Grant: Operating Grant

Antibodies are fundamental components of the immune system because they can recognize and neutralize almost any pathogen or toxin. We need to be able to produce a sufficiently large repertoire of antibodies to match a virtually infinite number of antigens. To do this, the antibody genes are changed (mutated) in each B lymphocyte after it first comes in contact with the antigen. These changes produce antibodies that better bind the antigen and that have acquired new functions to appropriately dispose of the antigen. These modifications of the antibody genes are essential for the immune response but have associated risks. They can predispose to cancer or produce antibodies that recognize our own tissues and cause autoimmune diseases. We study the mechanism modifying the antibody genes, focusing on the initiating enzyme that is named AID. Both, deficiency in, and exacerbation of, AID activity are pathogenic. This can be due to malfunction of AID itself or of factors that modify AID. We are studying the mechanisms that determine the amount and localization of AID in B lymphocytes. The amount of AID is determined in large part by modulating its stability (i.e. how long does it last). The right levels of AID are critical for adequate immune responses. The localization of AID is important because AID changes the genetic information. AID localization is regulated by restricting its access to the cellular compartment, which contains the genome, so as to minimize the possibility that it mutates off target. Understanding these processes is understanding fundamental biological processes important for the immune system. Our research also provides insight into the etiology of certain cancers and autoimmune diseases caused by AID as side effects. Our findings could suggest targets for diagnostic, prognostic and therapy for common human diseases.