A search for genes influencing autoimmunity - focus on rheumatoid arthritis and multiple sclerosis
(2000)- Abstract
- The causes of autoimmune diseases are largely unknown today, but there is evidence supporting a substantial complex genetic influence on many of these diseases as well as environmental factors and chance. In this thesis I have tried to get one step closer to the genetic causes of two autoimmune diseases through their induced counterparts in mice, namely rheumatoid arthritis (RA) and multiple sclerosis (MS). We show that experimental autoimmune encephalomyelitis (EAE), the model for MS, is controlled by two major genes. One is found to reside on mouse chromosome 15 (eae2) and the other on chromosome 3 (eae3). These genes work together giving a more severe disease. After eliminating the stronger eae2 gene by congenic breeding, we were able... (More)
- The causes of autoimmune diseases are largely unknown today, but there is evidence supporting a substantial complex genetic influence on many of these diseases as well as environmental factors and chance. In this thesis I have tried to get one step closer to the genetic causes of two autoimmune diseases through their induced counterparts in mice, namely rheumatoid arthritis (RA) and multiple sclerosis (MS). We show that experimental autoimmune encephalomyelitis (EAE), the model for MS, is controlled by two major genes. One is found to reside on mouse chromosome 15 (eae2) and the other on chromosome 3 (eae3). These genes work together giving a more severe disease. After eliminating the stronger eae2 gene by congenic breeding, we were able to identify an additional genetic factor and several putative regions also influencing disease. Furthermore, we define one region on chromosome 3 (cia5) and one on chromosome 13 that affect susceptibility to collagen induced arthritis (CIA), a mouse model of RA. In this experiment we find that the linked region on chromosome 3 is almost identical to the region found in the first study. Since these experiments were performed on the same strain combination, it is possible that the underlying genetic factor is the same in both diseases. Furthermore we were able to identify four regions that control different aspects of CIA on chromosomes 6, 7, 8 and 10 in a different cross. An interesting observation is that most linked regions are homologous to regions in the rat genome that also have been linked to CIA. This implies a common genetic pathway that promotes autoimmunity across species. (Less)
- Abstract (Swedish)
- Popular Abstract in Swedish
Autoimmuna sjukdomar är tillstånd där vårt immunförsvar angriper den egna kroppen. Det finns ett flertal sådana sjukdomar av vilka jag huvud-sakligen har intresserat mig för rheumatoid artrit (RA) och multipel skleros (MS). De behandlingar som finns för de drabbade är idag främst riktade mot ergonomi, smärtlindring och olika former av immunsupres-sion (tex TNFa antikroppar). Orsakerna till dessa sjukdomar är okända och har visat sig vara tämligen komplicerade att ringa in. I denna av-handling beskriver jag hur man genom att använda genetiska verktyg kan komma ett steg närmare de direkta orsakerna. Vi har använt oss av två inavlade musstammar som är valda så att när man inducerar sjukdom i dem... (More) - Popular Abstract in Swedish
Autoimmuna sjukdomar är tillstånd där vårt immunförsvar angriper den egna kroppen. Det finns ett flertal sådana sjukdomar av vilka jag huvud-sakligen har intresserat mig för rheumatoid artrit (RA) och multipel skleros (MS). De behandlingar som finns för de drabbade är idag främst riktade mot ergonomi, smärtlindring och olika former av immunsupres-sion (tex TNFa antikroppar). Orsakerna till dessa sjukdomar är okända och har visat sig vara tämligen komplicerade att ringa in. I denna av-handling beskriver jag hur man genom att använda genetiska verktyg kan komma ett steg närmare de direkta orsakerna. Vi har använt oss av två inavlade musstammar som är valda så att när man inducerar sjukdom i dem svarar den ena stammen och djuren blir sjuka medan den andra stammen är resistent och djuren förblir friska. Dessa stammar har syster–bror korsats under flera år, vilket gör att alla gener föreligger i homozygot form. Dessa två stammar korsas för att producera F2 djur, som alla har sin egen specifika kombination av gen-varianter eller alleler. Detta uppkommer under den naturliga process som bildar könscellerna (meiosen). Det genetiska materialet reduceras så att varje cell kommer att innehålla endast en kromosom av varje sort till skillnad mot alla andra celler i kroppen som innehåller två. Då kro-mosomernas antal reduceras sker samtidigt en överkorsning mellan pa-ternala och maternala kromosomer så att den resulterande könscellen innehåller kromosomer som är en blandning av dessa två utgångskro-mosomer. Detta sker slumpmässigt varför alla könsceller är olika. Sedan möts två könsceller under befruktningen och sammansmälter så att den normala statusen åter etableras, med två kromosomer av varje sort, i den befruktade cellen. Genom att inducera sjukdom i försöksdjuren och se-dan undersöka var överkorsningarna har skett kan vi knyta vissa regio-ner i arvsmassan till sjukdomsutveckling och sålunda ringa in generna grovt. Genom att sedan isolera dessa regioner i kongena stammar kan vi successivt minska omfattningen av regionerna så att generna lättare kan klonas och slutligen identifieras. Dessutom kan man studera dessa regi-oners effekt och på så sätt komma närmare en förståelse för genernas funktion. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/41052
- author
- Jirholt, Johan LU
- supervisor
- opponent
-
- Luthman, Holger
- organization
- publishing date
- 2000
- type
- Thesis
- publication status
- published
- subject
- keywords
- autoimmunity genetics eae cia linkage, cytogenetics, Genetics, cytogenetik, Genetik
- pages
- 116 pages
- publisher
- Johan Jirholt, Kollegievägen 107, 224 73 Lund
- defense location
- Fernströmsalen, BMC
- defense date
- 2000-12-15 10:15:00
- external identifiers
-
- other:ISRN: LUMEDW/MECM--00/1056--SE
- ISBN
- 91-628-4402-4
- 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
- 00040c1e-1b68-43df-ac83-0176c0318e88 (old id 41052)
- date added to LUP
- 2016-04-04 10:19:13
- date last changed
- 2018-11-21 20:58:05
@phdthesis{00040c1e-1b68-43df-ac83-0176c0318e88,
abstract = {{The causes of autoimmune diseases are largely unknown today, but there is evidence supporting a substantial complex genetic influence on many of these diseases as well as environmental factors and chance. In this thesis I have tried to get one step closer to the genetic causes of two autoimmune diseases through their induced counterparts in mice, namely rheumatoid arthritis (RA) and multiple sclerosis (MS). We show that experimental autoimmune encephalomyelitis (EAE), the model for MS, is controlled by two major genes. One is found to reside on mouse chromosome 15 (eae2) and the other on chromosome 3 (eae3). These genes work together giving a more severe disease. After eliminating the stronger eae2 gene by congenic breeding, we were able to identify an additional genetic factor and several putative regions also influencing disease. Furthermore, we define one region on chromosome 3 (cia5) and one on chromosome 13 that affect susceptibility to collagen induced arthritis (CIA), a mouse model of RA. In this experiment we find that the linked region on chromosome 3 is almost identical to the region found in the first study. Since these experiments were performed on the same strain combination, it is possible that the underlying genetic factor is the same in both diseases. Furthermore we were able to identify four regions that control different aspects of CIA on chromosomes 6, 7, 8 and 10 in a different cross. An interesting observation is that most linked regions are homologous to regions in the rat genome that also have been linked to CIA. This implies a common genetic pathway that promotes autoimmunity across species.}},
author = {{Jirholt, Johan}},
isbn = {{91-628-4402-4}},
keywords = {{autoimmunity genetics eae cia linkage; cytogenetics; Genetics; cytogenetik; Genetik}},
language = {{eng}},
publisher = {{Johan Jirholt, Kollegievägen 107, 224 73 Lund}},
school = {{Lund University}},
title = {{A search for genes influencing autoimmunity - focus on rheumatoid arthritis and multiple sclerosis}},
year = {{2000}},
}