Parry, Sarah L.; (1993) Studies of tolerance induction in B lymphocytes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The silencing and/or elimination of autoreactive clones in the B cell repertoire has been shown to occur at both immature and mature stages of B cell development. A number of factors which influence tolerance induction in B cells, such as the degree of antigen receptor crosslinking and the presence or absence of co-stimulatory signals have been identified. The main focus of the work presented in this thesis concerns an investigation of two in vitro models of B cell tolerance. In the first, the capacity of sIgM and sIgD receptors to generate negative signals was studied using sIgM+ immature B lymphomas and their sIgD+ transfectants. The data suggest that ligation of both sig isotypes by anti-Ig antibodies induced tolerizing signals leading to growth arrest in these cells. Extensive crosslinking of sIg was a key factor in inducing the growth inhibition. Multimerization of sIgM, but not sIgD, resulted in apoptotic cell death. In addition, extensive crosslinking of the transmembrane phosphatase CD45 with certain monoclonal antibodies caused growth inhibition, and induced apoptosis in a fraction of the immature B lymphoma cells. Crosslinked CD45 enhanced the growth inhibition induced by both anti-IgM and anti-IgD antibodies, suggesting CD45 may play a part in modulating tolerogenic signals generated via the antigen receptors in immature B cells. The second model employed mature murine splenic B lymphocytes. The data shows that extensive crosslinking of either sIgM or sIgD by anti-Ig antibodies induced unresponsiveness in these cells, leading to massive apoptotic cell death. Apoptotic nuclei were detected within 4 hours after anti-Ig stimulation, but cells which survived for 12–16 hours were abortively activated, as evidenced by increased levels of MHC Class II antigens. Both IL-4 and ligation of CD40 partially reversed the induction of sIg-mediated apoptosis, and the two stimuli together caused almost complete reversal. It is hoped that this system represents a polyclonal model of clonal deletion of mature B cells by highly crosslinking antigens.

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