High morbidity and >20,000 deaths per year in the US alone are caused by infection with influenza virus. Neutralizing antibodies are one immune mechanism that provides effective protection against this virus. Natural virus-binding antibodies secreted prior to infection and virus-induced antibodies generated in the absence of T cell help, are both crucial for survival from this infection. The underlying basis of their induction however, is poorly understood. This proposal aims to define the basic principles that underlie the induction of these antibodies. Thus, providing a first step for identification of the precise molecular mechanisms that regulate their induction. The central hypothesis that will be tested is that intrinsic differences in B cell subsets contribute significantly to the regulation of antiviral humoral responses and that B-1 cells are one B cell subset participating early in immune defense.
The first aim i s to characterize distinct virus-specific B cell populations induced to influenza virus A/PR8 in mice and to determine their in vivo function. This will include the analysis of two distinct idiotype-expressing B cells, differing in the kinetics of their responses, and of the B-1 cell subset, which secretes virus-binding natural antibodies. These studies will test the hypothesis that virus-specific B cell subpopulations differ in lifespan, ability to proliferate and to differentiate to antibody-secreting cells. Virus-responding B cell subsets will be characterized by 10-color flow cytometry. Proliferative responses will be assessed by in vivo labeling of dividing cells. Antibody secretion will be measured by ELISA and ELISPOT of FACS-purified B cell subsets. Immunohistochemistry will determine the precise tissue location of idiotype-expressing B cells.
The second aim i s to test whether the function and fate of virus-specific B cells is determined by their intrinsic regulatory properties. For this, B cell subset responses will be characterized in T cell-deficient mice, as for aim #1. B cell receptor-affinity will be assessed to determine its influence on antibody-kinetics. Phenotypic studies are expected to identify new molecules involved in the regulation of early virus-specific B cell responses.
The third aim i s to test whether B cell differentiation into short-lived antibody-secreting cells causes the rapid disappearance of the early expressed idiotypes. Molecular outcomes of B cell subset activation will be assessed by real-time RT-PCR and Western-blot analysis of genes known to regulate B cell differentiation. This study challenges the current paradigm of B cell activation. Successful outcome of this study would provide a new framework that explains better how protective antiviral B cell responses are induced. It would also form the basis for defining the precise molecular mechanisms of early virus-specific B cell activation, thus for identifying possible new targets for rationale vaccine design.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051354-04
Application #
6878644
Study Section
Virology Study Section (VR)
Program Officer
Lacourciere, Karen A
Project Start
2002-09-30
Project End
2007-12-14
Budget Start
2005-04-01
Budget End
2007-12-14
Support Year
4
Fiscal Year
2005
Total Cost
$259,875
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Nguyen, Trang T T; Graf, Beth A; Randall, Troy D et al. (2017) sIgM-Fc?R Interactions Regulate Early B Cell Activation and Plasma Cell Development after Influenza Virus Infection. J Immunol 199:1635-1646
Baumgarth, Nicole (2017) A Hard(y) Look at B-1 Cell Development and Function. J Immunol 199:3387-3394
Nguyen, Trang T T; Kläsener, Kathrin; Zürn, Christa et al. (2017) The IgM receptor Fc?R limits tonic BCR signaling by regulating expression of the IgM BCR. Nat Immunol 18:321-333
Nguyen, Trang T T; Baumgarth, Nicole (2016) Natural IgM and the Development of B Cell-Mediated Autoimmune Diseases. Crit Rev Immunol 36:163-177
Baumgarth, Nicole (2016) B-1 Cell Heterogeneity and the Regulation of Natural and Antigen-Induced IgM Production. Front Immunol 7:324
Nguyen, Trang T T; Elsner, Rebecca A; Baumgarth, Nicole (2015) Natural IgM prevents autoimmunity by enforcing B cell central tolerance induction. J Immunol 194:1489-502
Baumgarth, Nicole; Waffarn, Elizabeth E; Nguyen, Trang T T (2015) Natural and induced B-1 cell immunity to infections raises questions of nature versus nurture. Ann N Y Acad Sci 1362:188-99
Waffarn, Elizabeth E; Hastey, Christine J; Dixit, Neha et al. (2015) Infection-induced type I interferons activate CD11b on B-1 cells for subsequent lymph node accumulation. Nat Commun 6:8991
Elsner, Rebecca A; Hastey, Christine J; Olsen, Kimberly J et al. (2015) Suppression of Long-Lived Humoral Immunity Following Borrelia burgdorferi Infection. PLoS Pathog 11:e1004976
Savage, Hannah P; Baumgarth, Nicole (2015) Characteristics of natural antibody-secreting cells. Ann N Y Acad Sci 1362:132-42

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