HYPERSENSITIVITY REACTIONS:

Classification and mechanism

of induction

Dr.D.RATHNAMMA
Professor and Head
Dept. of Veterinary Microbiology, Veterinary
College, KVAFSU, Hebbal, Bengaluru-560 024
• Generally immune system (I.S) reacts to any foreign
substances by inducing I.R , some times I.S over
reacts to antigens causing an extensive damage to
the host tissues, and death occasionally, this
inappropriate I.R is termed as hypersensitivity
reactions.

• Hypersensitivity reactions(HSR) are harmful antigen-

specific immune responses, occur when an
individual who has been primed by an antigen
subsequently encounters the same antigen , produce
tissue injury and dysfunction.
Two French scientists, Charles Richet and Paul
Portier , were the first to recognize and describe
hypersensitivities.

• Richet coined the term “anaphylaxis ,” derived from the

Greek meaning “against protection”.

• Observed skin rashes in people taking bath in Mediterranean

sea, bitten by Jelly fish and extracted the proteins from jelly
fish.

• Administered to the dogs but on subsequent administration

of protein, they developed diarrhea, vomition, even death.

• They over reacted to the antigen instead of protecting (HSR).

• Richet was subsequently awarded the Nobel Prize in Physiology or

Medicine in 1913.
Classification of Hypersensitivity reactions(HSR)
• Two immunologists, P. G. H. Gell and R. R. A.
Coombs, classified HSR into four major types.
• Type I HSR : mediated by IgE antibodies, and
include many of the most common allergies to
respiratory allergens, such as pollen and dust
mites.
• Type II HSR: mediated by IgG or IgM, bind to the
surface of host cells, which are then destroyed by
complement- or cell-mediated mechanisms.
• Type III HSR: immune complexes deposited in
host tissues, subsequently complement mediated
destruction.
• Type IV HSR: mediated by cells, delayed type,
due to inappropriate T cell activation, TDTH cells
 Type I Hypersensitivity reaction
• Immediate type, mediated by IgE antibody, IgE is also
referred as ‘reagen’ or reagenic antibody
• Type I HSR is also referred as Allergy or Anaphylaxis ,
due to the release of large amount of chemical
mediators produced by activated mast cells.
• IgE is produced in response to parasitic antigens in
normal individuals and allergens in atopic individuals.
• Helminths preferentially stimulate IgE response,
animals with tape worms show respiratory distress and
urticaria.
• IL-4 from mast cells and TH2 cells induces class
switching to IgE production
STAGES OF TYPE I HYPER SENSITIVITY

A. Sensitization phase :
• first exposure to the allergen,
• IgE antibodies produced and release in circulation
• Binding of these Abs on to mast cells (Fc receptor for
IgE)

B. Effector phase:
• when the animal encounters the same allergen second
time
• directly binds to the antibodies bound the mast cells
• causing degranulation and releasing vasoactive amines.
• effectors reactions
Mechanism of induction of Type I Hypersensitivity
reaction
 Mast cells
• Specialized connective tissue cells found throughout the body
especially more in skin, GIT & RT. They act as sentinels cells and
release inflammatory molecules immediately after encountering
invaders.
• Play a key role in allergic diseases and innate immunity.

• Have large granules (stain with toluidine blue) containing variety of

vasoactive amines and proinflammatory molecules.

• Have got Fc receptors for IgE. When IgE attached on to the mast cell
cross links with a specific antigen /allergen causes degranulation and
it is the central event in the development of allergic reactions.

• Mast cells play important roles in both antimicrobial and

antiparasite immunity.
 Mechanism of type I hypersensitivity
Primary Generation
Allergen Individual IgE
Adhesion

IgE binds to the FcεRI on mast cell and basophil

Secondary Allergen binds to the IgE on primed target cell
Cross linkage of FcεRI

Degranulation and release the biological mediators

Preformed granule mediators New generated mediators

Histamine Bradykinin Leukotrienes PAF Prostaglandins

Dilate capillaries,increase permeability, increase mucus secretion, contract smooth muscle

Systemic anaphylaxis Skin Respiratory tract Digestive tract

Categories of Type-I HSR
a) Systemic anaphylaxis is a shock like and often fatal
due to respiratory failure that occurs within minutes
of exposure to an allergen
– Symptoms include labored respiration, a precipitous drop
in blood pressure leading to anaphylactic shock , followed
by contraction of smooth muscles leading to defecation,
urination, and bronchiolar constriction.
b) Localized anaphylaxis
– Atopic allergies include a wide range of IgE-mediated
disorders, such as allergic rhinitis (hay fever), asthma, atopic
dermatitis (eczema)
– food allergies are characterized by vomition, diarrhea, atopic
urticaria( hives).
Diagnosis and therapy
• Type I hypersensitivity is
commonly assessed by skin testing.

 Corticosteroids, Epinephrine (most common drug), Isoprenaline

and Antihistamines have been the most useful drugs for the
treatment of allergies.
 Hyposensitization therapy: Administering gradually increasing
doses of allergens to an animal to reduce severity of subsequent
allergic disease is termed hypo-sensitization or allergen specific
immunotherapy. This promotes TH1 response, cytokines from TH1
cells reducing TH2 response regulating antibody production (IgG is
produced instead of IgE) , useful in hay fever, asthma, insect
allergies,
 Therapeutic anti-IgE antibodies: binds the Fc region of IgE and
interferes with IgE-FcR interactions
Allergic diseases in animals:
• Atopic dermatitis is a complex multifactorial syndrome,
characterized by chronically inflamed and itchy skin, chronic
skin disorder that occurs in many species but has been
studied mostly in dogs.
• Pulmonary infiltration with eosinophilia occurs most
frequently in dogs
• Allergic asthma occurs most frequently in cats.
• Allergic bronchitis is most common in cats. It is manifest by a
low-grade cough, wheezing, some dyspnea
• Chronic allergic bronchitis has been diagnosed in dogs, dry,
harsh, hacking cough.
• Eosinophilic enteritis, the most severe form of allergic
intestinal disease, manifested by moderate to severe
inflammation of the intestines and a pronounced eosinophilia.
Milk allergy in Jersey cattle:
• Jersey cow may become allergic to alpha
casein of their own milk
• If the animals are not milked regularly or
milking is delayed , resulting increased
intramammary pressure, milk proteins enter
the circulation -- mild discomfort with
urticarial skin lesions to acute anaphylaxis and
death sometimes.
Food allergies
• Healthy immune system is tolerant to foods and is
unresponsive to potential food allergens.
• Oral tolerance is a natural process by which ingested
antigens are sampled by DC, macrophages or M cells ,
presented to intestinal T cells, development of IL-10
producing Treg cells, other immunosuppressive molecules;
retinoic acid, IDO(Indoleamine-pyrrole dioxygenase) and
TGF-β suppresses immune response.
• If this tolerance breaks down, TH2 response triggered by
IL-33 (a key inducer of TH2 cytokines), IL-4, -5 and -13 are
produced, inducing IgE class switching in B cells.
• 2 % of food protein is absorbed from intestine and peptide
fragments are processed initiating immune response
• 30% of skin diseases in dogs are due to food allergies,skin
lesions are papular, erythematous involving feet, eyes, ears
 Type II Hypersensitivity reaction
• Mediated by IgG or IgM antibody
• Antibody bound to a cell-surface antigen can induce
death of the antibody-bound cell (3 mechanisms)
a. certain immunoglobulin subclasses can activate the
complement system, damage the cell by MAC.

b. ADCC, in which cytotoxic cells bearing Fc receptors bind to the

Fc region of antibodies on target cells and promote killing of the
cells.

c. Antibody bound to a foreign cell also can serve as an opsonin,

enabling phagocytic cells with Fc or C3b receptors to phagocytose
the antibody-coated cell.
Type II Hypersensitivity reaction………….

Eg: 1. Incompatible blood transfusions

2. Haemolytic disease of newborns in
animals
3. Drug induced haemolytic anemia
4. Erythroblastosis fetalis in humans
Incompatible blood transfusions

• If donor and recipient RBCs are not identical

• If recipient possess isohemagglutinins or natural ab or
pre existing ab of IgM or IgG type
• Ab binds to the RBC ag, activating the complement,
resulting lysis of RBCs
• massive intravascular hemolysis of the transfused red
blood cells
• Or RBCs are also destroyed by ADCC
• In the absence of pre existing ab, foreign RBC stimulate
ab response in the recipient during first transfusion,
second transfusion with same RBCs , RBCs are
destroyed by complement, rapid destruction of RBCs
 Haemolytic disease of newborns in animals

• If the blood groups of mother and fetus are

different, mother may become sensitized to fetal
RBCs that are leaked into circulation during
pregnancy
• IgG antibodies are produced against fetal RBCs
• IgG get concentrated in colostrum and milk
• Newborns fed with colostrum, IgG enter the
circulation , bind to the RBCs
• Complement mediated destruction of RBCs
leading to anaemia
 Erythroblastosis fetalis in humans
• Severe hemolytic disease of the newborn, called erythroblastosis
fetalis, develops when maternal IgG antibodies specific for fetal
blood-group antigens(Rh) cross the placenta and destroy fetal
RBCs, most commonly develops when the Rh- (Rh negative)
mother carries Rh+ fetus.
• At the time of delivery, fetal umbilical cord blood enters the
mother’s circulation. These fetal RBCs stimulate production of Rh
specific antibodies in mother.
• IgM antibody clears the Rh+ fetal RBCs from the mother’s
circulation, but memory cells remain, a threat to any subsequent
pregnancy with an Rh+ fetus.
• Activation of IgG-secreting memory cells in subsequent
pregnancy results in the formation of IgG anti-Rh antibodies,
which, however, can cross the placenta and damage the fetal
RBCs. Mild to severe anemia can develop in the fetus, sometimes
fatal
Destruction of Rh positive red blood cells during erythroblastosis fetalis of the newborn.
Development of erythroblastosis fetalis (hemolytic disease of the newborn) is caused
when an Rh- mother carries an Rh+ fetus (left). The effect of treatment of mother with
anti-Rh antibody, or Rhogam, (right).
Drug induced haemolytic anemia
• Certain antibiotics (e.g., penicillin, cephalosporins
and streptomycin), as well as other well-known
drugs (ibuprofen, quinine, L-DOPA) bind to
proteins on the membrane of RBCs, RBCs are
modified and recognized as foreign,
• drug-protein complexes induce formation of
antibodies against RBCs
• Complement mediated destruction of RBCs
resulting haemolytic anemia
• When the drug is withdrawn, the hemolytic
anemia disappears.
Bovine Neonatal Pancytopenia
• In 2007, a dramatic hemorrhagic disease affecting calves
appeared in Europe; due to the use of a bovine viral
diarrhea vaccine.

• The vaccine virus was grown in bovine kidney cells. As a

result, it stimulated antibody formation in some
vaccinated cows directed against the cell’s MHC molecules.

• These antibodies concentrated in colostrum. When their

calves fed, the ingested antibodies destroy the calf’s bone
marrow stem cells and resulted in a massive and lethal
pancytopenia.
 Type III Hypersensitivity reaction
• Immune complex mediated, IgM and IgG
antibodies are involved
• When large amount of immune complexes are
generated, get deposited in the tissues,
activate complement and other inflammatory
mediators leading to tissue damage
• Two major types;
Localized (Arthus reaction)
Generalized (Serum sickness)
Arthus reaction
• If an antigen is injected S/c
into an animal already having specific
antibodies, acute inflammation develops
at the site.
• Ag+ Ab complex activates complement,
generating C3a, C5a which attract more
neutrophils and macrophages.
• Secrete proinflammatory chemokines
and cytokines, prostaglandins, and
proteases. Proteases digest the basement
membrane proteins collagen, elastin, and cartilage.
Tissue damage is further mediated by oxygen free radicals
released by the activated neutrophils
Classical Arthus reaction is frequently observed when antigens
are administered to hyper immunized animals.
In animals, Type III HSR are also observed in other
tissues.
• Blue eye in dogs: a condition observed in some
dogs either infected (recovery stage of infectious
canine hepatitis) or vaccinated with live canine
adenovirus type I, anterior uveitis, corneal
opacity and oedema.
• Cornea is infiltrated by neutrophils damaging
coneal epi.cells
• Virus+Ab complexes are detected in the lesion
• Resolves once virus+Ab complexes are eliminated
Hypersensitivity pneumonitis in cattle:
• Cattle fed with moldy hay containing spores
frequently, antibodies are produced, Ag+Ab
complexes in lungs resulting pneumonitis.
• Hypersensitivity pneumonitis also seen in
other conditions also;
• Hay sickness in horses: moldy hay
• Farmer’s lung: inhalation of moldy hay
• Pigeon breeder’s lung: dried pigeon feces
• Mushroom growers disease: spores from
actinomycetes in the soil
• Serum sickness is an example of a systemic
form of immune complex disease, which
resulted in arthritis, skin rash, and fever.
• Individual who receive large doses of horse
antibodies or monoclonal antibodies
• Immune complexes get localized in tissues
• Generalized vasculitis, erythema, oedema,
urticaria of skin, neutropenia, Lymph node
enlargement, joint swelling and proteinuria
 Soluble antigen Body Antibody

Immune complex

Small molecular soluble intermediate molecular soluble Large molecular insoluble

Immune complex Immune complex Immune complex

Deposit on the basement of capillaries Eliminate by phogacytosis

Combine and activate complement system

Basophils and mast cells C3a,C5a,C3b Platelets

Infiltration of neutrophils
Blood Clotting Mechanisms
Release of vasoactive amine Phagocytose complex Release of vasoactive amine
Aggregation of platlets

Increase vascular permeability Release the enzymes in lysosome

Thrombus Increase vascular permeability

Edema Tissue injury Bleeding Edema

Local or systemic immune complex diseases

 Type IV Hypersensitivity reaction
• Also know as ‘Delayed type of hypersensitivity’
• T cell mediated, TH1 cells (TDTH cells).
• In 1890, Robert Koch observed that individuals infected
with Mycobacterium tuberculosis developed a localized
inflammatory response when injected intra dermally
(in the skin) with a filtrate derived from a
mycobacterial culture.
• He therefore named this localized skin reaction a
tuberculin reaction .
• The hallmarks of a type IV reaction - initiation by T-
cells.
• Eg: Tuberculin reaction and contact dermatitis caused
by poison ivy
• DTH requires T cells to be sensitized to
antigen. Subsequent re exposure to antigen
results in cytokine generation, inflammation,
and the recruitment of macrophages, which
produce DTH symptoms(swelling,
erythema/redness ) 2 to 4 days after re
exposure.
• Eg: Tuberculin test in animals
DTH response includes, sensitization phase and effector phase

• In the sensitization phase after initial contact with

antigen (e.g., peptides derived from intracellular
bacteria), TH cells proliferate and differentiate into
TH1 cells. Cytokines are secreted by these T cells .
• In the effector phase after subsequent exposure of sensitized
TH cells to antigen, TH1 cells secrete a variety of cytokines and
chemokines. These factors attract and activate macrophages
and other nonspecific inflammatory cells.
• Activated macrophages are more effective in presenting
antigen, thus perpetuating the DTH response, and function as
the primary effector cells in this reaction.
• Other helper T-cell subsets are now thought to participate in
DTH (TH2 and TH17) and CD8 T cells also contribute.
TH1 cells are important initiators of DTH, but the principal
effector cells of the DTH response are activated macrophages

Lytic enzymes released from activated macrophages in a

granuloma can cause extensive tissue damage
A schematic diagram depicting the mechanism of a delayed hypersensitivity reaction.
contact-dermatitis :
- many contact antigens
Most of these substances are small molecules
that can complex with skin proteins.
In the reaction to poison oak, for example, a
pentadecacatechol compound from the leaves
forms a complex with skin proteins. When TH
cells react with this compound appropriately
displayed by local APCs, they differentiate into
sensitized TH1 cells.
A subsequent exposure to pentadecacatechol
will elicit activation of TH1 cells and induce
cytokine production. Approximately 48–72 h
after the second exposure, the secreted
cytokines cause macrophages to accumulate at
the site. Activation of these macrophages and
release of lytic enzymes result in the redness
and pustules.