Asthma is a chronic respiratory disease, which is potentially life-threatening and an increasingly significant public health problem. In the United States 16.4 million non-institutionalized adults and 7.0 million children currently have asthma, accounting for 7.3% and 9.4% of these total populations respectively. Asthma involves multiple conditions and a major problem in fighting asthma is that its cause is unknown;however, there is a clear association of immune allergies in about 40% of asthmatics, and as the prevalence of allergies has increased, so has asthma. The "hygiene hypothesis" links the increasing allergic and autoimmune phenomena to excessively sanitary conditions early in life. Despite the appeal of this hypothesis, there are no clear examples of beneficial effects of microbial exposure. Our long-term goal is to understand the link between early microbe exposure and protection from allergic asthma. We will identify mechanisms involved in the shaping of the antibody repertoire by common environmental organisms, resulting in the induction and maintenance of non-allergen specific antibodies which block cellular mechanisms leading to sensitization by allergens expressed by bacteria, mold and fungi. Preliminary data shows that neonatal exposure to defined conserved bacterial antigens shared by a variety of allergen bearing organisms induce dramatic and permanent changes in the resulting B cell repertoire and that significant protection against airway sensitization is dependent on the timing of induction and the antigen targets of these antibodies. The two aims are to determine how early exposure to environmental antigens controls the development of B cells that make antibodies to microorganisms bearing allergens and then determine the mechanism of antibody- mediated protection against allergic airway disease. These outcomes will reveal new information on plasticity of the B cell repertoire and define developmental windows within which B cell clonal development can be manipulated to maximize levels of allergic airway-protective antibodies. Our long range goal underlying this approach is that an understanding of the immunological mechanisms involved in this protection will provide new therapeutic or vaccination options for treatment/prevention of allergic asthma.

Public Health Relevance

The incidence of asthma, along with other autoimmune related diseases, is increasing in western-style societies. Based on the inverse correlation with human Group A streptococcal infection and asthma, we will investigate the modulating role of anti-Group A streptococcus and other bacteria-reactive B cells on the development and progression of allergic airway disease. New knowledge obtained from these studies may assist in the development of treatments, including a vaccination approach, that will prevent or dampen the allergy-associated processes that cause asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI014782-34
Application #
8431725
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Ferguson, Stacy E
Project Start
1978-09-01
Project End
2016-02-29
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
34
Fiscal Year
2013
Total Cost
$344,275
Indirect Cost
$109,275
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
Rivera, Johanna; Morgenstern, Alfred; Bruchertseifer, Frank et al. (2014) Microbicidal power of alpha radiation in sterilizing germinating Bacillus anthracis spores. Antimicrob Agents Chemother 58:1813-5
Foote, Jeremy B; Mahmoud, Tamer I; Vale, Andre M et al. (2012) Long-term maintenance of polysaccharide-specific antibodies by IgM-secreting cells. J Immunol 188:57-67
Mahmoud, Tamer I; Schroeder Jr, Harry W; Kearney, John F (2011) Limiting CDR-H3 diversity abrogates the antibody response to the bacterial polysaccharide ? 1?3 dextran. J Immunol 187:879-86
Kin, Nicholas W; Chen, Yao; Stefanov, Emily K et al. (2011) Cathelin-related antimicrobial peptide differentially regulates T- and B-cell function. Eur J Immunol 41:3006-16
Berbari, Nicolas F; Kin, Nicholas W; Sharma, Neeraj et al. (2011) Mutations in Traf3ip1 reveal defects in ciliogenesis, embryonic development, and altered cell size regulation. Dev Biol 360:66-76
You, Yuying; Myers, Riley C; Freeberg, Larry et al. (2011) Marginal zone B cells regulate antigen capture by marginal zone macrophages. J Immunol 186:2172-81
Foote, Jeremy B; Kearney, John F (2009) Generation of B cell memory to the bacterial polysaccharide alpha-1,3 dextran. J Immunol 183:6359-68
Thal, Melissa A; Carvalho, Thiago L; He, Ti et al. (2009) Ebf1-mediated down-regulation of Id2 and Id3 is essential for specification of the B cell lineage. Proc Natl Acad Sci U S A 106:552-7
Kearney, John F (2008) B cell subpopulations and secondary lymphoid organ architecture. Semin Immunol 20:1-3
Torii, Ikuko; Oka, Satoshi; Hotomi, Muneki et al. (2008) PIR-B-deficient mice are susceptible to Salmonella infection. J Immunol 181:4229-39

Showing the most recent 10 out of 11 publications