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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.
Jacobsen JT, Mesin L, Markoulaki S, Schiepers A, Cavazzoni CB, Bousbaine D, Jaenisch R, Victora GD. One-step generation of monoclonal B cell receptor mice capable of isotype switching and somatic hypermutation. J Exp Med. 2018 Oct 1;215(10):2686-2695.

Pasqual G, Chudnovskiy A, Tas JMJ, Agudelo M, Schweitzer LD, Cui A, Hacohen N, Victora GD. Monitoring T cell-dendritic cell interactions in vivo by intercellular enzymatic labelling. Nature. 2018 Jan 25;553(7689):496-500.

Degn SE, van der Poel CE, Firl DJ, Ayoglu B, Al Qureshah FA, Bajic G, Mesin L, Reynaud CA, Weill JC, Utz PJ, Victora GD, Carroll MC. Clonal Evolution of Autoreactive Germinal Centers. Cell. 2017;170(5):913-926.

Ersching J, Efeyan A, Mesin L, Jacobsen JT, Pasqual G, Grabiner BC, Dominguez-Sola D, Sabatini DM, Victora GD. Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase. Immunity. 2017 Jun 20;46(6):1045-1058.e6.

Mesin L, Ersching J, Victora GD.
Germinal Center B Cell Dynamics. Immunity. 2016 Sep 20;45(3):471-82.

Tas JMJ,* Mesin L,* Pasqual G, Targ S, Jacobsen JT, Mano YM, Chen CS, Weill JC, Reynaud CA, Browne EP, Meyer-Hermann M, Victora GD.
Visualizing antibody affinity maturation in germinal centers. Science, 18 Feb 2016 (epub ahead of print). DOI: 10.1126/science.aad3439

Victora GD*, Wilson PC*.
Germinal center selection and the antibody response to influenza. Cell. 2015 Oct 22;163(3):545-8.

Pasqual G, Angelini A, Victora GD.
Triggering Positive Selection of Germinal Center B Cells by Antigen Targeting to DEC-205. Methods Mol Biol. 2015;1291:125-34.

Victora GD. SnapShot: the germinal center reaction. Cell. 2014 Oct 23;159(3):700-700.e1.

Victora GD & Mesin L. Clonal and Cellular Dynamics in Germinal Centers. Curr Op Immunol. 2014, 28:90-96.

Victora GD. Stop, Go, and Evolve. Science. Dec 6;342(6163):1186.

Shulman Z, Gitlin AD, Targ S, Jankovic M, Pasqual G, Nussenzweig MC*, Victora GD*. In vivo dynamics of Tfh cells in Germinal Centers. Science. Aug 9;341(6146):673-7.

Dominguez-Sola D*, Victora GD*, Ying CY, Phan RT, Saito M, Nussenzweig MC, Dalla-Favera R.
The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nat Immunol. 2012 Nov;13(11):1083-91

Victora GD*, Dominguez-Sola D*, Deroubaix S, Holmes AB, Dalla-Favera R, Nussenzweig MC. Identification of human germinal center light and dark zone cells and their relationship to human B cell lymphomas. Blood. 2012 Sep 13;120(11):2240-8.

Meyer-Hermann M, Mohr E, Pelletier N, Zhang Y, Victora GD*, Toellner K-M*  A novel theory of germinal center B cell selection, division, and exit. Cell Reports. 2012 Jul 26;2(1):162-74.

Victora GD*, Nussenzweig, MC*. Germinal Centers. Annu Rev Immunol. 2012;30:429-57.

Schwickert TA*, Victora GD*, Fooksman DR, Kamphorst AO, Mugnier MR, Gitlin AD, Dustin ML, Nussenzweig MC. A dynamic T cell-limited checkpoint regulates affinity-dependent B cell entry into the germinal center. J Exp Med. 2011 Jun 6;208(6):1243-52.

Victora GD, Schwickert TA, Fooksman DR, Kamphorst AO, Meyer-Hermann M, Dustin ML, Nussenzweig MC. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell. 2010 Nov 12;143(4):592-605.

* equal contribution

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