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

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.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat

Patient Preferences for Disease-modifying Antirheumatic Drug Treatment in Rheumatoid Arthritis: A Systematic Review

OBJECTIVE: To summarize patients’ preferences for disease modifying anti-rheumatic drug (DMARD) therapy in rheumatoid arthritis (RA). METHODS: We conducted a systematic review to identify English-language studies in adult RA patients that measured patients’ preferences for DMARDs or health states and treatment outcomes relevant to DMARD decisions. Study quality was assessed using a published quality assessment tool. Data on the importance of treatment attributes and associations with patient characteristics was summarized across studies. RESULTS: From 7951 abstracts, we included 36 studies from a variety of countries. Most studies were in patients with established RA and were rated as medium (n=19) or high quality (n=12). The methods to elicit preferences varied, with the most common being discrete choice experiment (DCE) (n=13). Despite the heterogeneity of attributes in DCE studies, treatment benefits (disease improvement) were usually more important than both non-serious (6 of 8 studies), and serious adverse events (5 of 8), and route of administration (7 of 9). Amongst the non-DCE studies, some found patients placed high importance on treatment benefits, while others (in patients with established RA) found patients were quite risk averse. Subcutaneous therapy was often, but not always preferred over intravenous therapy. Patient preferences were variable and commonly associated with sociodemographics. CONCLUSION: Overall, the results showed that many patients place a high value on treatment benefits over other treatment attributes including serious or minor side effects, cost or route of administration. The variability in patient preferences highlights the need to individualize treatment choices in RA.Canadian Institutes of Health Research (CIHR

Hematopoietic Cell Transplantation for Systemic Sclerosis : A Review

Systemic sclerosis (SSc) is an autoimmune, multi-organ, connective tissue disease associated with significant morbidity and mortality. Conventional immunosuppressive therapies demonstrate limited efficacy. Autologous hematopoietic stem cell transplantation (HCT) is more efficacious but carries associated risks, including treatment-related mortality. Here, we review HCT as a treatment for SSc, its efficacy and toxicity in comparison to conventional therapies, and the proposed mechanisms of action. Furthermore, we discuss the importance of and recent developments in patient selection. Finally, we highlight the knowledge gaps and future work required to further improve patient outcomes.Medicine, Faculty ofNon UBCReviewedFacultyResearcherGraduat