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Hypersensitivity
Hypersensitivity or allergy refers to a condition in which immune response results in excessive or exaggerated
reactions leading to tissue damage, disease or even death.
The term “allergy” (allos, altered; ergon, action) originally coined by von Pirquet ‘(1905) was describd as the
altered reactivity of an animal to repeated contacts with a foreign antigen. Hypersensitivity occurs in certain
individuals who have previous contact with an antigen and exposed to the second dose of the same antigen.
Antigens involved are usually innocuous, noninjurious or bland substances, e.g. serum protein. Inducing
antigens are called allergens, which may be complete antigen or hapten.
Initial contact with antigen (sensitising dose) sensitises the immune system by priming or sensitising
appropriate B or T cells. Subsequent contact (shocking dose) with the same antigen leads to a variety of
abnormal reactions.
Classification
Hypersensitivity reactions are of two main types, immediate and delayed, based on time required by sensitised
host to respond to the shocking dose of the antigen. Immediate form is mediated by humoral antibody and
manifests in a few minutes to few hours while delayed form appears more slowly, usually after 24 hours which
reaches a peak after 48-72 hours and is mediated by T cells .
Distinguishing features of immediate and delayed types of hypersensitivity
Timing:
Immediate type
Delayed type
Reaction appears immediately
within minutes and recedes
rapidly usually in one hour.
Appears slowly in 24-72 hours and lasts
longer for days.
Antibody mediated reaction
Immune response : Passive transfer possible by
serum
Cell mediated reaction
Transfer possible only with lymphoid
cells or’ their extracts.
Desensitization
Easy but short lived
Difficult but long-lasting
Cellular response
Limited polymorphonuclear
infiltration
Predominantly mononuclear cell
infiltration
Classification of hypersensitivity reactions made by Coombs and Gel
(1963) is widely accepted which includes 4 major types, types Ito IV.
First 3 types (I, II, III) are antibody mediated (immediate type.) and
type IV is cell mediated (delayed type). Two additional types, type V
and VI are recently proposed; type V is antibody mediated and type
VI is both antibody and cell mediated.
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Type I
(Anaphylactic ) reaction
Anaphylaxis is a type of IgE mediated hypersensitivity reaction, which develops quickly after introduction of a
large shocking dose of antigen following one or more
small sensitizing doses. Anaphylaxis is the typical
example of type I hypersensitivity reaction. The term
anaphylaxis (ana, against; phylaxis, protection) was.
first described by Richet (1902) to describe a fatal
reaction in dog that followed a second sub lethal
injection of toxic extract of sea anemones. Systemic
anaphylaxis is a rare event in man and occasionally
observed in hypersensitive individuals by insect
stings (bees), injection of foreign serum (ATS, horse
serum) or penicillin.
Factors influencing anaphylaxis
1. Sensitization : Sensitization may occur by any
route such as injection, ingestion, inhalation or
contact. Parenteral administration of antigen is most
effective. Pollens, animal danders, house dust and
certain foods are common offenders. Minute dose
(0.1 ug) of antigen can sensitize susceptible animals. Once sensitized the individual remains so for long period.
2. Waiting period: An interval of 2-3 weeks between sensitizing and shocking dose is required, during which
cytotrophic antibody IgE produced against the antigen attaches to mast cells and basophils. It is the level of IgE
produced in the host in response to a particular antigen that will determine whether an anaphylactic reaction will
occur on subsequent exposure to the same antigen.
3. Shocking or eliciting dose: Shocking dose is most effective when administered intravenously; less effective
intraperitoneally or subcutaneously and least effective intradermally. When a massive shocking dose (0.1 to 10
mg) of soluble form of the same antigen, is injected rapidly intravenously, the antigen combines with cell bound
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antibody on mast cell rapidly. The Ag-Ab complex stimulates mast cell for prompt release of mediators that
causes clinical manifestations of anaphylaxis.
Mechanism of anaphylaxis
IgE is the major antibody (previously known as reaginic antibody) responsible for anaphylaxis. It does not pass
through placenta. Recent studies show that certain subsets of T helper cells produce particular profiles of
lymphokines which are responsible for the production of IgE by B cells.
IgE is formed in response to antigenic stimulus and when large amounts are formed, the stage is set for the
reaction. Mast cells are normally present in
large number in sub mucosal layers of
respiratory and gastrointestinal tract, skin and
vascular endothelium. IgE molecules are
bound to mast cells of tissues and basophils of
blood. A part of the Fc region of IgE (CH3
and CH4) is involved in binding to Fc
receptors (FcR) on mast cells and basophils.
Mast cells acquire IgE in regional lymph
nodes before migrating to tissues. On
subsequent exposure to a large dose of the
same antigen, antigen combines with Fab
fractions of IgE bound to mast cells and
basophils. Eosinophils and platelets can also bind IgE. Ag-Ab complex upsets adenylcyclase-cyclic AMP
system in cell- membrane leading to degranulations of mast cells and circulating basophils and release of
vasoactive amines (contained in granules) that cause anaphylactic reaction
Mechanism of Type I Hypersensitivity
Chemical mediators
Once IgE has bound to the FcR on mast cells and basophils, the signal for the release or production of
biologically active molecules is triggered by cross-linking of surface-bound IgE by antigen .The effects of
histamine is mediated by histamine receptors, Hi and H2. Chemical mediators are active only for some minutes
after release and are then inactivated.
1. Primary mediators: Histamine, serotonin, eosinophil chemotactic factor of anaphylaxis, neutrophil
chemotactic factor of anaphylaxis and various proteolytic enzymes. Primary mediators are preformed granules
of mast cells and basophils.
2. Secondary mediators: SRS, prostaglandin and platelet activating factor. These secondary mediators are newly
formed upon stimulation of mast cells, basophils and other leucocytes.
Features of anaphylaxis
1. Reaction occurs immediately within a few seconds to few minutes following administration of shocking dose
of antigen.
2. IgE antibody is synthesised probably in man only. It has got affinity for skin cells.
3. Symptoms result from constriction of smooth muscles such as bronchioles, and increased vascular
permeability.
4. Duration is short.
5. Slight êllular damage occurs:
6. Artificial induction by serum of sensitised animal is possible.
7. It is not a heritable disease.
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Chemical Mediator of Anaphylaxis
Manifestations of anaphylaxis
Manifestation of anaphylaxis depends on species of animal, amount of .shocking dose, site of injection and
portal of entry of antigen.
A.Systemic anaphylaxis
Systemic anaphylaxis is rare in man. It is a state of shock which usually follows administration of horse serum
such as ATS, ADS or AGS. Systemic anaphylaxis includes active anaphylaxis, passive anaphylaxis, cutaneous
anaphylaxis and organ anaphylaxis. Lunf is the principle shock organ in human.
B. Localised anaphylaxis
1. Mucosal anaphylaxis : Application of small dose of antigen on mucosal surface such as conjunctiva, nasal
mucosa, respirat.9ry tract leads to rhinorrhoea, conjunctivitis and bronchospasm respectively.
2. Cutaneous anaphylaxis : It is manifested by appearance of local wheal and flare response, urticaria or
angioneurotic oedema. It is induced both by qitaneous (intradermal) injection of antigen or by ingestion
(ingestion is followed by absorption).
Atopy
The term atopy (atopy, out of place or strangeness) was first coined by Coca (1923) is a type I hypersensitivity
reaction that occurs spontaneously in response to substances encountered in the environment in everyday life.
Atopy is typified by hay fever and asthma. About 10% of the population are prone to develop sensitization to
various environmental antigens such as pollens of ragweed, grasses or trees; foods and animal danders.
Features of atopy
1. Atopy shows marked familial distribution and it is suspected that the sensitization is inherited.
2. Reactions occur at the site of entry of the exciting Ag. e.g. respiratory organs in bronchial asthma and hay
fever.
3. Routes of entry Inhalations of pollens etc. affect lungs (bronchial asthma), ingestion leads to cutaneous
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eruptions or gastrointestinal disorders (fish, mushroom, milk, egg, nuts, drugs) and contact leads to local
allergy (conjunctivitis)..
4. Induction of atopy is difficult by artificial means because atopens are poorly antigenic.
5. Atopy is IgE mediated hypersensitivity reaction.
The atopen combines with the cell-bound IgE molecules which are already fixed on the surface of mast cells
and the basophils in tissues and Ag-Ab complex stimulates the release of mediators that set of the symptoms of
atopy.
Examples of anaphylactic reaction
1. Food allergy on shell fish, prawn, egg, mushroom.
2. Dust allergy on pollens of ragweeds, grasses or trees, animal danders and house dust.
3. Drug allergy on penicillin, sulphonamides.
Prausnitz-Kustner (PK) reaction
The special affinity of IgE for skin cells forms the basis of passive cutaneous anaphylaxis in animals as
demonstrated by Tests for anaphylaxis
These tests are performed before administration of foreign protein or antigen to an individual
1. Skin test : An amount of 0.1 ml of diluted serum or antigen (1:10) is injected intradermally on forearm,
characteristic wheal and flare appears in a few minutes in positive reaction. It is short-lasting.
2. Conjunctival test: One drop (1:10) diluted antigen when placed in conjunctival sac of one eye, redness of the
eye with itching and lacrimation develops in hypersensitive individuals in 5-20 minutes. Normal saline is placed
in control eye.
Desensitization in anaphylaxis
1. Acute desensiti.sation : Small amounts of antigen are administered at 15 minutes interval for an hour or two.
Small scale Ag-Ab complex formed during the process, releases chemical mediators from mast cells which are
insufficient to produce a major reaction. This technique is adopted while administering drug (penicillin) or
foreign serum (ATS) to a hypersensitive individual. Desensitisation is short-lasting as the hypersensitivity
returns after days or weeks.
2. Chronic desensitization : It is a long-term procedure where small amount of antigen is administered at weekly
internals to hypersensitive person to the antigen. Antigen stimulates production of IgG-blocking antibodies in
serum which prevents the antigen later from reaching IgE antibody on mast cells, thereby blocking a
hypersensitivity reaction. Desensitisation is long-lasting.
Depot therapy (injection of an antigen with oil
adjuvant) also leads to production of IgG-blocking
antibodies against the antigen.
Anaphylactoid reaction
A type of reaction that resembles anaphylactic shock clinically is provoked by intravenous injection of heavy
metal salts, trypsin, peptone, starch or polysaccharides. It has got no immunological basis, is a nonspecific
mechanism where the offending agent appears to activate the alternative complement pathway with release of
anaphylatoxins.
Type II (cytotoxic) reaction
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It is a cytotoxic
reaction mediated
by antibodies
directed towards
antigens present on
the surface of cell
or other tissue
components
resulting in damage
of the cell. The
antibody is directed
against an epitope
that can be a
microbial product
passively adsorbed
on to a cell or a
drug or a self
molecule. Both IgG
and 1gM antibodies
are produced in type II reaction. The antibody attaches o the antigen via Fab region and serves as bridge to
complement via Fc region of Ab . As a result, type II reaction may be a complement mediated lysis of cells as
occurs in autoimmune haemolytic anaemia, ABO transfusion reactions or Rh haemolytic disease. Examples
1. Isoimmune reactions such as ABO transfusion reactions, erythroblastosis foetalis.
2. Autoimmune reactions, e.g. autoimmune haemolytic anaemia, agranulocytosis or thrombocytopenia in which
individuals produce autoantibodies for obscure reasons, which destroy red cells, neutrophils or platelets.
3. Drug reactions are seen with penicillin, phenacetin, quinidine, sedermoid (not used now a days) and others.
4. Bacterial reactions are observed in certain salmonella and mycobacterial infections.
Demonstration of type II reaction
1. Direct antiglobulin test (Coombs test) is usually positive
2. Agglutination test with tanned red cells, CFT, precipitation and immunofluorescence are some important
diagnostic tests.
Type III (immune
complex) reaction
It is a type of humoral
antibody mediated
hypersensitivity
reaction characterized
by deposition of Ag-Ab
complexes in tissues
(particularly on
vascular endothelial
surfaces), activation of
complement and
massive infiltration by
polymorphonuclear
leucocytes leading to
tissue damage.
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Principle
When an antigen combines with its corresponding antibody, Ag-Ab complex is formed. Normally monocytes
and macrophages efficiently bind and remove these immune complexes. These cells of reticuloendothelium
system are efficient to remove large complexes. These cells are also able to remove smaller Ag-Ab complexes
made in antibody excess but are relatively inefficient in removing smaller complexes formed in antigen excess
which occasionally persist and are deposited in tissues causing several immune complex disorders.
When there is a defect in the system involving phagocytes and complement in the process of removal of the AgAb complex or when the system is overloaded, and the complexes are deposited in tissues, type III reactions
appear .
Two typical type III reactions are Arthus reaction (localized) due to relative antibody excess and serum
sickness (generalized) due to relative antigen excess.
A. Arthus reaction
Arthus (1903) observed that with repeated subcutaneous injections of antigen (horse serum) into rabbits,
high level of precipitating antibody appears in blood. When the same antigen is injected subcutaneously
or intradermally in that animal, intense local oedema and hemorrhage develop which reaches a peak in
3-6 hours. This type of reaction is also seen in man and is called Arthus reaction.
Antigen-antibody complexes formed at equivalence or slight antibody excess precipitate at the site of
antigen injection producing Arthus reaction. The reaction can occur wherever the antigens are injected
such as synovial joint space or pericardial sac.
B. Serum sickness
Serum sickness is systemic form of
immune complex diseases in which
only a single dose of antigen is
sufficient to produce the
hypersensitivity reaction. After a
single injection of high titre foreign
serum (or drug) such as ATS,
antigen is slowly cleared from the circulation and antibody production begins. The antibody level in serum
reaches high enough titre after 7-12 days. But still some amount of excess antigen remains in circulating
blood, which combines with Ab forming small and soluble Ag-Ab complexes. These immune complexes
formed in large antigen excess become soluble, which may circulate or may be filtered out in important
organs and tissues particularly in the endothelial lining of the capillaries of kidney, muscles, lymph node
and joints. The immune complexes damage the tissue in the same way as in Arthus reaction.
Typical serum sickness is characterized by fever, urticaria, arthralgia, lymphadenopathy and splenomegaly
usually 1-2 weeks after injection of a single dose of foreign serum. Symptoms subside with the elimination
of immune complex. Although manifestations of serum sickness appear several days after injection of
antigen (serum), it is included under immediate type hypersensitivity reaction because once immune
complex is formed, symptoms occur promptly .
Some important immune complex diseases include post-streptococcal glomerulonephritis and rheumatoid
arthritis1.
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Type IV delayed reaction (syn. CMI)
Delayed type of hypersensitivity is a
specially provoked, slowly evolving
(24-72 hours), mixed cellular reaction
involving lymphocytes and
macrophages, where tissue damaging
events is mediated by T lymphocytes
and not by antibody.
It is the principal pattern of
immunological response to a variety of
intracellular microbial agents such as
tubercie bacilli, brucellae, viruses etc.
Delayed hypersensitivity and cell mediated immunity are closely related. Type IV reaction is typified by the
tuberculin skin test.
Three types of delayed hypersensitivity reactions are well recognized, tuberculin (infection) type and contact
dermatitis both occur within 72 hours of antigen challenge, whereas granulomatous reaction develops over a
period of weeks.
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DTH type
Contact
Tuberculin
Reaction
time
48-72
hours
48-72
hours
Granulomatous 4 weeks
Delayed hypersensitivity reactions
Clinical
Histological appearance
appearance
Antigen
Infiltration of
lymphocytes, and later
macrophages, oedema of
epidermis
Epidermal: e.g.
nickel, rubber,
poison ivy usually a
hapten
.
Local hardening
and swelling ±,
fever
Infiltration of
lymphocytes, monocytes,
and macrophages
Intradermal, used
diagnostically:
tuberculin,
mycobacterial and
leishmanial antigens
Hardening e.g. in
skin or lung
.
Granuloma consisting of
epitheloid cells, giant
cells, and macrophages:
fibrosis ±, necrosis
Persistent Ag or AgAb complexes in
macrophages: or
“nonimmunological”
e.g. talcum powder.
Eczema
Contact dermatitis type
Delayed hypersensitivity may develop in a localized area of skin after repeated contact with a wide range of
sensitizing materials, such as,
(a) drugs : topical application of penicillin or other antibiotic in ointment or creams,
(b) metals : nickel, chromium,
(c) simple chemicals : hair dyes, picryl chloride, formaldehyde, dinitrochlorobenzene. cosmetics, soaps. These
substances act as haptens. After percutaneous absorption, small molecules of antigen combine with skin protein
and become antigenic. Cell mediated immunity is induced in skin by the antigen. Sensitization is particularly
liable to occur when a chemical in an oily base (ointment or cream) is applied on an inflamed area of the skin.
Most of the antigens being fat soluble, their likely portal of entry is the dermal route along the sebaceous
glands. The Langerhan’s cells of dermis are the antigen presenting cells for these antigens. They carry the
antigen to regional lymph node where T lymphocytes are sensitized. Sensitized T cells proliferate and then
mature in lymph node and some return to the site of entry of the offending hapten. On subsequent exposure of
the skin to the offending agent, sensitiseci T lympho- cytes release lymphokines which cause superficial
inflammation of skin characterised by redness, induration and vesiculation within 12-48 hours. The dermis is
infiltrated predominantly by lymphocytes and few macrophages with some oedema. Subsequent avoidance of
contact will prevent recurrence.
Granulomatous type
The most important clinical form of delayed hypersensitivity is the granulomatous hypersensitivity, that usually
results from persistence of micro-organisms or other particles within the macrophages, which the cell is unable
to destroy.
Granulomatous hypersensitivity shows granuloma containing epitheloid cells, giant cells and macrophages e.g.
Mitsuda reaction to leprosy antigens.
Examples : Diseases manifesting delayed hypersensitivity include mycobacterial, protozoal and fungal diseases,
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such as,
1. Tuberculosis
2. Leprosy
3. Leishmaniasis
4. Listeriosis
5. Deep fungal infections (e.g. blastomycosis)
6. Helminthic infections (e.g. schistosomiasis).
Type V stimulatory type reaction
It is a modification of Type II hypersensitivity reaction in which an interaction of antibodies with antigens occur
on cell surface that sometimes causes cell proliferation and differentiation instead of inhibition or killing. Such
antibodies are non- complement fixing, directed against certain cell surface components and reacts with the key
surface components such as hormone receptor of the cell. Antigen-antibody combination enhances the
functional activity of affected cell.
The classical example of stimulatory type of reaction is grave’s disease in which thyroid hormones are
produced in excess amount.
Thyroid stimulating antibody (LATS) is a specific thyroid autoantibody to thyroid membrane antigen.
Lymphocytic infiltration is prominent in thyrotoxic glands.
Antibody-Dependant Cell-Mediated Cytotoxicity (ADCC)
ADCC is mediated through natural killer NK cells and the cytotoxic mechanism is independent of complement.
Target cells coated with low concentration of antibody are killed by NK cells through an extra cellular
nonphagocytic mechanism. Most of them are lacking any surface marker and only a small proportion bear T
markers.
Antigen, after introduction into body, attaches on the target cell and induces antibody production. Ag-Ab
complex forms on target cells. Natural killer cells combine with Ag-Ab complex via Fc fragment of antibody
and causes lysis of the target cells (cytotoxicity). Shwartzmann phenomenon
It is .not an immune response, although it has superficial resemblance to hypersensitivity reaction. It is probably
a specialised type of disseminated intravascular coagulation (DIC) precipitated by endo toxin.
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Source: A Text Book pf Microbiology By P .Chakraborty.