Survivin as a Potential Mediator to Support Autoreactive Cell Survival in Myasthenia Gravis: A Human and Animal Model Study
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{"title"=>"Survivin as a potential mediator to support autoreactive cell survival in myasthenia gravis: A human and animal model study", "type"=>"journal", "authors"=>[{"first_name"=>"Linda L.", "last_name"=>"Kusner", "scopus_author_id"=>"6603252170"}, {"first_name"=>"Michael J.", "last_name"=>"Ciesielski", "scopus_author_id"=>"7004361029"}, {"first_name"=>"Alexander", "last_name"=>"Marx", "scopus_author_id"=>"55798019600"}, {"first_name"=>"Henry J.", "last_name"=>"Kaminski", "scopus_author_id"=>"7006723901"}, {"first_name"=>"Robert A.", "last_name"=>"Fenstermaker", "scopus_author_id"=>"7003400402"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84904701212", "sgr"=>"84904701212", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0102231", "pmid"=>"25050620", "pui"=>"373596190"}, "id"=>"306f90a7-cb94-35af-b689-c27e873a5882", "abstract"=>"The mechanisms that underlie the development and maintenance of autoimmunity in myasthenia gravis are poorly understood. In this investigation, we evaluate the role of survivin, a member of the inhibitor of apoptosis protein family, in humans and in two animal models. We identified survivin expression in cells with B lymphocyte and plasma cells markers, and in the thymuses of patients with myasthenia gravis. A portion of survivin-expressing cells specifically bound a peptide derived from the alpha subunit of acetylcholine receptor indicating that they recognize the peptide. Thymuses of patients with myasthenia gravis had large numbers of survivin-positive cells with fewer cells in the thymuses of corticosteroid-treated patients. Application of a survivin vaccination strategy in mouse and rat models of myasthenia gravis demonstrated improved motor assessment, a reduction in acetylcholine receptor specific autoantibodies, and a retention of acetylcholine receptor at the neuromuscular junction, associated with marked reduction of survivin-expressing circulating CD20+ cells. These data strongly suggest that survivin expression in cells with lymphocyte and plasma cell markers occurs in patients with myasthenia gravis and in two animal models of myasthenia gravis. Survivin expression may be part of a mechanism that inhibits the apoptosis of autoreactive B cells in myasthenia gravis and other autoimmune disorders.", "link"=>"http://www.mendeley.com/research/survivin-potential-mediator-support-autoreactive-cell-survival-myasthenia-gravis-human-animal-model", "reader_count"=>21, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Doctoral Student"=>1, "Student > Master"=>5, "Other"=>2, "Student > Bachelor"=>2, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Doctoral Student"=>1, "Student > Master"=>5, "Other"=>2, "Student > Bachelor"=>2, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Medicine and Dentistry"=>6, "Agricultural and Biological Sciences"=>6, "Design"=>1, "Sports and Recreations"=>1, "Psychology"=>1, "Immunology and Microbiology"=>2, "Biochemistry, Genetics and Molecular Biology"=>2}, "reader_count_by_subdiscipline"=>{"Design"=>{"Design"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>6}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"Germany"=>1, "Spain"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1604615"], "description"=>"<p>Rats were pre-treated with SVN53-67/M57-KLH (circles) or PBS (squares). <b>A</b>) Animals were injected with SVN53-67/M57-KLH at times marked by red arrows. Black arrows mark injection time of tAChR. Grip strength was measured throughout experiment and values are a mean of biweekly measurements. (* denotes <i>P</i><0.02, t-test) <b>B</b>) Table of clinical scores based on rats at day 47. <b>C</b>) Levels of total IgG, IgG1 and IgG2b were significantly higher in the PBS control group (<i>n</i> = 7) compared to SVN53-67/M57-KLH treated animals (<i>n</i> = 7). (<i>P</i><0.02 for all, t-test) <b>D</b>) SVN53-67/M57-KLH treated rats demonstrated statistically increased amount of AChR (red) at the NMJs compared to PBS-treated rats. <b>E</b>) Pixel density of the labeled AChR by Alexa Fluor 594 -bungarotoxin at the NMJ in SVN53-67/M57-KLH treated animals (<i>n</i> = 5) compared to PBS treated controls (<i>n</i> = 5) (<i>P</i> = 0.013, t-test).</p>", "links"=>[], "tags"=>["cell biology", "Cellular types", "Animal cells", "Immune cells", "immunology", "Vaccination and immunization", "vaccines", "Cancer vaccines", "autoimmunity", "neurology", "Neuromuscular diseases", "Animal studies", "Animal models of disease", "pre-treatment"], "article_id"=>1113993, "categories"=>["Biological Sciences"], "users"=>["Linda L. Kusner", "Michael J. Ciesielski", "Alexander Marx", "Henry J. Kaminski", "Robert A. Fenstermaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0102231.g006", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Therapeutic_effect_of_pre_treatment_of_SVN53_67_M57_KLH_on_active_EAMG_/1113993", "title"=>"Therapeutic effect of pre-treatment of SVN53-67/M57-KLH on active EAMG.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-22 02:49:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1604599"], "description"=>"<p>A) FITC labeled AChR-alpha subunit peptide binding to total myasthenic PBMC (0.44%), B) Excess unlabeled AChR-alpha subunit peptide followed by competitive binding of FITC-AChR peptide (0.03%). C) Control PBMC, subject number 19, (SVN+/CD38+/CD138+/CD20+ gated sub-population) showing FITC-AChR-alpha subunit peptide binding (0.33% of gated cells). D–F; Myasthenic patient PBMC (SVN+/CD38+/CD138+/CD20+ gated sub-population) showing FITC-AChR-alpha subunit peptide binding (1.55% (pt#10), 6.54% (pt#15) and 2.50% (pt#14) of total gated cells; <i>n</i> = 3).</p>", "links"=>[], "tags"=>["cell biology", "Cellular types", "Animal cells", "Immune cells", "immunology", "Vaccination and immunization", "vaccines", "Cancer vaccines", "autoimmunity", "neurology", "Neuromuscular diseases", "Animal studies", "Animal models of disease", "receptor", "alpha", "peptide", "binding", "survivin", "cells", "myasthenics", "facs"], "article_id"=>1113978, "categories"=>["Biological Sciences"], "users"=>["Linda L. Kusner", "Michael J. Ciesielski", "Alexander Marx", "Henry J. Kaminski", "Robert A. Fenstermaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0102231.g002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Acetylcholine_receptor_alpha_peptide_binding_to_survivin_positive_cells_in_myasthenics_by_five_color_FACS_analysis_/1113978", "title"=>"Acetylcholine receptor alpha peptide binding to survivin positive cells in myasthenics by five color FACS analysis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-22 02:49:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1604614"], "description"=>"<p>Survivin-specific iTag tetramer analysis of survivin-targeted CD8+ T cells in EAMG mice (<b>A</b>) PBS and (<b>B</b>) SVN53-67/M57-KLH-treatment. FACS analysis of PBMC with representative flow histograms of CD20+/SVN+ cells from (<b>C</b>) PBS and (<b>D</b>) SVN53-67/M57-KLH-treated mice. <b>E</b>) Mean values of groups were compared using two way ANOVA (<i>P</i> = 0.001). <b>F–I</b>) AChR specific total IgG (<b>F</b>), IgG1 (<b>G</b>), IgG2a (<b>H</b>) and IgG2b (<b>I</b>) levels were determined by ELISA on an AChR coated 96-well plate for PBS (<i>n</i> = 7) and SVN53-67/M57-KL (<i>n</i> = 7)-treated animals. Levels of total IgG, IgG1, IgG2a and IgG2b were significantly higher in the PBS treated group compared to SVN53-67/M57-KLH treated animals (<i>P</i> = 0.02 for total IgG and IgG2b; p<0.005 for IgG1 and IgG2a). <b>J–L</b>) AChR expression at the NMJ of PBS treated (<i>n</i> = 8) and SVN53-67/M57-KLH-treated (<i>n</i> = 8) mice was determined by imaging of Alexa Fluor 594 –bungarotoxin pixel density at the NMJ. Two representative images of PBS treated (<b>J</b>) and SVN53-67/M57-KLH-treated (<b>K</b>) mice are shown. Mean pixel density was determined (<b>L</b>) (<i>P</i> = 0.0001, t-test).</p>", "links"=>[], "tags"=>["cell biology", "Cellular types", "Animal cells", "Immune cells", "immunology", "Vaccination and immunization", "vaccines", "Cancer vaccines", "autoimmunity", "neurology", "Neuromuscular diseases", "Animal studies", "Animal models of disease", "post-treatment", "eamg"], "article_id"=>1113992, "categories"=>["Biological Sciences"], "users"=>["Linda L. Kusner", "Michael J. Ciesielski", "Alexander Marx", "Henry J. Kaminski", "Robert A. Fenstermaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0102231.g005", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Analysis_of_post_treatment_with_SVN53_67_M57_KLH_in_EAMG_mouse_model_/1113992", "title"=>"Analysis of post-treatment with SVN53-67/M57-KLH in EAMG mouse model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-22 02:49:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1604607"], "description"=>"<p>Representitive images from an analysis of eleven thymuses from MG patients were analyzed for survivin expression (immunosuppression treated, <i>n</i> = 7; immnosuppression naïve, <i>n</i> = 4). <b>A–D</b>) EOMG thymus from a 24-year-old woman who had clinical symptoms for 2 years and an AChR antibody level of 19.3 nmol and had never received immunosuppression or prednisolone showed a well developed cortex (C) and medulla (M), lymphofollicular hyperplasia with a germinal center (GC) close to Hassall's corpuscle (HC). <b>B,D</b>) High number of survivin positive cells in the cortex (C), cortico-medullary junction and the GC. <b>E–H</b>) EOMG thymus from a AChR antibody positive 21-year-old female with lymphofollicular hyperplasia after long-term immunosuppression showing cortical atrophy and a slightly regressive germinal center (GC) close to a Hassall's corpuscle (HC). <b>F,H</b>) Low number of survivin positive lymphocytes in the remnant cortical area (C), and the germinal center (GC) (A,B,E,F, ×100; C,D,G,H ×200).</p>", "links"=>[], "tags"=>["cell biology", "Cellular types", "Animal cells", "Immune cells", "immunology", "Vaccination and immunization", "vaccines", "Cancer vaccines", "autoimmunity", "neurology", "Neuromuscular diseases", "Animal studies", "Animal models of disease"], "article_id"=>1113986, "categories"=>["Biological Sciences"], "users"=>["Linda L. Kusner", "Michael J. Ciesielski", "Alexander Marx", "Henry J. Kaminski", "Robert A. Fenstermaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0102231.g003", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Survivin_expression_in_the_thymus_/1113986", "title"=>"Survivin expression in the thymus.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-22 02:49:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1604617", "https://ndownloader.figshare.com/files/1604618", "https://ndownloader.figshare.com/files/1604619"], "description"=>"<div><p>The mechanisms that underlie the development and maintenance of autoimmunity in myasthenia gravis are poorly understood. In this investigation, we evaluate the role of survivin, a member of the inhibitor of apoptosis protein family, in humans and in two animal models. We identified survivin expression in cells with B lymphocyte and plasma cells markers, and in the thymuses of patients with myasthenia gravis. A portion of survivin-expressing cells specifically bound a peptide derived from the alpha subunit of acetylcholine receptor indicating that they recognize the peptide. Thymuses of patients with myasthenia gravis had large numbers of survivin-positive cells with fewer cells in the thymuses of corticosteroid-treated patients. Application of a survivin vaccination strategy in mouse and rat models of myasthenia gravis demonstrated improved motor assessment, a reduction in acetylcholine receptor specific autoantibodies, and a retention of acetylcholine receptor at the neuromuscular junction, associated with marked reduction of survivin-expressing circulating CD20+ cells. These data strongly suggest that survivin expression in cells with lymphocyte and plasma cell markers occurs in patients with myasthenia gravis and in two animal models of myasthenia gravis. Survivin expression may be part of a mechanism that inhibits the apoptosis of autoreactive B cells in myasthenia gravis and other autoimmune disorders.</p></div>", "links"=>[], "tags"=>["cell biology", "Cellular types", "Animal cells", "Immune cells", "immunology", "Vaccination and immunization", "vaccines", "Cancer vaccines", "autoimmunity", "neurology", "Neuromuscular diseases", "Animal studies", "Animal models of disease", "mediator", "autoreactive", "myasthenia"], "article_id"=>1113995, "categories"=>["Biological Sciences"], "users"=>["Linda L. Kusner", "Michael J. Ciesielski", "Alexander Marx", "Henry J. Kaminski", "Robert A. Fenstermaker"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0102231.s001", "https://dx.doi.org/10.1371/journal.pone.0102231.s002", "https://dx.doi.org/10.1371/journal.pone.0102231.s003"], "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Survivin_as_a_Potential_Mediator_to_Support_Autoreactive_Cell_Survival_in_Myasthenia_Gravis_A_Human_and_Animal_Model_Study_/1113995", "title"=>"Survivin as a Potential Mediator to Support Autoreactive Cell Survival in Myasthenia Gravis: A Human and Animal Model Study", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-07-22 02:49:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1604616"], "description"=>"<p>Demographic and treatment characteristics of myasthenic patients (1–15) and controls (16–25) consisting of individuals with non-myasthenic neurologic conditions.</p>", "links"=>[], "tags"=>["cell biology", "Cellular types", "Animal cells", "Immune cells", "immunology", "Vaccination and immunization", "vaccines", "Cancer vaccines", "autoimmunity", "neurology", "Neuromuscular diseases", "Animal studies", "Animal models of disease", "myasthenic", "patients", "controls", "consisting", "individuals", "non-myasthenic", "neurologic"], "article_id"=>1113994, "categories"=>["Biological Sciences"], "users"=>["Linda L. Kusner", "Michael J. Ciesielski", "Alexander Marx", "Henry J. Kaminski", "Robert A. Fenstermaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0102231.t001", "stats"=>{"downloads"=>5, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Demographic_and_treatment_characteristics_of_myasthenic_patients_1_8211_15_and_controls_16_8211_25_consisting_of_individuals_with_non_myasthenic_neurologic_conditions_/1113994", "title"=>"Demographic and treatment characteristics of myasthenic patients (1–15) and controls (16–25) consisting of individuals with non-myasthenic neurologic conditions.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-07-22 02:49:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1604595"], "description"=>"<p><b>A,B</b>) Representative FACS analysis of total survivin expression of (A) myasthenic patient (7) and (B) control (24) PBMC. <b>C–H</b>) PBMC were stained with antibodies to indicated markers. Data reflect the percentage of total cells staining positive for: <b>C</b>) Survivin (SVN) (p = 0.010), <b>D</b>) CD20+/SVN+ (p = 0.0009), <b>E</b>) CD38+/SVN+ (p = 0.02), <b>F</b>) CD27+/SVN+ (p = 0.05), <b>G</b>) CD138+/SVN+ (p = 0.01) and <b>H</b>) CD8+/SVN+ (p = 0.4). Mean values of patients and controls were compared using two way ANOVA.</p>", "links"=>[], "tags"=>["cell biology", "Cellular types", "Animal cells", "Immune cells", "immunology", "Vaccination and immunization", "vaccines", "Cancer vaccines", "autoimmunity", "neurology", "Neuromuscular diseases", "Animal studies", "Animal models of disease", "myasthenia", "gravis", "patients"], "article_id"=>1113974, "categories"=>["Biological Sciences"], "users"=>["Linda L. Kusner", "Michael J. Ciesielski", "Alexander Marx", "Henry J. Kaminski", "Robert A. Fenstermaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0102231.g001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Survivin_expression_in_myasthenia_gravis_patients_1_8211_15_and_control_16_8211_25_PBMCs_/1113974", "title"=>"Survivin expression in myasthenia gravis patients (1–15) and control (16–25) PBMCs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-22 02:49:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1604609"], "description"=>"<p><b>A</b>) Animals were injected with SVN53-67/M57-KLH at times marked by red arrows. Black arrows mark injection times of tAChR. Grip strength was monitored throughout experiment. Mice were treated with SVN53-67/M57-KLH (circles, <i>n</i> = 9), or PBS (squares, <i>n</i> = 10) (* denotes <i>P</i><0.05, t-test). <b>B</b>) Table shows clinical scores of mice treated with SVN53-67/M57-KLH were significantly stronger than PBS treated mice (* denotes <i>P</i><0.05, t-test).</p>", "links"=>[], "tags"=>["cell biology", "Cellular types", "Animal cells", "Immune cells", "immunology", "Vaccination and immunization", "vaccines", "Cancer vaccines", "autoimmunity", "neurology", "Neuromuscular diseases", "Animal studies", "Animal models of disease", "post-treatment", "eamg"], "article_id"=>1113988, "categories"=>["Biological Sciences"], "users"=>["Linda L. Kusner", "Michael J. Ciesielski", "Alexander Marx", "Henry J. Kaminski", "Robert A. Fenstermaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0102231.g004", "stats"=>{"downloads"=>3, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SVN53_67_M57_KLH_post_treatment_on_active_EAMG_in_the_mouse_model_/1113988", "title"=>"SVN53-67/M57-KLH post-treatment on active EAMG in the mouse model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-22 02:49:41"}

PMC Usage Stats | Further Information

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Relative Metric

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