Identification of Genetic Polymorphisms that Promote Autoimmunity on New Zealand Black (NZB) Chromosome 1 and their Mechanisms of Action

Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disease characterized by the production of autoantibodies and the development of an immune complex-mediated glomerulonephritis (GN). The New Zealand Black (NZB) mouse is considered to be an excellent model of SLE. Identification of susceptibility loci and the mechanisms through which they act to produce autoimmunity has been greatly aided by the study of congenic mouse strains, in which homozygous intervals containing these loci have been introduced onto a non-autoimmune B6 genetic background. Genetic loci on NZB chromosome (c) 1 lead to antinuclear antibody (ANA) production and glomerulonephritis (GN). Previously our laboratory showed that mice with a homozygous NZB 70 to 100 cM c1 interval introgressed onto the B6 background develop fatal GN. Using a series of congenic mice with shorter NZB c1 intervals, the laboratory has demonstrated that there are at least three lupus susceptibility loci located within this region that are sufficient to lead to high titer anti-nuclear auto-antibody production and severe life-threatening GN. In this thesis I have sought to further characterize the cellular abnormalities and identify the genetic polymorphisms that produce the phenotype in c1(70-100)mice. In the second chapter, I have characterized the immune functional defects associated with the severity of disease in a series of sub-congenic mice with shorter intervals derived from this mouse strain. I showed that the severity of renal disease parallels expansion of Th1, Th17, and Tfh pro-inflammatory cell subsets. I also demonstrate that expansion of these cell subsets results from altered T cell and dendritic cell functional abnormalities, which is a consequence of interactions between at least 3 independent genetic loci. Next, I sought to identify the genetic polymorphism that leads to altered dendritic cell function in NZB chromosome 1 congenic mice. In chapter 3, I provide evidence suggesting that a polymorphism in EAT-2 leads to reduced levels of expression of this molecule in NZB c1 congenic mice, resulting in increased levels of cytokine secretion by myeloid DC that support expansion of pathogenic T cell subsets.Ph.D