Chapter 1 presents our investigation on how BCR signaling is affected by self-reactivity and how the dysregulation of PIP3 generation via the loss of PTEN leads to a break in B cell tolerance. The proliferation of antigen-specific lymphocytes and resulting clonal expansion are essential for adaptive immunity. Chapter 2 discusses the impact of the loss of CD98 on immune responses, particularly on the expansion of antigen-activated B cells. B cells adhere and migrate in response to chemokines in order to function and to differentiate. The molecular events downstream of BCR, S1P and chemokine stimulation leading to integrin activation are not completely understood. In Chapters 3 and 4, the roles of SHEP1 and [Beta]1 integrin are investigated in B cells. Finally, Chapter 5 presents a research proposal on the role of the inflammasome in the pathogenesis of gout, which was written during my clinical experience in Rheumatology as a Howard Hughes Med-Into- Grad Scholar

The proliferation of antigen-specific lymphocytes and resulting clonal expansion are essential for adaptive immunity. We report here that B cell-specific deletion of the heavy chain of CD98 (CD98hc) resulted in lower antibody responses due to total suppression of B cell proliferation and subsequent plasma cell formation. Deletion of CD98hc did not impair early B cell activation but did inhibit later activation of the mitogen-activated protein kinase Erk1/2 and downregulation of the cell cycle inhibitor p27. Reconstitution of CD98hc-deficient B cells with CD98hc mutants showed that the integrin-binding domain of CD98hc was required for B cell proliferation but that the amino acid-transport function of CD98hc was dispensable for this. Thus, CD98hc supports integrin-dependent rapid proliferation of B cells. We propose that the advantage of adaptive immunity favored the appearance of CD98hc in vertebrates.

Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors, such as chronic pancreatitis, acinar cell damage, and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed Kras^G12D acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. p62 accumulation promotes neoplastic progression by controlling the NRF2-mediated induction of MDM2, which acts through p53-dependent and -independent mechanisms to abrogate checkpoints that prevent conversion of differentiated acinar cells to proliferative ductal progenitors. MDM2 targeting may be useful for preventing PDAC development in high-risk individuals.