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Title: The role of p110δ and Vav proteins in BCR signalling
Author: Clayton, E.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2003
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B-lymphocytes participate in the generation of effective immune responses capable of specifically recognising and selectively eliminating foreign microorganisms and molecules. The binding of an antigen to receptors on B cells activates signalling cascades that induce B cell proliferation, differentiation into memory and antibody secreting plasma cells that facilitate elimination of the antigen. PI3K and Vav are activated downstream of B cell receptor (BCR) and the CD19 co-receptor, p110δ isoform of catalytic subunit of PI3Kinase was chosen as a candidate for immunological assessment as its expression pattern is limited to leukocytes unlike ubiquitously expressed α, β and γ isoforms. We determined the structure of p110δ gene and its deletion was achieved by Cre/LoxP recombination system. We have shown that p110δ function is required for BCR-mediated calcium flux, activation of PLCγ2 and Bruton's tyrosine kinase (Btk). p110δ-/- cells fail to activate protein kinase B (PKB) or upregulate Bcl-xL, they proliferate poorly in response to BCR or CD40 signals in vitro, and are prone to apoptosis. p110δ-/- mice have reduced numbers of Bl and marginal zone B cells, reduced levels of serum immunoglobulins, respond poorly to immunisation with Type II thymus-independent antigen (TI-2) and thymus-dependent (TD) antigen. The number of germinal centres is reduced. B2 cell numbers are reduced in 3-weeks old mice, but their maturation is normal (p85α-/- mice have reduced number of mature B cells). We also have demonstrated that Vav phosphorylation is not affected in p110δ deficient B cells. Vav proteins are guanine nucleotide exchange factors for the Rho family of GTPases. Using Vavl/2 deficient mice we confirmed that Vav proteins participate in the calcium pathway and we placed Vav upstream of Btk and PLCγ. It remains controversial as to whether Vavl/2 regulate lipid kinase activity of PI3K, as PKB activation is not diminished. Our results suggest that p110δ is required for the function of the BCR signalosome and PKB pathway, p110δ plays a critical role in B cell homeostasis and function and may be used as a target in regulation of autoimmune diseases and malignancies associated with unrestrained signalling of PI3K associated molecules.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available