Date of Award


Degree Type


Degree Name

Doctor of Philosophy


B cells are regulated early upon exposure to antigen by negative Fc signals generated by the crosslinking of antigen receptors with Fc receptors which is mediated by antigen-IgG-antibody complexes. This negative end-product feedback can be overcome by T helper cells, but in their absence, agents which bind to the Fc portion of IgG can replace the need for T cell help. Rheumatoid factor (RF) is a naturally occurring antibody with specificity for IgG-Fc and was investigated for its ability to block negative Fc signals. Monoclonal murine RF was shown to reconstitute, in an antigen-specific and dose-dependent fashion, both the primary and secondary T-dependent antibody response of T cell-depleted murine spleen cell cultures. In order to see this effect, cultures had to be antigen stimulated and T cell depleted. Reconstitution by RF could be abrogated by the addition of non-specific, intact, murine IgG and not by F(ab'){dollar}\sb2{dollar} or IgM.;The dysregulation of autoimmune responses was also investigated. It was demonstrated that normal, nonautoimmune-prone mice generated spontaneous anti-ssDNA antibodies in vitro of higher avidity than autoimmune-prone mice as determined by plaque inhibition assay using free ssDNA. Addition of RF to spleen cell cultures of normal mice resulted in a decrease of the IgM-anti-ssDNA antibody avidity as measured by both plaque inhibition and competitive inhibition ELISA assays. These results and the presence, in vivo, of low levels of autoantibody from high avidity antibody-producing cells in normals and high levels from low avidity antibody-producing cells in autoimmune-prone mice indicate that negative Fc signalling plays a role in the resulting spectrum of antibody avidities and possibly of class by being a key control element in the IgM to IgG switch.;This thesis offers a novel role for RF as an Fc signal blocking agent, but more importantly, implicates end-product feedback by endogenously produced IgG as a key immunoregulatory mechanism during critical stages of B cell activation. Furthermore, inefficient negative Fc signal transmission may be the prime deregulating element leading to conditions conducive for the emergence of clinical autoimmunity.



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