AsthMatic Inflammation and Neurocircuitry Activation (MINA)
Condition: Allergic Asthma
MeSH terms: Inflammation
Study type: Observational

Summary: 
      The investigators have identified areas of the brain that are activated in response to
      disease-related emotional information, following whole lung allergen challenge in asthma.
      They propose that activity in these central nervous system locations, as measured by fMRI, is
      associated with the intensity of allergic inflammation, provoked by segmental bronchial
      challenge, in the absence of significant airflow obstruction. The investigators predict that
      this relationship will be mediated by changes in expression of genes in the IL-1β/IL-17
      pathway.
    

Detailed description: 
      Asthma is characterized by airway inflammation, bronchial hyperresponsiveness and airflow
      obstruction. The development of symptoms in patients with asthma is initiated by exposure to
      a variety of airborne substances including aeroallergens. The inhalation of these allergens
      by asthmatic subjects initiates a series of complex, interactive immune events through
      activation of cell bound IgE, which serve to further existing airway inflammation, intensify
      underlying airway hyperresponsiveness and cause airflow obstruction. Although the immune
      events and processes associated with these reactions are largely localized to the airways
      themselves, a variety of other factors can contribute to the ongoing allergic response in
      either an enhancing or inhibitory manner. The regulation and modulation of these inflammatory
      actions is a key determinant to the eventual severity of asthma.

      The initial step in the activation of the allergic airway response is the ability of inhaled
      allergen to activate IgE molecules on the pulmonary mast cell to release stored mediators and
      generate synthesis of new products, which can acutely contract airway smooth muscle. The mast
      cell also is capable of generating a variety of cytokines, which, in turn, can cause
      persistence and progression of the allergic response by furthering the underlying
      inflammation. In addition to mast cell activation, inhaled allergens are capable of
      stimulating resident lymphocytes in the lung. It is proposed that these allergen-responsive
      lymphocytes belong to a subpopulation of T helper cells (Th2), which are capable of
      generating a variety of cytokines, i.e. interleukin (IL)-4, IL-5, and IL-13. These Th2
      cytokines can activate the local inflammatory response and can also serve to initiate events
      outside the lung, which can then further promote the persistence of the allergic inflammatory
      response.

      To illustrate the means by which newly generated lung mediators can affect allergic
      inflammation, investigators have shown that inhaled allergen is associated with enhanced bone
      marrow generation of eosinophils. This enhanced bone marrow production of eosinophils is
      associated with bone marrow cell generation of IL-5, which causes terminal differentiation of
      eosinophils and their release into the circulation. Presumably, these recently generated
      eosinophils enter the circulation and are recruited to the lung where they may further the
      development of eosinophilic inflammation and the severity of asthma.

      Other factors also influence the development and intensity of the allergic inflammatory
      response to inhaled allergen. In preliminary studies, the investigators have found that the
      stress associated with the final examination period in college students will enhance the
      eosinophilic inflammatory response to inhaled allergen. In addition, the investigators have
      found that during the final examination period, and independent of an allergen challenge,
      circulating eosinophils increase. Moreover, Marin and colleagues (2009) studied children with
      asthma over a two-year period and found that mononuclear cells from children who reported
      persistent life stress coupled with an acute stressful event produced elevated levels of
      asthma-promoting cytokines compared to asthmatic children without chronic stress or healthy
      controls. These findings suggest that the persistent stress associated with an acute stressor
      may promote allergic inflammatory events and that these processes include regulation of
      eosinophil numbers and recruitment to the lung.

      From these studies, the investigators have evidence to suggest that stress-related events can
      influence allergic inflammation and, presumably, that these peripheral responses are
      regulated by central nervous system (CNS) events. Although stress-related events can modulate
      inflammatory processes, the mechanisms and CNS-site of this activity are poorly understood.
      It is proposed that areas of the brain are activated by stress and that these areas of
      activation may represent sites in the CNS that integrate information concerning the internal
      state of the body and signal the generation of modulating factors in the enhancement or
      inhibition of the allergic airway inflammation. To visualize these potential sites of CNS
      activation in asthma, it is possible to use neuroimaging techniques, such as positron
      emission tomography (PET) or functional magnetic resonance imaging (fMRI). The investigators
      have completed two prior studies that used fMRI to evaluate the central mechanisms associated
      with allergic inflammation, and in both studies, the anterior insula was identified as a
      region activated by asthma-related emotional cues that predicted the subsequent development
      of airway inflammation (e.g. Rosenkranz, M et al (2005) Proceedings of the National Academy
      of Science 102, 13319-13324.). In addition, the investigators have completed a study using
      PET to evaluate the neural mechanisms through which stress along contributes to
      asthma-related inflammation in individuals with high and low levels of chronic stress. This
      study corroborated our findings using fMRI, showing involvement of the insula, and also
      revealed new mechanisms involving IL-1β/IL-17 as a potential pathway linking through which
      stress-reactivity primes airway inflammation.

      In the research described here, these two experimental paradigms will be merged to 1)
      determine the contribution of the IL-1β/IL-17 pathway in response of emotion neural circuitry
      provoked by airway inflammation in the absence of bronchoconstriction and 2) to determine the
      neural mechanisms and impact of acute stress on the airway inflammatory response to whole
      lung allergen challenge.
    

Intervention name(s): Whole lung antigen challenge, segmental allergen challenge
Intervention type(s): Biological
Intervention description(s): Whole lung antigen challenge with housedust mite, short ragweed or cat hair allergen extracts. Segmental allergen challenge with housedust mite, short ragweed or cat hair allergen extracts.
Other intervention name(s): House dust mite, short ragweed, cat hair allergen extracts
Observational model: Other
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Participants with mild allergic asthma and across the full range of chronic stress levels
        will be recruited for study. Investigators will ensure this population includes
        participants in the top and bottom 10th percentiles of chronic stress.