The long term goal is to understand immune responses to nucleic acids, especially the origins and nature of anti-DNA autoantibodies, which are associated with the autoimmune disease systemic lupus erythematosus (SLE). This project aims to identify structures required for antibody binding to various nucleic acid conformations, to determine whether lupus autoantibodies use the same V gene segments as antibodies to exogenous nucleic acid antigens, and to learn how the anti-DNA response is related to normal development of the B cell repertoire. Proposed experiments will test the autoreactivity of VH or VH-surrogate L chain complexes, because such autoreactivity might be a positive selection factor in development of the B cell repertoire.
Specific aims for the next period are: 1) to continue analysis of the DNA-binding roles of VH and VL domains and particular amino acids or structural motifs in anti-DNA antibodies, including antibodies induced by immunization with Z-DNA, poly(dC)-methylated BSA, a complex of Cro repressor protein with plasmid DNA containing a Cro repressor target sequence, autoantibodies from lupus mice (NZB/NZW and MRL/lpr) and control immunization-induced antibodies to unrelated exogenous protein antigens. 2) To determine the frequency with which VH domains in a cDNA library from the spleen of a newborn mouse bind to DNA and other autoantigens. 3) To determine whether association between VH and surrogate L chain components enhances or hinders autoreactivty of DNA-binding VH chains. 4) To test whether VH region gene rearrangements use for immunization-induced antibodies to nucleic acids are derived from precursor gene segments VH domains that bind DNA.
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