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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
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
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.
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
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
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