Inflammation is the major factor in the development and perpetuation of asthma. It is not precisely known how asthma is initiated in any given patient, but in a subset of asthma patients, known as atopic asthmatics, specific allergens are thought to participate in the generation of inflammation through the triggering of pulmonary mast cells (MC) (and possibly other Fc epsilon RI-expressing effector cells) in a type I (IgE-mediated) immediate allergic response. In other patients, known as non-atopic asthmatics, no clear allergen can be defined, leaving the mechanisms which initiate and/or sustain inflammation in these patients even less well understood. Our preliminary data demonstrate that a subset of non-atopic asthmatic patients have anti-FcepsilonRIalpha autoantibodies (autoAb) and that these autoAb can activate effector cells through Fc?RI, suggesting that these autoAb might be contributing to the asthma disease process in these, and possibly other, patients. This project will investigate the prevalence and pathogenic potential of anti- FcepsilonRIalpha autoantibodies:
Aim1 will assess the prevalence and titers of such autoAb in both atopic and non-atopic asthma patients and attempt to define qualitatively the characteristics of these autoAb.
Aim 2 will investigate in-vitro the pathogenic potential of these autoAb by assessing their ability to degranulate various types of mast cells and, in collaboration with project 2, whether they are able to exert a regulatory effect on FcepsilonRI surface expression.
Aim 3 will investigate the in-vivo pathogenic potential of the autoAb by assessing the effects of each autoAb using a novel """"""""humanized"""""""" mouse strain. Together, the data from these three aims will provide a detailed picture of how anti-FcepsilonRIalpha autoAbs relate to the asthma disease process by allowing the relative titer, in-vitro characteristics, and in-vivo effects of each autoAb to be correlated with a patient's disease characteristics and phase (active or inactive) of disease.
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