ROLES OF PLASMA MEMBRANE WOUNDING AND REPAIR IN B CELL ANTIGEN CAPTURE AND PRESENTATION
| dc.contributor.advisor | Song, Wenxia W | en_US |
| dc.contributor.author | van Haaren, Jurriaan Jan Hein | en_US |
| dc.contributor.department | Biology | en_US |
| dc.contributor.publisher | Digital Repository at the University of Maryland | en_US |
| dc.contributor.publisher | University of Maryland (College Park, Md.) | en_US |
| dc.date.accessioned | 2022-09-27T05:44:19Z | |
| dc.date.available | 2022-09-27T05:44:19Z | |
| dc.date.issued | 2022 | en_US |
| dc.description.abstract | The B cell-mediated humoral immune responses play a crucial role in neutralizing pathogens and unwanted foreign substances. B cells become activated upon antigen binding of their B cell receptor (BCR), and then internalize and process antigen for presentation on their MHCII for T cell recognition. acquiring T cell signaling through antigen presentation is essential for B cell differentiation into high-affinity antibody-producing cells and memory B cells. In vivo, Antigen encountered by B cells is often tightly associated with the surface of pathogens and/or antigen-presenting cells. When B cells engage surface-associated antigen, BCR signaling induces reorganization of the cytoskeleton, causing spreading and contraction of the B cell on the antigen-presenting surface. This allows the B cell to engage more antigen and gather the antigen into a central cluster for internalization. Internalization of surface-associated antigen has been shown to require myosin-generated forces and the exocytosis of lysosomal enzymes. However, the mechanism that initiates lysosomal exocytosis remains unknown.This research explored a possible mechanism for the triggering of lysosomal exocytosis of B cells during interaction with surface-associated antigen. We showed that BCR interaction with antigen tethered to beads, to planar lipid-bilayers (PLBs) or expressed on the surface of live cells causes permeabilization of the B cell plasma membrane (PM), an event that required strong BCR-antigen affinity, BCR signaling, and activation of non-muscle myosin IIA (NMIIA). Moreover, we showed that B cell PM permeabilization triggers a repair response that includes the exocytosis of lysosomes at the site of antigen interaction. Importantly, we showed that B cells undergoing PM permeabilization and subsequent repair internalize more antigen; and better activate T cells compared to unpermeabilized B cells. Thus, our research reveals a novel mechanism for B cells to capture surface-associated antigen: antigen affinity-dependent binding of the BCR indices localized B cell PM permeabilization and lysosome exocytosis as a repair response, which facilitates antigen internalization and presentation through the extracellular release of lysosomal hydrolases. In addition, we explored the molecular mechanism required for B cell PM permeabilization in response to surface-associated antigen. We showed that B cells that undergo PM permeabilization in response to PLB-associated antigen spread over the PLB at a faster rate and to a larger area in comparison to cells that remain intact. Furthermore, we showed that B cells that undergo PM permeabilization recruit more NMIIA at a faster rate, and display a higher level of NMIIA organization at the immune synapse. We additionally discovered a 2o B cell spreading and NMIIA recruitment event, approximately 25-30 minutes after antigen engagement, that facilitates B cell PM permeabilization. Thus, B cell PM permeabilization requires the engagement of a large amount of antigen through B cell spreading on the presenting surface, as well as strong NMIIA recruitment and organization at the immune synapse. This research suggests that B cell PM permeabilization in response to surface-associated antigen plays an important role in distinguishing B cells with various levels of BCR activation, providing novel insights into the mechanisms responsible for affinity differentiation during B cell activation. | en_US |
| dc.identifier | https://doi.org/10.13016/bdoe-czqe | |
| dc.identifier.uri | http://hdl.handle.net/1903/29376 | |
| dc.language.iso | en | en_US |
| dc.subject.pqcontrolled | Immunology | en_US |
| dc.subject.pqcontrolled | Cellular biology | en_US |
| dc.subject.pqcontrolled | Biology | en_US |
| dc.subject.pquncontrolled | Activation | en_US |
| dc.subject.pquncontrolled | affinity | en_US |
| dc.subject.pquncontrolled | antigen | en_US |
| dc.subject.pquncontrolled | B lymphocytes | en_US |
| dc.subject.pquncontrolled | Plasma membrane | en_US |
| dc.subject.pquncontrolled | Wounding | en_US |
| dc.title | ROLES OF PLASMA MEMBRANE WOUNDING AND REPAIR IN B CELL ANTIGEN CAPTURE AND PRESENTATION | en_US |
| dc.type | Dissertation | en_US |