Hyper Sens Tivity

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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.

Hyper Sens Tivity

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