Autoantibodies to T cell receptors in murine models: Specificity and gene usage

Abstract

The goal of this dissertation was to develop a murine model in which to study autoantibodies that arise naturally and are targeted towards T cell receptor beta chains. The method utilized was the production of monoclonal B cell hybridomas secreting these autoantibodies. The impetus for this work was the observation that the sera of mice, rabbits and humans carry antibodies directed towards peptide defined epitopes of the T cell receptor (TCR) beta chain, along with the findings that the levels of these autoantibodies are modulated with autoimmune disease. The first study involved motheaten mice, which develop spontaneous fatal autoimmune disease as a result of a recessive point mutation. Here we report on the novel gene usage of one monoclonal derived from motheaten mice that exhibits unusual binding activities. We also derived monoclonals from mice infected with the LP-BM5 retrovirus mixture. This infection results in an autoimmune state and is considered by us to be a good model of autoimmunity induced by an infectious agent. The retrovirally induced monoclonals bind TCR vp complementarity determining region 1 (CDR1) peptides, recombinant single chain TCR molecules and T cells. One monoclonal, ATM-1 binds a restricted panel of CDR1 peptides while ATM-2 exhibits a broad range of specificities for the CDR1 peptides. The Vbeta genes encoding these two autoantibodies represent distinct Vbeta subfamilies with amino acid replacements in the CDR2 being associated with the narrow binding specificity. Both monoclonal autoantibodies costimulate superantigen induced proliferation of unfractionated mouse splenocytes. The etiologic agents of anti-TCR autoantibody elaboration and consequences of overproduction are discussed in the context of infectious autoimmunity murine models and autoimmunity in general.