Immunoglobulin heavy chain isotype switch recombination is a regulated recombination event that occurs in antigen-activated B cells. Switch recombination joins the variable region of an expressed heavy chain gene to a constant region of a new class or isotype, deleting the DNA between. Since each of the different classes of constant region removes antigen in a specialized way, the result of switch recombination is to alter the antigen clearance properties of an immunoglobulin molecule without affecting its specificity for antigen, thereby increasing the efficiency of the immune response. The critical importance of switching is evidenced by the fact that certain immunodeficiency diseases are characterized by an inability to carry out switch recombination. The proposed research win study the molecular mechanism of isotype switch recombination.
The aims are: (1) to clone a cDNA that encodes LR1, an inducible factor that we have identified as a candidate regulator of isotype switching, and to characterize expression and function of the LRl DNA binding protein; (2) to study how LRl activity is regulated in response to cell activation; (3) to study the activation and targeting of switch recombination, using extrachromosomal substrates carrying switch region sequences in a sensitive transient recombination assay. Results from these experiments should provide important insights into the mechanism of a process that is central to the human immune response. The mechanism of this regulated and targeted recombination process may also prove relevant to certain of the deletion and recombination events that give rise to genetic disease.
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