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Novel strategies to explore The complex genetics of autoimmune diseases

Johannesson, Martina LU (2005)
Abstract (Swedish)
Popular Abstract in Swedish

Autoimmuna sjukdomar såsom reumatoid artrit (RA) och multipel skleros (MS) uppkommer av en felaktig immunrespons mot kroppens egen vävnad. Orsaken är okänd trots enormt mycket forskning om ämnet. Ett sätt att öka kunskapen vore att identifiera de gener som bidrar till sjukdomarna. För sådana relativt vanliga, komplexa sjukdomar finns det inte en gen som ?styr? sjukdomarna, utan snarare varianter av gener som i vissa kombinationer ökar sjukdomsrisken. Dessa gener interagerar med varandra och med faktorer i miljön runtomkring på ett sätt som vi idag inte kan följa. RA och MS är kliniskt heterogena sjukdomar med många och varierande symptom och olika gener, i olika människor, i olika miljöer, bidrar... (More)
Popular Abstract in Swedish

Autoimmuna sjukdomar såsom reumatoid artrit (RA) och multipel skleros (MS) uppkommer av en felaktig immunrespons mot kroppens egen vävnad. Orsaken är okänd trots enormt mycket forskning om ämnet. Ett sätt att öka kunskapen vore att identifiera de gener som bidrar till sjukdomarna. För sådana relativt vanliga, komplexa sjukdomar finns det inte en gen som ?styr? sjukdomarna, utan snarare varianter av gener som i vissa kombinationer ökar sjukdomsrisken. Dessa gener interagerar med varandra och med faktorer i miljön runtomkring på ett sätt som vi idag inte kan följa. RA och MS är kliniskt heterogena sjukdomar med många och varierande symptom och olika gener, i olika människor, i olika miljöer, bidrar till sjukdomsbilden. Därför är det svårt att göra genetiska studier i människa. Men vetskapen om vilka gener det är och hur de interagerar kan hjälpa oss att utveckla bättre, mer specifika behandlingar. Därför försöker vi identifiera dem genom att använda oss av djurmodeller för sjukdomarna, där vi kan studera sjukdomsutvecklingen i genetiskt lika, inavlade individer i en kontrollerad miljö.



I den här avhandlingen har vi utvecklat nya metoder för att studera genetiken bakom experimentella djurmodeller av sjukdomarna RA och MS. Vi har studerat collagen inducerad artrit i möss och identfierat flera gen-regioner som påverkar sjukdomen. Vi har sett att det inte är samma gen-regioner som styr när mössen blir sjuka som hur sjuka de blir. Dessutom styrs den akuta sjukdomsfasen av andra gen-regioner än den mer kroniska fasen. Vi har också sett att gen-interaktioner är en stor och viktig del av sjukdomsbilden, och utnyttjat interaktionerna för att hitta var i genomet generna finns. För att identifiera gener, viktiga för artrit, har vi också studerat genuttrycket under ett artrit förlopp och identifierat flera gener som vi nu ska undersöka vidare. Eftersom immunförsvaret är ett sådant komplext system med många faktorer beroende av varandra så innebär en störning nästan alltid stora effekter. Detta kan man se om man studerar möss som saknar någon gen i immunförsvaret; nästan alla har en påverkan på artrit. Det är därför det är viktigt att studera naturliga varianter av gener och hur de interagerar med varandra och med miljöfaktorer. (Less)
Abstract
Autoimmune diseases are dependent on both genetic and environmental factors in complex interplay. They arise from a faulty immune response against self-antigens, and causes great suffering in affected individuals. Despite large efforts and hundreds of thousands of research articles published, the disease etiologies remain largely unknown. Knowledge of which genes are involved and how they interact would increase the possibilities of understanding the diseases and to create specific treatments. The work in this thesis is focused on methods to identify genes involved in autoimmune diseases by using experimental animal models for the diseases, both on a large scale with different gene segregation-crosses and on a small scale with studies on... (More)
Autoimmune diseases are dependent on both genetic and environmental factors in complex interplay. They arise from a faulty immune response against self-antigens, and causes great suffering in affected individuals. Despite large efforts and hundreds of thousands of research articles published, the disease etiologies remain largely unknown. Knowledge of which genes are involved and how they interact would increase the possibilities of understanding the diseases and to create specific treatments. The work in this thesis is focused on methods to identify genes involved in autoimmune diseases by using experimental animal models for the diseases, both on a large scale with different gene segregation-crosses and on a small scale with studies on specific candidate genes.



The thesis is based on six papers with the aim to map genes in experimental mouse models for RA and MS, on a genome-wide level as well as a locus-based level. The commonly used F2 intercross is compared with alternative genome-wide strategies. The partial advanced intercross (PAI) strategy - a novel strategy for high-resolution mapping based on genetic interactions, is introduced as well as novel strategy for selection of candidate genes, the QTL-chip. These strategies were used to dissect the arthritis loci Cia5/Eae3 and Eae2 into three and four separate quantitative trait loci (QTLs) respectively, and to identify seven strong candidate-quantitative trait genes (QTGs) for Cia21 and Cia22. Genetic interactions were found to play a major role in collagen induced arthritis in mice, and we demonstrate that interactions can be used to increase the penetrance of a QTL with otherwise small effects. Moreover, we show that different genetic loci affect separate parts of the diseases, i.e. the onset, early phase, late phase or severity and that the sub-division of the phenotype could be a prerequisite for finding all underlying QTLs.



The major conclusions are that the autoimmune experimental models are highly dependent on genetic, environmental and sex- specific interactions. The immune system is a complex network of interacting factors and there is no reason to believe that the genetics behind a disease dependent on it would be otherwise. This knowledge is important for future investigations regarding complex autoimmune diseases. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Associate professor Broman, Karl, Johns Hopkins University, Baltimore Maryland, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
transplantation, Immunology, serology, Immunologi, serologi, cytogenetik, Genetik, cytogenetics, Genetics, collagen induced arthritis, QTL mapping, complex traits, autoimmunity, genetics
pages
161 pages
publisher
Medical Inflammation Research, Department of Experimental Medicine, Faculty of Medicine, Lund University
defense location
Rune Grupp Lecture hall, BMC Sölvegatan 19 Lund
defense date
2005-01-28 09:00
ISBN
91-628-6373-8
language
English
LU publication?
yes
id
931519e4-5631-4c7e-9e45-edc8af6ddc66 (old id 544197)
date added to LUP
2007-09-20 12:41:53
date last changed
2016-09-19 08:45:06
@phdthesis{931519e4-5631-4c7e-9e45-edc8af6ddc66,
  abstract     = {Autoimmune diseases are dependent on both genetic and environmental factors in complex interplay. They arise from a faulty immune response against self-antigens, and causes great suffering in affected individuals. Despite large efforts and hundreds of thousands of research articles published, the disease etiologies remain largely unknown. Knowledge of which genes are involved and how they interact would increase the possibilities of understanding the diseases and to create specific treatments. The work in this thesis is focused on methods to identify genes involved in autoimmune diseases by using experimental animal models for the diseases, both on a large scale with different gene segregation-crosses and on a small scale with studies on specific candidate genes.<br/><br>
<br/><br>
The thesis is based on six papers with the aim to map genes in experimental mouse models for RA and MS, on a genome-wide level as well as a locus-based level. The commonly used F2 intercross is compared with alternative genome-wide strategies. The partial advanced intercross (PAI) strategy - a novel strategy for high-resolution mapping based on genetic interactions, is introduced as well as novel strategy for selection of candidate genes, the QTL-chip. These strategies were used to dissect the arthritis loci Cia5/Eae3 and Eae2 into three and four separate quantitative trait loci (QTLs) respectively, and to identify seven strong candidate-quantitative trait genes (QTGs) for Cia21 and Cia22. Genetic interactions were found to play a major role in collagen induced arthritis in mice, and we demonstrate that interactions can be used to increase the penetrance of a QTL with otherwise small effects. Moreover, we show that different genetic loci affect separate parts of the diseases, i.e. the onset, early phase, late phase or severity and that the sub-division of the phenotype could be a prerequisite for finding all underlying QTLs.<br/><br>
<br/><br>
The major conclusions are that the autoimmune experimental models are highly dependent on genetic, environmental and sex- specific interactions. The immune system is a complex network of interacting factors and there is no reason to believe that the genetics behind a disease dependent on it would be otherwise. This knowledge is important for future investigations regarding complex autoimmune diseases.},
  author       = {Johannesson, Martina},
  isbn         = {91-628-6373-8},
  keyword      = {transplantation,Immunology,serology,Immunologi,serologi,cytogenetik,Genetik,cytogenetics,Genetics,collagen induced arthritis,QTL mapping,complex traits,autoimmunity,genetics},
  language     = {eng},
  pages        = {161},
  publisher    = {Medical Inflammation Research, Department of Experimental Medicine, Faculty of Medicine, Lund University},
  school       = {Lund University},
  title        = {Novel strategies to explore The complex genetics of autoimmune diseases},
  year         = {2005},
}