Identifying molecular factors influencing B cells in Type 1 Diabetes

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Copyright: Stolp, Jessica
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Abstract
Type 1 Diabetes is an autoimmune disease where the immune system destroys the insulin producing β cells within the pancreas. The incidence of this disease has risen steadily in developed countries for the last sixty years with both genetic and environmental factors playing a role. The Non-Obese Diabetic (NOD) mouse is used as a model of T1D due to their high susceptibility for this disease, which shares many characteristics with human patients. Research has found that CD4+ and CD8+ T cells are the final mediators of β cell destruction in T1D. However, recently B cells have been shown to play a critical role as antigen presenting cells for T1D development. While it is known that NOD mice have defective splenic B cell development and tolerance mechanisms the genes underlying these phenotypes are not well understood. Marginal zone (MZ) B cells have been implicated in disease pathogenesis in several mouse models of autoimmunity, including the NOD mouse. However, the cause of MZ B cell expansion in NOD mice is unknown. Thus, we investigated factors leading to aberrant B-cell development in this model. We have determined that skewed development of MZ B cells is independent of T-cell autoimmunity, BCR specificity, BCR signal strength and BAFF. Since the factor/s responsible for MZ B cells expansion were found to be intrinsic to NOD B cells, microarray analyses were conducted between B6 and NOD splenic B cell subsets. These studies revealed differential expression of various candidate genes influencing cell migration. Cxcr7 was the most differentially expressed gene in T2MZ and MZ B cell subsets from B6 and NOD mice. Further investigations into this gene have found that it affects the chemotaxis of B cells in response to CXCL12 however, not MZ B cell development. Interestingly, Cd19 expression, which our microarray analyses revealed was upregulated on all NOD B cell subsets compared to B6, does contribute to the expanded MZ B cells in NOD mice. Utilising a congenic mouse strain (termed NR4), we previously identified a region on Chromosome 4 (Idd9/11) that contributes to the diabetogenic activity of B cells, as well as influences the ability of autoreactive B cells to be anergised and respond to IgM mediated stimulation. To further refine the genetic regions containing genes that control the diabetogenic activity of B cells within this Chromosome 4 locus, we generated various sub-congenic mouse strains (termed NR4S1-5), which were first subjected to T1D incidence studies to identify smaller regions of resistance. While none of the Chromosome 4 sub-congenic strains conferred the same level of resistance observed in the full congenic strain we have identified a 6.22Mb region that is affecting diabetogenic capacity of B cells. We have also mapped genetic regions controlling the anergic and hyper-responsive phenotypes. Microarray analyses conducted on splenic B cells from NOD and NR4 mice have revealed some interesting candidate genes, EphB2 and Padi2. These genes encode proteins that influence immune cell function, thus it is certainly conceivable that their altered expression may be capable of altering the diabetogenic function of B cells. Data presented in this thesis has identified genetic and molecular aberrations that give rise to pathogenic B cells in NOD mice. In Future, the identification of homologous genes or pathways in human patients will lead to the development of new therapeutic strategies, specifically targeting the production of diabetogenic B cells.
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Author(s)
Stolp, Jessica
Supervisor(s)
Silveira, Pablo
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Publication Year
2011
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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