Date of Award
1990
Degree Type
Dissertation
Degree Name
Doctor of Philosophy
Abstract
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.
Recommended Citation
Panoskaltsis, Angela, "Regulation Of Immune Responses To Self And Nonself" (1990). Digitized Theses. 1897.
https://ir.lib.uwo.ca/digitizedtheses/1897