Genetic studies of complex autoimmune disease
In complex autoimmune diseases, there are both genetic and environmental factors that influence our immune system and contribute to the development of disease. The pathways, interactions and mode of inheritance are difficult to unravel, and many discoveries are yet to be done. Here, I have studied three major autoimmune diseases, Type 1 Diabetes (T1D), Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA). They all have an inflammatory component, and share their genetic predisposition in the Human Leucocyte Antigen (HLA) genes. In T1D, the -cells in the pancreatic Islets of Langerhans are very specifically destroyed in an autoimmune attack, lead by the CD8+ T-cells. This leads to the inability to produce insulin, and a lifelong treatment with daily injections is necessary. The elevated blood glucose levels leads to long-term damages of microvascular circulations, and co-morbidities like neuropathy and cardiovascular disease. In MS, auto-reactive lymphocytes enter the central nervous system (CNS) and causes demyelination and neuronal damage. It results in a periodical occurrence of sclerotic plaques in the brain and spinal cord, and leads to increasing neurological disability. RA is a systemic inflammatory disease induced by activation of auto-reactive T-cells, where the release of antibodies and formation of immune complexes contributes to the severity in anti-citrullinated protein antibody (ACPA) positive but not ACPA negative disease. The target tissue is the synovial joints, but other organs like heart and kidney will also be affected. The inflammation breaks down cartilage and bone and can lead to severe pain and disability.
In this thesis I present my investigations of two candidate genes, CIITA and VAV1, in these diseases. CIITA is the major control factor for transcription of the HLA class II genes, and associated to all three diseases. In paper I we demonstrate genotype variation for markers in the CIITA gene, depending on age among healthy controls. This finding is also replicated in an independent cohort. The consequence of this can be faulty conclusions in association studies, and hence age should be corrected for in genetic case-control studies. We find that association to T1D remains after controlling for age for rs11074932 (p=0.004) and rs3087456 (p=0.001), two markers in the promoter area that also are found to associate to RA but for the opposite allele (paper III). In paper II we replicate the previously reported association between CIITA rs4774 and MS in cases carrying the HLA-DRB1*15 allele (p=0.01, OR: 1.21) but also report association to MS for the same marker when stratifying for the MS protective HLA allele A*02 (p=0.01, OR: 1.33). Interaction between rs4774 and both MS associated HLA alleles is demonstrated. Finally, in paper III we show that the markers found to associate to T1D, MS and RA control the expression of CIITA and MHC class II genes with minor allele homozygotes leading to lower levels of mRNA of the transcripts. In paper IV we investigate the VAV1 gene, important in regulating signals downstream the T-cell receptor. VAV1 has been shown to associate to MS and lead to increased levels of inflammatory cytokines in the CNS. Here we report that the same rs2546133-rs2617822 C-A haplotype is associated only to the ACPA negative subgroup of Rheumatoid Arthritis (p=0.004, OR: 1.28). We also demonstrate that a SNP in the Vav1 gene in rat affects disease severity in pristane-induced arthritis, but not collagen II-induced arthritis, such that the disease in PIA is less severe.
Taken together we suggest that these results for VAV1 reflect the heterogeneity between subgroups in human RA disease. In conclusion I have demonstrated genetic susceptibility factors and pathways that are shared between different autoimmune diseases but also that susceptibility genes can be of different importance in subgroups of patients for one disease.
List of scientific papers
I. Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes. A Gyllenberg, S Asad, F Piehl, M Swanberg, L Padyukov, B Van Yserloo, EA Rutledge, B McNeney, J Graham, M Orho-Melander, E Lindholm, C Graff, C Forsell, K Åkesson, M Landin-Olsson, A Carlsson, G Forsander, SA Ivarsson, H Larsson, B Lindblad, J Ludvigsson, C Marcus, Å Lernmark, L Alfredsson, K Åkesson, T Olsson, I Kockum, the Swedish Childhood Diabetes Study Group, the Diabetes Incidence in Sweden Study Group, and the Better Diabetes Diagnosis Study group. Genes and Immunity. (2012) 13, 632–40.
https://doi.org/10.1038/gene.2012.44
II. Variability in the CIITA gene interacts with HLA in multiple sclerosis. A Gyllenberg, F Piehl, L Alfredsson, J Hillert, IL Bomfim, L Padyukov, M Orho Melander, E Lindholm, M Landin-Olsson, Å Lernmark, The Swedish Childhood Diabetes Study Group, The Diabetes Incidence in Sweden Study Group, T Olsson and I Kockum. Genes and Immunity. (2014), 1–6.
https://doi.org/10.1038/gene.2013.71
III. Genetic control of isoform expression of human MHC class II transactivator. M Ronninger, A Gyllenberg, M Lindén, M Seddighzadeh, T James, S K Bedri, D Gomez-Cabrero, F Piehl, T Olsson, I Kockum, L Padyukov. [Manuscript]
IV. VAV1 shows association to anti-citrullinated protein antibody (ACPA) negative Rheumatoid Arthritis in a Swedish patient cohort. Ulrika Norin, André Ortlieb Guerreiro-Cacais, Alexandra Gyllenberg, Rasmus Berglund, Amennai Daniel Beyeen, Rikard Holmdahl, Elisabeth Petit Teixeira, François Cornélis, Abdelhadi Saoudi, Gilbert J. Fournié, Leonid Padyukov, Ingrid Kockum, Maja Jagodic and Tomas Olsson. [Manuscript]
History
Defence date
2014-04-11Department
- Department of Clinical Neuroscience
Publisher/Institution
Karolinska InstitutetMain supervisor
Kockum, IngridPublication year
2014Thesis type
- Doctoral thesis
ISBN
978-91-7549-500-2Number of supporting papers
4Language
- eng