Immunology and Serology (dVT2153)

Universiti Malaysia Kelantan

Faculty oF veterinary medicine

HYPERSENSITIVITY

Lecture by: Dr. Erkihun Aklilu

16 April 2012
 FOUR TYPES OF HYPERSENSITIVITY
REACTIONS

 Type I: Immediate Hypersensitivity. Anaphylactic

reactions mediated by IgE antibodies binding to
mast cells

 Type II: Antibody-Dependent Cellular Cytotoxicity

 Type III: Immune complex reactions

 Type IV: Cell-mediated immunity (DTH- delayed

type hypersensitivity)
HYPERSENSITIVITY REACTIONS
 HYPERSENSITIVITY TERMS

 Atopic individuals are genetically predisposed to

respond to certain antigens with an IgE, Th2
response.
 Elevated levels of serum IgE, and eosinophils

 ADCC: Antibody Dependent Cellular Cytotoxicity

 Anaphylaxis: a severe allergic reaction to

systemically administered antigen that causes
circulatory collapse due to tracheal swelling.
 HYPERSENSITIVITY TYPE I
 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

 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
Mediators involved in type I hypersensitivity reactions
Physiological Effects of Mast cell Degranulation
TYPE I HYPERSENSITIVITY IN HOST DEFENSE
IN THE AFFERENT IMMUNE RESPONSE

 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
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 antibody-dependent 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
Common allergens associated with
type I hypersensitivity
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
 HYPERSENSITIVITY I
 Clinical Examples
• Allergic rhinitis (hay fever)
• Allergic Asthma
• Urticaria (hives)
• Eczema (itchy rash)
• Systemic anaphylaxis

 Clinical Diagnosis
 Skin testing: Intradermal injection of allergen
 “Wheal and Flare” reaction
 Erythema: Vascular dilation
 Edema: Vascular permeability
 Symptoms manifest in 10-15 minutes
 Wheal: edema (fluid in tissue)
 Flare: erythema (redness)
 Positive Test indicates presence of allergen-specific IgE on
mast cells in tissues
HYPERSENSITIVITY TYPE I
 HYPERSENSITIVITY TYPE I

A n a p h y la c tic r e sp o n se to b e e stin g
 HYPERSENSITIVITY TYPE I

Diffuse urticaria
 CLINICAL INTERVENTION
 Allergen Avoidance

 Allergen-specific Immunotherapy (Hyposensitization):

 Administration of very low doses of allergen over months to induce “blocking”
IgG (e.g. “allergy shots” for grass allergies) and possibly regulatory T cells

 Desensitization: Administration of very low doses of allergen

every
 10-15 minutes to slowly trigger all mast cells via IgE (e.g., desensitization to
penicillin is done in ICU)

 Mast cell Stablization: drugs that block degranulation of

mast cells and basophils (sodium cromoglycate)

 Mediator antagonists: antihistamines, epinephrine

 Immunosuppressants: corticosteroids - work by blocking

arachadonic acid pathway for synthesis of leukotrienes

 Anti-IgE Monoclonal Antibodies: Omalizumab binds Fc

portion of IgE to block IgE from binding to Fcε receptor.
Mechanisms of actions of some drugs used to treat
hypersensitivity type I diseases
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
 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

 Affinityof antigens for specific tissues may

direct IC to particular sites
 CLINICAL EXAMPLES
 Transfusion reactions : pre-formed natural anti-ABO,
anti-Rh and other anti-RBC Abs

 Autoimmune hemolytic anemia : autoimmune

response against RBC generally after an infection

 Erythroblastosis fetalis : Rh incompatability induces

anti-Rh antibodies in mother-IgG crosses placenta in
subsequent child
HYPERSENSITIVITY TYPE II
 CLINICAL EXAMPLES

 Goodpasture’s syndrome : antibody binds directly to

basement membrane (smooth deposit of Ab seen by
immunofluorescence)- causes pulmonary hemmorhage
and glomerulonephritis-sometimes also misclassified
as Type III Hypersensitivity

 Rheumatic fever: Ab to Streptococcus damages heart

and kidney
 CLINICAL EXAMPLES

 Drug-induced reaction: drug binds to cells, anti-drug

Abs damage cells

 Anti-receptor autoimmune diseases: myasthenia

gravis, Graves’ disease

 Hyperacute graft rejection: preformed Abs to

transplantation antigens cause immediate, severe
and non-reversible damage to graft
 TYPE III HYPERSENSITIVITY
(IMMUNE COMPLEX)

 Immune Mechanism:

 Abs combine with soluble Ag to make insoluble

complexes, which deposit on blood vessel walls

 Ag-Ab complexes activate complement, fragments of

which are chemoattractants and anaphylatoxins

 PMNs release lysosomal enzymes and damage the

vessel and adjacent tissue
 CLINICAL EXAMPLES OF TYPE III
HYPERSENSITIVITY
 Serum Sickness: Formation of immune complexes due to Ab
response to passive immunotherapy with foreign protein.

 Rheumatoid Arthritis: Rheumatoid Factor (IgM specific for IgG

Fc)

 Infectious Diseases: malaria, persistent viral infections, leprosy

 Occupational Diseases: Ab to soluble environmental antigen(e.g.

Farmer’s lung-- reaction due to spores in moldy hay--
pneumonitis)

 Arthus Reaction: repeated injection of antigen, local formation

of immune complexes in tissue next to blood vessel, FcγR on
tissue mast cells binds to immune complex and degranulates
causing inflammatory cells to be attracted to site. Vessel
occlusion and/or rupture may occur.
THE VARIANTS OF TYPE IV
(DELAYED) HYPERSENSITIVITY
 Contact
 Eczematous reaction at the point of contact with allergen, usually
hapten, occurs within 72 hours of antigen challenge

 Tuberculin
 An area of red firm swelling of the skin, 48-72 hrs after injection

 Granulomatous
 Formation of granuloma at 21-28 days following antigen exposure
 Intracellular pathogens that induce
delayed type hypersensitivity (IV)
 Intracellular bacteria  Intracellular viruses
 Mycobacterium tuberculosis  Herpes simplex
 Mycobacterium leprae  Measles virus
 Listeria monocytogenes  Variola (smallpox)
 Brucella abortus
 Contact Antigens
 Intracellular fungi  Picrylchloride
 Pneumocystis carinii  Hair dyes
 Candidia albicans  Nickel salts
 Cryptococcus neoformans  Poison ivy
 Histoplasma capsulatum  Poison oak

 Intracellular parasites
 Leishmania spp
DISEASES WITH TYPE IV GRANULOMATOUS
HYPERSENSITIVITY

 Chronic pulmonary tuberculosis

 Borderline leprosy

 Sarcoidosis

 Crohn’s disease

 Schistosomiasis

 Some fungal diseases