Immunology of Asthma

Student Doc Martinez

AT Still University
School of Osteopathic Medicine in Arizona
Asthma: Asthma Triggers:
• Chronic, • Unknown
inflammatory – Spontaneous
disorder of the • Non-specific
airways giving rise – Exercise
to recurrent – Smoke
respiratory – Fumes
symptoms • Allergic
associated with – Inhaled allergens
widespread,
variable and
reversible
airflow
obstruction and
Allerg Infectio
Chemicals
y n

Airway
inflammation

Susceptible
airway

Bronchial Chronic
irratability changes

Wheeze and Fixed

bronchospa airway
sm obstruction
 Allergic asthma
• Occurs in previously sensitized
individuals
• Mechanism: IgE antibody bound to
mast cells (type 1 Hypersensitivity Reaction)
– 50-70% of all cases of asthma
• Antigens “allergens” are airborne
(Extrinsic Asthma)
• Re-exposure to antigen can produce
immediate response and a late
reaction
Allergic Asthma: Infections and
• Starts in childhood Asthma:
or teen years • Early respiratory
• Environmental viral infections
factors protect against
– Allergies allergy and asthma
– Housing design (rugs, development
bedding, humidity) – Leads to immune
– Air pollution (vehicles, deviation
ozone, diesel) • Stimulation of TH1
– Diet (new foods, food response
processing) • Once established,
– Infections viral infections
trigger asthma
symptoms
– Exacerbate airway
 Hygiene Hypothesis
• Increased incidence of asthma in
developed countries
• Immune system of newborn biased to a
TH2 response – needs stimuli to create
balance
• Factors enhancing TH1 response
include:
– Viral infections (measles, mumps, hepatitis)
– M. tuberculosis infection
– Older siblings and early day care
– Rural environment
• Atopy: exaggerated
tendency to form IgE
to a variety of
environmental
antigens
– Total IgE elevated;
eosinophilia; hay
fever
– Strong familial basis
• Several genes
implicated
• Environmental
variation
– Atopic individuals
often present with:
• Eczema (dermatitis or
imflamation of
Immune Response
Systemic Genes
Genes
• IL-4 and IL-4 receptor • ADAM 33
– Promote TH2 response
– Metalloproteinase
– Enhance isotype switch to
IgE expressed on:
• IgE receptor β chain • Bronchial smooth
muscle cells
– Increases affinity of FcεRI on
mast cells • Lung fibroblasts
• MHC class II genes – Variation in airway
– Alters HLA molecule remodeling
presentation of antigen to
CD4 + T cells • β2-adrenergic
• TCR α gene receptor
– Provides TCR specificity – Smooth muscle
• TIM gene family responses to mediators
– T cell, immunoglobulin
domain, mucin domain • 5-lipoxygenase
– Regulation of TH1:TH2 – Leukotriene production
balance
• Code for T cell surface
receptors
• Codes for subunit of IL-12
– Promotes TH1 responses
Mechanism of sensitization in allergic asthma

• Targets for
Intervention:
– CD4 T cells must develop
TH2 phenotype

– B cells must switch to IgE

isotype
• What causes this switch:
– Genetics and age of the
individual

– Low IL-12 and high IL-4

– Presence of IL-13

– Environment of respiratory
track

– IgE must bind mast cells

 Isotype Switching
• Presence of IL-4 will activate the
enzymes responsible for switching
the constant region of the
immunoglobulin gene from μ and δ to
ε
• Once formed, IgE
antibodies bind to a
high affinity Fc receptor
on mast cells.
•

• The IgE molecules

found on any mast cell
can represent a variety
of specificities (i.e. they
are not all the same).
•

• Allergen must cross

link two IgE molecules,
both of which are
specific for the epitopes
on the allergen, to
 Mast Cell Mediators
• Histamine
• Tryptase
• Chymase
• Proteoglycans
• Arachidonic acid
metabolites
– Prostaglandins
– Leukotrienes
• Cytokines
– IL-1,2,3,4,5
– GM-CSF
– IFN-γ
– TNF-α
 Early Asthmatic Response
• Occurs 10 to 15 minutes post-
inhalation
• Degranulation of mast cells
– Constriction of bronchial smooth
muscles
– Histamine and leukotrienes in airways
– Prostaglandins involved
• Peaks 30 to 60 minutes post-
inhalation
 Late Asthmatic Response
• Starts 3 to 4 hours
after initial challenge
• Occurs in about 50%
of patients
• Lasts for 6 to 24
hours
• Endothelial
adhesion
molecules
expressed
– Neutrophils,
eosinophils and T
cells migrate
– Edema develops;
 Therapy
• Goal: long-term suppression of
airway inflammation
– Inhaled corticosteroids
– Aerosolized beta-agonists
(bronchodilators)
– Long-acting beta agonists
– Theophylline
– Leukotriene antagonists
– Anti-histamines
 Immunotherapy
• Desensitization – injection with
increasing doses of responsible
allergen
– Induces immune deviation (TH1 or IgG
response)
• Peptide vaccination
– Induces T cell anergy (decreased
cytokine levels)
• Anti-IgE monoclonal antibody
(omalizumab)