The emerging threat of bioterrorism calls for the development of new or improved vaccine strategies against infectious agents. Vaccines require innate immune cell activation by adjuvants in order to effectively elicit protective immune responses, including B cell production of neutralizing antibodies. The long-term goal of this proposal is to analyze the mechanisms by which innate stimuli regulate antibody production in human B cells. Antibody production includes two intriguing processes known as Ig heavy chain class switch DMA recombination (CSR), which diversifies the antibody effector functions, and Ig V(D)J gene somatic hypermutation (SHM), which increases the antibody affinity for antigen. Complex antigens, such as microbial proteins, elicit CSR, SHM and antibody production through a mechanism involving engagement of CD40 on B cells by CD40 ligand on CD4+ T cells. Although inducing protective high-affinity antibodies and long-lasting immune memory, T cell-dependent B cell responses do not provide immune protection for the initial five to seven days, which is too much of a delay to neutralize quickly replicating pathogens such as viruses and encapsulated bacteria. To compensate for this limitation, B cells rapidly undergo T cell-independent antibody production in response to antigens with repetitive structure, also known as pathogen-associated molecular patterns (PAMPs). These antigens include viral envelope glycoproteins, bacterial capsule polysaccharides and bacterial wall lipopolysaccharides. In this proposal we argue that T cell-independent antibody responses require the activation of innate immune cells by PAMPs. Engagement of Toll-like receptors (TLRs) by PAMPs would induce innate immune cells to release BAFF and APRIL, two CD40 ligand-like molecules that activate B cells through TACI, BCMA and BAFF-R receptors. PAMPs would further enhance T cell-independent antibody production by stimulating B cells through the B cell antigen receptor and innate antigen receptors, including TLRs and complement receptors.
Three specific aims are proposed.
Aim 1 is to elucidate how TLR-binding microbial products and small antiviral compounds, including guanine nucleoside analogues and imidazoquinolines, stimulate innate immune cells to up-regulate BAFF and APRIL.
Aim 2 is to dissect the relative contribution of TACI, BCMA and BAFF-R to the induction of CSR, SHM, and antibody production in B cells.
Aim 3 is to determine the role of B cell-bound TLRs in the initiation of CSR, SHM, and antibody production. Findings resulting from these studies may support the use of recombinant BAFF and synthetic TLR-binding compounds as B cell-stimulating adjuvants for vaccines against bioterrorism agents. In addition to facilitating the development of new vaccine strategies, the proposed studies should lead to a better understanding of the fascinating interplay between the innate and adaptive immune systems.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IHD (01))
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Palker, Thomas J
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Shan, Meimei; Carrillo, Jorge; Yeste, Ada et al. (2018) Secreted IgD Amplifies Humoral T Helper 2 Cell Responses by Binding Basophils via Galectin-9 and CD44. Immunity 49:709-724.e8
Barbet, Gaetan; Sander, Leif E; Geswell, Matthew et al. (2018) Sensing Microbial Viability through Bacterial RNA Augments T Follicular Helper Cell and Antibody Responses. Immunity 48:584-598.e5
Magri, Giuliana; Comerma, Laura; Pybus, Marc et al. (2017) Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals. Immunity 47:118-134.e8
Sintes, Jordi; Gentile, Maurizio; Zhang, Shuling et al. (2017) mTOR intersects antibody-inducing signals from TACI in marginal zone B cells. Nat Commun 8:1462
Chorny, Alejo; Casas-Recasens, Sandra; Sintes, Jordi et al. (2016) The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells. J Exp Med 213:2167-85
Ruane, Darren; Chorny, Alejo; Lee, Haekyung et al. (2016) Microbiota regulate the ability of lung dendritic cells to induce IgA class-switch recombination and generate protective gastrointestinal immune responses. J Exp Med 213:53-73
Magri, Giuliana; Cerutti, Andrea (2015) Role of group 3 innate lymphoid cells in antibody production. Curr Opin Immunol 33:36-42
de Inocencio, Jaime; Mensa-Vilaro, Anna; Tejada-Palacios, Pilar et al. (2015) Somatic NOD2 mosaicism in Blau syndrome. J Allergy Clin Immunol 136:484-7.e2
Gutzeit, Cindy; Nagy, Noemi; Gentile, Maurizio et al. (2014) Exosomes derived from Burkitt's lymphoma cell lines induce proliferation, differentiation, and class-switch recombination in B cells. J Immunol 192:5852-62
Gutzeit, Cindy; Magri, Giuliana; Cerutti, Andrea (2014) Intestinal IgA production and its role in host-microbe interaction. Immunol Rev 260:76-85

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