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.

A germinal center reaction in a lymph node
of an
immunized mouse. It is within this structure that B cells mutate their
antibody genes, in a process that ultimately leads to the generation of
high-affinity antibodies.

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.