Genetics of the Early and Late Response to Allergen Challenge
Condition: Asthma; Allergic Rhinitis
MeSH terms: Rhinitis; Rhinitis, Allergic
Study type: Observational

Summary: 
      The investigators are investigating the early and late responses to allergen challenge. The
      research participants who the investigators will study (from three cohorts) will be part of
      independently-approved studies involving allergen challenge. Due to the uniqueness of the
      cohorts for novel genetic study, it is logical that the investigators should initially
      undertake hypothesis-generating experiments. The investigators will obtain blood samples from
      the participants, both pre-challenge and post-challenge. The investigators will determine
      gene expression and protein differences between these samples, and investigate if there are
      inherited genetic differences between individuals that may predict their specific responses
      to allergens.
    

Detailed description: 
      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.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Asthmatic and/or allergic rhinitis ('hay fever') individuals, 19 years or older
      
Biospecimen description: 
      Whole blood, plasma, white cells
    
Keywords: allergen challenge; blood draw; gene expression analysis; protein analysis; genetics