The immune system has the peculiar ability to respond to foreign substances (or antigens) by producing antibody molecules that bind to these antigens with extremely high affinity and a remarkable degree of specificity. In order to achieve this high level of affinity, B cells – the cells that produce antibodies – must undergo a series of steps that culminate in the generation of an anatomical structure known as the germinal center (GC). Within this structure, B cells introduce random mutations into their antibody genes and, in a process reminiscent of Darwinian evolution, B cells that have acquired affinity-enhancing mutations proliferate, and are eventually directed to differentiate into antibody-producing plasma cells or memory cells that can re-expand upon future contact with the same antigen.
It is this process that allows vaccines to work, and that makes us immune to catching certain diseases more than once. On the flip side, failures in the GC reaction can result in the production of high- affinity antibodies against innocuous substances or even components of one’s own body – leading to allergies and autoimmune diseases such as lupus and rheumatoid arthritis. Furthermore, when misplaced the mutations introduced during the GC reaction can cause genetic lesions that may ultimately lead to lymphomas and other malignancies.
In the Victora lab, we combine a number of cutting-edge techniques – from the development of novel mouse models to intravital multiphoton microscopy – to shed light on the intricacies of the GC reaction and its regulation. For example, using multiphoton-based geotagging of GC cells in a newly developed photoactivatable mouse, we have been able to define the cellular and molecular characteristics of different subpopulations of GC B cells, as well as their dynamic behavior and its relationship to selection. The characteristics we defined in mice are now being used in human studies to better understand the events leading to B cell lymphoma. We believe that unveiling the molecular mechanisms of the GC reaction will be essential if we wish to design better vaccines, develop treatments for allergies and autoimmune diseases, and dissect the molecular basis of lymphomagenesis.