Genetics of the Early and Late Response to Allergen Challenge

Asthmatic and/or allergic rhinitis ('hay fever') individuals respond differently, but reproducibly, to allergen challenge. Some individuals develop an isolated early response while others also go on to develop a late response. In asthmatic individuals, airway narrowing represents the early phase of the asthmatic response to airway challenge; early phase onset can be detected within ten minutes of allergen inhalation, reaches a maximum within thirty minutes, and typically resolves within three hours. In 50-60% of allergic asthmatic adults, the early response is followed by the late phase asthmatic response, which usually starts between three and four hours after allergen inhalation challenge, and is characterized by cellular inflammation of the airway, increased lung tissue permeability, and mucus secretion. Thus, approximately half of allergic asthmatic subjects are 'dual responders' (developing both an early- and late-phase response following allergen inhalation challenge), 30-40% of allergic asthmatic adults develop an 'isolated early response', and \<10% adults show an 'isolated late response'. In any given individual, the pattern of response is generally consistent. In allergic rhinitis individuals challenged by environmental exposure to pollen, equivalent differences exist in the proportions of subjects undergoing isolated early or dual phase nasal responses, with these responses measured by clinical end-points such as common symptoms of allergic rhinitis ('hay fever'). The role that inherited genetic variation might play in these differential early and late responses has so far been unexplored. However, recent experimental data in mouse models provide strong evidence that genetics could play an important role. When a specific intracellular pathway is disrupted by specific mouse gene-knockouts, this leads to the inhibition of a late response to allergen challenge, whilst maintaining the early response. The pathway is known as the Bcl10/Malt1 pathway, and it normally responds to allergen exposure by activating the expression of genes that code for pro-inflammatory proteins. The uncoupling of the late response from the early response suggests a possibility that genetic variation in genes involved in the human Bcl10/Malt1 pathway may influence the nature of the allergic response in humans. We will investigate whether there is a genetic basis for why some individuals develop an isolated early-phase response after allergen challenge whilst other individuals develop early- and late-phase responses (dual response). We will recruit human allergic subjects undergoing experimentally-controlled allergen challenges. The specific airway responses of these individuals will be carefully and precisely measured, and blood samples will be collected just prior to, and two hours after, the allergen challenge. Due to the uniqueness of our cohorts for novel genetic study, it is logical that we should initially undertake hypothesis-generating experiments. Such experiments will involve the determination of differential changes in genome-wide gene expression in white blood cells and changes in the protein and lipid composition of the blood plasma, post-challenge compared to pre-challenge. We will then formulate and test hypotheses based on the results from these initial studies, as well as the specific following hypothesis: inherited genetic variation within the Bcl10/Malt1 pathway influence the early- and late-phase allergic response to allergen challenge. Despite tremendous interest, the differences between the pathways leading to the dual response and those leading to the isolated early response are not completely understood. Understanding these differences is important for evaluating allergic diseases such as asthma and allergic rhinitis. In contrast to the more transient isolated early response, development of the late response is associated with the hallmark inflammatory features of chronic allergic disease. The combined cohorts represent a unique resource for the study of a fundamental physiologic response in allergy, and will provide genetic insight into new pathways for pharmacologic targeting in the treatment of chronic asthma and allergic rhinitis.