T cells, Cytokines, and Genetic Factors in Autoimmunity Studies of experimental models of arthritis and sialadenitis
(2001)- Abstract
- To understand the pathogenesis of autoimmune diseases we have to consider the problem from different angles. Animal models provide a tool to further understand these complex diseases, as the influence of genetic and environmental factors could be limited. Moreover, modern transgenic techniques have made it possible to study the role of certain genes and gene products in the development of diseases. To gain further knowledge about the pathogenesis and the genetic control of collagen-induced arthritis and sialadenitis (experimental models for rheumatoid arthritis and Sjögren’s syndrome respectively), we used two different approaches. The first aimed at studying the role of candidate genes such as <i>Il10, Cd4, Cd8, Tcrb</i> and... (More)
- To understand the pathogenesis of autoimmune diseases we have to consider the problem from different angles. Animal models provide a tool to further understand these complex diseases, as the influence of genetic and environmental factors could be limited. Moreover, modern transgenic techniques have made it possible to study the role of certain genes and gene products in the development of diseases. To gain further knowledge about the pathogenesis and the genetic control of collagen-induced arthritis and sialadenitis (experimental models for rheumatoid arthritis and Sjögren’s syndrome respectively), we used two different approaches. The first aimed at studying the role of candidate genes such as <i>Il10, Cd4, Cd8, Tcrb</i> and <i>Tcrd</i> in arthritis, and the second to identify genetic regions that harbor arthritis and/or sialadenitis modifying genes.
By investigating inbred mouse strains we showed that the genetic background had a major impact on lymphocyte subsets and cytokine production by T cells, indicating the importance of carefully phenotyping strains when using transgenic techniques in model systems. Furthermore, the complexity of cytokines in the pathogenesis of arthritis came to focus when IL-10 deficient mice were studied. The importance of IL-10 in reducing the severity of arthritis was clearly shown, but curiously IL-10 also seemed to promote arthritis as IL-10 deficiency protected against antibody-transfer induced arthritis. In addition, it was demonstrated that alfabeta T cells, especially the CD4+ T cells, were important for CIA development and the production of anti-collagen type II antibodies, whereas gammadelta T cells and CD8+ T cells were of minor importance. Finally, we identified two loci, <i>Cia2</i> and <i>Cia9</i>, that controlled the severity of CIA and one locus, <i>Nss1</i>, that controlled the severity of sialadenitis in gene segregation experiments involving the B10.Q and the NOD.Q strains.
These results have shed some light on the pathogenesis of arthritis and sialadenitis but further knowledge is needed to understand these complex diseases. Revealing and understanding the pathogenesis of autoimmune diseases may form a basis for new therapeutic strategies. (Less) - Abstract (Swedish)
- Popular Abstract in Swedish
Ärftliga orsaker till ledgångsreumatism och Sjögrens syndrom
Ett välfungerande immunförsvar är nödvändigt för att kroppen ska kunna mostå angrepp från virus, bakterier och andra mikroorganismer. Vid en autoimmun sjukdom tror man att immunförsvaret av misstag börjar angripa kroppens egna vävnader, vilket leder till att de förstörs. Hur dessa sjukdomar uppkommer känner man inte till idag, men man har upptäckt att det finns en ärftlig faktor.
Ledgångsreumatism och Sjögrens syndrom är två utav de vanligaste autoimmuna sjukdomarna i västvärlden och drabbar tillsammans ett par procent av befolkningen. Ledgångsreumatism kännetecknas av ledvärk och stelhet till följd... (More) - Popular Abstract in Swedish
Ärftliga orsaker till ledgångsreumatism och Sjögrens syndrom
Ett välfungerande immunförsvar är nödvändigt för att kroppen ska kunna mostå angrepp från virus, bakterier och andra mikroorganismer. Vid en autoimmun sjukdom tror man att immunförsvaret av misstag börjar angripa kroppens egna vävnader, vilket leder till att de förstörs. Hur dessa sjukdomar uppkommer känner man inte till idag, men man har upptäckt att det finns en ärftlig faktor.
Ledgångsreumatism och Sjögrens syndrom är två utav de vanligaste autoimmuna sjukdomarna i västvärlden och drabbar tillsammans ett par procent av befolkningen. Ledgångsreumatism kännetecknas av ledvärk och stelhet till följd av en kronisk ledinflammation, medan patienter med Sjögrens syndrom lider av gruskänsla i ögonen samt muntorrhet p.g.a. en kronisk inflammation i tår- och spottkörtlar.
För att studera hur immunsystemet kan orsaka sjukdom använde vi oss av djurmodeller. Kollageninducerad artrit är en modell för ledgångsreumatism, där ledinflammation framkallas genom att man injicerar möss med ett brosk protein (kollagen typ II). Känsligheten för kollageninducerad artrit är delvis ärftlig, eftersom enbart vissa musstammar som t.ex. B10.Q utvecklar ledinflammation medan andra stammar som t.ex. NOD.Q är helt resistenta. NOD.Q mössen utvecklar å andra sidan spontant en Sjögerns syndrom liknande inflammation i spott- och tårkörtlar.
Genom att korsa NOD.Q möss med B10.Q möss, kunde vi identifiera två regioner i arvsmassan som styr ledinflammation samt en region som styr spottkörtelinflammation. Ytterliggare arbete är dock nödvändigt för att påvisa vilka gener det är som döljer sig i dessa regioner. Vidare har vi använt oss av möss med kända gendefekter för att studera olika proteiners och cellers funktion vid ledinflammation. Vi har därigenom kunnat visa att interleukin-10, en molekyl som överför signaler mellan immunsystemets celler, skyddar mot ledinflammation samt att sjukdomen är beroende utav en av immunsystemets celltyper, de så kallade T hjälpar cellerna.
Vår förhoppning är att hitta de gener som leder till led- och spottkörtelinflammation och sedan förstå vilka effekter de har på immunsystemet. När vi väl förstår varför autoimmuna sjukdomar uppkommer ökar möjligheterna att finna botemedel. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/41823
- author
- Johansson, Åsa LU
- supervisor
- opponent
-
- Dr Wicker, Linda S., The Wellcome Trust Centre for Molecular Mechanisms in Disease, University of Cambridge, UK
- organization
- publishing date
- 2001
- type
- Thesis
- publication status
- published
- subject
- keywords
- rheumatology locomotion, Collagen-induced arthritis/ Sialadenitis/ Mice/ Knockout/ Linkage analysis/ T cells/ Cytokines, muscle system, Skeleton, reumatologi, muskelsystem, Skelett
- pages
- 127 pages
- publisher
- Medical Inflammation Research, Department of Experimental Medicine, Faculty of Medicine, Lund University
- defense location
- Rune Grubb salen, BMC
- defense date
- 2001-10-19 10:15:00
- ISBN
- 91-628-4958-1
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Medical Inflammation Research (013212019)
- id
- 07917d74-6d05-4a7f-a8e5-f76127b53abb (old id 41823)
- date added to LUP
- 2016-04-04 12:09:52
- date last changed
- 2018-11-21 21:09:22
@phdthesis{07917d74-6d05-4a7f-a8e5-f76127b53abb,
abstract = {{To understand the pathogenesis of autoimmune diseases we have to consider the problem from different angles. Animal models provide a tool to further understand these complex diseases, as the influence of genetic and environmental factors could be limited. Moreover, modern transgenic techniques have made it possible to study the role of certain genes and gene products in the development of diseases. To gain further knowledge about the pathogenesis and the genetic control of collagen-induced arthritis and sialadenitis (experimental models for rheumatoid arthritis and Sjögren’s syndrome respectively), we used two different approaches. The first aimed at studying the role of candidate genes such as <i>Il10, Cd4, Cd8, Tcrb</i> and <i>Tcrd</i> in arthritis, and the second to identify genetic regions that harbor arthritis and/or sialadenitis modifying genes.<br/><br>
<br/><br>
By investigating inbred mouse strains we showed that the genetic background had a major impact on lymphocyte subsets and cytokine production by T cells, indicating the importance of carefully phenotyping strains when using transgenic techniques in model systems. Furthermore, the complexity of cytokines in the pathogenesis of arthritis came to focus when IL-10 deficient mice were studied. The importance of IL-10 in reducing the severity of arthritis was clearly shown, but curiously IL-10 also seemed to promote arthritis as IL-10 deficiency protected against antibody-transfer induced arthritis. In addition, it was demonstrated that alfabeta T cells, especially the CD4+ T cells, were important for CIA development and the production of anti-collagen type II antibodies, whereas gammadelta T cells and CD8+ T cells were of minor importance. Finally, we identified two loci, <i>Cia2</i> and <i>Cia9</i>, that controlled the severity of CIA and one locus, <i>Nss1</i>, that controlled the severity of sialadenitis in gene segregation experiments involving the B10.Q and the NOD.Q strains.<br/><br>
<br/><br>
These results have shed some light on the pathogenesis of arthritis and sialadenitis but further knowledge is needed to understand these complex diseases. Revealing and understanding the pathogenesis of autoimmune diseases may form a basis for new therapeutic strategies.}},
author = {{Johansson, Åsa}},
isbn = {{91-628-4958-1}},
keywords = {{rheumatology locomotion; Collagen-induced arthritis/ Sialadenitis/ Mice/ Knockout/ Linkage analysis/ T cells/ Cytokines; muscle system; Skeleton; reumatologi; muskelsystem; Skelett}},
language = {{eng}},
publisher = {{Medical Inflammation Research, Department of Experimental Medicine, Faculty of Medicine, Lund University}},
school = {{Lund University}},
title = {{T cells, Cytokines, and Genetic Factors in Autoimmunity Studies of experimental models of arthritis and sialadenitis}},
year = {{2001}},
}