Identification of genetic variants and their implications in autoimmunity
Author: Norin, Ulrika
Date: 2017-03-24
Location: Samuelssonsalen Karolinska Institutet Scheeles väg 2, Solna
Time: 09.00
Department: Inst för medicinsk biokemi och biofysik / Dept of Medical Biochemistry and Biophysics
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Thesis (3.219Mb)
Abstract
Autoimmune disorders start to develop when the body’s immune system recognizes organs and tissues as foreign and initiates uncontrolled immune reactions against them. Most of these disorders are regarded as complex with both environmental and genetic factors contributing to disease development. Current treatment of autoimmune disorders such as Rheumatoid arthritis (RA) is associated with lack of efficacy, development of resistance and serious side-effects and accentuates the need for development of new therapeutics. Improved understanding of the underlying genetic pathways that convey pathogenicity in arthritis is key to discover more efficient and safe therapies. The heterogenetic nature of autoimmune diseases and the interaction with environmental factors delays the discovery of susceptibility genes in humans, which suggests the use of animal models where both genetic background and environment can be controlled. In this thesis we have used rat models to identify genes that regulate the induction of autoimmune arthritis.
In study one, we identify the gene encoding Endophilin A2 as a major determinant in regulating the induction of autoimmunity and show that the Endophilin A2 mediated protection is regulated via T cell responsiveness. In study two, we investigate the role of the Vav1 gene, previously associated to multiple sclerosis, for its role in arthritis in rats and humans and show that natural variants in the Vav1 gene regulate T cell dependent arthritis. In study three, we determine by functional studies that the increase in reactive oxygen species conveyed by the Ncf1 gene, is responsible for reduced arthritis severity seen in Ncf1 congenic rats. In study IV, we use high resolution mapping in a rat heterogeneous stock to identify genes regulating expression of cell surface molecules and frequency of different leukocytes in blood.
By combining animal studies and human data we have in this thesis identified new genes involved in the pathogenesis of arthritis, which further illustrates the heterogenic nature of RA and the shared peripheral tolerance pathways regulating different autoimmune disorders. Furthermore, the results in this thesis have demonstrated the value of using animal studies to identify genes and pathways relevant to human disorders.
In study one, we identify the gene encoding Endophilin A2 as a major determinant in regulating the induction of autoimmunity and show that the Endophilin A2 mediated protection is regulated via T cell responsiveness. In study two, we investigate the role of the Vav1 gene, previously associated to multiple sclerosis, for its role in arthritis in rats and humans and show that natural variants in the Vav1 gene regulate T cell dependent arthritis. In study three, we determine by functional studies that the increase in reactive oxygen species conveyed by the Ncf1 gene, is responsible for reduced arthritis severity seen in Ncf1 congenic rats. In study IV, we use high resolution mapping in a rat heterogeneous stock to identify genes regulating expression of cell surface molecules and frequency of different leukocytes in blood.
By combining animal studies and human data we have in this thesis identified new genes involved in the pathogenesis of arthritis, which further illustrates the heterogenic nature of RA and the shared peripheral tolerance pathways regulating different autoimmune disorders. Furthermore, the results in this thesis have demonstrated the value of using animal studies to identify genes and pathways relevant to human disorders.
List of papers:
I. Spontaneous mutation reveals Endophilin A2 as a major regulator of autoreactive T cells and a potential new target in autoimmune disease. Ulrika Norin, Carola Rintisch, Florian Forster, Liesu Meng, Diana Ekman, Jonatan Tuncel, Katrin Klocke, Johan Bäcklund, Min Yang, Klementy Shchetynsky, Hanna Axelsson, Martin Haraldsson, Thomas Lundbäck, Maria Bergquist, Leonid Padykov, Inger Gjertsson, Pietro de Camilli, Norbert Hubner, Liselotte Bäckdahl, Rikard Holmdahl. [Manuscript]
II. VAV1 regulates experimental autoimmune arthritis and is associated with anti-CCP negative rheumatoid arthritis. André Ortlieb Guerreiro-Cacais, Ulrika Norin, Alexandra Gyllenberg, Rasmus Berglund, Amennai Daniel Beyeen, Rheumatoid Arthritis Consortium International, Elisabeth Petit-Teixeira, François Cornélis, Abdelhadi Saoudi, Gilbert J. Fournié, Rikard Holmdahl, Lars Alfredsson, Lars Klareskog, Maja Jagodic, Tomas Olsson, Ingrid Kockum, Leonid Padyukov. Genes Immun. 2017 Jan;18(1):48-56.
Fulltext (DOI)
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III. Positioning of a Polymorphic Quantitative Trait Nucleotide in the Ncf1 Gene Controlling Oxidative Burst Response and Arthritis Severity in Rats. Malin Hultqvist, Outi Sareila, Fredrik Vilhardt, Ulrika Norin, Lina M. Olsson, Peter Olofsson, Ulf Hellman, Rikard Holmdahl. Antioxidants and redox signaling. 2011, 14, 2373-2383.
Fulltext (DOI)
Pubmed
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IV. Combined sequence-based and genetic mapping analysis of complex traits in outbred rats. Amelie Baud, Roel Hermsen, Victor Guryev, Pernilla Stridh, Delyth Graham, Martin W McBride, Tatiana Foroud, Sophie Calderari, Margarita Diez, Johan Ockinger, Amennai D Beyeen, Alan Gillett, Nada Abdelmagid, Andre Ortlieb Guerreiro-Cacais, Maja Jagodic, Jonatan Tuncel, Ulrika Norin, Elisabeth Beattie, Ngan Huynh, William H Miller, Daniel L Koller, Imranul Alam, Samreen Falak, Mary Osborne-Pellegrin, Esther Martinez-Membrives, Toni Canete, Gloria Blazquez, Elia Vicens-Costa, Carme Mont-Cardona, Sira Diaz-Moran, Adolf Tobena, Oliver Hummel, Diana Zelenika, Kathrin Saar, Giannino Patone, Anja Bauerfeind, Marie-Therese Bihoreau, Matthias Heinig, Young-Ae Lee, Carola Rintisch, Herbert Schulz, David A Wheeler, Kim C Worley, Donna M Muzny, Richard A Gibbs, Mark Lathrop, Nico Lansu, Pim Toonen, Frans Paul Ruzius, Ewart de Bruijn, Heidi Hauser, David J Adams, Thomas Keane, Santosh S Atanur, Tim J Aitman, Paul Flicek, Tomas Malinauskas, E Yvonne Jones, Diana Ekman, Regina Lopez-Aumatell, Anna F Dominiczak, Martina Johannesson, Rikard Holmdahl, Tomas Olsson, Dominique Gauguier, Norbert Hubner, Alberto Fernandez-Teruel, Edwin Cuppen, Richard Mott & Jonathan Flint. Nature Genetics. 2013 Jul;45(7):767-75.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Spontaneous mutation reveals Endophilin A2 as a major regulator of autoreactive T cells and a potential new target in autoimmune disease. Ulrika Norin, Carola Rintisch, Florian Forster, Liesu Meng, Diana Ekman, Jonatan Tuncel, Katrin Klocke, Johan Bäcklund, Min Yang, Klementy Shchetynsky, Hanna Axelsson, Martin Haraldsson, Thomas Lundbäck, Maria Bergquist, Leonid Padykov, Inger Gjertsson, Pietro de Camilli, Norbert Hubner, Liselotte Bäckdahl, Rikard Holmdahl. [Manuscript]
II. VAV1 regulates experimental autoimmune arthritis and is associated with anti-CCP negative rheumatoid arthritis. André Ortlieb Guerreiro-Cacais, Ulrika Norin, Alexandra Gyllenberg, Rasmus Berglund, Amennai Daniel Beyeen, Rheumatoid Arthritis Consortium International, Elisabeth Petit-Teixeira, François Cornélis, Abdelhadi Saoudi, Gilbert J. Fournié, Rikard Holmdahl, Lars Alfredsson, Lars Klareskog, Maja Jagodic, Tomas Olsson, Ingrid Kockum, Leonid Padyukov. Genes Immun. 2017 Jan;18(1):48-56.
Fulltext (DOI)
Pubmed
III. Positioning of a Polymorphic Quantitative Trait Nucleotide in the Ncf1 Gene Controlling Oxidative Burst Response and Arthritis Severity in Rats. Malin Hultqvist, Outi Sareila, Fredrik Vilhardt, Ulrika Norin, Lina M. Olsson, Peter Olofsson, Ulf Hellman, Rikard Holmdahl. Antioxidants and redox signaling. 2011, 14, 2373-2383.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Combined sequence-based and genetic mapping analysis of complex traits in outbred rats. Amelie Baud, Roel Hermsen, Victor Guryev, Pernilla Stridh, Delyth Graham, Martin W McBride, Tatiana Foroud, Sophie Calderari, Margarita Diez, Johan Ockinger, Amennai D Beyeen, Alan Gillett, Nada Abdelmagid, Andre Ortlieb Guerreiro-Cacais, Maja Jagodic, Jonatan Tuncel, Ulrika Norin, Elisabeth Beattie, Ngan Huynh, William H Miller, Daniel L Koller, Imranul Alam, Samreen Falak, Mary Osborne-Pellegrin, Esther Martinez-Membrives, Toni Canete, Gloria Blazquez, Elia Vicens-Costa, Carme Mont-Cardona, Sira Diaz-Moran, Adolf Tobena, Oliver Hummel, Diana Zelenika, Kathrin Saar, Giannino Patone, Anja Bauerfeind, Marie-Therese Bihoreau, Matthias Heinig, Young-Ae Lee, Carola Rintisch, Herbert Schulz, David A Wheeler, Kim C Worley, Donna M Muzny, Richard A Gibbs, Mark Lathrop, Nico Lansu, Pim Toonen, Frans Paul Ruzius, Ewart de Bruijn, Heidi Hauser, David J Adams, Thomas Keane, Santosh S Atanur, Tim J Aitman, Paul Flicek, Tomas Malinauskas, E Yvonne Jones, Diana Ekman, Regina Lopez-Aumatell, Anna F Dominiczak, Martina Johannesson, Rikard Holmdahl, Tomas Olsson, Dominique Gauguier, Norbert Hubner, Alberto Fernandez-Teruel, Edwin Cuppen, Richard Mott & Jonathan Flint. Nature Genetics. 2013 Jul;45(7):767-75.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Holmdahl, Rikard
Co-supervisor: Bäckdahl, Liselotte; Bäcklund, Johan
Issue date: 2017-03-03
Rights:
Publication year: 2017
ISBN: 978-91-7676-561-6
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