Novel strategies to explore The complex genetics of autoimmune diseases

Martina Johannesson

Research output: ThesisDoctoral Thesis (compilation)

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.

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.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Immunology
Supervisors/Advisors
  • Holmdahl, Rikard, Supervisor
Award date2005 Jan 28
Publisher
Print ISBNs91-628-6373-8
Publication statusPublished - 2005

Bibliographical note

Defence details

Date: 2005-01-28
Time: 09:00
Place: Rune Grupp Lecture hall, BMC Sölvegatan 19 Lund

External reviewer(s)

Name: Broman, Karl
Title: Associate professor
Affiliation: Johns Hopkins University, Baltimore Maryland, USA

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<div class="article_info">Åsa Johansson, Martin Sundler, Peter Kjellén, Andrew D. Cook, Anna-Karin B. Lindquist, Martina Johannesson, Britt Nakken, Anne Isine Bolstad, Roland Jonsson, Marta Alarcón-Riquelme and Rikard Holmdahl. <span class="article_issue_date">2001</span>. <span class="article_title">Genetic control of collagen induced arthritis in a cross with NOD and C57Bl/10 mice is dependent on gene regions encoding complement factor 5 and FcgRIIb and is not associated with loci controlling diabetes.</span> <span class="journal_series_title">European Journal of Immunology</span>, <span class="journal_volume">vol 31</span> <span class="journal_pages">pp 1847-1856</span>. <span class="journal_distributor">Wiley</span></div>
<div class="article_info">Martina Johannesson, Jenny Karlsson, Patrik Wernhoff, Kutty S. Nandakumar, Anna-Karin B. Lindqvist, Lina Olsson, Andrew D. Cook, Åsa Andersson and Rikard Holmdahl. <span class="article_issue_date">2005</span>. <span class="article_title">Identification of epistasis through a partial advanced intercross reveals 3 arthritis loci within the Cia5 QTL in mice.</span> <span class="journal_series_title">Genes and Immunity</span>, <span class="journal_distributor">Nature Publishing Group</span> (inpress)</div>
<div class="article_info">Jenny Karlsson, Martina Johannesson, Therese Lindvall, Patrik Wernhoff, Rikard Holmdahl and Åsa Andersson. <span class="article_issue_date">2005</span>. <span class="article_title">Genetic interactions in Eae2 control collagen induced arthritis and CD4 /CD8 T-cell ratio.</span> <span class="journal_series_title">Journal of immunology</span>, <span class="journal_volume">vol 174</span> <span class="journal_pages">pp 533-541</span>. <span class="journal_distributor">American association of immunologists</span></div>
<div class="article_info">Martina Johannesson, Lina Olsson, Anna-Karin B. Lindqvist, Steffen Möller, Dirk Koczan, Lena Wester-Rosenlöf, Saleh Ibrahim and Rikard Holmdahl. <span class="article_issue_date">2005</span>. <span class="article_title">Gene expression profiling of arthritis using a QTL-chip reveals a complex gene regulation of the Cia5 region in mice.</span> <span class="journal_distributor">Medical Inflammation Research</span> (manuscript)</div>
<div class="article_info">Ann-Sofie Hansson, Martina Johannesson, Lars Svensson, Dick Heinegård and Rikard Holmdahl. <span class="article_issue_date">2004</span>. <span class="article_title">B cells, antibodies to matrilin-1 and complement factor 5 play pathogenic roles in matrilin-1 induced relapsing polychondritis.</span> <span class="journal_series_title">American journal of pathology</span>, <span class="journal_volume">vol 164</span> <span class="journal_pages">pp 959-66</span>. <span class="journal_distributor">The American Society for Investigative Pathology</span></div>
<div class="article_info">Martina Johannesson, Kutty S. Nandakumar, Anna-Karin B. Lindqvist, Ingrid Teige and Rikard Holmdahl. <span class="article_issue_date">2005</span>. <span class="article_title">A locus close to, but excluding the complement factor 5 gene (Hc), confers reduced severity of MOG-induced EAE</span> <span class="journal_distributor">Medical Inflammation Research</span> (manuscript)</div>


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)

Subject classification (UKÄ)

  • Immunology in the medical area

Keywords

  • transplantation
  • Immunology
  • serology
  • Immunologi
  • serologi
  • cytogenetik
  • Genetik
  • cytogenetics
  • Genetics
  • collagen induced arthritis
  • QTL mapping
  • complex traits
  • autoimmunity
  • genetics

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