Download Asthma and immune dysregulation: A tale of antibodies “gone bad”

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For adequate preparation, read all case material including the following reference available
online. (Problem answers will be synthesized during case discussion.)
Review: Ahrshad, S.H., and Holgate, S. 2001. The role of IgE in allergen-induced
inflammationand the potential for intervention with a humanized monoclonal
anti-IgE antibody. Clinical and Experimental Allergy 31:1344-1351.
Lectures: Imm-8, Imm-13
Reactive airway disease (RAD or “asthma”) results from reversible airway obstruction, which
can be triggered by a variety of mechanisms. Although bronchial constriction can be
induced by exposure to cold air, by viral or Mycoplasma infections, or by local irritants such
as sulfur dioxide, more than 70% of asthma patients have either a family history or a
personal history of other allergic symptoms such as hay fever. Evidence that “allergic
asthma” is the result of an abnormal immune response comes from its demonstrable
antigen-specificity and from the presence of unusually high levels of IgE antibodies in many
affected individuals. There is good evidence that the initial step in allergic asthma is often
the generation of allergen-specific IgE antibodies. Because allergy tends to cluster in
families, it has long been thought that susceptibility to developing this type of antibody
response is genetically controlled.
Problem A
1. Describe the mechanism for generating an antibody response skewed toward IgE
production. Consider site of antigen presentation, cellular interactions, and the cytokines
responsible for these responses.
2. Outline mechanisms that might prevent or reverse this skewing.
Initially, therapy for asthma was directed primarily at inhibiting the activity of proinflammatory
and vasoconstrictive mediators released by IgE immune complex binding to IgE Fc
receptors on tissue granulocytes, particularly mast cells.
Medical Microbiology 2004-2005
Case: Asthma Page 2
Problem B
1. Review the process by which antigen-specific IgE antibodies can induce “immediate
hypersensitivity reactions” after exposure to their cognate antigen. What are the
mediators involved?
2. Describe how this response results in airway constriction.
For many years, therapy was restricted to use of “bronchodilators” such as beta-adrenergic
agonists or phosphodiesterase inhibitors, which both increase cAMP levels in airway
smooth muscle cells causing relaxation. Later, anticholinergic agents were introduced.
These agents enhance or maintain relaxation of smooth muscle cells when used in
conjunction with bronchodilators. Even more recently, inhibitors of leukotriene production or
signaling have been shown to be effective in reducing the frequency of acute exacerbations
in a significant minority of individuals. Such agents are still extremely useful as chronic
maintenance therapy or, in the case of bronchodilators, to treat acute exacerbations of
disease. However, understanding the importance of the immune response in pathogenesis
has led to more reliance on agents with the potential to suppress the underlying abnormal
immune responses and inflammation, such as glucocorticoids.
Problem C
1. Describe how glucocorticoids reverse or suppress inflammation.
2. Describe the potential complications of high-dose glucocorticoid therapy.
Medical Microbiology 2004-2005
Case: Asthma Page 3
Monoclonal antibodies specific for IgE have been proposed as adjunct treatment for severe
(high-dose steroid-dependent) asthma. These targeted therapies are proposed as “steroidsparing” agents that might decrease the adverse immunological and endocrinological effects
of long-term steroid use. High circulating levels of allergen-specific IgE are present in a
significant fraction of severe asthmatics. In addition, stable complexes of surface IgE with its
receptor can persist for periods of weeks on mast cells in vivo, allowing triggering of mast
cell degranulation after cross-linking through binding of specific antigens.
Although some anti-IgE antibodies can also cause mast cell degranulation and mediator
release through cross-linking of surface IgE/IgE receptor complexes on mast cells,
antibodies specific for the IgE receptor binding site (non-activating antibodies) are capable
of both blocking binding of IgE .to its receptor(s) and clearing IgE by an IgG Fc receptormediated mechanism. Published data from clinical trials suggests that either subcutaneous
or intravenous non-activating anti-IgE can reduce circulating IgE levels as well as decrease
surface expression of IgE receptors on mast cells. These changes are associated with
reductions in steroid dose, decreases in acute exacerbations, and improvement in airflow in
a substantial minority of individuals with severe asthma. In contrast, administration of
inhaled non-activating anti-IgE had no effect on either circulating levels of IgE or clinical
disease.
Problem D
1. What problems would you anticipate from prolonged or chronic intermittent exposure
to non-activating anti-IgE antibodies?
2. Why is local administration via inhalation ineffective?
3. Based on what you have learned about the control of isotype switching, what other
strategies might you propose for decreasing IgE levels?
4. Would you expect carriers of intestinal parasites, with high circulating IgE levels, to
be more or less susceptible to the development of allergic asthma?
5. Treatment with “benign” intestinal parasites to induce a Th2-type immune response is
being studied in controlled trials for the treatment or prevention of autoimmune
disease. Would you expect this therapy to produce changes in serum IgE levels?
Would you expect that this treatment would increase or decrease symptoms of
allergic disease in affected individuals?
For those who want a detailed review of the mechanisms in this disease, please see the
following excellent review:
Oettgen, H.C., and Geha, R.S. 1999. IgE in asthma and atopy: cellular and molecular
connections. The Journal of Clinical Investigation 104:829-835.