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Lecture 9
HYPERSENSITIVITY
Jan Żeromski
POINTS TO BE DISCUSSED
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Definition of hypersensitivity
Four types of hypersensitivity
Type I – anaphylactic
Type II – cytotoxic
Type III – immune complex mediated
Type IV – contact, tuberculin and
granulomatous
HYPERSENSITIVITY TYPE I –
KEY POINTS
• IgE antibody response directed against
innocuous environmental Ag’s such as animal
dander, house-dust mites, pollen, industrial
pollutants, etc.
• IgE becomes coated on mast cells or
basophiles via their Fc receptors
HYPERSENSITIVITY TYPE I –
KEY POINTS - 2
• Binding of allergen by IgE results in
degranulation of mast cells and mediator
release
• Allergic manifestations ensue such as hay
fever, asthma, skin eczema, anaphylaxis
TYPE I HYPERSENSITIVITY
IN HOST DEFENSE IN THE
AFFERENT IMMUNE RESPONSE
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IgE-mediated allergen capture
IgE-mediated allergen processing
IgE-mediated allergen presentation
Immune deviation toward Th2
responses via release of key cytokines
via innate immune responses
EXAMPLES AND SYMBOLS OF PURIFIED
ALLERGENS
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Betula verrucosa (birch) Corylus avellana (hazel) Felis domesticus (cat)
Rattus norvegicus (rat)
Cavia porcellus (guinea pig) –
Equus caballus (horse)
Gallus domesticus (hen)
Apis mellifera (honey-bee) Arachis hypogea (nuts)
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Bet v 1
Cor a 1
Fel d 1
Rat n 1, n 2
Cav p 1
Equ c 1
Gal d 1
Api m 1
Ara h 1
TYPE I HYPERSENSITIVITY IN HOST
DEFENSE IN THE EFFERENT IMMUNE
RESPONSE
• Induction of mast cells and basophil
early phase by innate immunity
(complement, defensins)
• Induction of mast cells and basophile
early phase by IgE antibody
TYPE I HYPERSENSITIVITY IN HOST
DEFENSE IN THE EFFERENT IMMUNE
RESPONSE
• Induction of IgE-mediated antibodydependent cellular cytotoxicity (ADCC)
and release of inflammatory molecules
from macrophages, eosinophils and
neutrophils
• Induction of Th2 CD4+ cells with their
direct and indirect participation in the
host response
TWO TYPES OF MAST CELLS IN MAN
• MCT tryptase positive
• Equivalent of mucosal
mast cells in rodents
• Produce preferentially
IL-5 and Il-6
• Sodium cromoglycane
(Intal) sensitive
• MCTC tryptase and
chymase positive
• Equivalent of connective
tissue MC
• Produce preferentially
IL-4
• Sodium cromoglycane
insensitive
• Functionally more mature
than MCT
FACTORS REGULATING THE LEVEL
OF TYPE I HYPERSENSITIVITY
1. Genetic linkage controlling total IgE level
2. HLA-D encoded genes for allergen-specific
response
3. Allergen-driven Th2 predominance
4. Effects of environmental exposures
5. Individual sensitivity to inflammatory
mediators
ASTHMA PATHOGENESIS
• It is a chronic inflammatory disorder of
the airways: mucosal inflammation,
reversible airway obstruction, bronchial
hyperresponsiveness
• Bronchial epithelium, mast cells, Thelper cells and eosinophils are known
to drive this process
ASTHMA PATHOGENESIS
• It is consequence of dysregulation of
selective cytokine networks in the
airways due to Th2 cells
• Chronic mucosal inflammation, at least
in part, leads to „airway remodeling”.
ROLE OF MAST TRYPTASE IN
ASTHMA
Mast tryptase induces:
1. Bronchoconstriction and
hyperresponsiveness
2. Stimulation of proliferation of fibroblasts,
smooth muscle and epithelial cells
3. Generation of kinins
4. Stimulation of IL-8 release
5. Eosinophil chemotaxis
TYPE II HYPERSENSTIVITY
REACTIONS
• Are caused by IgG and IgM antibodies
directed against cell surface, extracellular
matrix and intracellular antigens. The latter
are usually non-pathogenic but diagnostically
useful
• Transfusion reactions to erythrocytes are due
to antibodies to blood group antigens
• The antibodies damage cells and tissues by
activating complement and by binding and
activating Fc receptor + effector cells
TYPE II HYPERSENSITIVITY –
EXAMPLES FROM PATHOLOGY
• Hyperacute graft rejection
• Hemolytic disease of the newborn (Rhesus D
incompatibility)
• Autoimmune hemolytic anemias
• Goodpasture’s syndrome
• Pemphigus
• Myasthenia gravis
• Lambert-Eaton syndrome
CHARACTERISTICS OF IMMUNE
COMPLEXES
1. Formed by the non-covalent union of
antigen and antibody
2. Can be formed in the circulation or in tissues
3. Removed from the circulation by the host’s
mononuclear phagocyte system
4. Can lodge in tissue, activate complement,
and produce tissue damage
5. Tend to be solubilized by complement
AGENTS IMPORTANT IN DEPOSITION AND
CLEARANCE OF IMMUNE COMPLEXES
• Complement deficiency impairs clearance
• The size of IC affects their deposition
• Immunoglobulin classes of IC affect the rate
of their clearance (IgG vs. IgA)
AGENTS IMPORTANT IN DEPOSITION AND
CLEARANCE OF IMMUNE COMPLEXES
• Phagocyte defects allow complexes to persist
• An increase in vascular permeability, high
blood pressure and local turbulence triggers
deposition
• Affinity of antigens for specific tissues may
direct IC to particular sites
THE VARIANTS OF TYPE IV
(DELAYED) HYPERSENSITIVITY
• Contact one – eczematous reaction at the point of
contact with allergen, usually hapten, occurs within
72 hours of antigen challenge
• Tuberculin one – an area of red firm swelling of the
skin, 48-72 hrs after injection
• Granulomatous one – formation of granuloma at 2128 days following antigen exposure
DISEASES WITH TYPE IV
GRANULOMATOUS
HYPERSENSITIVITY
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Chronic pulmonary tuberculosis
Borderline leprosy
Sarcoidosis
Crohn’s disease
Schistosomiasis
Some fungal diseases
THANK YOU!