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Hypersensitivity
By HIMANSHI DUBEY
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Introduction
An immune responsemobilizes a battery
of effector moleculesthat act to removeantigen by various
mechanisms.
Generally, theseeffector moleculesinduce a localized
inflammatoryresponse that
eliminates antigenwithout extensivelydamaging the hosts
tissue.
Under certaincircumstanceshowever, thisinflammatory
response can havedeleterious effects,
resulting insignificant tissuedamage or even
death.
This inappropriate
immune responseis termed
hypersensitivity orallergy.
Portier and Richet coined the term anaphylaxis.
loosely translated from Greek to mean the opposite ofprophylaxis, to describe this overreaction.
Richet was subsequently awarded the Nobel Prize in Physiology
or Medicine in 1913 for his work on anaphylaxis.
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The four types of hypersensitivity response
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ALLERGENS
Allergens are nonparasite antigens that can stimulate atype I hypersensitivity response.
Allergens bind to IgE and trigger degranulation ofchemical mediators.
Characteristics of allergens:
Small 15-40,000 MW proteins.
Specific protein components-Often enzymes.
Low dose of allergenMucosal exposure
Most allergens promote a Th2 immune.
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Atopy Atopy is the term for the genetic trait to have
a predisposition for localized anaphylaxis.
Atopic individuals have higher levels of IgE and
eosinophils.
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Genetic Predisposition
Type I hypersensitivity
Candidate polymorphic genes include:
IL-4 Receptor.
IL-4 cytokine (promoter region).
FceRI.
High affinity IgE receptor.
Class II MHC (present peptides promoting Th2
response).
Inflammation genes.
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Type I hypersensitive reactions
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Mechanisms of allergic response Sensitization
Exposure to an allergen activates B cells to form IgEsecreting plasma cells.
The secreted IgE molecules bind to IgEspecific Fc
receptors on mast cells and blood basophils. (Many
molecules of IgE with various specificities can bind to
the IgE-Fc receptor).
Second exposure to the allergen leads to crosslinking
of the bound IgE, triggering the release ofpharmacologically active mediators, vasoactive
amines, from mast cells and basophils.
The mediators cause smooth-muscle contraction,
increased vascular permeability, and vasodilation
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Schematic diagrams of the high-affinity FcRI and low-affinity FcRII receptors that bind the Fc region of IgE. (a)
Each chain of the high-affinity receptor contains an ITAM, a motif also present in the Ig-/Ig- heterodimer of
the B-cell receptor and in the CD3 complex of the T-cell receptor. (b) The low-affinity receptor is unusual
because it is oriented in the membrane with its NH2 terminus directed toward the cell interior and its COOH-
terminus directed toward the extracellular space.
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IgE Crosslinkage Initiates Degranulation
Schematic diagrams of mechanisms that can trigger degranulation of mast cells.
Note that mechanisms (b) and (c) do not require allergen; mechanisms (d) and (e)
require neither allergen nor IgE; and mechanism (e) does not even require
receptor crosslinkage.
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Allergen crosslinkage of bound IgE results in FcRIaggregation and activation of protein tyrosinekinase (PTK).
PTK then phosphorylates phospholipase C, whichconverts phosphatidylinositol-4,5 bisphosphate(PIP2) into diacylglycerol (DAG) and inositoltriphosphate (IP3).
DAG activates protein kinase C (PKC), which withCa2+ is necessary for microtubular assembly andthe fusion of the granules with the plasmamembrane.
IP3 is a potent mobilizer of intracellular Ca2+stores .
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Crosslinkage of FcRI also activates an enzyme thatconverts phosphatidylserine (PS) intophosphatidylethanolamine (PE).
Eventually, PE is methylated to form phosphatidylcholine(PC) by the phospholipid methyl transferase enzymes Iand II (PMT I and II).
The accumulation of PC on the exterior surface of theplasma membrane causes an increase in membranefluidity and facilitates the formation of Ca2+ channels.
The resulting influx of Ca2+ activates phospholipase A2,which promotes the breakdown of PC intolysophosphatidylcholine (lyso PC) and arachidonic acid.
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Arachidonic acid is converted into potent mediators: theleukotrienes and prostaglandin D2.
FcRI crosslinkage also activates the membrane adenylatecyclase, leading to a transient increase of cAMP within 15 s.
A later drop in cAMP levels is mediated by protein kinase and isrequired for degranulation to proceed.
cAMP-dependent protein kinases are thought to phosphorylatethe granule-membrane proteins, thereby changing thepermeability of the granules to water and Ca2+.
The consequent swelling of the granules facilitates fusion withthe plasma membrane and release of the mediators.
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Principal mediators involved in type I hypersensitivity
PRIMARY
Histamine, heparin Increased vascular permeability; smooth-muscle
contraction
Serotonin Increased vascular permeability; smooth-muscle
contraction
Eosinophil chemotactic factor (ECF-
A)
Eosinophil chemotaxis
Neutrophil chemotactic factor (NCF-
A)
Neutrophil chemotaxis
Proteases Bronchial mucus secretion; degradation of blood-
vessel basement membrane;generation of
complement split products
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SECONDARY
Platelet-activating factor Platelet aggregation and degranulation;
contraction of pulmonary smooth muscles
Leukotrienes (slow reactive
substance
of anaphylaxis, SRS-A)
Increased vascular permeability; contraction of
pulmonary smooth muscles
Prostaglandins Vasodilation; contraction of pulmonary smooth
muscles; platelet aggregation
Bradykinin Increased vascular permeability; smooth-
muscle contraction
Cytokines
IL-1 and TNF-aIL-2, IL-3, IL-4, IL-5, IL-6, TGF-,
and GM-CSF
Systemic anaphylaxis; increased expression of
CAMs on venular endothelial cells Variouseffects
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Continuation of sensitization cycle
Mast cells control the immediate response. Eosinophils and neutrophils drive late or chronic
response.
More IgE production further driven by activated Mastcells, basophils, eosinophils.
Eosinophils
Eosinophils play key role in late phase reaction.
Eosinophils make enzymes,cytokines (IL-3, IL-5, GM-CSF),Lipid mediators (LTC4, LTD4, PAF)
Eosinophils can provide CD40L and IL-4 for B cellactivation.
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Localized anaphylaxis
Target organ responds to direct contact withallergen.
Digestive tract contact results in vomiting,
cramping, diarrhea. Skin sensitivity usually reddened inflamed
area resulting in itching.
Airway sensitivity results in sneezing and
rhinitis OR wheezing and asthma.
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Systemic anaphylaxis
Systemic vasodilation and smooth muscle
contraction leading to severe bronchiole
constriction, edema, and shock.
Similar to systemic inflammation.
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Treatment for Type I
Pharmacotherapy Drugs
Non-steroidal anti inflammatories
Antihistamines block histamine receptors.
Steroids
Theophylline OR epinephrine -prolongs or increases cAMPlevels in mast cells which inhibits degranulation.
Immunotherapy
Desensitization (hyposensitization) also known as allergyshots.
Repeated injections of allergen to reduce the IgE on Mastcells and produce IgG.
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Hyposensitization treatment of type I
allergy. Injection of ragweed antigenperiodically for 2 years into a ragweed
sensitive individual induced a gradual
decrease in IgE levels and a dramatic
increase in IgG. Both antibodies were
measured by a radioimmunoassay.
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Antibody-Mediated
Cytotoxic (Type II)
Hypersensitivity
a)Structure of
terminal sugars, which
constitute the
distinguishing
epitopes, in the A, B,and O blood antigens.
b) ABO genotypes and
corresponding
phenotypes,
agglutinins, andisohem agglutinins
Antibody
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Antibody
mediated
cytotoxicity
Drug reactions
Drug binds torbc surface andantibody against
drug binds andcauses lysis ofrbcs.
Immune systemsees antibodybound to"foreignantigen" oncell. ADCC
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Hemolytic disease of newborn
Rh factor incompatibility
IgG abs to Rh an innocuous rbc antigen.
Rh+ baby born to Rh- mother first time fine.
2nd time can have abs to Rh from 1st pregnancy.
Ab crosses placenta and baby kills its own rbc.Treat mother with ab to Rh antigen right after
birth and mother never makes its own immuneresponse.
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Hemolytic Disease of the Newborn
Is Caused by Type II Reactions
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Antigen antibody immune complexes.
IgG mediated
Immune Complex Disease Large amount of
antigen and antibodies form complexes in
blood.
If not eliminated can deposit in capillaries or
joints and trigger inflammation.
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Drug-Induced Hemolytic
Anemia Is
a Type II Response
A type II hypersensitive reaction
occurs when antibody reacts
with antigenic determinants
present on the surface of cells,leading to cell damage or death
through complement mediated
lysis or antibody-dependent cell-
mediated cytotoxicity (ADCC).
Transfusion reactions andhemolytic disease of the
newborn are type II reactions.
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Immune Complex Mediated
(Type III) Hypersensitivity
Development of a localized Arthusreaction (type III hypersensitive
reaction).
Complement activation initiated by
immune complexes (classical pathway
produces complement intermediates
That
(1) mediate mast-cell degranulation,
(2) chemotactically attract
neutrophils, and
(3) stimulate release of lytic enzymes
from neutrophils
trying to phagocytose C3b-coated
immune complexes.
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Type IV hypersensitive
reaction
A type IV hypersensitivereaction involves the cell-
mediated branch of the
immune system. Antigen
activation of sensitized
TH1 cells induces releaseof various cytokines that
cause macrophages to
accumulate and become
activated. The net effect
of the activation ofmacrophages is to release
lytic enzymes that cause
localized tissue damage.
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Several Phases
of the DTH Response
In the sensitization phaseafter initial contact with
antigen (e.g., peptides
derived from intra-cellular
bacteria), TH cellsproliferate and
differentiate into TH1 cells.
Cytokines secreted by
these T cells are indicated
by the dark blue balls.
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Several Phases
of the DTH Response
In the effector phase aftersubsequent exposure of
sensitized TH1 cells to
antigen, the TH1 cells secrete
a variety of cytokines and
chemokines.
These factors attract andactivate macrophages and
other nonspecific
inflammatory cells.
Activated macrophages are
more effective in presenting
antigen, thus perpetuating
the DTH response, and
function as the primary
effector cells in this reaction.
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Contact Dermatitis Is a
Type of DTH Response
Development of delayed-type hypersensitivity reaction
after a second exposure to
poison oak.
Cytokines such as IFN-,
macrophage-chemotacticfactor (MCF), and migration-
inhibition factor
(MIF) released from
sensitized TH1 cells mediate
this reaction.Tissue damage results from
lytic enzymes released from
activated macrophages.
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