B cells develop in a series of programmed developmental stages. These in-built mechanismsare subject to selective forces through the B cell receptor (BCR) from both self and extrinsicantigens. It is proposed that interactions through the BCR influence the fate of individual cells with respect to their phenotype and function. The localization of follicular (FO), marginal zone (MZ) B cells in the spleen and B-1 cells in the peritoneal cavity reflects the different functions of each with respect to the types of antigens recognized by each subset and their roles as antibody producers and antigen presenters. MZ B cells are strategically located in the spleen where they are able to interact with blood borne antigens. The hypothesis will be tested that this B cell subset expresses BCR's that bind common bacterial antigens and certain self or modified self-antignes and can mount a rapid, protective T cell-independent antibody response to blood borne organisms. The MZ is a late developing site with the important consequence, that in man and mouse, neonates are particularly susceptible to bacterial infections including Gram positive organisms. A variety of transgenic and gene targeted mice will be used to determine the developmental origins of this area of the spleen. Monoclonal antibodies (Mabs) specific for MZ B cells will be used to (i) identify these and related B cells in other tissues, and (ii)to define molecules expressed by these cells that are involved in localizing them in the MZ and endow them with unique functions. MZ B and B-1 cells, different from FO B cejls, appear to be chronically activated by self-antigen and have special survival mechanisms that permit them to remain as useful members of the B cellrepertoire despite their self-reactivity. Genes will be sought that are uniquely expressed in these subsets, that keep them in this activated state, and that are responsible for their survival. A third majorgoal will be to study the role of MZ B cell interactions with dendritic cells in response to bacterial antigens. The overall goals of this proposal are to determine the role that these B cell subsets play in the development of the normal immune system. As a result, new information will be forthcoming with respect to the immune response to bacterial infections, immnodeficiencies, autoimmune diseases, and B cell neoplasia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI014782-31
Application #
7770853
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Nasseri, M Faraz
Project Start
1978-09-01
Project End
2011-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
31
Fiscal Year
2010
Total Cost
$343,026
Indirect Cost
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Patel, Preeyam S; Kearney, John F (2017) CD36 and Platelet-Activating Factor Receptor Promote House Dust Mite Allergy Development. J Immunol 199:1184-1195
Hammad, Hamida; Vanderkerken, Matthias; Pouliot, Philippe et al. (2017) Transitional B cells commit to marginal zone B cell fate by Taok3-mediated surface expression of ADAM10. Nat Immunol 18:313-320
Azzam, Kathleen M; Madenspacher, Jennifer H; Cain, Derek W et al. (2017) Irgm1 coordinately regulates autoimmunity and host defense at select mucosal surfaces. JCI Insight 2:
Patel, Preeyam; Kearney, John F (2016) Immunological Outcomes of Antibody Binding to Glycans Shared between Microorganisms and Mammals. J Immunol 197:4201-4209
Patel, Preeyam S; King, R Glenn; Kearney, John F (2016) Pulmonary ?-1,3-Glucan-Specific IgA-Secreting B Cells Suppress the Development of Cockroach Allergy. J Immunol 197:3175-3187
New, J Stewart; King, R Glenn; Kearney, John F (2016) Manipulation of the glycan-specific natural antibody repertoire for immunotherapy. Immunol Rev 270:32-50
Kearney, John F; Patel, Preeyam; Stefanov, Emily K et al. (2015) Natural antibody repertoires: development and functional role in inhibiting allergic airway disease. Annu Rev Immunol 33:475-504
Honjo, Kazuhito; Kubagawa, Yoshiki; Kearney, John F et al. (2015) Unique ligand-binding property of the human IgM Fc receptor. J Immunol 194:1975-82
Wharton, Rebekah E; Stefanov, Emily K; King, R Glenn et al. (2015) Antibodies generated against Streptococci protect in a mouse model of disseminated aspergillosis. J Immunol 194:4387-96
Patel, Preeyam S; Kearney, John F (2015) Neonatal exposure to pneumococcal phosphorylcholine modulates the development of house dust mite allergy during adult life. J Immunol 194:5838-50

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