Patrick C. Wilson, Ph.D.

B Cell Immunity and Autoimmunity: B Cells in Health and Disease

Research Summary

With a particular emphasis on antibody specificity, two primary interests have emerged in the lab: We study the fate and differentiation of autoreactive B cells and we characterize the human B cell response to infectious diseases. We combine the use of powerful mouse models of B cell selection with various clinical partnerships to link observations in laboratory models to the direct study of human B cell biology.

B cell selection in the context of receptor editing: The random nature of antibody gene production leads to unavoidable autoreactivities that are avoided by either receptor editing (to change the B cell specificity) or by culling the offensive cells from the repertoire by deletion or inactivation.  Further adaptation of B cell specificity by somatic hypermutation can lead to both new autoreactive B cells or to high affinity autoantibodies that cause diseases such as lupus and arthritis. Our recent work has demonstrated that the very processes protecting us from autoreactive B cells can rather lead to the unforeseen inclusion of autoreactive B cells in the functional repertoire. Specifically, we found that receptor editing causes up to 10% of mouse B cells to express two antibody kappa variable gene alleles simultaneously. Presumably, in most cases one of these two alleles encodes an autoantibody, posing a threat for susceptible individuals.  We are therefore interested in learning the fate of these cells and their consequences for autoimmune pathology. With this in mind we are studying the selection of B cells in the context of receptor editing using several mouse models.

 Anergic B cells in humans: immune tolerance or tolerance escape: It has been known for some time that in mouse models autoreactive B cells can enter the mature repertoire but with functional attenuation so that they are unresponsive to binding with our own molecules.  These anergic B cells have long caused a conundrum to immunologists because while being functionally inactivated they maintain their autoreactive specificity.  Importantly, it is known that anergic B cells can be induced by proper stimulation to become fully activated and secrete autoantibodies. For the first time we have now characterized a subset of human B cells that are fully mature but carry autoreactive immunoglobulins.  As in mouse models, these cells are anergic but can be induced to full immune responsiveness ex vivo.  We are now studying the means for the functional inactivation and the role that these anergic human B cells might play in autoimmune diseases such as lupus.

The human B cell response to infectious diseases: The basis of vaccination is often to generate protective titers of blood-borne antibody and memory B cells that can protect against infectious diseases. We have recently devised powerful approaches to rapidly generate monoclonal antibodies that for the first time allow an evaluation of the specificity of ongoing immune responses in humans.  We are working with various collaborators to understand human B cell responses to various infectious diseases of central importance to world health.  In particular we are studying the immune responses to influenza, avian influenza, yellow fever virus, and dengue virus immunization. Our goals are several-fold and include a better understanding of how human B cell responses are mounted, to improve vaccines to these diseases, and finally to generate monoclonal antibodies that could prove to be powerful diagnostic or therapeutic reagents.

Selected Papers

Zheng, N.Y., Wilson, K., Wang, X., Boston, A., Kolar, G., Jackson, S.M., Liu, Y.J., Pascual, V., Capra, J.D., and Wilson, P.C. (2004) Human immunoglobulin selection associated with class-switch and possible tolerogenic origins for C(Delta) class switched B cells. J Clin. Invest.  113:1188-1201.

Meffre, E., Schaefer, A., Wardemann, H., Wilson, P., Davis, E., and Nussenzweig, M.C.  (2004) Surrogate light chain expressing human peripheral B Cells produce self-reactive antibodies.  J Exp Med.199(1):145-150.

Zheng, N.Y., Wilson, K., Jared, M., and P.C. Wilson. (2005) Intricate targeting of immunoglobulin somatic hypermutation maximizes the efficiency of affinity maturation. J. Exp. Med. 2005;201(9):1467-1478.

Casellas, R., Q. Zhang, N.Y. Zheng, M.D. Mathias, K. Smith, and P.C. Wilson. (2007)  Ig{kappa} allelic inclusion is a consequence of receptor editing. J Exp Med . 204:153-160.

Crouch,E., Li, Z., Takizawa, M., Fichtner-Feigl, S., Gourzi, P., Montano, C., Feigenbaum, L, Wilson, P., Janz, S., Papavasiliou, F.N., and R. Casellas.  (2007) Regulation of AID expression in the immune response. J Exp Med. May 14;204(5):1145-1156

Teague, B. N., Mudd, P.A.,  Nakken, B., Pan, Y., Zhang, Q.,  Kim-Howard, X, Wilson, P.C., and A. D. Farris. (2007) Transitional t3 b cells do not give rise to mature B cells, have undergone selection, and are reduced in murine lupus. J. Immunol. (Cutting edge report). 178:7511-7515.

Koelsch, K., N.Y. Zheng, Q. Zhang, A. Duty, L.A. Abraham, C. Helms, M.D. Mathias, M. Jared, K. Smith, and Wilson, P.C. (2007) Mature autoreactive B cells from healthy people permanently class switch to the IgD antibody isotype. J Clin Invest. Jun;117(6):1558-1565

Wrammert, J., Smith, K., Miller, J., Langley, T., Kokko, K., Larsen, C., Zheng, N. Y., Mays, I., Helms, C., James, J., Air, G., Capra, J. D., Ahmed, R., and Wilson, P. C. (2008) Rapid cloning of high affinity human monoclonal antibodies against influenza virus. Nature. May 29;453(7195):667-71.

Jackson, S. J., Wilson, P.C., James, J., and J. D. Capra. (2008) Human B Lymphocyte populations. Adv Immunol. 98:151-224.

Duty, J.A., Szodoray, P., Zheng, N.Y., Koelsch, K.A., Zhang, Q., Swiatkowski, M., Mathias, M., Nakken, B., Jared, M., Smith, K., Farris, D., Wilson, P.C. (2009) Functional anergy in a subpopulation of naïve B cells expressing autoreactive receptors in humans. J Exp Med. 206: 139-151.

Smith, K., Garman, L., Wrammert, J., Zheng, N.Y., Capra, J.D., Ahmed, R., and Wilson, P.C. (2009) Rapid generation of fully human monoclonal antibodies specific to a vaccinating antigen. Nature Protocols. On press.