Regulation of B cell metabolic activation, germinal center responses and autoimmunity by Tandem PH domain-containing proteins
| dc.contributor.author | Jayachandran, Nipun | |
| dc.contributor.examiningcommittee | El-Gabalawy, Hani (Immunology) HayGlass, Kent (Immunology) Triggs-Raine, Barbara (Biochemistry and Medical Genetics) Wither, Joan (University of Toronto) | en_US |
| dc.contributor.supervisor | Marshall, Aaron (Immunology) | en_US |
| dc.date.accessioned | 2017-09-07T14:29:08Z | |
| dc.date.available | 2017-09-07T14:29:08Z | |
| dc.date.issued | 2012 | en_US |
| dc.date.issued | 2016 | en_US |
| dc.degree.discipline | Immunology | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Regulation of PI3K signaling is critical for B cells to generate an effective adaptive immune response and prevent the development of autoimmunity and malignancy. PI3K pathway activated upon B cell antigen receptor (BCR) crosslinking generates membrane phosphoinositide such as PI(3,4,5)P3 and PI(3,4)P2 which are lipid second messenger molecules that recruit various effector proteins to the membrane to mediate downstream signaling. Although the role of PI(3,4,5)P3 is extensively studied in PI3K signaling, PI(3,4)P2 dependent mechanisms are not well understood. Tandem PH domain containing proteins (TAPPs) are adapter proteins which strictly bind to PI(3,4)P2 via its C-terminal PH domain to get recruited to the membrane upon PI3K activation. To investigate the role of TAPPs interacting with PI(3,4)P2 in B cell signaling, studies were carried out in mice bearing targeted mutations within their C-terminal PH domains that disrupt their ability to interact with the membrane. These animals developed splenomegaly, antinuclear antibodies and showed IgG deposition within the glomeruli of the kidney as they age. Additionally, an increase in titre of anti-dsDNA antibodies with age that corresponds to the development of chronic GC in TAPP KI mice together resembles the characteristics of lupus. Disrupting the GC reversed autoantibody production in these aging TAPP KI mice.The mixed bone chimera approach showed that TAPP KI B cell signaling defect alone is sufficient to drive the development of chronic GCs and autoimmunity. TAPP KI B cell showed enhanced PI3K signaling upon BCR crosslinking and exhibited hyperresponsiveness.These B cells exhibited metabolic abnormalities that include increase in rate of glycolysis, enhanced expression of glucose transporter (GLUT1) and elevated glucose. TAPP KI B cell intrinsic defects were reversed by blocking PI3K signaling. GCB cells from TAPP KI mice exhibited a significant increase in glucose uptake and GLUT1 expression in vivo. Targeting glycolysis in aging TAPP KI mice with the inhibitor of glycolysis, reversed chronic GC and autoimmunity. Together these findings suggest that interaction of TAPPs with PI(3,4)P2 regulates PI3K signaling to attenuate B cell metabolic activation. Disruption of this regulatory circuit results in chronic B cell activation and germinal center responses, leading to autoantibody production. | en_US |
| dc.description.note | October 2017 | en_US |
| dc.identifier.citation | Times New Roman | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/32486 | |
| dc.language.iso | eng | en_US |
| dc.publisher | Wiley publishing (European Journal of Immunology) | en_US |
| dc.rights | open access | en_US |
| dc.subject | Metabolic regulation of B cells | en_US |
| dc.subject | Chronic germinal centres | en_US |
| dc.subject | Murine lupus | en_US |
| dc.title | Regulation of B cell metabolic activation, germinal center responses and autoimmunity by Tandem PH domain-containing proteins | en_US |
| dc.type | doctoral thesis | en_US |