Grant: Operating 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. Unfortunately, these antibodies usually bind weakly to their specific antigen. However, B cells have developed a way to make antibodies bind more tightly to antigens by making small changes (mutations) in antibody genes. This process is called somatic hypermutation. Through this mechanism, those B cells that produce a stronger binding antibody are then stimulated to become antibody producing B cells. B cells also change the stalk of the antibody through a process called class switch recombination. By changing the antibody stalk, the properties of the antibody are changed. For example, IgM antibodies can be changed to IgG antibodies that can be used by macrophages to engulf bacteria that are coated by these antibodies, while IgA antibodies are secreted into mucosal tissue and can neutralize pathogens in the lung or the gut. Recently, some of the enzymes that are involved in somatic hypermutation and class switch recombination have been identified, such as AID. However, much still needs to be investigated about how these two processes are accomplished in B cells and the enzymes that are involved. Our current proposal will focus on class switch recombination. We have recently identified novel genes that function in class switch recombination, and propose to investigate how these genes function in this process. Our proposed work will allow us to determine how an effective antibody response is generated. In addition, because AID and the class switch recombination process are linked to the development of lymphomas, our work will advance our knowledge on the etiology of these types of cancers.