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Genetic characterization to dissect the phenotypic complexity of autoimmunity

Karlsson, Jenny C LU (2005)
Abstract (Swedish)
Popular Abstract in Swedish

Rheumatoid Artrit (RA) och Multipel Skleros (MS) är autoimmuna sjukdomar som drabbar ca 1 % respective 0.2 % av den nordeuropeiska befolkningen där kvinnor drabbas oftare än män. Dessa sjukdomar orsakas av att immunförsvaret attackerar kroppsegen vävnad. En fortgående inflammation förstör vävnaden och leder till nedsatt funktion. I RA angrips framför allt leder kan bli deformerade och förlora sin rörlighet. Även andra organ kan ibland vara inblandade och därför anses RA vara en systemisk sjukdom. MS är däremot en mer organ specifik sjukdom och drabbar det centrala nervsystemet (CNS). Det skyddande myelinet som omger nervfibrer bryts ned och beroende på var inflammationen är i hjärna och ryggmärg... (More)
Popular Abstract in Swedish

Rheumatoid Artrit (RA) och Multipel Skleros (MS) är autoimmuna sjukdomar som drabbar ca 1 % respective 0.2 % av den nordeuropeiska befolkningen där kvinnor drabbas oftare än män. Dessa sjukdomar orsakas av att immunförsvaret attackerar kroppsegen vävnad. En fortgående inflammation förstör vävnaden och leder till nedsatt funktion. I RA angrips framför allt leder kan bli deformerade och förlora sin rörlighet. Även andra organ kan ibland vara inblandade och därför anses RA vara en systemisk sjukdom. MS är däremot en mer organ specifik sjukdom och drabbar det centrala nervsystemet (CNS). Det skyddande myelinet som omger nervfibrer bryts ned och beroende på var inflammationen är i hjärna och ryggmärg påverkas olika funktioner. Dubbelseende är ofta ett tidigt symptom i MS och orsakas av demyelinisering av den optiska nerven. Accumulering av sklerotiska plack i CNS leder så småningom till en successiv försämring som kan leda till svåra funktionshinder och förlamning.



Orsaken till dessa mycket komplexa sjukdomar är okänd men flera gener samt miljöfaktorer är inblandade. För att öka kunskapen om sjukdomarna och finna bättre mediciner är det viktigt att identifiera dessa gener. Den genetiska arvsmassan skiljer sig stort mellan individer och pga att olika kombinationer av många gener orsakar sjukdomarna. Detta gör det mycket svårt att finna nyckel generna i människa. Djurmodeller av de mänskliga sjukdomarna har fördelen att vi har kontroll över både miljöfaktorer och genetiken då vi använder inavlade stammar. I denna avhandling har vi utvecklat nya metoder för att förstå genetiken bakom RA och MS. Vi har visat att kollagen inducerad artrit, djurmodellen för RA samt djurmodellen för MS, experimentell autoimmun encefalomyelit (EAE) styrs av flera olika gener. Vi har visat att initeringsfasen och den kroniska fasen av artrit ej styrs av samma gener samt att interaktion av flera gener leder till olika förlopp. Vi har hittat genområden som styr vissa celltyper involverade i MS och RA. Vår forskningen hjäper oss att bättre förstå hur olika gener agerar tillsammans i utvecklingen av autoimmuna sjukdommar. I förlängningen kan detta leda till utveckling av nya och bättre läkemedel. (Less)
Abstract
Autoimmune diseases are dependent on multiple genes and unknown environmental factors. Great efforts in the identification of genes conferring susceptibility to autoimmune diseases like Rheumatoid Arthritis (RA) and Multiple Sclerosis (MS) have recently been rewarding. A few genes have so far been associated to several autoimmune disorders and the understanding of the role of these genes in the pathogenesis and the identification of additional genes will be of great use in the designing of new and better therapies. The fine characterization of each disease is of importance in order to define sub-groups, which may respond differently to treatments.



The work in this thesis was done in mouse models for RA and MS and is... (More)
Autoimmune diseases are dependent on multiple genes and unknown environmental factors. Great efforts in the identification of genes conferring susceptibility to autoimmune diseases like Rheumatoid Arthritis (RA) and Multiple Sclerosis (MS) have recently been rewarding. A few genes have so far been associated to several autoimmune disorders and the understanding of the role of these genes in the pathogenesis and the identification of additional genes will be of great use in the designing of new and better therapies. The fine characterization of each disease is of importance in order to define sub-groups, which may respond differently to treatments.



The work in this thesis was done in mouse models for RA and MS and is based on four papers where the aim was to identify genes associated with these diseases. We have studied crosses between a susceptible and a resistant mouse strain to assess the genetic context for a disease-linked locus to appear. In an F2 intercross between the two strains, the Eae2 locus on chromosome 15 was previously linked to disease in the MS model Experimental Autoimmune Encephalomyelitis (EAE) through interaction with Eae3 on chromosome 3. The locus homologous to Eae2 on human chromosome 5 was later associated with MS in a Finnish population. In order to identify additional loci, EAE was studied in an F2 intercross where the Eae2 locus was neutralized (paper I) and in a N2 backcross (paper II). In paper III and IV a new strategy to study the interaction between Eae2 and Eae3 is described. Mice congenic for the Eae2 and Eae3 regions were bred in a Partial Advanced Intercross (PAI), which allows for the segregation of genes in the congenic intervals. More than 1000 PAI mice were investigated for Collagen Induced Arthritis (CIA). Different traits of disease were linked to seven sub-QTL within Eae2 and Eae3. Furthermore, the importance of sub-phenotypes in order to identify disease-modifying genes was investigated and is discussed. (Less)
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author
supervisor
opponent
  • Professor Alarcón-Riquelme, Marta, Department of genetics and pathology, Rudbeck laboratory, Uppsala, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
keywords
transplantation, Immunologi, serologi, serology, epistasis, EAE, autoimmunity, Immunology, CIA, QTL
pages
91 pages
publisher
Medical Inflammation Research, Department of Experimental Medicine, Faculty of Medicine, Lund University
defense location
Segerfalk´s salen BMC Sölvegatan 19 221 84 Lund
defense date
2005-11-26 09:00
ISSN
1652-8220
ISBN
91-85481-04-1
language
English
LU publication?
yes
id
1b20ff9c-0920-43eb-9bac-2ed49ce96040 (old id 545625)
date added to LUP
2007-09-20 15:39:11
date last changed
2016-09-19 08:44:59
@phdthesis{1b20ff9c-0920-43eb-9bac-2ed49ce96040,
  abstract     = {Autoimmune diseases are dependent on multiple genes and unknown environmental factors. Great efforts in the identification of genes conferring susceptibility to autoimmune diseases like Rheumatoid Arthritis (RA) and Multiple Sclerosis (MS) have recently been rewarding. A few genes have so far been associated to several autoimmune disorders and the understanding of the role of these genes in the pathogenesis and the identification of additional genes will be of great use in the designing of new and better therapies. The fine characterization of each disease is of importance in order to define sub-groups, which may respond differently to treatments.<br/><br>
<br/><br>
The work in this thesis was done in mouse models for RA and MS and is based on four papers where the aim was to identify genes associated with these diseases. We have studied crosses between a susceptible and a resistant mouse strain to assess the genetic context for a disease-linked locus to appear. In an F2 intercross between the two strains, the Eae2 locus on chromosome 15 was previously linked to disease in the MS model Experimental Autoimmune Encephalomyelitis (EAE) through interaction with Eae3 on chromosome 3. The locus homologous to Eae2 on human chromosome 5 was later associated with MS in a Finnish population. In order to identify additional loci, EAE was studied in an F2 intercross where the Eae2 locus was neutralized (paper I) and in a N2 backcross (paper II). In paper III and IV a new strategy to study the interaction between Eae2 and Eae3 is described. Mice congenic for the Eae2 and Eae3 regions were bred in a Partial Advanced Intercross (PAI), which allows for the segregation of genes in the congenic intervals. More than 1000 PAI mice were investigated for Collagen Induced Arthritis (CIA). Different traits of disease were linked to seven sub-QTL within Eae2 and Eae3. Furthermore, the importance of sub-phenotypes in order to identify disease-modifying genes was investigated and is discussed.},
  author       = {Karlsson, Jenny C},
  isbn         = {91-85481-04-1},
  issn         = {1652-8220},
  keyword      = {transplantation,Immunologi,serologi,serology,epistasis,EAE,autoimmunity,Immunology,CIA,QTL},
  language     = {eng},
  pages        = {91},
  publisher    = {Medical Inflammation Research, Department of Experimental Medicine, Faculty of Medicine, Lund University},
  school       = {Lund University},
  title        = {Genetic characterization to dissect the phenotypic complexity of autoimmunity},
  year         = {2005},
}