Dissecting the genetics of autoimmune diseases

Jordan, Margaret Agnes (2011) Dissecting the genetics of autoimmune diseases. PhD thesis, James Cook University.

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Abstract

Autoimmune diseases occur when the immune system mistakenly attacks its own healthy tissue. There are more than 80 different types of autoimmune diseases and they are classified as either systemic or tissue specific depending on the antigen/s targeted and the effector mechanism involved. Although not necessarily pathological, autoimmunity may lead to clinically relevant tissue damage in some individuals. Three-point-five percent of Western populations are afflicted, causing a huge burden on the country's resources. Many of the diseases are related with members of a cluster commonly occurring in an individual or a family suggesting some commonality in inheritance. Uncovering genes involved in one autoimmune disease may therefore also be relevant in other autoimmune diseases as well as in their underlying mechanisms. The "candidate gene" approach was for many years the only option for tackling the genetics of complex diseases but although biologically sound it led to initial elation at discovering a gene being turned to disappointment when it didn't stand up to scrutiny and/or could not be replicated by independent researchers. As the effects of a single gene may be small and the disease or animal model often pleiotropic with overlapping phenotypes, family based linkage studies too have achieved only limited success, mainly due to limitations in identifying common variants with modest effects. In the course of this thesis, I have used mouse models of disease with previously identified linkage regions and the powerful tools of a positional cloning approach coupled with microarray gene expression analyses to identify genes contributing to an important immuno-regulatory cell type, NKT cell number, as well as genes contributing to experimental autoimmune gastritis. Candidate genes identified were subsequently validated by real time PCR and FACS analyses on new sample sets and polymorphic differences in gene structure were identified between strains positive for the phenotype compared to those phenotypically negative for it as a possible explanation for the observed differential expression patterns. To this end, thirty-nine sub-congenic mouse lines of the gastritis linkage region on chromosome 4 were produced and microarray gene expression analyses were carried out on the most informative of these to reveal at least four chromosomal regions contributing to the gastritis phenotype. Two of these regions contain a single candidate gene: Cap1 and Apitd1 that are both involved in apoptosis. A subcongenic approach to identifying NKT cell genes revealed a minimum of four candidates, with at least one on chromosome 1 and three or more on chromosome 2. One of the candidate genes, Slamf1, was subsequently confirmed through transgenic complementation, while a previously unknown role for peroxisomes in NKT cell biology identified by microarray analyses and confirmed using a knock-out mouse system.

Item ID: 18971
Item Type: Thesis (PhD)
Keywords: autoimmunity, NKT cells, autoimmune gastritis, autoimmune susceptibility genes, congenic mice, transgenic mice, knock-out mouse system, microarray analysis, immune regulation, candidate genes, genetic linkage
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Publications arising from this thesis are available from the Related URLs field. The publications are:

Jordan, Margaret A., Fletcher, Julie M., Jose, Roby, Chowdhury, Shahead, Gerlach, Nicole, Allison, Janette, and Baxter, Alan G. (2011) Role of SLAM in NKT cell development revealed by transgenic complementation in NOD mice. Journal of Immunology, 186 (7). pp. 3953-3965.

Fletcher, Julie M., Jordan, Margaret A., Snelgrove, Sarah L., Slattery, Robyn M., Dufour, Francois D., Kyparissoudis, Konstantinos, Besra, Gurdyal S., Godfrey, Dale I., and Baxter, Alan G. (2008) Congenic analysis of the NKT cell control gene Nkt2 implicates the peroxisomal protein Pxmp41. Journal of Immunology, 181 (5). pp. 3400-3412.

Jordan, Margaret A., Fletcher, Julie M., Pellicci, Daniel, and Baxter, Alan G. (2007) Slamf1, the NKT cell control gene Nkt1. Journal of Immunology, 178 (3). pp. 1618-1627.

Ang, Desmond K.Y., Brodnicki, Thomas C., Jordan, Margaret A., Wilson, Wendy E., Silveira, Pablo, Gliddon, Briony L., Baxter, Alan G., and van Driel, Ian R. (2007) Two genetic loci independently confer susceptibility to autoimmune gastritis. International Immunology, 19 (9). pp. 1135-1144.

Jordan, Margaret A., and Baxter, Alan G. (2008) The genetics of immunoregulatory T cells. Journal of Autoimmunity, 31 (3). pp. 237-244.

Jordan, Margaret A., and Baxter, Alan G. (2008) Quantitative and qualitative approaches to GOD: the first 10 years of the clonal selection theory. Immunology and Cell Biology, 86 (1). pp. 72-79.

Biros, Erik, Jordan, Margaret A., and Baxter, Alan G. (2005) Genes mediating environment interactions in type 1 diabetes. Review of Diabetic Studies, 2 (4). pp. 192-207.

Baxter, Alan G., Jordan, Margaret A., Silveira, Pablo A., Wilson, Wendy E., and van Driel, Ian R. (2005) Genetic control of susceptibility to autoimmune gastritis. International Reviews of Immunology, 24 (1-2). pp. 55-62.

Baune, Bernhard T., Dannlowski, Udo, Domschke, Katharina, Janssen, Debbie G.A., Jordan, Margaret A., Ohmann, Patricia, Bauer, Jochen, Biros, Erik, Arolt, Volker, Kugel, Harald, Baxter, Alan G., and Suslow, Thomas (2010) The interleukin 1 beta (IL1B) gene is associated with failure to achieve remission and impaired emotion processing in major depression. Biological Psychiatry, 67 (6). pp. 543-549.

Jordan, Margaret A., Poulton, Lynn D., Fletcher, Julie M., and Baxter, Alan G. (2009) Allelic variation of Ets1 does not contribute to NK and NKT cell deficiencies in type 1 diabetes susceptible NOD mice. The Review of Diabetic Studies, 6 (2). pp. 104-116.

Date Deposited: 14 May 2012 00:53
FoR Codes: 06 BIOLOGICAL SCIENCES > 0604 Genetics > 060406 Genetic Immunology @ 34%
06 BIOLOGICAL SCIENCES > 0604 Genetics > 060408 Genomics @ 33%
06 BIOLOGICAL SCIENCES > 0604 Genetics > 060412 Quantitative Genetics (incl Disease and Trait Mapping Genetics) @ 33%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 34%
97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 33%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920110 Inherited Diseases (incl. Gene Therapy) @ 33%
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