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Title: Mechanism employed by germinal centre B cells for promoting affinity maturation
Author: Stewart, Isabelle
ISNI:       0000 0004 8506 9575
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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The adaptive immune system has the extraordinary ability to develop bespoke antibodies against almost any invading agent to which the host may be exposed. These antibodies are produced through affinity maturation, a dynamic process of iterative diversification and refinement. This process occurs in germinal centres (GCs), microanatomic loci physically divided into dark zones (DZs), in which the immunoglobulins are diversified though somatic hypermutation (SHM), and light zone (LZs), in which cells are selected such that the population can be refined. Accurate selection requires that cells fully replace surface B cell receptors (BCRs) following SHM, but whether this happens before LZ entry is not clear. We found that most GC B cells degrade pre-SHM receptors before leaving the DZ, and that B cells acquiring crippling mutations during SHM rarely reached the LZ. Instead, apoptosis was triggered preferentially in late G1, a stage wherein cells with functional BCRs re-entered cell cycle or reduced surface expression of the chemokine receptor CXCR4 to enable LZ migration. Ectopic expression of the anti-apoptotic gene Bcl2 was not sufficient for cells with damaging mutations to reach the LZ, suggesting that BCR-dependent cues may actively facilitate the transition. We postulated that a BCR mediated signal may be required as a "LZ promoting cue". Thus, BCR replacement and pre- screening in DZs prevents the accumulation of clones with non-functional receptors and facilitates selection in the LZ.
Supervisor: Bannard, Oliver ; Cornall, Richard Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available