Herbert, J.; (1996) The regulation of specific antibody secretion by human B cells through contact and non-contact dependent mechanisms. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Antibody responses by human B cells to T-dependent antigens requires both cell contact-dependent signals and signals mediated by soluble molecules (cytokines) secreted by activated lymphocytes and accessory cells. This project utilised a well- established experimental system to study the role of CD40 and its ligand (CD40L) and selected cytokines in the regulation of specific antibody production in vitro. Cross-linking of CD40 expressed on human tonsil B cells with monoclonal antibodies or exogenous CD40L profoundly inhibited specific antibody production. Inhibition was an early event and was lost if CD40 ligation occurred beyond the first 24 - 48 hours during a seven day culture period. We propose that following antigenic challenge, ligation of CD40 on antigen-specific B cells prevents immediate terminal differentiation into antibody forming cells and favours clonal expansion and memory cell formation. The importance of CD40-CD40L in immune responses is highlighted by patients with hyper-IgM syndrome. In the X-linked form of the disease, the defect is caused by a mutation in the CD40L gene but non-X-linked patients may have a B cell defect. It was shown that, in some X-linked patients, IgG or IgA secretion could be restored in vitro by the addition of a functional CD40L and IL-10. Studies with cytokines showed that IL-4 inhibited antibody secretion without any preferential effect on any isotype or subclass whilst IL-13 had no consistent effect. In contrast, IL-15 was able to support specific antibody secretion in the absence of T cells indicating that it may have a similar role to IL-2 in specific antibody responses. These findings are consistent with a vital role for CD40 and cytokines (IL-2 and IL-15) in regulating specific antibody responses but highlights the fact that biological activity cannot always be predicted from polyclonal (mitogenic) activation of human B cells.

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