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Hypersensitivity Reactions
basics
Dr.T.V.Rao MD
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Hypersentivity Reactions
Allergies Greek = altered reactivity
1906 – von Pirquet coined term: hypersensitivity
Hypersensitivity reactions – ‘over reaction’ of the
immune system to harmless environmental
antigens
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Definition
• Definition :
Hypersensitivity
refers to the
injurious
consequences in
the sensitized host
,Following contact
with specific
Antigen
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How we classify Hypersensitivity
• 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.
• Hypersensitivity reactions can be divided into
four types: type I, type II, type III and type IV,
based on the mechanisms involved and time
taken for the reaction.
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Hypersensitivity
Immunity protects against
Infections, Toxins.
Many other functions.
But Immunity can be Injurious,
When exaggerated causes
Tissue Damage,
Disease and Death
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Immune response is
altered • In hypersensitivity
Antigen is not
Important But what
happens as a
result of Immune
reaction
• Allergy a Synonym
for Hypersensitivity.
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What happens in Hypersensitivity
• Initial contact sensitizes the
Immune system. The antigen acts
as priming dose
• Causes the priming of B/T
Lymphocytes,
• Subsequent dose a shocking
dose. 7 Dr.T.V.Rao MD
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Classification of Hypersensitivity
Coombs and Gell • Classified into 4 types on Mechanism and
Pathogenicity
• Type I
Generalized – Anaphylactic shock.
Localized - Hay fever, Asthma
Type II Cytotoxic ( Antigen + Antibody )
Type III Immune complex
Type IV Cell Mediated.
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Hypersensitivity reactions
Type Mechanism Antigen Onset
I IgE-Ag triggers
Mast cell mediators Allergen minutes
II IgG or IgM binds to
cell surface; ADCC
or complement
Cell surface
molecule Few
hours
III
Immune complexes,
inflammation Soluble or
particulate Few
hours
IV Cytokines (T cells,
Macrophages, CTL) Chemicals,
intracellular 1-3
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Classification of Hypersensitivity
• Immediate and Delayed.
Immediate type
Also called as Immediate
Hypersensitivity
Popularly called as B cell Mediated
Hypersensitivity
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Examples of Immediate
Hypersensitivity
• Anaphylaxis
• Atopy,
• Antibody mediated cell
damage.
• Arthus Phenomenon
• Serum sickness
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Hypersensitivity-1
• Inappropriate immune responses
• Type I are immediate type, in which
antigen binds to IgE on mast cells,
histamine released.
– Histamine: smooth muscle contraction,
vasodilatation.
– Results in asthma, diarrhea, shock depending
on where antigen enters body. Ex. Bee sting
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Type II Hypersentivity
• Type II are cytotoxic reactions like the Rh factor problem and bad blood transfusions.
– Rh is one of many blood groups, like ABO
– An Rh+ fetus in an Rh- mother means she gets immunized by baby’s blood cells, makes Antibodies.
– Second pregnancy, fetal RBCs are attacked.
– Solution: give Rho-gam during 1st pregnancy.
• .
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Type III and IV
• Type III are immune complex
disorders, where too many agn-
aby clumps cause inflammation
• Type IV are delayed type, T cell
produces various cytokines which
affect macrophages.
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Type IV
• Type IV are delayed type, T cell
produces various cytokines which
affect macrophages.
–The bar fight scenario: come, stay, get
angry.
–Angry macrophages cause much tissue
damage.
–Ex. Poison ivy; urushiol-coated cells
killed. 15 Dr.T.V.Rao MD
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Delayed Hypersensitivity
T Cell Mediated
• Tuberculin
type.
• Contact
dermatitis.
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Type I Hypersensitivity
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Examples of Immediate
Hypersensitivity
• Anaphylaxis
• Atopy,
• Antibody mediated cell damage.
• Arthus Phenomenon
• Serum sickness
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Type I hypersensitivity
• Anaphylaxis = Ana means without
Phylaxis protection ( Rich )
Sensitizing dose more effective when given parentally
Antigen can hapten also may take 2-3 weeks to produce sufficient IgE
Shocking dose is effective if given IV
The nature of antigen should correspond to antibodies
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Type I
• Anaphylactic Ig E ( Reagin )
• Antibodies are fixed on Tissue cells
• Eg Mast cells and Basophils
• Antigen + Antibody combination causes
release of Pharmacologically active
substances
• Occurs in Acute and Chronic or recurrent
form (Non Fatal and localized Atopy)
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Anaphylaxis
• Classical Immediate Hypersensitivity
• Experiments in dogs with Sea anemones
• Guinea pigs
• By any route with Antigens and Haptens
• 2-3 weeks later with sensitizing or
shocking dose I V
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The type I – anaphylaxis involves
• The target organs are several vital organs
and tissues,
• On the target tissue, causes
oedema,decreased coagabulity of Blood
• Leads to fall of Blood pressure
• Leucopenia and thrombocytopenia
• Guinea pigs are highly sensitive
• Human are intermediate in reactivity
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Experiment in Guinea pig
• A guinea pig is
injected with small
dose of antigen eg
Egg albumin no
reaction observed.
• The same animal
injected with egg
albumin after 2 weeks
by IV route
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2nd dose produces Anaphylaxis
• The 2nd produced anaphylactic shock
• Manifested with
Restlessness
Chewing and rubbing nose
Wheeze
Developed convulsions
Animal died
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Same is experienced in
Humans
• With bee
sting
• Penicillin
administration
• Happens in
sensitized
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Local reactions happen
• Asthma
• Hay fever
• The reactions depend on the level of IgE
• The biologically active molecules are
present in in the mast cells and Basophilic
granules synthesize to active production
after triggering with antigenic stimulations.
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Nature of IgE
• Present in low
fractions compared
with other
Immunoglobulin's
• IgE is heat sensitive
inactivated at 560c in
2 – 4 hours heat
causes damage to Fc
particle
• IgA deficiency produces
excessive IgE
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The biological mediator on effect stage 1. Histamine:
Dilate blood vessel Increase vascular permeability
2. Leukotriene's:
Bronchial smooth muscles contract Asthmas
3. Prostaglandin:
High concentration of PGE Inhibit the secretion of histamine
low concentration of PGE promote the release of histamine
4. Platelet activating factor (PAF) :
Agglutinate and activate platelets to release histamine
5. Eosinophil chemotactic factor(ECF-A):
6. Bradykynin :
Vasodilator function 29 Dr.T.V.Rao MD
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Important chemical and substances
produced to cause reaction
• Histamine: Dilates and increases
permeability of blood vessels (swelling
and redness), increases mucus
secretion (runny nose), smooth muscle
contraction (bronchi).
• Prostaglandins: Contraction of smooth
muscle of respiratory system and
increased mucus secretion.
• Leukotriene's: Bronchial spasms.
– Anaphylactic shock: Massive drop 30 Dr.T.V.Rao MD
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4. Skin allergy:
4. Common disease of type I hypersensitivity
1. Systemic anaphylaxis: a very dangerous syndrome
1) Anaphylactic drug allergy :penicillin
2) Anaphylactic serum allergy :
2. Respiratory allergic diseases :
1) Allergic asthma:acute response, chronic response
2) Allergic rhinitis
3. Gastrointestinal allergic diseases :
The lack of SIgA protein hydrolase Undigested protein Allergen
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Atopy
• When the antigen and antibody IgE react
produce certain pharmacologically active
substances
Can cause
Conjunctivitis,
Rhinitis
G E involvement
Dermal involvement Urticaria
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p. 374
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Primary Mediators of
Anaphylaxis • Histamine an vasoactive in human Anaphylaxis
• Histidine on Decarboxylation to Histamine
• Stimulates the sensory nerves
• Causes burning and itching
• Causes vasodilatation and hyperemia
• Smooth muscle stimulation
• Affects the Intestines, Uterus, Especially
bronchioles
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Effects of type I reactions
Systemic anaphylaxis
Respiration becomes difficult
Blood pressure drops
Smooth muscles of bladder and GI tract
contract
Bronchoconstriction
Countered by epinephrine
relaxes smooth muscles
decreases vascular permeability
improves cardiac output
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Mechanism of Anaphylaxis
• Ig E cell fixed on Mast cells and
Basophiles.
• Antigen + Antibody
• Bridges the gap
• Leads to deregulation
• Releases Biologically active substances
from granules of the cells.
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Histamine release occurs within
minutes
Binds to receptors on target cells
smooth muscles contract
eosinophil's attracted
mucus secretion
platelet activation
blood vessel dilation
Blocked by various compounds: antihistamines,
Epinephrine, corticosteroids 38 Dr.T.V.Rao MD
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Secondary mediators of
Anaphylaxis
• Prostaglandins Leukotriene's
• Thromboxane's,
Lead to manifestation with
1Transient constriction of
Bronchioles
2 Dilatation of capillaries,
3 Platelet activation factor, 39 Dr.T.V.Rao MD
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Serotonin
• Produces on Decarboxylation of
Tryptophan
• Found in Intestines, Mucosa, Brain tissue,
Platelets
• Causes smooth muscle contraction
• Increases capillary permeability
• Vasoconstriction
• Human ?
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Other factors
• Heparin Not
in human
• Enzymatic
mediators
proteases
and
hydrolases
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Effects of Histamine
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Many of us suffer
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Secondary factors in
anaphylaxis
• Prostaglandins and Leukotriene's releases
from disrupted cell membranes
• Mast cells and other leukotriene's
• Slow reacting substances
• Prostaglandins affects secretion by
mucosal glands
• Platelet activating factor – aggregates
platelets ad release vasoactive amines
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Other Mediators
• By complement
activation
• Bradykynin
• Anphylactoid
reactions can be
caused due to IV
Peptone, Trypsin
by IV routes
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Clinical effects • Causes smooth muscle contraction.
• Increased vascular permeability
• Many organs Target organ – shock organ
• Causes
Edema Fall of BP, Coagulation of Blood, Leucopenia, thrombocytopenia
Guinea pigs most susceptible
Humans Intermediate
Bee stings, Penicillin,
Causes the constriction of smooth muscles( Bronchioles )
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Clinical effects in Humans
• Itching of scalp, Tongue
• Flushing of skin, Bronchial spasm
• Hypotension
• Loss of consciousness and Death
• Previously with serum
• Now with Antibiotics.
• Adrenaline is life saving 0.5 ml 1:1000 dils
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Clinical effects
Cutaneous Anaphylaxis • Intradermal Injection
in sensitized host
• Wheal and flare
reaction
• Useful in skin testing
( But dangerous )
• Passive cutaneous
anaphylaxis.
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Skin tests
Skin test via intra
dermal injection of
allergens: if an
individual is allergic
to the substance
injected, local mast
cells de granulate
producing a “wheel
and flare” response
within minutes
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Secondary Mediators of
Anaphylaxis
• Slow reacting
substances
• Prostaglandins,
• Platelet
activating factors
Cytokines
• IL3, IL4, IL5
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Atopy
• Agent Inhaled – Pollens /Dust
• Ingested – Egg , Milk
• Contact with skin – Conjunctiva
• Ig E is over produced
• Bottle fed infants
• Estimation of Ig E by RAST
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5. Therapy of type I hypersensitivity
1. Allergen avoidance : Atopy patch test
2. Desensitivity therapy / Hyposensitization :
1) Allogenic serum desensitivity therapy:
2) Specific allergen desensitivity therapy
Repeated injection small amounts of allergen, Temporality
IgG+allergen Neutralizing antibody, Blocking antibody
3. Drug therapy:
1) Stabilization of triggering cells
sodium cromoglycate stabilize the membrane, inhibit mast cell degranulation
2) Mediator antagonism
Chlor-Trimeton Antihistamine
Acetylsalicylic acid Bradykinin antagonism
3) Improve the responsibility of target organs
4. New immunotherapy :
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Hypersensitivity type II
Reactions
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Type II Hypersensitivity
• Type II hypersensitivity or cytotoxic
hypersensitivity is caused by
antibody-mediated reactions. When
the immune system reacts to antigens
it produces various Immunoglobulin's
or antibodies, usually long-lasting
immunoglobulin G (IgG) antibodies.
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Type II (Cytotoxic) Reactions
– Involve activation of complement by IgG or IgM binding to an antigenic cell.
– Antigenic cell is lysed.
– Transfusion reactions:
• ABO Blood group system: Type O is universal donor. Incompatible donor cells are lysed as they enter bloodstream.
• Rh Blood Group System: 85% of population is Rh positive. Those who are Rh negative can be sensitized to destroy Rh positive blood cells.
– Hemolytic disease of newborn: Fetal cells are destroyed by maternal anti-Rh antibodies that cross the placenta.
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What Happens in type II
• Ig G and Ig M combines with antigenic determinants on the cells.
• Leads to cytotoxic and catalytic effects
Eg - Anti erythrocyte antibodies in autoimmune anemia's and hemolytic disease of the new born.
Other free antigens or hapten may be absorbed on the cell surface
Subsequent reactions will lead to cell damage
Drugs too behave in the same way
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Type II Hypersensitivity
• LATS Antibodies
stimulate
determinants on
Thyroid – Leads to
excessive
secretion of
Thyroid hormones
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Haptens too can produce type
II Hypersensitivity • . The antigens are
normally endogenous,
although exogenous
chemicals (haptens)
which can attach to
cell membranes can
also lead to type II
hypersensitivity.
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Type II Hypersensitivity
• The binding of these antibodies to
the surface of host cells then
leads to:
• opsonization of the host cells
whereby phagocytes stick to host
cells by way of IgG, C3b, or C4b
and discharge their lysosomes
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Type II Hypersensitivity (Contd)
• Anti erythrocyte antibodies
• Autoimmune Anemia's Hemolytic
anemia's.
• Antigen + Antibody =Cell damage
• Even Hap tens act in the place of Antigen
• Disrupts the normal function
• Graves disease , Myasthenia gravis.
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Opsonization During Type-II
Hypersensitivity, Step-1
The Fab of IgG reacts with epitopes on the host cell membrane. Phagocytes bind to the Fc portion
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Opsonization During Type-II Hypersensitivity,
Step-2
Phagocytes binding to the Fc portion of the IgG and discharge their lysosomes causing cell
lysis.
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Examples of Type II Hypersensitivity.
• Pemphigus: IgG antibodies that react with the intracellular substance found between epidermal cells.
• Autoimmune haemolytic anaemia (AHA): This disease is generally inspired by a drug such as penicillin that becomes attached to the surface of red blood cells (RBC) and acts as hapten for the production of antibody which then binds the RBC surface leading to lysis of RBCs.
• .
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Good pasture's syndrome
• Good pasture's
syndrome: Generally
manifested as a
glomerulonephritis,
IgG antibodies that
react against
glomerular basement
membrane surfaces
can lead to kidney
destruction
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Type II Hypersensitivity
• Salmonella , and Mycobacterium can produce Hemolytic crisis
• Diagnostic tests include detection of circulating antibody against the tissues involved and the presence of antibody and complement in the lesion (biopsy) by immunofluorescence
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Type III Hypersensitivity
Reactions
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Introduction • Immune
complexes(Ag and Ab)
deposit in tissues
such as blood vessels
and glomeruli.
• activate
complement, and
cause tissue injury
or dysfunctional
responses.
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Arthus reaction • Injecting repeatedly sc Normal horse serum
• Later injections leads edema, indurations
hemorrhagic necrosis
manifest as localize from of generalized hypersensitivity
Damage is caused due to Antigen and antibody complexes, leads to activation of complement
Release of inflammatory molecules
Vascular permeability, infiltration of neutrophils.
Causes tissue necrosis
Eg Inhalation of Actinomyctes from mouldy hay grain causes Farmer’s lung
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Type III Hypersensitivity
• Example of a Type III hypersensitivity is
serum sickness, a condition that may
develop when a patient is injected with a
large amount of e.g. antitoxin that was
produced in an animal. After about 10
days, anti-antitoxin antibodies react with
the antitoxin forming immune complexes
that deposit in tissues.
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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 erythematous, Arthurs reaction),
kidneys (e.g., lupus nephritis), lungs (e.g.,
Aspergillosis), blood vessels (e.g., polyarteritis),
joints (e.g., rheumatoid arthritis) or other organs.
This reaction may be the pathogenic mechanism
of diseases caused by many microorganism
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Type III Hypersensitivity
• Antigen and Antibody complexes
• Accumulate around the small blood vessels cause damage to cell
• Arthus Reaction
Occurs as a local manifestation
Antigen + Antibody complexes
Releases Inflammatory molecules,
Infiltration with Neutrophils
Reduces blood supply
Other example – Inhaled antigens produce Farmers lung
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Neutrophil
C1 C2
C4
C3b & C5b
C5-C9
C3
C3a & C5a
Type III Hypersensitivity mechanism
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2- Serum Sickness * A systemic immune complex phenomenon
* Injection of large doses of foreign serum
* Antigen is slowly cleared from circulation
* Immune complexes are deposited in various sites
fever
urticaria
* 10 days after injection Arthralgia
lymphadenopathy
splenomegaly
glomerulonephritis
antidiphtheritic serum
e.g. treatment with penicillin
sulphonamides
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Mechanism of damage in type-III
hypersensitivity
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Deposition of immune complexes
in blood vessel walls
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Disorders of the Immune System: Immune Complex Disease
Glomerular basement membrane of kidney
Large complex
Endothelial cell
Small complex 76 Dr.T.V.Rao MD
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Type III Hypersensitivity (Cont )
• Serum Sickness –
Systematic form of Type III
Diphtheria Antiserum produces antibodies
Produces
Fever,
Lymphadenopathy
Splenomegaly
Arthritis
Glomerulonephritis
Endocarditis and Vasculitis
Mechanism – Foreign serum and antibodies Deposit in Endothelial Lining on Blood vessels.
Many times self limited.
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Serum Sickness
• May last for 7-10 days.
• Bacterial Viral and Parasitic infection produce serum sickness.
• Important Diseases
Post Streptococcal Glomerulonephritis
Hepatitis B Infections
Auto immune conditions.
Disseminate malignancies.
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Diagnosis and Treatment
• The presence of immune complexes in
serum and depletion in the level of
complement are also diagnostic.
Polyethylene glycol-mediated turbidity
(Nephelometry), binding of C1q and Raji
cell test are utilized to detect immune
complexes. Treatment includes anti-
inflammatory agents.
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Type IV Hypersensitivity
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Type IV Hypersensitivity
• Type IV hypersensitivity is often
called delayed type hypersensitivity
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
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Type IV Reaction
Delayed Hypersensitivity • Also called as Cell Mediated
Immunity,
• Stimulates – Sensitizes CD4/CD8.
• Secretion of Lymhokines
Fluid/Phagocytes accumulate.
Not Induced by antibodies
T Cell Th1 Th2 Tc Take
active part
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Delayed hypersensitivity.
• The reaction elicited by antigen occurs
relatively slowly (hence the name "delayed
hypersensitivity").
• The hypersensitivity is mediated via T-
cells and macrophages.
• The hypersensitivity illustrates both
antigen-specific (T-cell) and antigen non-
specific (macrophage) characteristics
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Type IV hypersensitivity is T cell
mediated
• The type IV hypersensitivity differs from the other three types of reactions in that it is not caused by antibodies, but by immunocompetent cells (lymphocytes). These lymphocytes are immunologically specific with receptors for the antigens, which can be different tissues (tissue antigens) or small molecular substances which, when fixed to the cell membrane, can function as antigens.
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Type IV Reactions
• Type IV reactions, which are also called
delayed hypersensitivity reactions, as a
rule occur 12 - 48 hours after exposure to
the antigen. Type IV reactions lead to
inflammatory tissue damage and
infiltration of cells, which are principally
mononuclear (lymphocytes and
macrophages).
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Type IV reactions
• The inflammatory reaction leads to
irreversible damage with deterioration of
the tissue. The classical examples of type
IV hypersensitivity are the positive
tuberculin reaction, contact dermatitis
(e.g. caused by nickel or chrome) and
rejection of tissues transplanted from other
individual
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Mechanisms of damage in delayed
hypersensitivity
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Several diseases based on
Delayed Hypersensitivity
• Type IV hypersensitivity is involved in the
pathogenesis of many autoimmune and
infectious diseases (tuberculosis, leprosy,
blastomycosis, Histoplasmosis,
toxoplasmosis, leishmaniasis, etc.)
granulomas due to infections and foreign
bodies
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Tuberculin Type ( IV )
• Tuberculin reaction.
• Tuberculin Injection
• Sensitized to Tuberculin protein.
• Indurations develop at the site < 48 hours.
• Unsensitized
No response
Bacteria,
Fungi,
Viruses,
Parasites
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Tuberculin Test
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Measurement of Induration
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Immune Complex Mediated
Hypersensitivity
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Other agents stimulating Type IV
Hypersensitivity
• Topical application of Penicillin in
creams
• Lange ham cells in epidermis absorb
the drug or chemical T Cells are
stimulated
• Lymph nodes acts as store houses
• Repeated applications leads to
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3. Common disease of type IV hypersensitivity
1) Infectious delayed type hypersensitivity
OT( Old Tuberculin ) test
2) Contact dermatitis :
Paint, drug red rash, papula, water blister, dermatitis
3) Acute rejection of allogenic transplantation and
immune response in local tumor mass
Same disease (SLE), multiple immune injury ,hypersensitivity involved
Same drug (penicillin), several types of hypersensitivity
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*a contact-sensitizing agent is usually a small molecule that
penetrates the skin then binds to self-proteins, making the
protein “look” foreign
Can be caused by poison ivy and mango sap Contact Dermatitis
DTH as a result of a contact-sensitizing agent*
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Contact dermatitis
• Contact dermatitis
or Irritant dermatitis
is a term for a skin
reaction resulting
from exposure to
allergens (allergic
contact dermatitis) or
irritants (irritant
contact dermatitis).
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Contact Dermatitis ( IV )
• Delayed hypersensitivity – Skin contact.
• Cell Mediated response.
• Nickel, Chromium, Dyes , Penicillin's
• Antigens absorbed,
• Langerhams cells capture – Migrate to
draining lymph nodes,
• Present the processed Antigens with MHC
molecules to Immune cells.
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• Created by Dr.T.V.Rao MD for Undergraduate
Medical and Paramedical students in the
Developing world
Dr.T.V.Rao MD 101