This dissertation is focused on circulating T cells and the role they play in the immunopathogenesis of two autoimmune kidney diseases: anti-neutrophil cytoplasmic autoantibody (ANCA) disease and minimal change disease (MCD). Results demonstrated in the subsequent chapters explain known regulatory T cell defects in ANCA disease, reveal altered effector T cell dynamics in ANCA disease and present novel data of autoantibody/autoantigen interactions in minimal change disease.
Data presented in Chapter 1 addresses the known defect of regulatory T cell suppression in patients with ANCA disease. The lack of T cell suppression by ANCA disease regulatory T cells is confirmed in our patient cohort. However, our data reveal that a splice variant of FOXP3 lacking exon 2 is highly prevalent in ANCA disease patients and expression of exon 2-deficient FOXP3 correlates with a decreased suppressive function of the same regulatory T cells. Yet, the data in Chapter 1 also demonstrates that defective regulatory T cells are not the sole culprit of effector T cell non-suppression in ANCA disease patients.
Additional data in Chapter 1 demonstrates that ANCA disease patients have an expansion of a CD25intermediate T cell which comprises the majority of their peripheral T cell pool. These CD25intermediate T cells produce pro-inflammatory cytokines, are antigen-experienced and are resistant to suppression by regulatory T cells from healthy individuals. As such, T cell dysfunction and aberrant proliferation in ANCA disease stems from both altered regulatory T cells and an expanded CD25int population which is difficult to suppress by conventional means.
Chapter 2 focuses on the discovery of anti-TCR autoantibodies found in patients with minimal change disease. These anti-TCR autoantibodies target a specific subset of circulating T cells found at a higher frequency in MCD patients compared to healthy individuals. Additionally, this autoantibody/autoantigen interaction induces cellular activation leading to cytokine production from targeted cells. We hypothesize that these interactions and downstream effects ultimately lead to the immunopathogenesis of MCD by causing injury to podocytes. In sum, the data presented herein comprise a comprehensive body of work which reveals previously unknown roles of circulating T cells in ANCA disease and minimal change disease.
|Advisor:||Falk, Ronald J.|
|Commitee:||Cook, Donald, Fedoriw, Yuri, Jennette, Charles, Su, Maureen A.|
|School:||The University of North Carolina at Chapel Hill|
|School Location:||United States -- North Carolina|
|Source:||DAI-B 74/09(E), Dissertation Abstracts International|
|Keywords:||Anti-neutrophil cytoplasmic autoantibodiy disease, Autoantibodies, Autoimmune diseases, Circulating T cells, Kidney disease, Minimal change disease|
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