Hypersensitivity

Dr.Kumaran Ganesan
Associate professor, IHSM
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

 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.
Musts for
Hypersensitivity
 Contact with allergen

 Sensitizing/priming dose

 Induction of AMI/CMI

 Shocking dose
Classification of Hypersensitivity
reactions
I. Immediate hypersensitivity (B cell or Ab
mediated)
Anaphylax
is 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 2. Antigen or hapten
by any route intradermally or with Freund’s
adjuvant or by skin contact
3. Circulating antibodies present 3. Circulating Abs may be
and responsible for reaction; absent and not responsible for
(Ab mediated reaction) reaction; cell mediated reaction
4. Passive transfer possible 4. Cannot be transferred with
with serum serum; but possible with T cells
or transfer factor
5. Desensitization easy but 5. Difficult, but long lasting
short lived
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

Type-I hypersensitivity
The common allergy
 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
 Anaphylaxi
s
Classical immediate hypersensitivity reaction

Ana = without

Phylaxis = protection

Coined by Richet (1902)

Experiment on Dog

Theobald’s smith (1902)

Similar phenomenon in guinea pig

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

Type I
Reactions
Humans –

Itching of scalp & tongue, flushing of skin,



difficult in breathing due to bronchial spasm

nausea, vomiting, diarrhea sometime blood
in stool, acute hypotension, loss of
consciousness, death (rare)

CausesSerum therapy, antibiotics, insect



stings

 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
SDC&H,
10/04/2011--------------------------------
------------
a congestion of the blood, occurring
in any part of the body
 PROPERTIES OF IgE

• Can not be demonstrated by conventional serological tests.

• Test –
• Skin prick test
• Radio Allergo Sorbent Test (RAST)– used to detect serum level of
allergen specific IgE
• Radio immune sorbent test (RIST) - used to detect total serum
IgE.

• IgE is homocytotrophic (species specific)

Eg: PK reaction (PRAUSNITZ-KUSTNER REACTION)
• IgE is heat sensitive.
• Can not cross placenta.
 Mediators for
Anaphylaxis

Primary mediators
Histamine : vasoactive amine formed by decarboxylation of histidine


found in mast cells, basophils and platelets


Serotonin

 Decarboxylation of tryptophan found in intestinal mucosa, brain tissue and

platelets

 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

Anaphylact oid
react ion
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

DEFINITION: “Means out of place”.

It is type I hypersensitivity that occurs spontaneously in response to

substances encountered in the environment in our daily life.
Causes:
Inhalants like pollen,house dust
Ingestants like eggs,milk
Features of Atopy:

• Atopens are not good antigens when given IV

• Mediated by Ig E,response is preponderant than normal
individual
• Familial distribution
• Reaction occurs at the site of entry of antigen
Eg :-Bronchial asthma and hay fever
• Routes of entry: ingestion, inhalation, direct contact.
At op
y
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

HYPERSENSITIVITY TYPE II
 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 II - Antibody-dependent cytotoxic hypersensitivity
Involves IgG Ab against cell surface Ag
Transfusion reactions and hemolytic disease of the newborn (HDNB)
Leads to cell surface tissue damage through effector cell and complement
activation
Examples of Type II Hypersensitivity

• Blood transfusion reactions

• Hemolytic disease of the newborn (Rh disease)

• Autoimmune hemolytic anemias

• Drug reactions

• Drug-induced loss of self-tolerance

• Hyperacute graft rejection

• Myasthenia gravis (acetylcholine receptor)

• Sensitivity to tissue antigens

 DEMONSTRATION OF TYPE II REACTION

• Direct antiglobulin test (coombs test) –positive

• Agglutination tests, CFT, precipitation

tests,immunofluorescence
Result Interpretation of Coomb’s Test
 Applications of Coomb’s Test

1. Coombs’ tests are used for detection of anti-Rh antibodies.

2. It is also used to detect incomplete antibodies in brucellosis.
3. The indirect Coombs test is used in prenatal testing of pregnant
women.
4. The test is done on the newborn’s blood sample, usually in the setting
of a newborn with jaundice.
5. It helps in the detection of conditions like hemolytic anemia, chronic
lymphocytic leukemia, erythroblastosis fetalis, infectious
mononucleosis, mycoplasmal infection, syphilis, systemic lupus
erythematosus etc.
• humoral antibody mediated hypersensitivity reaction

• Deposition of Ag-Ab complexes in tissues

• Characterised by deposition of ag – ab immune complexes in organs

which activate complement and cause inflammatory damage.
• Antigen can be endogenous ( Auto immunity) or exogenous
 Persistant infection
eg: Malaria, Hepatitis B
Staphylococcal endocarditis,
Post streptococcal glomerulornephritis
Polyarteritis nodosa (PAN)

 Autoimmunity
eg: Systemic lupus erythematosus,
Rheumaoid arthritis
2 forms :

• Arthus reaction:
a local manifestation of generalised anaphylaxis

• Systemic anaphylaxis : Serum sickness

A generalised form
 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
Hypersensitivity pneumonitis :
• Inhalation – exogenous Ag-allergic alveolitis

eg:
• Farmer’s lung (spores thermophilic actinomycetes)
• Bagassosis (sugarcane) inhalation of fibrous cane sugar
• Cheese-washer’s (penicillium spores)

Hypersensitivity due to internal antigens :

• Filarial worms (dead)
• Dapsone therapy in leprosy( release of bacterial antigens)
 Arthus reaction
Arthus reaction Wheal & flare reaction
Type-III Type-I

Repeated subcutaneous injection of antigen (horse)into rabbits

High precipitating antibody appears in blood

Same Ag injected subcutaneously / ID

intense local edema- reaches peak in 3-6 hrs

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 sickness
 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


• Cutaneous Basophil hypersensitivity
• Tuberculin type
• Contact dermatitis type (with in 72 hrs )
Group organisms
• Bacteria M.tuberculosis, M.leprae,
Listerria monocytogenes, Salmonella
Yersinia pestis, Brucella, Rickettsiae

 Fungus Histoplasma capsulatum

 Protozoa Toxoplasma gondii, Leishmania donovani

 Jones Mote reaction
• Cutaneous basophil hypersensitivity

• different from classical delayed and immediate type

• basophils on arrival at local site -degranulation , released

vasoamine having protective and regulatory effects

• induced by:
viruses, allografts, parasite, fungal antigens etc

• reaction mediated by both T and B LYMPHOCYTES

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
Mantoux Test
 Positive test :
Earlier Infected / vaccinated

Skin test :
 Tuberculin test:
 Lepromin test: Positive in tuberculoid type
 Frei test : lymphogranuloma venerum
 Histoplasmin & Toxoplasmin
 Viral infections: Herpex simplex, Mumps
 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.
 DHT- develops at localised area of skin due to repeated contact

Act as haptens.

Sensitising materials:
 Drugs:
topical application
penicillin/antibiotic/ creams
 Metals:
nickel, chromium
 chemicals:
hair dyes, picryl chloride,
formaldehyde, dinitrochlorobenzene,
cosmetics, soaps
 Contact dermatitis reaction

Detection by patch test:

 Suspected allergen applied on a small area of skin under an adherent

dressing.

 Sensitised individual develops itching in 4-5 hrs

• Modification of type II

• Interaction of Ab with Ag on cell surface

• cell proliferation
• Instead of binding to cell surface components thus,
impairing cell signalling

• Eg: stimulatory type is Graves disease

Thyroid hormones produced in excess
• Not an immune response
• Specialised type of disseminated intravascular coagulation (DIC)
• Resemblance to hypersensitivity reaction
• Precipitated by endotoxin

Eg: S.typhi culture filtrate

• route of endotoxin : 2 doses- IV after 24 hrs

• A haemorrhagic necrotic lesion(RES block)

• Consequently DIC (RES fails to remove endotoxin )

• Meningococcal septicaemia
• Dengue haemorrhagic fever
Comparison of
hypersensitivity reactions
characteristic Type-I Type-II Type-III Type-IV
antibody IgE IgG, IgM IgG, IgM none
antigen exogenous cell surface soluble intracellular
response 15-30 min. Min.-hrs 3-8 hours 48-72 hours
time or longer
appearan Wheal & Lysis & Erythema & Erythema &
ce flare necrosis edema induration

histology baso- and Ab and PMN and Monocytes &

eosinophils complement complement lymphocytes
transfer with antibody antibody antibody T-cells
examples hay pemphigus, farmers’ TB test,
fever, Goodpastur lung, poison ivy,
asthma e SLE granuloma