Asthma is a chronic respiratory disease that is potentially life-threatening and an increasingly significant public-health problem. In the United States, 16.4 million non-institutionalized adults and 7 million children currently have asthma, accounting for 7.3% and 9.4% of these total populations respectively. A major problem in fighting asthma is that it has multiple etiologies; 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 attempts to link the increasing allergic phenomena to excessively sanitary conditions early in life, and polarization of CD4+ T helper cells defaulting toward TH2 cytokine-polarized responses. Despite the appeal of this hypothesis, there are few empirical data supporting beneficial effects of microbial exposure. Furthermore, despite the highly critical contributions of B cells and their antibody products to both immune and to para-immune conditions and to physiological homeostasis, little attention has been paid to the effects of early microbial exposure on the B cell antigen-recognition repertoire prior to allergic airway disease onset. Our long-term goal is to understand the link between early microbe exposure and protection from allergic airway diseases. In the previous grant period we produced compelling experimental evidence that manipulation of B cell repertoires by perinatal exposure to bacterial vaccines expressing conserved polysaccharide antigens resulted in antibody dependent dampening of adult development of allergic airways disease associated with Aspergillus fumigatus. In this proposal, we will test the hypothesis that B cell clones arising in early life and reactive to conserved bacteria-associated antigens have the potential to prevent sensitization to allergenic moieties associated with allergy-associated organisms expressing these conserved antigens. In three specific aims, we will identify: (i) mechanisms shaping the antibody repertoire by common environmental organisms, (ii) mechanisms involved in antibody-dependent inhibition of sensitization by allergens expressed by house dust mites and fungi, and (iii) strategies to enhance local protective antibody production at sites of allergen exposure. Outcomes from these aims will reveal new information about B cell repertoire plasticity and define developmental windows within which B cell clonal development can be manipulated to maximize levels of allergic airway-protective antibodies. Underlying this approach is our long-range goal to understand immunological mechanisms involved in protection against the development of allergic airway disease and provide new therapeutic or vaccination options for treatment and prevention of allergic asthma.
The incidence of asthma, along with other auto-immune related diseases, is increasing in western-style societies. Based on the intense antibody response to bacterial polysaccharides in humans and in our mouse models, 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 will assist in the development of treatments, including a vaccination approach, that will prevent or dampen the allergy-associated processes that cause asthma.
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