serum were less likely to have parameters associated with more severe disease, suggesting a protective role for anti-STIP1 IgG. In addition, I defined a genetic interaction between the src tyrosine kinase, Lyn, and the Ets family transcription factor, Ets1, in autoimmunity. Lyn is both a positive and negative regulator of BCR signaling; however its net effect is inhibitory. Lyn deficiency results in hyperactive B cells and Lyn-/- mice serve as a murine model of SLE. Ets1 is a regulator of plasma cell differentiation, and Ets1-/- mice have a similar phenotype to Lyn-/- mice. Lyn and Ets1 are in a shared pathway in which Lyn maintains Ets1 levels, thus limiting plasma cell accumulation. Compound heterozygotes of Lyn and Ets1 were used to determine whether partial loss of Lyn and Ets1 results in accelerated autoimmunity. Lyn and Ets1 were found to synergize in limiting the accumulation of activated and memory T cells, myeloid dendritic cells, age associated B cells, and IgM, but not IgG autoantibodies.Item Peripheral Blood Gene Expression in Discoid Lupus Erythematosus and Systemic Lupus Erythematosus Patients(2016-01-19) Bishop, Allison; Tseng, Lin-Chiang; Chong, Benjamin F.BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease with variations in clinical presentation that can affect the kidney, blood vessels, heart, lungs, joints, CNS, and/or the skin. The most common cutaneous form is discoid lupus erythematosus (DLE). DLE can occur with or without SLE, and differentiating between the two disease states can be ambiguous. Recent studies have shown type I interferon-related genes to be upregulated in peripheral blood mononuclear cells (PBMCs) of SLE patients and DLE patients compared with normal controls. Other studies have suggested that cytokines could serve as biomarkers of disease progression from DLE to SLE. Identifying differences in the transriptomes of DLE patients versus SLE patients could aid in distinguishing these two groups and forecasting progression from DLE to SLE. AIM: This study aimed to analyze differences in the expression levels of type I interferon-related genes and cytokine genes in whole blood samples of DLE patients, SLE patients, and normal controls. We hypothesized that SLE patients would have increased expression levels of these genes compared to DLE patients, due to their widespread systemic disease. METHODS: Blood samples were collected from DLE, SLE, and normal patients recruited at the outpatient UTSW and Parkland Hospital Dermatology clinics. Reverse transcription polymerase chain reaction (RT-PCR) analysis of ten genes, including five type I interferon-related genes (MX1, LY6E, OAS1, OASL, and ISG15) and five cytokine genes (CXCL10, TNF-α, IL-6, IL-10, and IL-12), was performed. RNA was extracted using RNeasy Lipid Tissue Mini kit, and the RNA was reverse transcribed to cDNA. cDNA of selected genes was amplified with SYBR Green PCR Master Mix using forward and reverse primers. Cycle threshold (Ct) values were standardized to the housekeeping gene GAPDH and converted to fold change using the 2-ΔΔCT formula. Gene expression levels were compared between these groups using the Kruskal-Wallis test. RESULTS AND CONCLUSIONS: All of the interferon-related genes were found to be significantly overexpressed (p<0.05) in the whole blood of DLE and SLE patients compared to normal controls. However none of the interferon-related genes showed a significant difference in gene expression between DLE and SLE patients. Expression of cytokine genes either did not show any significant differences between groups or was too low to detect. Future directions include RT-PCR analyses of cytokine gene expression of stimulated patient PBMCs, and whole blood gene expression of other candidate biomarker genes identified from our whole blood microarray data.