The role of human CD23 in lgE homeostasis & allergic disease

CD23, the low affinity receptor for IgE on B cells, exists in membrane and soluble<br/>forms. CD23 also binds CD21 with a distinct binding site to IgE. Soluble CD23<br/>(sCD23) fragments are released from trimeric membrane CD23 (mCD23) by the<br/>endogenous metalloprotease, ADAM10. It has been suggested that trimeric sCD23 fragments can co-ligate membrane IgE (mIgE) and membrane CD21 (mCD21) on the surface of human B cells, in a similar way to C3d-antigen complexes and mIgM, to upregulate IgE synthesis and provoke allergic responses.<br/>To test this hypothesis, purified tonsil B cells were stimulated with IL-4 and anti-CD40 to induce class switching to IgE in vitro. mCD23 was up-regulated and sCD23 accumulated in the medium prior to IgE synthesis. IL-10 and IL-21 were shown to enhance IgE synthesis by increasing cell division and plasma cell differentiation. siRNA inhibition of CD23 synthesis or inhibition of mCD23 cleavage by an ADAM10 inhibitor, GI254023X, were shown to suppress IgE synthesis. Addition of a recombinant trimeric sCD23, triCD23, enhanced IgE synthesis. This occurred even when endogenous mCD23 was protected from cleavage by GI254023X, indicating that IgE synthesis is positively controlled by sCD23. triCD23 was shown to bind to cells coexpressing mIgE and mCD21 and caused capping of these proteins on the B cell membrane. triCD23-mediated up-regulation of IgE secretion and capping of mCD21 was blocked in the presence of an anti-CD21 monoclonal antibody. Up-regulation of IgE secretion by sCD23 occurred after class switch recombination and the effects were isotype-specific. Together, these results suggest that mIgE and mCD21 co-operate in the sCD23-mediated positive regulation of IgE synthesis by IgEcommitted<br/>B cells. These results have improved our understanding of the regulation of IgE in human B cells and provide evidence for sCD23 as a potential therapeutic target in allergy and asthma.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

King's College London

Year dc:date.issued

2013

Author dc:creator

• Cooper, Ali

Advisors dc:contributor.advisor

• Sutton, Brian John
• Gould, Hannah Jane

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/9cf99ae7-3243-441e-b146-4a63c01127ec

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/9cf99ae7-3243-441e-b146-4a63c01127ec