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UBC Theses and Dissertations

The role of Rap and phosphoinositide 3-kinase delta in B lymphocyte function Durand, Caylib

Abstract

B cells eliminate pathogens by producing antibodies, activating other immune cells, and secreting cytokines. To carry out these functions, B cells must traffic from the bone marrow into the blood and then into secondary lymphoid organs to encounter antigens and become activated. As a result, B cell trafficking is highly regulated and critical for the activation of self-reactive B cells that contribute to autoimmunity and the spread of malignant B cells. The Rap GTPases regulate integrin activation and in chapter two I showed that Rap1 activation is required for B cell migration and adhesion. Because, lipid mediators including Sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) are potent regulators of cell adhesion and migration, I asked whether LPA regulates B cell adhesion and migration. I found that LPA reduces B cell migration by favoring strong integrin-mediated adhesion. Phosphatidylinositide 3-kinase (PI3K) controls multiple proteins that regulate cell motility, survival and activation. Therefore in the third chapter I investigated the role of p110δ, the major isoform of PI3K in B cells, in the activation, migration, and function of conventional and innate-like B cells. B-2 cells are involved in T cell-dependent antibody responses while B-1 and marginal zone (MZ) B cells are innate-like lymphocytes that mediate T cell-independent responses to microbial antigens. Importantly, these cells are also responsible for many antibody-mediated autoimmune diseases. I showed that p110δ is needed for the activation and chemotaxis of B-2, B-1 and MZ B cells. I also showed that the in vitro adhesion and in vivo localization of MZ B cells is dependent on p110δ activity. Interestingly, I found that p110δ activity is needed for Rap1 activation, making p110δ a key regulator of B cell trafficking. B-1 and MZ B cells produce natural antibodies in the absence of immunization that often recognize self-antigens. We showed that the production of natural antibodies, both protective and pathogenic, depends on p110δ activity and that p110δ inhibition can reduce the levels of pathogenic auto-antibodies in collagen-induced arthritis. This work suggests that by regulating Rap, p110δ, or LPA, it may be possible to control B cell-mediated diseases including inflammation, autoimmunity, and cancer.

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