The specific aims of this application are based upon our preliminary studies aimed to develop an understanding of cellular and molecular mechanism governing the synthesis of autoantibodies. The research objective are: (1) To study the activation of self- reactive clones by foreign antigens and antiidiotypic antibody carrying the internal image of foreign antigens. (2) To determine the frequency of self-reactive antibodies among hybridomas obtained from meV and to study VH and VK gene families used by autoantibodies. (3) To clone the germline genes from """"""""unique"""""""" restriction enzymatic fragments present in NZB and MEV mice strains in which Ly1.B cells are overrepresented or predominant. To compare the sequence of VH and VK rearranged genes of Ly1.B hybridomas producing antoantibodies with the sequence of germline genes cloned from """"""""unique"""""""" and """"""""shared"""""""" restriction enzymatic fragments in order to determine whether or not there is a subset of germline genes from which derive the genes coding for autoantibodies produced by Ly1.B cells (4) To prepare transgenic mice containing the VH gene of a nephritogenic anti- DNA antibodies. These mice will be used to study if a pathogenic transgene accelerates the onset of disease, to determine the genetic requirments for the occurrence of lupus syndrome and to investigate if there are naturally occurring T cells which recognize the idotopes encoded by this V gene. (5) To focus the activity of cytolytic T cells specific for influenza virus on autoreactive B cells by using bifunctional hybrid molecules directed against T cell receptor of CTL and the idiotype of anti- DNA antibody in order to prevent or delay the onset of lupus syndrome. These studies should add to our knowledge of mechanisms responsible for the diversity of autoantibodies and regulation of self-reactive clones.
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