The random nature of V(D)J recombination, whose primary purpose is to produce antibodies that bind a broad range of potential targets, often inadvertently creates antibodies that recognize self antigens. Such autoreactive antibodies are often associated with autoimmune diseases that adversely affect the wellbeing of millions and represent a significant financial burden on society. During early development, mechanisms exist for managing autoreactive B cells, including deletion, modification, or silencing. In the periphery, B cells undergoing affinity maturation are subject to peripheral tolerance mechanisms to prevent acquisition of high affinity autoreactivity. Indeed, a myriad of selection and tolerance mechanisms, spanning the entirety of the B cell lineage from early pro-B cells to long-lived plasma cells, exert massive influence on the composition of the human antibody repertoire. Although the repertoire-shaping effects of selection and tolerance are thought to be quite large, we still have only a limited understanding of the ways in which B cell repertoire composition is regulated by selection. The long-term research focus of my laboratory is to use high-throughput sequencing to gain a more complete understanding of the development, maturation and function of the human B cell repertoire. Continuing technological advances, including emerging single-cell analysis techniques, allow the construction of increasingly detailed molecular profiles for large numbers of individual cells. The extremely high resolution of such datasets will allow study of the humoral immune system at an unprecedented level of depth and detail. Over the next five years, we will leverage these advances to address significant knowledge gaps in the following areas. (1) Discovery of specific features or feature patterns encoded by B cell receptors that are selectively depleted or modified by central tolerance. (2) Identification of early B cell development checkpoints at which selection and tolerance homogenize the repertoires of different individuals. (3) Characterization of global patterns of affinity maturation which, independent of any particular antigen, globally shape the composition of the memory repertoire. A more complete understanding of the processes and mechanisms that shape the B cell repertoire is vitally important and broadly relevant to ongoing research in infectious disease, autoimmunity, and rational vaccine development.

Public Health Relevance

The human antibody repertoire is massively diverse, allowing recognition of a broad range of potentially pathogenic epitopes, although the random recombination process responsible for generating this diversity also produces antibodies that react with self proteins. Immune tolerance mechanisms operate throughout B cell development with the purpose of removing or altering the specificity of autoreactive B cell clones, but the repertoire-shaping effects of these pervasive selection processes are poorly understood. Here, we propose the construction of rich, multilayered profiles of individual developing B cells that integrate genetic, phenotype and functional information and will allow exceptionally high resolution deconvolution of the influence of tolerance and selection on the B cell repertoire.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZGM1)
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Smith, Ward
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Scripps Research Institute
La Jolla
United States
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