Subject - Immunology

Hypersensitivity Reactions

Allergies Greek = altered reactivity

1906 – von Pirquet coined term: hypersensitivity

Hypersensitivity reactions – ‘over reaction’ of

the immune system to harmless
environmental antigens

Definition
• Hypersensitivity refers to undesirable (damaging, discomfort-
producing and sometimes fatal) reactions produced by the
normal immune system.
• Hypersensitivity reactions require a pre-sensitized (immune)
state of the host.
• Nearly 45 years ago Gell and Coombs proposed a classification
scheme which defined 4 types of hypersensitivity reactions
• Hypersensitivity reactions -four types: type I, type II, type III
and type IV, based on the mechanisms involved and time
taken for the reaction.
 TYPES OF HYPERSENSITIVITY
The four types of hypersensitivity are:
I. Type I Hypersensitivity- IgE mediated
(classical immediate hypersensitivity)

II. Type II Hypersensitivity- Antibody mediated

(cytotoxic hypersensitivity)

III. Type III Hypersensitivity- immune complex

(immune-complex mediated hypersensitivity)

III. Type IV Hypersensitivity- cell mediated

(mediated or delayed hypersensitivity)

The first three are mediated by antibody, the fourth by T cells.

Hypersensitivity reaction depends

on:

1) chemical nature of allergen

2) route involved in sensitization i.e.
inhalation, ingestion, injection…
3) physiological state of individual / genetic
potential
Type 1 - immediate (or atopic, or anaphylactic)
Main article: Allergy
Type 1hypersensitivity is an allergic reaction provoked by re-exposure to a
specific type of antigen referred to as an allergen.[2] Exposure may be
by ingestion, inhalation, injection, or direct contact. The difference between
a normal immune response and a type I hypersensitive response is that
plasma cells secrete IgE. This class of antibodies binds to Fc receptors on the
surface of tissue mast cells and blood basophiles. Mast cells and basophiles
coated by IgE are "sensitized." Later exposure to the same allergen, cross-
links the bound IgE on sensitized cells resulting in de-granulation and the
secretion of pharmacologically active mediators such as
histamine, leukotriene, and prostaglandin that act on the surrounding
tissues. The principal effects of these products are vasodilation and smooth-
muscle contraction. The reaction may be either local or systemic. Symptoms
vary from mild irritation to sudden death from anaphylactic shock.
Treatment usually involves epinephrine, antihistamines, and corticosteroids.
If the entire body gets involved, then anaphylaxis can take place; an acute,
systemic reaction that can prove fatal. Some examples:

 Allergic asthma
 Allergic conjunctivitis
 Allergic rhinitis ("hay fever")
 Anaphylaxis
 Angioedema
 Urticaria (hives)
 Eosinophilia
 Penicillin
 Cephalosporin
 Type I
• Common among population in developed nations
• Prerequisite: need prior sensitization to antigen
• the binding of antigen to antigen specific IgE bound
on mast cells
• Rapid liberation of active chemicals such as
histamine and serotonin
• A hypersensitivity due to excessive production of
the class of antibody known as IgE. Reactions
between allergens and IgE bound to mast cells and
basophiles cause a greatly heightened inflammatory
response.

Pollen grain entry into nasal cavity

Allergen- POLLEN GRAIN
STEP 1:
EXPOSURE OF ANTIGEN TO ANTIGEN
PRESENTING CELL
1.2- RECOGNITION BY T- HELPER CELLS

STEP 2:
ACTIVATION OF B-CELLS INTO PLASMA AND MEMORY
CELLS
AND

SECRETION OF ANTIBODIES (IgE)

STEP 3:
IgE BINDS TO HIGH AFFINITY RECEPTORS
(FC EPSILONRI)
ON THE SURFACE OF MAST CELLS

SUBSEQUENT EXPOSURE
STEP 4:
SUBSEQUENT EXPOSURE OF ANTIGEN

ANTIGEN BINDS WITH IgE ON THE SURFACE OF MAST

CELLS
STEP 5:
RELEASE OF PRIMARY INFLAMMATORY METABOLTES

ACTIVATION OF SECONDARY METABOLITES

Typical responses to these chemicals:

• Increased capillary permeability
Urticaria [hives]
• Excessive mucus production
Allergic rhinitis [hay fever]
Diarrhea or vomiting
Asthma
 MECHANISM OF ACTION
MOLECULE EFFECTS
PRIMARY MEDIATORS
HISTAMINE VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION

SEROTONIN VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION

ECF-A EOSINOPHIL CHEMOTAXIS

NCF-A NEUTROPHIL CHEMOTAXIS
PROTEASES MUCUS SECRETION, CONNECTIVE TISSUE DEGRADATION

SECONDARY MEDIATORS
LEUKOTRIENES VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION

PROSTAGLANDINS VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION

AND PLATELET ACTIVATION

BRADYKININ VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION

CYTOKINES NUMEROUS EFFECTS INC. ACTIVATION OF VASCULAR ENDOTHELIUM,

EOSINOPHIL RECRUITMENT AND ACTIVATION
 SPECIAL NOTES

The reactions, mediated by agents without IgE-

allergen interaction, are not hypersensitivity
reactions although they produce the same
symptoms.

.
Corticosteroids and other immunosuppressive agents
ANTI-INFLAMMATORY DRUGS

Epinephrine (pen-injection)
 THERAPY
THERAPY
Hypo sensitization
2X weekly, for 20 weeks
Highest dosage-Every 4 weeks for 5 years
 Usually, there are 10-12 allergens for which hypo
sensitization is done through the same lab.
 Hypo sensitization is contraindicated in Hymenoptera
venom-allergic children treated with cyclosporine.
 DeSpecific hypo sensitization is the practice of
administering gradually increasing quantities of a
specifically relevant allergen to allergic patients until
reaching a maintenance dose or loss of symptoms.
 Hypo sensitization: Hypo sensitization is used when
a patient’s allergies  span the seasons or are year
round; when symptoms are not controlled by
reasonable amounts of medication; or
when corticosteroids  cannot be used for other health
reasons.
 Ring Summary: Specific hypo sensitization is the
practice of administering gradually increasing
quantities of a specifically relevant allergen to
allergic patients until reaching a maintenance dose
or loss of symptoms.
 DIAGNOSTICS

Prick Test

IgE, a special type of antibody, mediates Allergic (type 1 hypersensitivity) reactions. When it

encounters a specific allergen IgE activates specialized cells called mast cells to produce

chemicals such as histamine and leukotrienes that cause the visible symptoms typical of an

allergic response. The skin prick assay is an ‘exposure’ test that uses this hypersensitivity

reaction, under controlled conditions, to identify what a person may be allergic to by measuring

the overactive immune response to the potential allergen.

In the allergy clinic, the patient is asked to sit and role their sleeves up. A marker pen is used to

identify on the arm where the allergens are to be applied. For every different allergen a solution

is prepared that contains the proteins that may cause an adverse reaction. Some of these

solutions are commercially produced specifically for skin prick testing but they can also be

prepared in the clinic using fresh extract from the substance suspected of causing the allergy. A

fine needle is used to gently prick the skin under the allergen solution. If IgE is present that

specifically recognizes the allergen it will activate mast cells to produce histamine, the outcome

of this will be a raised circle of reddened skin called a wheal and flare around the point of

allergen application. The presence of this wheal indicates that the patient has become

sensitized to the particular substance via a previous exposure. To check if the test is working

correctly a positive control is applied that contains histamine and should produce a reaction in

all individuals. Also a negative control is used; this is simply a saline (salty) solution.
Type 2 - antibody-dependent
In type 2 hypersensitivity, the antibodies produced by the immune response
bind to antigens on the patient's own cell surfaces. The antigens recognized
in this way may either be intrinsic ("self" antigen, innately part of the
patient's cells) or extrinsic (absorbed onto the cells during exposure to some
foreign antigen, possibly as part of infection with a pathogen). These cells
are recognized by macrophages or dendritic cells which act as antigen
presenting cells, this causes a B cell response where antibodies are produced
against the foreign antigen. An example here is the reaction to penicillin
where the drug can bind to red blood cells causing them to be recognised as
different, B cell proliferation will take place and antibodies to the drug are
produced. IgG and IgM antibodies bind to these antigens to form complexes
that activate the classical pathway of complement activation for eliminating
cells presenting foreign antigens (which are usually, but not in this case,
pathogens). That is, mediators of acute inflammation are generated at the
site and membrane attack complexes cause cell lyses and death. The
reaction takes hours to a day. Another form of type 2 hypersensitivity is
called antibody-dependent cell-mediated cytotoxicity (ADCC). Here, cells
exhibiting the foreign antigen are tagged with antibodies (IgG or IgM). These
tagged cells are then recognized by natural killer (NK) cells and
macrophages (recognized via IgG bound (via the Fc region) to the effectors
cell surface receptor, CD16 (FcγRIII)), which in turn kill these tagged cells.
Some examples:

 Autoimmune hemolytic anemia
 Goodpasture's syndrome
 Pemphigus
 Pernicious anemia (if autoimmune)
 Immune thrombocytopenia
 Transfusion reactions
 Hashimoto's thyroiditis
 Graves disease (see type V below)
 Myasthenia gravis (see type V below)
 Rheumatic fever
 Hemolytic disease of the newborn (erythroblastosis fetalis)
 Acute transplant rejection
 Type II
• Type II Hypersensitivity
• Type II hypersensitivity is also known as
cytotoxic hypersensitivity and may affect a
variety of organs and tissues. The antigens are
normally endogenous, although exogenous
chemicals (haptens) which can attach to cell
membranes can also lead to type II
hypersensitivity.

Type II
• A hypersensitivity resulting from antibodies mistakenly
reacting with normal self antigens on body cells.
Binding of the antibodies to these normal cells results
in immune destruction

• Drug-induced haemolytic anaemia, granulocytopenia

and thrombocytopenia are such examples. The
reaction time is minutes to hours. Type II
hypersensitivity is primarily mediated by antibodies of
the IgM or IgG classes and complement (Figure 2).
Phagocytes and K cells may also play a role (ADCC)
 Type II
• small molecules bound to cells and make a structure perceived
as foreign by immune cells
[ blood transfusion reactions. Erythroblastolysis foetalysis]
• Allergens create a situation that induces cytolysis or cytotoxicity.
• Antibodies involved are
IgG OR IgM
IN THIS CASE
1. MADE AGAINST SELF ANTIGENS

2. ATTACH TO THE SURFACES OF CELLS HAVING SELF EPITOPS

SELF ANTIGEN=Any constituent of the body's own tissues capable

of stimulating autoimmunity

Complement (are also involved)

• Blood proteins – initiate a series of
enzymatic reactions leading to the ‘fixing’
of complement fragments to the
pathogen’s surface – tagging it for
destruction
• Allergens trigger the classical complement
pathway: antibody binds to specific antigen
 recruitment of inflammatory cells,
opsonization  facilitating phagocytosis
 OPSONIZATION
MECHANISM
THE OPSONIZATION IS OF THE HOST CELL

PHAGOCYTES STICK TO MEMBRANES OF HOST CELL

VIA IgG, C3B, C4B

PHAGOCYTES DISCHARGE THEIR LYSOSOMES

OPSONIZATION
RESULT:
LYSIS OF HOST CELL
 MAC LYSIS
MECHANISM

TYPE-3
Type 3 - immune complex
Type 3 hypersensitivity occurs when antigens and antibodies are present in
roughly equal amounts, causing extensive cross-linking. Large immune
complexes that cannot be cleared are deposited in vessel walls and induce
an inflammatory response. The reaction can take hours, days, or even weeks
to develop. Some clinical examples:

 Rheumatoid arthritis
 Immune complex glomerulonephritis
 Serum sickness
 Subacute bacterial endocarditis
 Symptoms of malaria
 Systemic lupus erythematosus
 Arthus reaction
 Farmer's lung (Arthus-type reaction)
 Type III Hypersensitivity

• Type III hypersensitivity is also known as immune

complex hypersensitivity.
• The reaction may be general (e.g., serum sickness) or
may involve individual organs including skin (e.g.,
systemic lupus erythematosus, Arthus reaction),
kidneys (e.g., lupus nephritis), lungs (e.g.,
aspergillosis), blood vessels (e.g., polyarteritis), joints
(e.g., rheumatoid arthritis) or other organs.

MECHANISM OF ACTION
STEP 1
Large quantities of soluble antigen-antibody complexes form
in the blood and are not completely removed by
macrophages.
 MECHANISM OF ACTION
STEP 2
These antigen-antibody complexes lodge in the blood vessels
between the endothelial cells and the basement membrane.
 .
• The reaction may take 3 - 10 hours after
exposure to the antigen
• It is mediated by soluble immune complexes.
They are mostly of the IgG class, although IgM
may also be involved.

Type III
• soluble protein complexes found in blood
bound to IgG [ when non human proteins are
given therapeutically – can be side effect]
• Cause acute inflammatory reactions
• Immune complexes can become deposited
in walls of small blood vessels in alveoli 
ANAPHYLAXIS

Type 4 - cell-mediated (delayed-type hypersensitivity, DTH)

See also: Cell mediated immunity
Type 4 hypersensitivity is often called delayed type as the reaction takes two
to three days to develop. Unlike the other types, it is not antibody mediated
but rather is a type of cell-mediated response. CD8+ cytotoxic T cells and
CD4+ helper T cells recognise antigen in a complex with either type 1 or
2 major histocompatibility complex. The antigen-presenting cells in this case
are macrophages which secrete IL-12, which stimulates the proliferation of
further CD4+ T cells. CD4+ T cells secrete IL-2 and interferon gamma,
further inducing the release of other Type 1 cytokines, thus mediating the
immune response. Activated CD8+ T cells destroy target cells on contact
while activated macrophages produce hydrolytic enzymes and, on
presentation with certain intracellular pathogens, transform into
multinucleated giant cells. Some clinical examples:

 Contact dermatitis (poison ivy rash, for example)

 Atopic dermatitis (eczema)
 Temporal arteritis
 Symptoms of leprosy
 Symptoms of tuberculosis
 Mantoux test
 Coeliac disease
 Chronic transplant rejection

Type IV Hypersensitivity

• Type IV hypersensitivity is also known as cell

mediated or delayed type hypersensitivity (cytotoxic
T-lymphocytes and cytokines)
• The classical example of this hypersensitivity is
tuberculin reaction which peaks 48 hours after the
injection of antigen (PPD or old tuberculin).
• The lesion is characterized by indurations and
erythema.


 MECHANISM OF ACTION
T-H CELLS INDUCED
STEP 1
ANTIGEN ENTERS THE BODY

ENGULFED BY MACROPHAGES

PRESENTED TO T-H CELLS

T-H CELLS BECOMES ACTIVATED AND INCREASED

IN NUMBER

MECHANISM OF ACTION
T-H CELLS INDUCED
STEP 2
SECOND EXPOSURE

ENGULFED BY MACROPHAGES

PRESENTED TO T-H CELLS

T-H CELLS RELEASE CYTOKINES

 MECHANISM OF ACTION
T-H CELLS INDUCED
STEP 3
T-H 1 or TD CELLS RELEASE
CYTOKINES T-H 2 CELLS RELEASE
IL-4 AND IL-5
ATTRACTION FOR MORE
MACROPHAGES AT THE
SITE OF ATTACK
PROMOTE EXTRACELLULAR
KILLING BY EOSINOPHILS
MORE INFLAMMATION
TISSUE DAMAGE
SKIN LESIONS
 .
• Type IV hypersensitivity is involved in the
pathogenesis of many autoimmune and
infectious diseases (tuberculosis, leprosy,
blastomycosis, histoplasmosis, toxoplasmosis,
leishmaniasis, etc.)

Tuberculin Test
Tuberculin is an antigen used to aid in the diagnosis
of tuberculosis infection. An infection with the bacterium that causes
tuberculosis frequently leads to a sensitivity to these antigens. Tuberculin
was discovered by German scientist and physician Robert Koch in 1890.
The original tuberculin discovered by Koch was a glycerin extract of the
tubercle bacilli and was developed as a remedy for tuberculosis, but it was
ineffective in this role. Clemens von Pirquet discovered that patients who
had previously received injections of horse serum or smallpox vaccine had
quicker, more severe reactions to a second injection, and he coined the
word allergy to describe this hypersensitivity reaction. Soon thereafter von
Pirquet discovered the same type of reaction took place in those infected
with tuberculosis, and he thus found the utility of what would become the
tuberculin skin test. The test used in the United States at present is referred
to as the Mantoux test, in the United Kingdom it is referred to as the Heaf
test. Both of these tests use "Purified Protein Derivative", or "PPD", which is
a tuberculin derivative.
Measure of area of skin reacting to the injected antigen is tally with standard
medical graphs to confirm infection.

Measurement of Mx
CHARACTERISTI type-I type-II type-III type-IV
CS (anaphylactic) (cytotoxic) (immune (delayed type)
complex)
ANTIBODY IgE IgG, IgM IgG, IgM None

ANTIGEN exogenous cell surface soluble tissues & organs

RESPONSE TIME 15-30 minutes minutes-hours 3-8 hours 48-72 hours

APPEARANCE weal & flare lyses and erythema and erythema and
necrosis edema, necrosis indurations
HISTOLOGY basophiles and antibody and complement and monocytes and
eosinophil complement neutrophils lymphocytes
TRANSFERRED antibody antibody antibody T-cells
WITH
EXAMPLES allergic asthma, Erythro- Farmer's lung tuberculin test,
hay fever blastosis disease poison ivy,
fetalis, granuloma
 Book;
Kuby-Book on Immunology
Net;
http://www.science4u.info/virtuallab/allergy/skinpricktestbackground.htm
http://www.steadyhealth.com/encyclopedia/Hyposensitization
http://emedicine.medscape.com/article/136217-overview
http://www.bookrags.com/wiki/Hypersensitivity#Type_3_-_immune_complex
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1658254/
http://www.vaccinetruth.org/tb_testing.htm

Video;
http://www.youtube.com/watch?v=y3bOgdvV-_M
http://www.youtube.com/watch?v=olFD1R5Gu-A&feature=related
http://www.youtube.com/watch?v=tASI4UrS2T0&feature=related

Lecturer in-charge- Mrs., Beena Vinod

Salman Khan

II Sem, M.Sc Biotechnology

CMRIMS