Hypersensitivity

Hypersensitivity
Mohammad Mukhit Kazi Lecturer SDCH Pune

Objectives
To know difference between immunity and hypersensitivity
To know different types of hypersensitivity
To know mechanisms involved in hypersensitivity

Introduction
Immunity
A protective process
Helps body to overcome infections
Specific response to antigens
Immune response – sometime injurious to host
A damage to the host, mediated by preexisting
immunity to self or foreign antigen.

Definition of hypersensitivity
The injurious consequences in the sensitized host, following
contact with the specific antigen.
For induction of hypersensitivity reactions the host should
have had contact with the antigen (allergen)
Initial contact sensitizes the immune system, leading to the
priming of the appropriate B or T lymphocytes this is known
as sensitizing or priming dose
Subsequent contact with the allergen causes manifestations of
hypersensitivity as shocking dose.

Difference between Immunity and
Hypersensitivity
Focus is on antigen
and what happens to
it
Antigen are of little
concern or often
innocuous or bland
substances such as serum
proteins or pollen
e.g. killing of bacterium
or neutralization of toxin
It is concerned with what happens
to the host as a result of the
immune reaction

Musts for Hypersensitivity
Contact with allergen
Sensitizing/priming dose
Induction of AMI/CMI
Shocking dose

Allergy
Originally used by von Pirquet means
An altered state of reactivity to an antigen and included both
types of immune responses protective as well as injurious
Also referred as all immune processes harmful to the host such
as hypersensitivity and autoimmunity
Commonly used as hypersensitivity

Classification of Hypersensitivity
reactions
I. Immediate hypersensitivity (B cell or Ab mediated)
Anaphylaxis
Atopy
Antibody mediated cell damage
Arthus phenomenon
Serum sickenss
II. Delayed hypersensitivity (T cell mediated)
Infection (tuberculin) type
contact dermatitis type

Immediate hypersensitivity Delayed Hypersensitivity
1. Appears and recedes rapidly 1. Appears slowly, lasts longer
2. Induced by antigen or haptens by
any route
2. Antigen or hapten intradermally
or with Freund’s adjuvant or by
skin contact
3. Circulating antibodies present
and responsible for reaction; (Ab
mediated reaction)
3. Circulating Abs may be absent
and not responsible for reaction;
cell mediated reaction
4. Passive transfer possible with
serum
4. Cannot be transferred with
serum; but possible with T cells or
transfer factor
5. Desensitization easy but short
lived
5. Difficult, but long lasting

Coombs and Gell (1963) classified hypersensitivity
reactions into 4 types based on different
mechanisms of pathogenesis
Type I (Anaphylactic, IgE or reagin dependent)
Type II ( cytotoxic or cell stimulating)
Type III ( Immune complexes or toxic complex disease)
Type IV ( Delayed or cell mediated hypersensitivity)

A = Type I - Anaphylaxis Reaction
C = Type II - Cytotoxic Mediated Hypersensitivity Reaction
I = Type III - Immune Complex Mediated Hypersensitivity
Reaction
D = Type IV - Delayed Hypersensitivity Or Cell Mediated
Hypersensitivity Reaction

Type I Reactions (IgE dependent)
Occurs in two forms
The acute : potentially fatal, systemic form called anaphylaxis
The chronic or recurrent : Non fatal, typically localized form
called atopy

Type-I hypersensitivityType-I hypersensitivity
The common allergy

Anaphylaxis
Classical immediate hypersensitivity reaction
Ana = without
Phylaxis = protection
Coined by Richet (1902)
Experiment on Dog
Theobald’s smith (1902)
Similar phenomenon in guinea pig
Ehrlich named this ‘Theobald Smith phenomenon’

Type I Reactions
Humans –
Itching of scalp & tongue, flushing
of skin, difficulty in breathing,
nausea, vomiting, diarrhea, acute
hypotension, loss of consciousness,
death (rare)
Causes
Serum therapy, antibiotics, insect
stings
Treatment
Adrenalin 0.5 ml (1 in 1000
solution) SC/IM repeated up to
2 ml in 15 min

Sensitization is most effective given parenterally
But may occur by any route
Minute doses can sensitize the host
Antigens and haptens can induce anaphylaxis
There should be interval of 2-4 weeks between sensitizing dose
and shocking dose
Shocking dose more effective when given IV
It should be identical to sensitizing dose

The clinical effects are due to smooth muscle contraction and
increased vascular permeability
There is also edema, decreased coagulability of blood, fall in BP
and temp. leucopenia and thrombocytopenia
Guinea pigs are more susceptible and rats are resistant
Rabbits, dogs and humans are intermediate susceptible

In human beings fatal anaphylaxis fortunately rare
Signs and symptoms begin with itching of the scalp and tongue,
flushing of the skin over whole body and difficult in breathing
due to bronchial spasm
There may be nausea, vomiting, abdominal pain and diarrhea,
sometime blood in stool
Acute hypotension, loss of consciousness & death follows

Insect stings cause anaphylaxis in human beings
Prompt treatment with adrenalin is life saving
0.5 ml of a 1 in 1000 solution SC or IM
Repeat dose to total 1 ml over 15 minutes if necessary
Cutaneous anaphylaxis
Local wheal and flare response after Ag is administered intradermally
Wheal – pale central area
Flare – hyperemia and erythema

Passive cutaneous anaphylaxis (PCA)
Developed by Ovary (1952)
For detection of Abs e.g. IgG Ab
Anaphylaxis in vitro
Schultz – Dale phenomenon : Isolated tissues from sensitized guinea pig held in
Ringers solutions will contract vigorously

Mediators for Anaphylaxis
Primary mediators
Histamine : imp vasoactive amine formed by decarboxylation of histidine found
in mast cells, basophils and platelets
Released into skin stimulates nerves producing burning and itching sensations
Causes vasodilatation and hyperemia, edema by increasing capillary permiability

Induces smooth muscle contraction and stimulates
Serotonin
 Decarboxylation of tryptophan found in intestinal mucosa, brain tissue and platelts
 Causes smooth muscle contraction
 Increased capillary permeability and vasoconstriction
Chemotactic factors
 Eosinophil chemitactic factors are acidic tetrapeptides released from mast cell granules
 Strongly chemotactic

Secondary mediators
Prostaglandins and leukotrienes
 Formed from disrupted cell membrane of mast cells & other leucocytes
 They are powerful bronchoconstrictors
 Prostaglandins also affect secretion by mucous glands, platelet adhesion, permeability & dilatation
of capillaries and the pain threshold
Platelet activating factor
 Low molecular weight lipid causes aggregation of platelets and release vasoactive amines
Other mediators of anaphylaxis
Anaphylatoxin released by complement activation and bradykinin

Anaphylactoid reaction
Intravenous injection of peptone, trypsin provokes a clinical reaction
resembling anaphylactic shock termed as anaphylactoid reaction
Resemblance is due to same chemicals participating in the reaction
It has no immunologic basis
Non specific mechanism

Atopy
Introduced by Coca (1923)
Naturally occurring : hay fever and asthma
Antigens are inhalant or ingestants
Difficult to induce artificially
Genetically determined probably linked to MHC genotypes
Produce large quantity of IgE antibodies
Bottle fed infants tend to develop atopy in later life
IgE differs from other immunoglobulin in many ways
Clinical expression depends portal of entry
Conjunctivitis, rhinitis, gastrointestinal symptoms, dermatitis

1. Cannot be demonstrated in conventional serological reactions
2. Commonly occur in humans not easy in experimental animals
3. IgE is homocytotropic ie species specific
4. Heat sensitive and is inactivated at 56o
c in 2 – 4 hours.
5. Does not pass through placenta

Type II Reaction: Cytolytic and Cytotoxic
Involve a combination of IgG antibodies with antigenic
determinant on the surface of cells
Leading o cytotoxic or cytolytic effects
Lysis of RBCs by antiRBCS antibodies

Type III Reactions: Immune complexes Diseases
Arthus reaction
Arthus in 1903 observed after repeated injection of normal horse
serum in rabbits subcutaneously develops edema, indurations and
hemorrhagic necrosis
Tissue damage is due to antigen – antibody precipitates causing
complement activation and release of inflammatory molecules
This leads to increased vascular permeability and infiltration of the
site with neutrophils
Leukocyte platelet thrombi are formed that reduces the blood supply
and lead to tissue necrosis

Arthus reactionArthus reaction
Arthus reaction
Type-III
Wheal & flare reaction
Type-I

• Serum Sickness
 systemic form of type III hypersensitivity
Described by von Pirquet 1905
Appeared 7 – 12 days following a single injection of high concentration of
foreign serum such as diphtheria antitoxin
 Clinical syndrome consists of
 Fever
 Lymphadenopathy
 Splenomegaly
 Arthritis
 Glomerulonephritis
 Endocarditis
 Vasculitis
 Urticarial rashes
 Abdominal pain
 Nausea
 Vomiting
Pathogenesis is the formation immune complex get depositied on inner
lining of blood vessels in various parts of body causing inflammatory
infiltration

Serum sicknessSerum sickness

Depletion of complement
Disease is self limited
Single injection can serve both as the sensitizing dose and the
shocking dose
Immune complexes occurs in many diseases including bacterial,
viral and parasitic infections, disseminated malignancies and
autoimmune conditions

Type IV Reactions: Delayed hypersensitivity
Provoked by intra cellular parasites or haptens
Reaction due to sensitized T cells which on contact with specific
antigen releases cytokines that causes biological effects
Cannot be transferred passively
But can be transferred by lymphocytes
Two types
Tuberculin
Contact dermatitis type

Tuberculin type
When small dose of tuberculin is injected intradermally in an
individual sensitized to tuberculoprotein by prior infection or
immunization an indurated inflammatory reaction develops
at the site within 48 – 72 hours
In unsensitized individuals no response
Useful indication of the state of DH to the bacilli

Contact dermatitis type
Due to variety of chemicals, metals, dyes
Contact dermatitis is an inflammation of the skin caused
by direct contact with an irritating or allergy-causing
substance (irritant or allergen). Reactions may vary in the
same person over time. A history of any type of allergies
increases the risk for this condition.

Contact dermatitis reactionContact dermatitis reaction

Allergic Contact Dermatitis Response to
Poison Ivy Hapten

Type-IVType-IVType-IIIType-IIIType-IIType-IIType-IType-Icharacteristiccharacteristic
Comparison of hypersensitivity
reactions
Comparison of hypersensitivity
reactions
TB test, poisonTB test, poison
ivy, granulomaivy, granuloma
farmers’farmers’
lung, SLElung, SLE
pemphigus,pemphigus,
GoodpastureGoodpasture
hay fever,hay fever,
asthmaasthma
examplesexamples
antibody IgE IgG, IgM IgG, IgM none
antigen exogenous cell surface intracellularsoluble
response
time
15-30 min. Min.-hrs 3-8 hours 48-72 hours
or longer
appearance Wheal &
flare
Lysis &
necrosis
Erythema &
edema
Erythema &
induration
baso- and
eosinophils
Ab and
complement
histology PMN and
complement
Monocytes &
lymphocytes
T-cellsantibodyantibodyantibodytransfer with
Mohammad Mukhit Kazi Lecturer SDCH
Pune

Autoimmunity
Self antigens are not immunogenic
Autoimmunity is a condition in which structural or
functional damage is produced by the action of
immunologically competent cells or antibodies against the
normal components of the body.
Autoimmunity literally means – protection

Mechanism of autoimmune
diseases
Cells undergo antigenic alteration due to physical, chemical
or biological influences
This results in immune response
Physical agents – irradiation
Chemicals – drugs
Biological – infectious agents such as viruses

Classification of Autoimmune
diseases
Hemolytic autoimmune disease
- Autoimmune hemolytic anemias
- Autoimmune thrombocytopenia
- Autoimmune leucopenia

Localized autoimmune diseases
- Hashimoto’ disease (enlargement of thyroids)
- Grave’s disease (Abs to thyroglobulin)
- Addision’s disease (lymphocyte infiltration in adrenal glands)
- Autoimmune orchitis
- Myasthenia gravis (malfunction of myoneural junction)
- Autoimmune disease of eye
- Pernicius anemia
- Autoimmune disease of nervous system
- Autoimmune disease of skin

Systemic autoimmune disease
Systemic lupus erythematosus
Rheumatoid arthritis
Polyarteritis nodosa
Sjogran’s sundrome

Hypersensitivity

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