Transcript Type I

Chapter 16 Hypersensitivity Reaction
I . Hypersensitivity reaction
II. Type I Anaphylactic Reactions
III. Type II Antibody-mediated
cytotoxic hypersensitivity
IV. Type III Immune complexmediated hypersensitivity
V. Type IV T cell-mediated
hypersensitivity
教学大纲
 掌握超敏反应的概念、各型超敏反应的
特点及发生机制；
 熟悉各型超敏反应引起的常见临床疾病。
 了解I型超敏反应的防治原则
Hypersensitivity reaction
1. Concept
2. Types of Hypersensitivity Reaction
1. Concept
Under some circumstances, immunity,
rather than providing protection,
produces damaging and sometimes fatal
results.
Such deleterious reactions are known
collectively as hypersensitivity reactions,
but it should be remembered that they
differ from protective immune reactions
only in that they are exaggerated or
inappropriate and damaging to the host.
The cellular and molecular
mechanisms of the two types of reaction
are virtually identical.
2. Types of Hypersensitivity Reaction
Hypersensitivity reaction were divided into
four classes, designated types I- IV, by
Gell and Coombs
Type I: Anaphylactic Reactions
Type II: Antibody-mediated
cytotoxic hypersensitivity
Type III: Immune complex-mediated
hypersensitivity
Type IV: T cell-mediated hypersensitivity
Type I: Anaphylactic Reactions
1. Concept of Type I
2. Characteristics of type I
3. Mechanism of type I
a. Sensitization phase
b. Activation phase
c. Effect phase
4. Clinical aspects of type I
1. Concept of type I
Anaphylactic reaction are mediated
by IgE antibodies, which bind to
receptors on mast cells and basophils.
When cross-linked by antigen, the
IgE antibodies trigger the mast cells
(basophils) to release several
pharmacologically active agents that
are responsible for the characteristic
symptoms of anaphylaxis. Reactions
are rapid, occurring within minutes
after challenge antigen.
mediated
by IgE
IgE bind to FcR on mast cells and
basophils
release several pharmacologically
active agents
Reactions are rapid, occurring
within minutes
Allergens associated with Type I
hypersensitivity
Proteins
:foreign serum
Plant pollens
Insect products :bee or wasp venom
Mold spores , dust mites
Animal hair and dander
Foods : seafood , Eggs, milk
Drugs :penicillin ,sulfonamides ,local
anesthetics
2. Characteristics of type I
a. Anaphylactic reaction are rapid,
occurring within minutes after
challenge, exposure to same antigen. Its
reaction has its peak within 10-15
minutes; then it fades without leaving
any residual damage, if it isn’t fatal.
b. IgE antibodies-mediated and IgG4(a
little), without IgA, IgM, IgG1,2,3 and
complements.
2. Characteristics of type I
C .The mast cells and basophils are
the main effectors of type I reaction,
and many pharmacologically active
agents released by the mast cells
and basophiles.
d. The symptoms of anaphylaxis seen in
systemic reactions. This would induce
a typical wheal and flare reaction
consisting of blood vessel dilation and
increase in permeability and induce
difficulty in breathing because of
constriction of bronchiolar muscles,
uterine cramps, or involuntary
urination and defecation.
e. The different individual have distinct
difference. （individual difference)
Characteristics
without
leaving any residual
damage
IgE , IgG4
mast cells and basophils release
vasoactive mediators
individual difference
3. Mechanism of type I
Sensitization phase
b. Activation phase
c. Effect phase
- preformed mediators
- Newly synthesized mediators
a.
Mechanism:
Allergen
TCR MHC-II
B cell
Th cell
CD4
Bm
IL-4
Allergen
Plasma
cell
IgE
mast cell
mast cell
FcR
Sensitized
Degranulation
Smooth muscle cell, Small blood vessel, Mucous gland,
Blood platelets,Sensory nerve endings, Eosinophil,
And so on.
Principal mediators involved in type I hypersensitivity
Mediator
Activities
primary
1. Histamine:
Increased vascular permeability;
Smooth muscle contraction.
2. Serotonin:
Increased vascular permeability;
Smooth muscle contraction.
3. Eosinophil chemotactic
factor: (ECF-A)
Eosinophil chemotaxis
4. Neutrophil chemotactic
factor: (NCF-A)
Neutrophil chemotaxis
5. Proteases:
bronchial mucous secretion
Degradation of blood-vessel basement
Principal mediators involved in type I hypersensitivity
Mediator
Activities
Secondary
1. Platelet-activating Platelet
aggregation and degranulation.
Factor:(PAF) Contraction of pulmonary smooth muscles.
2. Leukotrienes: Increased vascular permeability;
( SRS-A)
Contraction of pulmonary smooth muscles.
3. Prostaglandins: Vasodilation;
Contraction of pulmonary smooth muscles.
Platelet aggregation.
4. Bradykinin: Increased vascular permeability;
Smooth-muscles contraction.
4. Clinical aspects of type I
a. Anaphylactic shock ( drug anaphylactic
reaction)
b. Anaphylactic reaction of respiratory
system ( bronchial asthma )
c. Allergic dermatitis (eczema)
d. Intestinal allergy
初次接触
花粉
B细胞产生
特异性IgE
再次接触
花粉
IgE结合于肥大
细胞的FcεRⅠ
脱颗粒
花粉症
penicillin degrade
青霉噻唑酸及青霉烯酸
(hapten)
protein
（carrier）
hapten-carrier complex
clinical symptoms
（mechanism）
sensitive state
Release bioactive
mediators
Activation phase
Type-I hypersensitivity
The common allergy
Many organ are be affected by
“allergy”
The nasopharynx
Rhinorrhea
Many organ are be affected by
“allergy”
The nasopharynx
Nasal polyp
Many organ are be affected by
“allergy”
The nasopharynx
Tonsillitis
Many organ are be affected by
“allergy”
The skin
Urticaria
hives
Many organ are be affected by
“allergy”
The skin
Eczema（湿疹）
Many organ are be affected by
“allergy”
The eye
Conjunctivitis
（结膜炎）
Ⅰ型超敏反应的防治原则
Hyposensitization
III. Type II: Antibody-mediated
cytotoxic hypersensitivity
1. Concept of type II
2. Characteristics of type II
3. Mechanism of type II
4. Clinical aspects of type II
1. Concept of type II
A type II hypersensitivity reaction
(cytotoxic reaction) occur when IgM or
IgG antibodies bind to antigen on the
surface of cells and activate the
complement cascade, leading to cell
damage through complement-mediated
lyses or Ab-dependent cell-mediated
cytotoxicity (ADCC).
cytotoxic
reaction
IgM or IgG bind with Ag
Mechanism of damage
complement activation and
ADCC
Several antigens of type II
Allogenic
antigen
Forssman Ag
autoantigen
Foreign antigen or hapten
2. Characteristics of type II
a. IgM and IgG antibodies-mediated
b. In type II hypersensitivity binding
of the appropriate antibody directly
to an antigen on the surface of a cell
produces damage to that cell
through a variety of mechanisms.
2. Characteristics of type II
c. The mechanisms of type II
hypersensitivity involve either the
complete complement sequence and
eventual lyses of the cell or opsonic
effects mediated by receptors for Fc
or C3b, which lead to phagocytosis
and destruction of the cell by
macrophages, neutrophils and NK
cells (ADCC).
3. Mechanism of type II
Cell-surface Ag
Fc
1.
NK
IgG
Target
cell
3.
Cytotoxic action (ADCC) CR
2.
Antibody
C
Phagocyte
Target
cell
Complement mediated lyses
opsonization
4. Clinical aspects of type II
a. Transfusion
reactions
b. Rh incompatibility reaction*
c. Drug-induced reaction
d. Autoimmune type II hypersensitivity
-- Autoimmune haemolytic anemia
-- Goodpasture’s syndrome
-- Anti-receptor auto-antibody disease
-- Anti-hormone auto-antibody disease
Haemolytic disease of the newborn
First birth
postborn
subsequent pregnancy
RhD
mother
RhD red cells
Bcell
Anti-Rh
IgG
Anti-RhD
lysis
RhD fetus
RhD fetus
免疫性血细胞减少症
自身免疫性溶血性贫血
+ 药物
自身抗体
药物过敏性血细胞减少症
毒
性
甲
状
腺
肿
的
发
病
机
制
Type III Immune complex-mediated
hypersensitivity
1. Concept of type III
2. Characteristics of type III
3. Mechanism of type III
4. Clinical aspects of type III
Systemic lupus erythematosus
1. Concept of type III
A type III hypersensitivity -Immune complex reaction--occur when
complexes of antigen and IgM or IgG
antibody accumulate in the circulation
or in tissue and activate complement.
Neutrophils are attracted to the site of
activation, and damage results from the
release of lytic enzymes from their
granules. Reaction occur within hours
of challenge with antigen.
2. Characteristics
of type III
a. IgM and IgG-mediated
b. When antigen and antibody meet at
the appropriate concentrations, they
form insoluble antigen-antibody
complexes(IC).
2. Characteristics
of type III
c. IC can activate the complement
cascade. Release C3a and C5a causes a
local increase in vessel permeability
and permits the release of serum
(edema) and chemotactic attraction of
neutrophils. The neutrophils release
degradative lysosomal enzymes that
produce tissue damage.
2. Characteristics
of type III
d. IC accumulate in or near vessel walls and
deposit in such tissues as kidney , joints, or
skins. If the site of reaction is a vessel wall,
the outcome is hemorrhage and necrosis; If
the site is a glomerular basement membrane,
loss of integrity and release of protein and
red blood cells into the urine results; and if
the site is a joint meniscus, destruction of
synovial membrane and cartilage occurs.
3. Mechanism of type III
a. Immune complexes production and
deposition
 The amounts of antibodies and deposition
 Immune complexes size and deposition
 The sites of deposition of the complexes
b. The mechanisms of damage
3. Mechanism of type III
Antigen+antibody
Platelets
Immune complexes
Complement
Microthrombi Vasoactive Anaphylatoxins
amines
Mast cell
Vasoactive
amines
Macrophages
lysis
Attract
Neutrophils
Activation and release
of IL-1 and reactive
Oxygen intermediates
Release granular
Increased vascular permeability contents
Vasodilation
Immune complex deposit
Activating complement
Mediate mast-cell
and basophil
Activating
platelet
C3a. C5a.C567
chemotaxis
Releasing vasoactive
Neutrophil infiltrating
microthrombosis
Capillary permeability
Releasing lysosomal
Tissue Ischemic ,necrosis
Local congestion, edema
vasculitis
4. Clinical aspects of type III
a. Arthus’ reaction
b. Serum sickness
c. Infection-associated syndrome
- glomerulonephritis
- Rheumatic fever
- Rheumatoid arthritis
- Other infectious diseases
Arthus’ reaction
Inject Ag
intradermally or
subcutaneously into an animal, produce
specific Ab ,form localized IC
IC mediate acute Arthus reaction
within 4-8h
Localized tissue and vascular
damage :edema , erythema , tissue
necrosis
Serum sickness
返回
Serum sickness
Inject
foreign protein (horse serum ) ,
leads to Ab response ,Ab binds with
circulating Ag to form IC
IC activate complement and
phagocyte , cause fever; deposited in
small vessels , lead to vascular
nephritis and arthritis.
Clinical symptoms: fever , joint
tenderness , urticaria , proteinuria
Systemic lupus erythematosus
Systemic Lupus Erythematosus (SLE)
Auto-antibodies
to a vast array of tissue
antigens , such as DNA , histones ,
RBCs ,platelet ,leukocyte , and clotting
factors.
Hemolytic anemia , thrombocytopenia
IC deposit in small blood vessel, cause
vasculitis and glomerulonephritis .
Rheumatoid Arthritis
Auto-antibodies
(rheumatoid factor) ,
reactive with determinants in the Fc
region of IgG.
Auto-Ab bind with circulating
IgG ,form complexes that are deposited
in joints.
Activate complement ,lead to chronic
inflammation of the joints.
Rheumatoid Arthritis
Type IV: T cell-mediated
hypersensitivity
1. Concept of type IV
2. Characteristics of type IV
3. Mechanism of type IV
4. Clinical aspects of type IV
Poison ivy / poison oak reaction
active hapten molecule
Contact dermatitis reaction to
mango sap
Contact dermatitis reaction to
leather
1. Concept of type IV
called delayed-type
hypersensitivity(DTH)--is mediated by T
cells rather than by antibody.
Upon activation, the T cells release
cytokines that cause accumulation and
activation of macrophages, which, in turn
release lysosomal enzymes that cause local
damage. This type of reaction has a delayed
onset and may occur 1-2days after challenge
with antigen.
2. Characteristics of type IV
a. DTH, when activated by contact with an
antigen presented by APC, T cells release
soluble mediators, cytokines, some of which
attract and activate other mononuclear cells
such as monocytes, macrophages, and
lymphocytes.
b. This type of reaction has a delayed onset
and may occur 1-2 days after challenge with
Ag.
2. Characteristics of type IV
c. The reaction reveals that the
mononuclear infiltrates appear as a
perivascular region before extensively
invading the site of deposition of
antigen. Later reaction show a more
complexes pattern, with the arrival of
lymphocytes and the formation of
granuloma in persistent lesions.
d. The reaction have not apparent
individual difference.
3. Mechanism of type IV
antigen
T cell
Inflammatory
mediators
cytokines
Activated macrophages
4. Clinical aspects of type IV
Dermatitis
a. Contact Sensitivity ( skin inflammatory
reaction)
b. Allograft Rejection （HVGR）
c. Graft Versus Host Reaction (GVHR)
d. Infectious Disease
Mycobacterium tuberculosis
(传染性变态反应）
OT test
AID－DTH
insulin-Dependent diabetes mellitus (IDDM)
 Multiple Sclerosis (MS) 多发性硬化症
 Hashimoto’s Thyroiditis 桥本甲状腺炎
 Inflammatory Bowel Disease (IBD) 炎性肠病
Crohn’s disease
ulcerative colitis

Ⅰ、Ⅲ、Ⅳ型超敏反应皮肤实验
1：15分钟出现1cm的界限清晰的风团
2：5-12小时出现超过5cm的红肿、出血、坏死
3：24-48小时出现的1cm的红肿、硬结
Granuloma in a leprosy patient
Questions
Describe
the types and features of
hypersensitivity .
Which
kind of hypersensitivity
reaction disease can penicillin cause?
Describe their developmental
mechanism.