CLASS II GENES IN AUTOIMMUNE RODENTS

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The class II molecules play a central role in both normal and abnormal immune responses, and a number of autoimmune diseases both in man and mouse appear to be linked to class II molecules. We propose to evaluate the qualitative and quantitative contribution of the class II molecules from the NZW mouse strain to autoimmunity in the (NZWxNZB)F mouse. The qualitative structure function relationship of class II molecules in autoimmunity will be evaluated by seeking unusual sequences in NZW cDNA's. We will develop monoclonal antibodies specific for the NZW/NZB hybrid class II molecules to examine whether hybrid class II molecules exist in vivo, and determine if these hybrid molecules might contribute to the development of autoimmunity. Using transfections we will also determine whether the "u" haplotype is immunodominant, which would help explain the NZW contribution to accelerated autoimmunity. In addition, we plan to produce transgenic NZB mice, in which NZW class II transgenes are placed into NZB mice. To evaluate whether there is a quantitative contribution of class II molecules to autoimmunity, we will isolate NZB and NZW genes and examine both cis and trans acting factors which regulate the expression of class II genes. Cis acting factors will be evaluated by determining whether the 5' flanking region of the class II genes of NZW and NZB have unusual sequences. cDNA's encoding trans acting factors will be isolated by a Southwestern methodology whereby labeled oligonucleotides corresponding to the NZB and NZW 5' regulatory regions are used to probe NZB and NZW lambda gt11 libraries. These cDNA's will be examined for unusual sequences. These studies will evaluate both the quantitative and qualitative contributions of class II genes to autoimmunity.