Presentation on topic of hypersensitivity

1. Hypersensitivity
Dr. Jayanta Das

2. The term Hypersensitivity refers to undesirable injurious consequences in a sensitized
host,following contact with specific antigens
Hypersensitivity reaction denotes an immune response resulting in exaggerated or
inappropriate reactions harmful to host.
It is a harmful immune response in which tissue damage is induced by exaggerated or
inappropriate immune responses in a sensitized individual on re-exposure to the same antigen.
Both the humoral and cell-mediated arms of the immune response may participate in
hypersensitivity reactions.
Hypersensitivity essentially has two components. First priming dose (first dose) of antigen is
essential which is required to prime the immune system, followed by a shocking dose (second
dose) of the same antigen that results in the injurious consequences.
Definition

3. Depending on the time taken for the reactions, and the mechanisms that cause the tissue damage,
hypersensitivity has been broadly classified into immediate type and delayed type. In the former, the
response is seen within minutes or hours after exposure to the antigen and in the latter, the process takes
days together to manifest as symptoms.
Gell and Coombs (1963) classified hypersensitivity reactions into FOUR CATEGORIES based on the time
elapsed from exposure of antigen to the reaction and the arm of immune system involved.
Type I (Anaphylactic)
Type II (Cytotoxic)
Type III (Immune Complex)
Type IV (Delayed or Cell mediated)
Later on Type V hypersensitivity reaction was also described
Classification

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

5. Type I hypersensitivity
Antibodies are fixed on the surface of tissue cells (mast cells and basophils) in sensitised individuals.
The antigen combines with the cell-fixed antibody, leading to release of pharmacologically active
substances (vasoactive amines) which produce the clinical reaction.
These occur in two forms: the acute, potentially fatal systemic form called anaphylaxis and the
chronic or recurrent, non-fatal, typically localised form called atopy
Antigens or haptens can induce anaphylaxis. There should be an interval of at least 2-3 weeks
between the sensitising dose and the shocking dose.
The clinical features of anaphylaxis are the same with any antigen but vary between species. The
clinical effects are due to smooth muscle contraction and increased vascular permeability.
The organs affected vary with the species. Tissues or organs predominantly involved in the
anaphylactic reaction are known as 'target tissues' or 'shock organ. Other changes seen in
anaphylaxis are edema, decreased coagulability of blood, fall in blood pressure and temperature,
leucopenia and thrombocytopenia.

6. Symptoms and signs of anaphylactic shock begin with itchmg of the and tongue flushing of the skin over
the whole body and difficulty in breathing due to bronchial spasm. Nausea, vomiting, abdominal pain and
diarrhea, sometimes with blood in the stool may be present. Acute hypotension, loss of consciousness
and death follow.
Types:
1. Cutaneous anaphylaxis
2. Passive cutaneous anaphylaxis
3. Anaphylaxis in vitro
Cutaneous anaphylaxis
When a small shocking dose of an antigen is administered intradermally sensitised host, there will be a
local wheal-and-flare response (local anaphylaxis).

7. Passive cutaneous anaphylaxis (PCA)
A small volume of the antibody is injected intradermally into a normal animal. If the antigen, along with a
dye such as Evans blue, is injected intravenously 4-24 hours afterwards, there will be immediate blueing at
the site of intradermal injection due to vasodilatation and increased capillary permeability (wheal-and-flare
reaction). PCA can be used to detect the human IgG antibody which is heterocytotropic (capable of fixing
to cells of other species) but not lgE which is homocytotropic (capable of fixing to cells of homologous
species only).

8. Anaphylaxis in vitro
Isolated tissues, such as intestinal or uterine muscle strips from sensitised guinea pigs, held in a
bath of Ringer's solution will contract vigorously on addition of the specific antigen to the bath. This
is known as the Schultz-Dale phenomenon
The reaction is specific and will be elicited only by the antigen to which the animal is sensitive.
Tissues from normal animals can be passively sensitised by treatment with serum from sensitised
animals.

9. Pharmacological mediators:
1. Histamine: released from granules of mast cells,basophils,platelets. It causes burning and itching
sensation,vasodilation and hyperemia by an axon reflex and edema by increasing capillary permeability
2. Serotonin: found in intestinal mucosa, brain tissue and platelets.It causes smooth muscle contraction,increased
capillary permeability and vasoconstriction
3. Eosinophil chemotactic factor,neutrophil chemotactic factor
4. Enzymatic mediator: protease,hydrolase
5. Prostaglandin and leukotriene
6. Platelet activating factor
7. Slow reacting substance of anaphylaxis: These are produced by leukocytes. These consist of several
LEUKOTRIENES, which do not occur in preformed state but are produced during reactions of anaphylaxis.
Other mediators of anaphylaxis: Several biologically active substances such as the anaphylatoxins released by
complement
Anaphylactoid reaction:
Intravenous injection of peptone,trypsin and certain other substances provokes a clinical reaction resembling
anaphylactic shock. This is termed 'anaphylactoid reaction'. The only difference is that anaphylactoid shock has no
immunological basis and is a non-specific mechanism involving the activation of complement and the release of
anaphylatoxins
Mediators of Anaphylaxis

10. Atopy
Atopy refer to naturally occurring familial hypersensitivities of human beings, typified by hay fever and asthma.
Predisposition to atopy is genetically determined, probably linked to MHC genotypes. Atopy therefore runs in
families. What is inherited is not sensitivity to a particular antigen or particular atopic syndrome but the
tendency to produce IgE antibodies in unusually large quantities.
All individuals are capable of forming IgE antibodies in small amounts but in atopics, IgE response is
preponderant. About 10 per cent of persons have this tendency to overproduce IgE

11. Type. II (cytotoxic)
This type of reaction is initiated by IgG (or rarely IgM) antibodies that react either with cell surface or tissue
antigens. Cell or tissue damage occurs in the presence of complement or mononuclear cells. Type II reactions are
intermediate, between hypersensitivity and autoimmunity. Combination with antibody may in some instances,
cause stimulation instead of damage.
Antibodies bind to an antigen on cell surface and cause
i) phagocytosis of the cell through opsonic or immune adherence
ii) cytotoxicity by NK cells
iii) lysis through activation of complement system

12. Type 2 reactions occur by 3 broad mechanisms
1. Complement dependent reactions: The Fc region of antibody (bound with antigen) can activate the
classical pathway of complement system. Activation of classical pathway leads to host cell injury.Example
– ABO incompatibility,Rh incompatibility,Autoimmune hemolytic anemia,Drug induced hemolytic
anemia(eg – penicillin,quinidine,phenacetin),pemphigus vulgaris
2. Antibody dependent cellular cytotoxicity: IgG antibodies can coat on the target cells by interacting with
the surface antigens through Fab region. The Fc portion of IgG in turn binds to Fc receptors on various
effector cells such as NK cells which result in destruction of the target cells . ADCC is involved in
destruction of the targets that are too large to be phagocytozed, e.g. parasites, tumors or graft rejection
3. Autoantibody Mediated (Antibody-dependent Cellular Dysfunction or ADCD): In this condition, the host
produces certain autoantibodies which bind and disturb the normal function of human self antigens. Eg –
Graves disease,Myasthenia gravis

13. Type III(Immune complex diseases)
Here the damage is caused by antigen-antibody complexes. These may precipitate in and around
small blood vessels, causing damage to cells secondarily, or on membranes, interfering with their
function.
Immune complexes fix complement and are potent activators of the complement system
Activation of the complement results in the formation of complement components such as C3a-
and C5a anaphylotoxins that stimulate release of vasoactive amines.
The C5a attracts neutrophils to the site, but these neutrophils fail to phagocytose large
aggregated mass of immunocomplexes and instead release lysosomal enzymes and lytic
substances that damage host tiissue
Types: 1. Arthus reaction, 2. Serum sickness

14. Arthus reaction
Arthus reaction is a local manifestation of generalized hypersensitivity. Arthus (1903) observed that when rabbits
were repeatedly injected subcutaneously with normal horse serum, the initial injections had no local effect but
with later injections, there occurred intense local reaction consisting of edema, induration and hemorrhagic
necrosis.This is known as Arthus reaction.
Examples :
In skin: (1) following insect bites or (2) during allergic desensitization treatment wherein repeated injections of
the same antigen is given for long periods
In lungs, following inhalation of bacteria, fungi, spores or proteins may produce intrapulmonary lesions. Example –
Hypersensitivity pneumonitis(Farmers lung, Bird fanciers disease)

15. Serum sickness
This is another historical example of type III reaction. This condition is not seen nowadays, it was seen in the
past, following serum therapy, i.e. administration of foreign serum, e.g. horse anti-tetanus serum, to treat
tetanus cases.
The horse serum proteins being foreign can induce antibody formation in the host, leading to generation of
large number of immune complexes
Typically, after 7–8 days, the individuals begin to show various manifestations which are collectively called
serum sickness. The symptoms include fever, weakness, vasculitis, edema, erythema and rarely
lymphadenopathy and glomerulonephritis
It subsides gradually once the immune complexes are cleared and free antibodies accumulate.
Serum sickness differs from other types of hypersensitivity reactions in that a single injection can serve both
as the sensitising dose and the shocking dose. As heterologous serum injections are not used often now, the
syndrome is currently more commonly seen following injection of penicillin or other antibiotics.

16. Type IV (delayed or cell-mediated hypersensitivity)
This is a cell-mediated response. The antigen activates specifically sensitized CD4 and CD8 T cells,leading to
secretion of lymphokines and phagocyte accumulation
Type IV hypersensitivity reactions differ from other types in various ways:
1. It is delayed type (occurs after 48–72 hours of antigen exposure)
2. It is cell-mediated; characteristic cells called TDTH cells (delayed type of hypersensitivity T cells) are the
principal mediators of type IV reactions
3. Tissue injury occurs predominantly due to activated macrophages.

17. Two types of delayed hypersensitivity are recognised: the tuberculin (infection) type and the contact dermatitis
type
Tuberculin type
The archetype of delayed hypersensitivity is the tuberculin reaction. When a small dose of tuberculin is
injected intradermally in an individual sensitised to tuberculoprotein by prior infection or immunisation, an
indurated inflammatory reaction develops at the site within 48-72 hours. In unsensitised individuals, the
tuberculin injection provokes no response
Tuberculin type hypersensitivity develops in many infections with bacteria, fungi, viruses and parasites,
especially when the infection is subacute or chronic and the pathogen intracellular.A similar hypersesitivity is
developed in allograft reactions and in many autoimmune diseases.

18. Contact dermatitis type
Delayed hypersensitivity sometimes results from skin contact with a variety of chemicals-metals such as nickel
and chromium, simple chemicals like dyes, picryl chloride, dinitrochlorobenzene, drugs such as penicillin, plant
allergen (parthenin from parthenium) and toiletries. Sensitisation is particularly liable when contact is with an
inflamed area of skin and when the chemical is applied in an oily base
Mechanism: Langerhans’ cell of the skin capture locally applied hapten, along with the modified tissue proteins,
and migrate to the draining lymph nodes where they present the processed antigen along with MHC molecules
to T cells. The sensitised T cells travel to the skin site, where on contacting the antigen they release various
lymphokines. Th 1 cells secrete IFNy and IL2 which activate macrophages and other lymphocytes. Th2 cells
release IL4, IL5, GM-CSF and other factors that lead to an influx of eosinophils and tissue damage.
The lesions varying from macules and papules to vesicles that break down, leaving behind raw weeping areas
typical of acute eczematous dermatitis. Hypersensitivity is detected by the 'patch test'.

20. Type V (stimulatory hypersensitivity)
Other allergy mediated reactions, where instead of binding to cell surface components, the antibodies
recognise and bind to the cell surface receptors. This is a modified form of Type II reaction.
Here, the antibody activates receptor sites and enhances the activity of the cell. A few examples are
the 'long acting thyroid stimulator' (LATS), an antibody against some determinant on thyroid cells,
which stimulates excessive secretion of the thyroid hormone; Stevens Johnson syndrome;
sulphonamide-induced Morbilliform rash etc

21. Schwartzman reaction
This is not an immune reaction but rather a perturbation in factors affecting intravascular coagulation. It is
traditionally described along with hypersensitivity reactions because of a superficial resemblance.
Shwartzman (1928) observed that if a culture filtrate of S. Typhi is injected intradermally in a rabbit, followed 24
hours later by the same filtrate intravenously, a hemorrhagic necrotic lesion develops at the site of the
intradermal injection. The intradermal and intravenous injections need not be of the same or even related
endotoxins. Culture suspensions or filtrates of a variety of bacteria will sensitise the skin to intravenous injection
by an equally wide variety of cultures. or filtrates. This absence of specificity and the short interval between the
two doses preclude any immunological basis for the reaction.
Mechanism: It has been suggested that mechanisms similar to the Shwartzman reaction may operate in some
clinical conditions such as the pururic rashes of meningococcal septicemia and the acute hemorrhagic adrenal
necrosis found in overwhelming infections (Waterhouse-Friderichsen syndrome) . Massive activation of
complement by the alternative pathway, associated with release of thromboxane A2 and prostaglandins from
platelets, may lead to disseminated intravascular coagulation. The mechanism may be the excessive release of
cytokines such as the tumour necrosis factor and interleukins 1 and 6 by macrophages and endothelial cells in
response to contact with large quantities of lipopolysaccharide endotoxin. Some Gram-positive infections may
also cause similar effects.