Regulation of extrafollicular immunoglobulin class switch recombination

George, Laura (2014). Regulation of extrafollicular immunoglobulin class switch recombination. University of Birmingham. Ph.D.

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Abstract

The humoral immune response is characterised by the production of antibody secreting B cells. Some of these cells have cycled through the germinal centre, diversifying and optimising their antigen receptors to produce affinity-matured, class switched antibody. As this is a relatively slow process, the first class switched antibody is produced by non-mutated B blasts that have differentiated independently of the germinal centre reaction outside B-cell follicles. Extrafollicular foci of plasmablasts provide the first line of defence within the adaptive antibody response.
IRF4 has been shown to be essential for Ig class switching and plasma-cell differentiation. Two expression levels of IRF4 were reported, with intermediate levels proposed to regulate CSR in the GC, while high levels regulate plasma-cell differentiation. We have correlated the two phases of IRF4 induction with specific stages of B-cell differentiation. Following immunisation of quasi-monoclonal mice with NP-Ficoll, intermediate levels of IRF4 protein are expressed by all B blasts as they move to the outer T zone and before the formation of germinal centres or plasma cells. This is followed by expression of AID and CSR. In contrast, plasma-cell differentiation occurs with high level expression of IRF4, expression of Blimp1 and complete suppression of AID and CSR. The NFκB family signalling molecules C-REL and NFκB1 have been shown to be required for the induction of IRF4 protein in B cells following stimulation. We show that these signalling molecules are not necessary to induce the early rapid intermediate level expression of IRF4, and extrafollicular expression of AID and CSR occur normally when they are absent. IRF4-high expression and plasma-cell differentiation, however, are blocked in the absence of these molecules.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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