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 #
5R01AI014782-35
Application #
8610216
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
2014-03-01
Budget End
2015-02-28
Support Year
35
Fiscal Year
2014
Total Cost
$366,250
Indirect Cost
$116,250
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; King, R Glenn; Kearney, John F (2016) Pulmonary α-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
Patel, Preeyam; Kearney, John F (2016) Immunological Outcomes of Antibody Binding to Glycans Shared between Microorganisms and Mammals. J Immunol 197:4201-4209
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
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
Weindel, Chi G; Richey, Lauren J; Bolland, Silvia et al. (2015) B cell autophagy mediates TLR7-dependent autoimmunity and inflammation. Autophagy 11:1010-24
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
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
Vale, Andre M; Kapoor, Pratibha; Skibinski, Greg A et al. (2013) The link between antibodies to OxLDL and natural protection against pneumococci depends on D(H) gene conservation. J Exp Med 210:875-90

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