Grant: Project Grant

The immune system plays a major role in protecting humans from bacteria, viruses, and toxins (known as antigens). One of the ways that the immune system accomplishes this is by producing antibodies that bind to and neutralize these antigens. Antibodies are small molecules made by B cells. Each B cell makes only one type of antibody which will bind to only one antigen. By changing the antibody stalk, the properties of the antibody are changed. For example, IgM antibodies can be changed to IgG antibodies which can be used by macrophages to engulf bacteria that are coated by these antibodies, or to IgA antibodies that can be secreted into mucosal tissue and can neutralize pathogens in the lung or the gut. Changing the antibody class is accomplished by the class switch recombination process, and the key enzyme that initiates this process is called AID. Much still needs to be investigated about how class switch recombination is accomplished in B cells and the enzymes that are involved. We have recently identified novel genes that function in class switch recombination, namely RNF20, RNF40, and USP22, and propose to investigate how these genes function in this process using cell lines. Our current work suggests it functions by repairing DNA breaks that occur in B cells. We have also made mice where we can specifically delete USP22 in any tissue of our choice. We will specifically delete USP22 in B cells to determine whether B cell development and class switch recombination require USP22. Hence, our proposed work will allow us to determine how an effective antibody response is generated. Since enzymes involved in DNA repair are typically found to suppress tumor development, and because AID and the class switch recombination process are linked to the development of lymphomas, we will also test whether USP22 is critical for the development of lymphomas and colon cancer.