HypersensitiviHypersensitivityty

Xi’an Jiaotong University Health Science Center

Lin ShiLin Shi

Definition

Hypersensitivity also named allergy ， denotes a condition in which an immune response results in exaggerated or inappropriate reactions when the individual meets the same antigen again .

Allergen is any antigen (complete antigen or hapten) that causes allergy.

Allergen

B

T

plasmocyte

actived T

Ab

IgE

IgG

IgM

IgA

Allergen reaction

tissue damage, dysfunction

Body

Classification

Type of Ig or cellsType of Ig or cells

IgEIgE

Classification

TypeⅠ immediate hypersensitivity

IgMIgM 、、 IgGIgG

Type Ⅱcytotoxic hypersensitivity

Type Ⅲimmune complex hypersensitivity

humoral im

munity

humoral im

munity

cellular cellular immuniimmunityty

TcTc 、、 TTDTHDTH

Type Ⅳdelayed hypersensitivity

Immediate hypersensitivity; AllergyImmediate hypersensitivity; Allergy

Carl Prausnitz-Giles 1876-1963 P-K test

Küstner (sensitive to fish) serum

Prausnitz hip skin

Fish extractAfter 24h

pimple, erythema

no reaction

P-K test

15min later

reagin or skin sensitizing antibody (SSA)

(Passive transfer test)

Inhalant allergenInhalant allergenpollenpollendust mitesdust mitesmold sporesmold sporesanimal hair and danderanimal hair and dander

DrugsDrugspenicillinpenicillinsulfonamidessulfonamideslocal anestheticslocal anestheticssalicylatessalicylates

FoodsFoodsnutsnutsseafoodseafoodmilkmilkpeas, beanspeas, beans

AllergenAllergen （变应（变应原）原）Ag which can induce hypersensitivityInsectInsect

bee venombee venomant venomant venom

IgEIgE The concentration of IgE in

allergic individuals is increased

IgE bind to a receptor

specific for the Fc region of

the ε heavy chain (( FcεR)FcεR)

AllerginAllergin （（ reaginic antibodyreaginic antibody ））————IgEIgE

FcεRІFcεRІ FcεRПFcεRП （（CD23CD23 ））•On the mast

cells and basophils suface

•High affinity with Fc region of IgE.

Bind with heavy Bind with heavy chain CH3 of chain CH3 of

IgEIgE

Magnify signalMagnify signal

Signal transductionSignal transduction

•On the suface of B cell,actived T cell, eosinophil and macrophage•Low affinity•功能：（ 1 ）膜CD23 结 合 IgE/ IgE免疫复合物，降低 B 的 IgE 合 成（ 2 ） sCD23 与 B细胞的 CD21结合可促进 IgE合成。

FcεRFcεR

mast cellmast cell

The cells induce Type hypersensitivityⅠ

basophilbasophilBasophilic granuleBasophilic granule

eosinophil

Resting mast cell 5 min after actived 60 min after actived

Degranulation

the mediators be preformed and store in the granule

histaminhistaminchemotactic factor chemotactic factor (ECF-A,NCF-(ECF-A,NCF-A)A)kininogenasekininogenaseproteasesproteases

leucotrienes (LTsleucotrienes (LTs ）） (SRS-A) (SRS-A) prostaglandinsprostaglandins

primary

primary

SecondarySecondaryplatelet activity factor (PAF)platelet activity factor (PAF)

the newly synthesized mediators

Mediator Effects

Histamine Increase vascular permeability, smooth-muscle contraction, vasodilation (capillary vessel), increase gland secretion

Kininogenase Increase vascular permeability, smooth-muscle contraction

Eosinophil chemotactic factor (ECF)

Eosinophil chemotaxis

Leukotriene (LT)

Increase vascular permeability, contraction of smooth muscles, leading edema

prostaglandin D2 (PGD2)

Vasodilation (capillary vessel), contraction of smooth muscles, cause edema

platelet activaty factor (PAF)

platelet aggregation (release of vasoactive mediators: serotonin), smooth muscle contraction

• These mediators collectively cause increased vascular permeability, vasodilation, bronchial and visceral smooth muscle contraction, increased gland secretion, and local inflammation.

ischemic shock

increased vascular permeability edema

vasodilation decreased blood pressure

bronchial or throatsmooth muscle contraction wheezing, dyspnea,

asphyxiationincreased gland secretion

local inflammation swelling, erythema

systemic

phlegm

Mechanism

Sensitization phase Effector phase

First time meet allergenFirst time meet allergen Meet the same allergenMeet the same allergen

sIgEsIgE IgE bind to the mast IgE bind to the mast cell surfacecell surface

Receptor crosslinkage

Allergen Body IgEFirst Generation

Subsequent IgE binds the FcεR I on the surface of mast cells

Reaction of allergen and IgE on the surface of sensitized target cells

Degranulation of mast cell and release mediators

Newly synthesizedPreformed

Histamine serotonin Leukotriene PGD2 PAF

Contraction of smooth muscle, dilatation of capillaries, increase of permeability, gland hypersecretion

Systemic(anaphylactic shock)

Skin(urticaria)

Digestive tract(anaphylactic gastroenteritis)

Respiratory tract(asthma)

The mechanism of type I hypersensitivity

‘immediate reaction’ takes place in seconds after meeting allergen, and may last out several hours

‘late phase reaction ’ takes place in 2 ～ 4h after meeting allergen, and may last out 1 ～ 2 days or more long time, eosinophil infiltration is its character

histaminehistamine

chemotactic factor

bradykininbradykinin Expansion of small blood vesselsExpansion of small blood vessels

Increased vascular permeabilityIncreased vascular permeability

Smooth muscle contractionSmooth muscle contraction

Leukotriene

platelet activity factor prostaglandin D2

Infiltration of Infiltration of neutrophil neutrophil /eosinophil/eosinophil

Increased mucus secretionIncreased mucus secretion

Effector phase of type I hypersensitivity

systemicsystemic（ （ Anaphylactic shock ））

respiratory tractrespiratory tract（ （ Allergic asthmAllergic asthmaa ））

digestive tractdigestive tract

（（ Allergic gastroenteropathy ））

skinskin

（（ hives ））

effector organ

The diseases induced by type hypersensitivityⅠ( 一 ) Anaphylactic shock

1. medication anaphylactic shock 2. serum anaphylactic shock

treat: hyposensitization (short interval, small dose inject serum)

( 二 ) respiratory tract allergic reaction 1. Allergic asthma bronchoconstriction, airway edema, mucus secretion, airway obstruction

2. Allergic rhinitis watery exudation, sneezing and coughing

eyelid swelling (edema)

( 三 ) Digestive tract allergic reaction

e.g. e.g. allergic gastroenteropathy: nausea, vomiting, diarrhea, abdominal pain

( 四 ) Cutaneous allergies

1. Urticaria (hives)

2. Atopic dermatitis

allergallergen en

skin skin trialtrial

TreatmentTreatment

Drugs block Drugs block synthesizing synthesizing and and release of allergic release of allergic mediatorsmediators

antagon of mediatorinjectinject

IgG

desensitization desensitization therapytherapy

to improve the effect organ

responsibility

antihistamineantihistamine

aspirinaspirin adrenalinadrenalin intalintal

adrenalinadrenalin

calgluconcalglucon

body

body

histaminehistaminebradykininbradykinin

LTsPAF

PGE D2

AvoidanAvoidanceceallergenallergen

IgE

bronchospasmbronchospasm, , mucus secretionmucus secretion, smooth muscle smooth muscle contractioncontraction

expansion of expansion of small vesselssmall vessels

Anti-Anti-IgEIgE

1 rapidly 2 mediated mainly by IgE 3 the mediators play an important role 4 don’t injury tissue in general ； 5 be relative to the genetics of the individual

The characteristic of Type hypersensitivity Ⅰ

Type II hypersensitive reactions involve

antibody (IgG/IgM) mediated destruction of

the cells. So it is also termed cytotoxic

hypersensitivity.

Mechanismthe antigen place a premium on Type hypersensitivityⅡ *alloantigen blood type antigen of RBC

* modified auto-antigen

* common antigen / heterophile antigen

*hapten adsorbing on the surface of cell

the mechanism to destroy target cell• *complement dependent cytotoxicity• * antibody dependent opsonization • * antibody dependent cytotoxicity (ADCC)

Mechanism

The Ab induced type IIThe Ab induced type II—— IgMIgM 、、 IgGIgG

IgGIgM

亲细胞作亲细胞作

用用

allergen

cell

plasmaantibodies

B. phagocytosis

C. Opsonization

D. ADCC

A. Activation complement

Cell damaging Mechanism of Type HypersensitivityⅡ

The familiar diseases in clinic of type II hypersensitivity

11 、、 transfusion reaction ：： different ABO blood type different ABO blood type

22 、、 hemolytic disease of newborn ：： different Rh different Rh blood type between mother and childblood type between mother and child33 、、 autoimmune hemolytic anemia ：： component on the component on the surface of RBC membrane is changedsurface of RBC membrane is changed

44 、、 medication anaphylactic hypocytosis ：： certain certain antibiotics (e.g. penicillin) can adsorb nonspecifically to antibiotics (e.g. penicillin) can adsorb nonspecifically to protein on RBC membrane, forming a complex similar to protein on RBC membrane, forming a complex similar to hapten-carrier complex.hapten-carrier complex.

77 、、 Graves’ disease (stimulatory hypersensitivity))

55 、、 Goodpasture’s syndrome66 、、 Myasthenia gravis: produce blocking auto-Ab to the AchR (acetylcholine receptor)

*The antibodies are belong to the class of IgG and IgM . *The main component which injury cell

are complement ， Mφand NK cell. *The target cell are blood cell and some

tissue.

The characteristic of Type hypersensitivityⅡ

（ Immune complex disease ）

The reaction of antibody with antigen generates immune complexes (IC). Generally this IC are removed by the phagocytic cells. In some cases, however, they persist and eventually deposit in a range of tissues and organs. The complement and effector cell (neutrophil/nature killer) mediated damage that follows is known as a type hypersensitivity.Ⅲ

The formed size of IC Ag>Ab Ab=Ag Ag<Ab

Exgenous Ag——pathogenic microorganism 、 foreign serum

Endogenous Ag——degenerative IgG 、 nucleo antigen of SLE

S: sedimentation coefficient

mechanismmechanism

ICIC

complement

C3aC3a 、、 C5aC5a

Basophil/mast cell degranulate

mediators

blood blood vesselvessel

• In some cases, IC deposit at local tissue

• Actived complement produce anaphylatoxin, which cause basophil/mast cell degranulate

histaminhistaminchemotactic factorchemotactic factorProteasesProteasesplatelet activaty factorplatelet activaty factoretc.etc.

chemotactic factorPAF

platelet aggregation

thrombosis

vasculitis

• Increased vascular permeability cause more IC deposit•neutrophil phagocytize the IC and relesase enzyme which can damage the local tissue• platelet aggregation, form microthrombus, cause ischemia of local tissue

enzyme

IC

neutrophil

Damage induced by the aggregation of IC

① The effect of complement

② The effect of neutrophils

③ The effect of platelet

MAC cause local tissue damage ； anaphylatoxin (C3a, C5a) attract and activate neutrophil

Neutrophil release lytic enzymes (lysosome, proteolytic enzyme) induce blood vessel basement membrane and near tissue damage

Release vasoactive mediators (e.g. histamine) cause vascular permeability increase and activate blood coagulation, form microthrombus, cause ischemia, bleeding and necrosis of local tissue.

Immune complex deposit

Activation complement

anaphylatoxin (C3a,C5a)Mediate mast cell and basophil

Releasing vasoactive mediators

Capillary permeabilityincrease

Local edema

Activating platelet

microthrombosis

Tissue ischemia ,necrosis

chemotaxis

Neutrophil infiltration

Releasing lytic enzymes

vasculitis

11 、、 Arthurs reactionArthurs reaction ：：

22 、、 Arthus-like reactionArthus-like reaction ：：e.g. patient of e.g. patient of insulin dependent diabetes mellitus repeat insulin dependent diabetes mellitus repeat inject insulin.inject insulin.

I I Local immune complex disease

The familiar diseases in clinic of type Ⅲhypersensitivity

11 、、 Serum Sickness ：： in humans is a reaction to proteins in antiserum derived from a non-human animal source, occurring 4–10 days after exposure. The term serum sickness–like reaction (SSLR) is occasionally used to refer to similar illnesses that arise from the introduction of certain non-protein substances. 22 、、 poststreptococcal glomerulonephritis ：： Acute Acute glomerulonephritis is characterized by the sudden appearance glomerulonephritis is characterized by the sudden appearance of hematuria, proteinuria, red blood cell casts in the urine, of hematuria, proteinuria, red blood cell casts in the urine, edema, and hypertension with or without oliguria. It can follow edema, and hypertension with or without oliguria. It can follow streptococcal infections. streptococcal infections.

II Systemic II Systemic immune complex disease

自身抗体与可溶性自自身抗体与可溶性自身抗原形成免疫复和身抗原形成免疫复和物，沉积于皮下、关物，沉积于皮下、关节和肾小球基底膜等节和肾小球基底膜等处。处。

3 、 rheumatoid arthritis(RA)

4 、 systemic lupus erythematosus (SLE)individuals produce auto-antibodies to a vast array of tissue antigens, such as DNA, histones, RBCs, platelet, leukocytes. Interaction of these auto-antibodies with their specific antigens produce various symptoms. e.g. hemolytic anemia vasculitis

immunofluorescence

1 Antibody IgG and IgM 2 It is the key to form solube immune complex that is middling size 3 The tissue damage is caused mainly by complement activation and release of lytic enzymes from neutrophils 4 The character of local inflammation is neutrophils infiltration.

The characteristic of Type hypersensitivityⅢ

（（ Delayed Type Hypersensitivity, DTDelayed Type Hypersensitivity, DTHH ））

DTH reactions are elicited by CD4+ T cells of the Th1 subset and CD8+

T cells, both of which secrete cytokines that activate macrophages (e.g.

IFN- γ) and induce inflammation (e.g. TNF). In some T cell-mediated

disorders, CD8+ T cell directly kill target cells bearing class I MHC-

associated antigens. The T cells that cause tissue injury may be

autoreactive, or they may be specific for foreign proteins that are present

in or bound to cells or tissues.

antigen

APC processing

and presentation

T cell(CD4+,CD8+)

Sensitized T cell(CD4+,CD8+)

Antigen re-exposure

CD4+T cell

CD8+T cell

CytokineIL-2IFN-γTNF-βMCFMIF

Monocyteinfiltratio

nT cell

proliferation

exudation

cytotoxicity

Killing targetcells

Tissuelesion

The mechanism of type IVIV hypersensitivity hypersensitivity

Familiar diseases in clinic of type IV hypersensitivity

1. infectivity allergy Cell-mediated immune responses to microbes and other foreign

antigens may also lead to tissue injury at the sites of infection or antigen exposure.

Examples:(1) Intracellular bacteria (mycobacterium tuberculosis) induce strong T

cell and macrophage response that results in granulomatous and fibrosis. These may cause extensive tissue destruction and functional impairment.

(2) CTL responses to viral infection can lead to tissue injury by killing infected cells. Even if the virus itself has no cytopathic effects. e.g. viral hepatitis in humans.

2. contact dermatitisA variety of skin diseases that result from topical exposure to chemicals and environmental antigens (e.g. nickel, poison ivy/oak, drugs, cosmetic), are due to DTH reaction, presumably against neoantigens formed by the binding of the chemicals to self proteins. Develops erythema, itching, vesicles, or necrosis of skin within 12-48 hours.

3. Graft rejection

4. Insulin-dependent diabetes mellitus (IDDM) Infiltrate of lymphocytes and macrophages are found around the islets of langerhans in the pancreas, with destruction of insulin-producing βcells in the islets and a resultant deficiency in insulin production.

5. Multiple sclerosis (MS) An autoimmune disease of the central nervous system in which CD4+ T cells of the Th1 subset react against self myelin antigens. The DTH reaction of macrophages around nerves in the brain and spinal cord, destruction of the myelin, abnormalities in nerve conduction, and neurologic deficits

The characteristic of Type IV hypersensitivity

⒈ Develop slowly ， delayed ⒉ There is no relative to Ab and coplement. ⒊ Tissue damage is caused by cytotoxin and CK.

4. The character of local inflammation is neutrophils infiltration.

⒌ There is almost no individual difference.

变应原皮肤实验

变应原皮肤试验

Rh+

Rh–

再孕

Rh+

Rh–

初孕

胎儿红细胞 致敏母亲新生儿溶血 健康新生儿

新生儿溶血 母胎母胎 RhRh 血型不符血型不符母胎母胎 ABOABO 血型不符血型不符

首次妊娠 再次妊娠抗 Rh 血清

passplacenta

The possible reason of producing IgE

(1) the genetic of the individual;

(2) environmental factors (pollution) that condition mucosal tissue of the immune system to produce interleukin-4 (IL-4) which then predisposes a Th2 response;

(3) that regulation of response through Th1 cells is defective.

The person who trends to generate IgE antibody to the allergen is called atopic individual

Goodpasture’s syndromevirus (A2 type influenza virus) 、 organic solvent

lung tissue damage

inhale

autoantibody

glomerule damage

produceThere have common antigen in alveolus wall and glomerule basement membrane of kidney

cross reaction

Myasthenia gravis

• Disease marked by progressive weakness and loss of muscle control

• Classified as a “B cell” disease• Autoantibodies against nicotinic acetylcholine

receptors (AchR)

thyroid gland

垂体 B cell

Ab to TSHR

TSH: thyroid-stimulating hormone

Auto-Ab mimics the action of TSH

hyperthyroidism

Negative feedback

Horse serum inject to rabbit many times

The injected local place appear inflammatory reaction, skin inflame, bleeding and necrosis

produce

Rabbit anti-horse-serum antibady

IC aggradation

After 4-6 times inject

IC (horse serum-rabbit Ab) formed

Arthus-like reaction

An injection high dose of a foreign protein (horse serum, penicillin, etc)

Inducing fever, symptoms of vasculitis nephritis and arthritis, joint tenderness, urticaria, proteinuria

4-10 days later

Antibody for the foreign protein formed

IC

reaction

Remnant foreign protein

form

Serum sickness

Serum sickness

streptococcus infect

Deposit at glomerular basement membraneglomerulonephritis

induce

anti-streptococcus Ab

IC

2-3 weeks

Streptococcal Ag-Ab

form

Poststreptococcal glomerulonephritis

RF—antibody for auto-denatured-IgG （ IgM ）

arthrosis synovial membrane

bind

Auto-denatured-IgG in circle

chronic inflammation of the joint

form

soluble Ag-Ab complex

repeatedly deposit

Rheumatoid arthritis

tuberculosis

tuberculin test

Mechanism of damage in contact  hypersensitivity  

Contact dermatitis