Date of Award
Level of Access Assigned by Author
Doctor of Philosophy (PhD)
Biochemistry and Molecular Biology
Second Committee Member
Keith W. Hutchison
Third Committee Member
Systemic lupus erythematosis, or SLE, is a chronic autoimmune disease in which the immune system attacks multiple organs through the secretion of pathogenic antibodies generally directed against nuclear antigens of self-origin. The BXSB. Yaa inbred mouse strain develops a spontaneous and severe autoimmune disease resembling human SLE. It develops a severe and accelerated autoimmunity induced by a mutant locus found on the Y chromosome, designated the Y-linked autoimmune accelerator (Yaa). This locus had evaded molecular identification since its discovery in 1979, by Murphy and Roths at The Jackson Laboratory. Characterization of the Yaa mutation promises to yield valuable insights regarding general mechanisms implicated in the development of B-cell mediated autoimmunity. While it is known that Yaa enhances autoimmune responses against autoantigens through intrinsic effects on B-cell activation, the genetic origin of Yaa, its direct role in SLE and the signaling pathways affected are poorly understood. We demonstrate that the Y chromosome of Yaa mice contains an expansion of the short X-Y pairing pseudoautosomal region (PAR). This result, in agreement with other recent studies, demonstrates that Yaa is a duplication to the Y chromosome of at least 17 X chromosome genes. One candidate gene is TLR7, a gene with restricted expression in B cells and dendritic cells. Here it is reported that B cells from Yaa mice display novel phenotypes, including increased signaling through rapamycin and NFkB pathways and apoptotic resistance through multiple receptors, including the toll-like receptors, TLR4, TLR7, TLR9, and the B cell receptor (BCR). These results suggest that TLR7 and other Yaa duplicated genes, including Midi, may contribute collectively toward disease acceleration by enhancing autoimmune responses against autoantigens by generic effects on B cell activation. Such signaling aberrations lead to the abnormal proliferation and apoptosis of B cells, factors thought to contribute towards human SLE. Importantly, as these candidate genes are also found on the human X chromosome, they may contribute towards understanding the 10:1 female prevalence seen in human SLE. In addition, the copy number polymorphism underlying Yaa may provide an example of how multiple genes within a densely defined genetic region contribute towards disease phenotypes.
Brown, Aaron Clifford, "Molecular and Phenotypic Characterization of the Y-Linked Autoimmune Accelerator (YAA)" (2007). Electronic Theses and Dissertations. 783.
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