Item – Theses Canada

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OCLC number
1019470797
Link(s) to full text
LAC copy
Author
Loh, Christina.
Title
Identification of Genetic Loci that Contribute to the Immunopathogenesis of Systemic Lupus Erythematosus using Congenic Mouse Strains.
Degree
Ph. D. -- University of Toronto, 2011
Publisher
Ottawa : Library and Archives Canada = Bibliothèque et Archives Canada, 2012.
Description
1 online resource
Notes
Includes bibliographical references.
Abstract
<?Pub Inc> Systemic lupus erythematosus (SLE) is an autoimmune disorder that is characterized by the production of antibodies directed against self-antigens, such as nuclear components. Genetic analyses of lupus patients have consistently demonstrated a complex genetic basis for disease susceptibility that involves multiple genes. Identifying genes and pathways that promote disease genesis has been aided by murine studies. In particular, congenic mouse studies that examine the role of chromosomal intervals from inbred lupus-prone mouse strains on a non-autoimmune background have been useful in dissecting the genetic contribution of novel susceptibility loci in lupus pathogenesis. In this thesis, the role of New Zealand Black (NZB) chromosomes 4 and 13 are examined in non-lupus prone C57BL/6 (B6) congenic mouse strains, denoted B6.NZBc4 and B6.NZBc13, respectively. Although repeatedly mapped to contain disease augmenting alleles, NZBc4 alone was not sufficient to initiate disease, despite an expansion of NKT and B1a cells - both with controversial pathogenic roles in lupus. Instead, by crossing the B6.NZBc4 mouse with another congenic mouse strain that develops fatal lupus autoimmunity, NZBc4 was unexpectedly found to contain a suppressor locus; disease suppression was mediated by a shift away from pathogenic immunoglobulin isotypes and associated with changes in the NKT and B1a cell compartments. In contrast to the NZBc4 locus, the NZBc13 locus is sufficient to initiate polyclonal B cell activation, ANA production and mild GN, similar to NZB mice. A B cell intrinsic defect was found to be responsible for initiating the abnormal cellular phenotype in B6.NZBc13 mice. Functional analyses of the B cell subset in B6.NZBc13 mice revealed normal BCR-signaling responses and tolerance mechanisms; however, they were hyper-responsive to TLR3 stimulation, resulting in increased survival and proliferation. Thus, the study of these NZB congenic mouse strains has been instrumental in confirming the presence of loci on NZB chromosomes 4 and 13 that modulate the development of disease and highlights that disease onset is mediated by a balance of both susceptibility and suppressor alleles. Collectively, these findings contribute to the current field of lupus immunogenetics and confirm the power of congenic mouse models in understanding the genetic basis of SLE.
ISBN
9780494778579
0494778571