Date of Award


Degree Type


Degree Name

Doctor of Philosophy


B cells can be stimulated to produce antibody by antigens or by polyclonal activators such as bacterial lipopolysaccharide (LPS). Mechanisms of regulation of LPS driven antibody responses are often interpreted in terms of antigen driven responses even though there is much evidence to suggest that LPS and antigen trigger distinct activation pathways. LPS stimulated antibody responses can be prevented by ligation of the B cell antigen receptor (BCR), while antigen driven responses are shut down by the crosslinking of the BCR to the receptor for the Fc portion of IgG (Fc{dollar}\gamma{dollar}R). The present studies on murine splenic B cells in vitro demonstrate that prior signaling through the BCR mediated by crosslinking F(ab{dollar}\sp\prime{dollar})2 antibody to surface immunoglobulin ({dollar}\alpha{dollar}sIg), shuts off polyclonal antibody production induced by LPS, but does not inhibit antigen specific antibody responses induced by antigen. These differences between antigen- and LPS-induced B cell activation were employed to investigate the regulatory mechanisms involved in the spontaneous activation of anti-single stranded DNA ({dollar}\alpha{dollar}ssDNA) specific B cells in vitro. The spontaneous {dollar}\alpha{dollar}ssDNA antibody forming cell response was not inhibited by prior BCR signaling, however the response of small but not large B cells was inhibited by blocking the antigen receptor with Fab {dollar}\alpha{dollar}sIg antibody. The response could also be inhibited by Fc{dollar}\gamma{dollar}R signals mediated by intact IgG {dollar}\alpha{dollar}sIg. Fc{dollar}\gamma{dollar}R signals inhibited the increase in intracellular calcium triggered by the BCR, and the regulation of calcium by the BCR and Fc{dollar}\gamma{dollar}R was not aberrant in B cells from NZB mice, a strain with dysregulated antibody responses to ssDNA. However, BCR signals were greatly reduced in their ability to shut off LPS-induced antibody production in B cells from NZB, NZB/W and BXSB lupus-prone mice but not MRL/lpr or NZW mice. The defect in NZB B cells occurred in both young and old mice, was not dependent on the activation status of the B cell population, was independent of T cells or macrophages, and was apparent at the level of mRNA for secreted IgM. The defect appeared to be specific to BCR signals as inhibition of LPS activation by ligation of MHC II occurred normally in NZB B cells. Bypassing the BCR by direct stimulation of second messengers did not overcome the defect, suggesting that differences in the BCR itself are not responsible for the reduced ability to inhibit the LPS response.These studies help define the role of the BCR, Fc{dollar}\gamma{dollar}R and LPS receptor on B cells and demonstrate a novel defect in BCR mediated regulation of antibody production that may be a predisposing factor in systemic autoimmune disease.



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