The adaptive immune system is characterized by the diversity of its antigen-receptors and the formation of memory. Two random mechanisms generate B cell antigen-receptor diversity. The first one is somatic immunoglobulin (Ig) gene recombination by which functional Ig genes are assembled from a large number of germline encoded small Ig heavy and Ig light chain gene segments during the early stages of B cell development in bone marrow. The second mechanism is somatic mutations of functionally rearranged Ig genes in B cells, which have been activated by antigen in the presence of T cell help. The random nature of the two processes generates antibodies against a plethora of diverse pathogens, but the downside is the production of potentially harmful autoantibodies and antibodies directed against non-pathogenic foreign antigens or microbes. Thus, constant shaping of the antibody repertoire by positive and negative selection during B cell development and differentiation is essential to allow the generation of highly efficient and specific humoral immune responses to invading pathogens while maintaining tolerance to self and non-pathogenic foreign microbes, e.g. commensal bacteria in the gut. The overall goal of our research is to establish how antibody diversity is shaped by self- and foreign antigen-driven selection in health and disease. To measure the diversity of the antibody repertoire we have previously developed a strategy that allows the efficient cloning and expression of antibodies from single isolated B cells. Fluorescent activated cell sorting is used to isolate single cells belonging to defined B cell subpopulations from peripheral blood, organs or tissues. Further, the strategy allows the isolation of antigen-specific cells if fluorescently labeled antigen is used in the isolation strategy. Research in our group is focused around this technology. We are currently investigating the human and murine antibody repertoire under normal conditions, in systemic autoimmunity, under chronic inflammatory conditions and in response to vaccination and infection.

Perspective

The long-term goal of our laboratory is (1) to define additional tolerance checkpoints in humans, (2) to enumerate the frequency of developing self-reactive antibodies in the periphery and (3) to study how the immune system keeps the balance between an efficient antibody response to invading pathogens and prevention of autoimmunity.

Selected publications

Mouquet, H., Scheid, J.F., Zoller, J.M., Krogsgaard, M., Ott, R.G., Shukair, S., Artyomov, M.N., Pietzsch, J., Connors, M., Pereyra, F., Walker, B.D, Ho, D.D., Wilson, P.C., Seaman, M.S., Eisen, H.N., Chakraborty, A.K., Hope, T.J., Ravetch, J.V., Wardemann, H., Nussenzweig, M.C.: Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation. Nature. 467:591-5 (2010).

Tiller, T., Tsuiji, M., Yurasov, S., Velinzon, K., Nussenzweig, M.C., Wardemann, H.: Autoreactivity in human IgG+ memory B cells. Immunity. 26:205-13 (2007).

Wardemann, H., Yurasov, S., Schaefer, A., Young, J.W., Meffre, E., Nussenzweig, M.C.: Predominant autoantibody production by early human B cell precursors. Science. 301:1374-7 (2003).