Download immediate hypersensitivity

Hypersensitivity (超敏反应)
Qingqing Wang
Institute of Immunology
Zhejiang University School Of Medicine
[email protected]
 Hypersensitivity
Some immune responses can give
rise to an excessive or inappropriate
reaction, resulting in significant
tissue damage or even death.
 The classification: type I~IV
CAUSES OF HYPERSENSITIVITY DISEASES
 Autoimmunity
 Reactions against microbes
 Reactions against environmental
antigens
I型
----
速发型 （IgE）
II型 ---IgM）
细胞毒型（IgG，
III型 ----
免疫复和物型（IgG）
IV型
迟发型（TDTH）
----
---------------------------------------------
Robin Coombs
Philip George Houthem Gell
1921 - 2006
1914 - 2001
Types of
hypersensitivity
diseases.
In the four major
types of
hypersensitivity
reactions, different
immune effector
mechanisms cause
tissue injury and
disease
Type I hypersensitivity
(immediate hypersensitivity)
Richet和Porteir提出了过敏反应的概念，
二人因此获1913年诺贝尔奖。
初次注射
海葵毒素
导致狗死亡
再次注射
海葵毒素
无明显反应
anaphylaxis
Type I hypersensitivity
Carl Prausnitz-Giles 1876-1963
1921
Prausnitz-Kustner test --- “reagin”
1966
Reagin = IgE
Kimishige Ishizaka（1925-）and
Teruka Ishizaka
1.
Characteristics of Type I
hypersensitivity
1. Rapid:
react and disappear quickly on re-exposure to Ag
2. Dysfunction:
dysfunction rather than severe tissue and cell
damage occurs
3. Strong hereditary tendency:
obvious individual difference and genetic correlation
 Mediated by IgE antibodies
 Typical examples include polymorphisms
of the promoter region for IL-4 and
polymorphism of the gene for IL-5, either
of which can directly influence the IgE
production to allergens.
 ‘atopy’: An IgE-dependent allergy often
arising from exposure to an unknown Ag.
II. Components involved in type I
hypersensitivity
 Allergen is an antigen that gives rise
to immediate hypersensitivity.
protein or chemicals
For example: pollen, house dust
mite, animal hair, dander, some
foods, foreign serum, drugs.
 Allergin is a specific IgE that gives
rise to immediate hypersensitivity.
Allergen
格链孢子
禾本科花粉
长蠕孢子
豚草花粉
The property of being allergenic may also reside in the
chemical nature of the antigen itself.
These features include low
to medium molecular weight (5 to 70 kD), stability,
glycosylation,
and high solubility in body fluids.
Anaphylactic
responses to foods are typically induced by highly
glycosylated small proteins. These structural features
probably protect the antigens from denaturation and
degradation
in the gastrointestinal tract and allow them to
be absorbed intact.
 The majority of humans mount significant
IgE response only as a defense against
parasitic infections. After an individual has
been exposed to a parasite, serum IgE levels
increase and remain high until the parasite
is successfully cleared from the body.
 Atopic individuals allow non-parasitic Ags to
stimulate inappropriate IgE production,
leading to type I hypersensitivity.
 Most allergic IgE response occur on
mucous membrane surfaces in
response to allergens that enter the
body by either inhalation or
ingestion.
mast cells
basophils
Two major subsets of mast cells:
gastrointestinal tract, connective tissues
eosinophils
• mast cells, basophils and eosinophils
 Mast cells are found throughout
connective tissue, particularly near blood
and lymphatic vessels.
 Some tissues, including skin and mucous
membrane surfaces of the respiratory and
gastrointestinal tracts, contain high
concentrations of mast cells.
 Basophils and eosinophils are
granulocytes that circulate in the blood of
most vertebrates.
 Mast cells
 Basophils
 Eosinophils
They express FcRI
Their granulated cytoplasm
contain pharmacologically
active mediators
Mediators released by eosinophil:
eosinophil cationic protein
eosinophil peroxidase
LTs, PAF, etc.
IgE分子及其受体
FcεRⅠ（高亲和力）：αβγγ
FcεRⅡ（CD23）（低亲和力）
IgE 分 子 及 其 两 种 Fc 受 体
NH2
COOH
H2N
NH2
NH2
COOH
NH2
COOH
HOOC COOH
FcRI
NH2
NH2
FcRII
FcεRⅠ
FcεRⅠ
III. Pathogenic mechanisms
Th1 (IFN-, IL-12)
 allergen→body→B cell← Th2 (IL-4, IL-13)
↓ Fc
IgE→masts cell or basophils
(FcRI )
↓
Ag cross-linking IgE on FcR
↓
signal transduction occurring
through the  chain of FcRI
↓
the mediators are ← degranulation
synthesized and released
Re-exposure
The sequence of
events in
immediate
hypersensitivity
The activation
of mast cells
C, D: light micrographs
E, F: electron micrographs
IgE Antibody Binds To
Mast Cells & Basophils
To Arm Them For
Mediator Release
Cross-linking of bound IgE by antigen
is thought to activate protein tyrosine
kinases (Syk and Lyn), which in turn
cause activation of a MAP kinase
cascade and a phosphatidylinositolspecific phospholipase C (PI-PLCγ).
PI-PLCγ
catalyzes the release of IP3 and DAG
from membrane PIP2. IP3 causes
release of intracellular calcium from
the endoplasmic reticulum. Calcium
and
DAG activate PKC, which
phosphorylates substrates such as
myosin light chain protein and
thereby leads to the degradation and
release of preformed
mediators. Calcium and MAP kinases
combine to activate the enzyme
cytosolic phospholipase A2 (PLA2),
which initiates the synthesis of lipid
mediators,
including prostaglandin D2 (PGD2)
and leukotriene C4 (LTC4).
Biochemical events in mast cell activation
静息肥大细胞
激活后 5 分钟
激活后 60 分钟
Mediators
The preformed mediators include:
histamine, kinnogenase, eosinophil chemotactic
factor of anaphylaxis (ECF-A)
The mediators newly synthesized include:
prostaglands (PG), leukotrienes (LTs, 白三烯),
platelet activating factor (PAF), cytokines (IL-4, IL-13)
phospholipid
↓phospholipase A2
arachidonic acid (花生四烯酸)
cyclooxygenase ↓
↓5-lipooxygenase
postaglandins
leukotrienes
•Arachidonic Acid Metabolites
1. cyclooxygenase products: prostaglandins
(PG) PGD2
2. lipooxygenation products:
leukotrienes (LTs) LTB4, LTC4, LTD4, LTE4.
LTB4 is a potent chemoattractant. LTC4, LTD4 and LTE4
induce smooth muscle contraction, bronchoconstriction,
and secretion in the airways and the reaction in the skin.
platelet activating factor (PAF)
PAF is synthesized and released, along with histamine
and leukotrienes, by mast cells and platelets.
Biologic effects of mediators of immediate hypersensitivity
Immediate phase
The immediate phase of the inflammatory response is due
to preformed mediators (especially histamine) stored in the
mast cell granules and also to certain rapidly synthesized
arachidonate derivatives. It reaches maximal intensity
within about 15 minutes after antigen re-exposure.
This phase is characterized grossly by erythema, localized
edema in the form of a wheal, and pruritus (itching).
Microscopic examination at this stage reveals only
vasodilatation and edema. The granule contents, however,
also induce local expression of the VCAM-1, as well as
secretion of chemokines, which recruit subsequent
inflammatory cells to the site.
Late phase
 Manifestation of the late phase are due in part to
presynthesized TNF- and in part to other mediators
(principally PAF, LT, IL-4, etc.) whose synthesis begins after
the mast cell degranulates.
 The effects of these mediators become apparent about 6
hours after antigen contact and are marked by an infiltration
of eosinophils and neutrophils.
 Clinical features of the late phase include erythema,
induration, warmth, pruritus, and a burning sensation at the
affected site. Fibrin deposition probably occurs transiently.
TNF- not only functions in the short term as a leukocyte
chemokine but also can stimulate local angiogenesis,
fibroblast proliferation, and scar formation during prolonged
hypersensitivity reactions.
The wheal and flare reaction in the
skin
风团-红斑
IV. Type I hypersensitivityassociated diseases
 The clinical manifestations of type I
hypersensitivity can range from
serious life-threatening conditions,
such as systemic anaphylaxis and
asthma, to hay fever (枯草热) and
eczema（湿疹）, which are merely
annoying.
Clinical manifestations of immediate hypersensitivity reactions
1. Systemic anaphylaxis (shock)
 Systemic anaphylaxis is a shock-like and
often fatal state whose onset occurs within
minutes of a type I hypersensitivity
reaction. If not treated quickly, these
reactions can be fatal.
 Allergens:
penicillin, antitoxin, etc.
2. Localized anaphylaxis (atopy)
 Allergic rhinitis（过敏性鼻炎）
It is the most common atopic disorders. It results from
the reaction of airborne allergens with sensitized mast
cells in the conjunctivae and nasal mucosa to induce the
release of pharmacologically active mediators from the
mast cells. These mediators then cause localized
vasodilation and increased capillary permeability. The
symptoms include watery exudation of the conjunctivae,
nasal mucosa, and upper respiratory tract, as well as
sneezing and coughing.

Bronchial asthma
 In some cases, airborne or blood-borne allergens, such
as pollens, dust, fumes, insect products, or viral
antigens, trigger an asthmatic attack.
 Asthma is triggered by degranulation of mast cells with
release of mediators, but instead of occurring in nasal
mucosa, the reaction develops in the lower respiratory
tract. The resulting contraction of bronchial smooth
muscles leads to bronchoconstriction.
 Respiratory viral and bacterial
infections are a predisposing
factor in the development of
asthma or exacerbations of
preexisting asthma.
 hygiene hypothesis.
• Anaphylaxis to foods
 Various foods can induce localized
anaphylaxis in allergic individuals. Allergen
crosslinking of IgE on mast cells along the
upper and lower gastrointestinal tract can
induce localized smooth muscle contraction
and vasodilation.
 Vomiting and diarrhea are the most
common symptoms of food allergies.
荨麻疹
• Atopic dermatitis（特应性皮炎，湿疹）
 Atopic dermatitis is an inflammatory disease of skin
that is frequently associated with a family history of
atopy.
 The disease is observed most frequently in young
children, often developing during infancy.
 The reaction is characterized by infiltration of
neutrophils, eosinophils, macrophages, lymphocytes,
and basophils.
 The localized late-phase response also may be
mediated by cytokines released from mast cells.
V. Immunoprophylaxis & immunotherapy
1. Skin test to identify allergen and avoid the
offending allergen
2. Hyposensitization or desensitization with
allergens
1) For antitoxin: stimulation with small dose of
Ag provokes a minimal amount of mediators
release, and the latter are rapidly resolved.
2) For specific allergens
 Gradually increasing quantities of Ag are
injected subcutaneously.
 This is a form of immunotherapy aimed at
stimulating the production of IgG blocking
antibody that binds the offending antigen
and prevents its combining to IgE.
 The response to treatment includes an
increase in IgG antibodies, a decrease in
IgE antibodies in the serum.
Types of antibody-mediated diseases
Effector mechanisms
of antibody-mediated
disease
Type II hypersensitivity
(cytotoxic type)
 Type II hypersensitivity reactions are
mediated by IgG and IgM antibody binding
to specific cells or tissues. The damage
caused is thus restricted to the specific cells
or tissues bearing the antigen.
 The antibodies damage cells and tissues by
activating complement, and by binding and
activating effector cells carrying FcR.
I. Pathogenic mechanisms
Ags on the surface of target cells
↓
body→IgG, IgM
↓
1. damage the target cell
1) activation of complement
2) opsonization: FcR, C3bR
3) ADCC: NK cells, M
2. target cell dysfunction
NK cell
opsonization
Effector
mechanisms of
Ab-mediated
diseases
Graves’
disease
In myasthenia gravis
the Abs against Ach
receptor inhibit
neuromuscular
transmission and cause
paralysis
II. Clinical disease
1. Transfusion reactions
A型血
输血
A型血输入B型血体内
B型血体内存在抗A抗体
A型血抗原
血细胞溶解
补体
抗原
抗体
反应
2. Hemolytic disease of the newborn
Mainly occurs when an Rh- mother gives
birth to an Rh+ infant.
Prevention: The administration of anti-Rh Ab
to an Rh- mother within 72 hours of
delivering an Rh+ infant will prevent
sensitization and problems with subsequent
pregnancies.
母体内的IgG与胎
儿体内的Rh抗原
结合，导致胎儿出
生后发生新生儿溶
血症。
3. Autoimmune hemolytic disease
Some drugs or viruses stimulate Ab
formation by changing the erythrocyte
surface components to form new epitopes.
The resulting Abs can cross react with
epitopes on unmodified RBCs.
4. Drug-induced reaction to blood components
These diseases have been associated with
many different chemotherapeutics, such as
penicillin, the sulfonamides. These drugs
stimulate Ab formation by forming new epitopes
with serum proteins, which then adsorb
nonspecifically to the red blood cell surface so
that its new epitopes are expressed.
5. Graves’ disease
The patients produce antibodies to
thyrotropin (thyroid stimulating hormone,
TSH) receptor. The end
result
is
overproduction of thyroid hormone and
hyperthyroidism.
Type III hypersensitivity
(immune complex type)
Immune complexes (IC) deposit in
basement membranes of small
blood vessels in various organs.
I. Pathogenic mechanisms
Ag→body→IgG, IgM, IgA
↓
immune complexes (IC)
↓
soluble IC
↓
ICs are deposited from the circulation
into vascular basement membranes
①↓
② ↓FcR
activation of complement plat. and basophils
↓
C3a, C5a →mast cell → release of vasoactive amines
↓
basophils
③ Neutrophils
vasodilation
aggravate
↓
lysosomal
edema
enzymes→damage the tissue
IC are capable of triggering a variety
of inflammatory processes
 ICs interact with the complement system to
generate C3a and C5a. These complement
fragments stimulate the release of vasoactive
amines and are chemotactic factors for mast
cells and basophils, eosinophils and neutrophils.
 ICs interact directly with basophils and platelets
(via FcR) to induce the release of vasoactive
amines.
 Neutrophils exocytose their lysosomal enzymes
onto the site of IC deposition and damage the
underlying tissue.
Deposition of IC in tissues
 An increase in vascular permeability
In general, complement, mast cells, basophils and
platelets must all be considered as potential producers of
vasoactive amines.
 Local high blood pressure and turbulence
The blood pressure in the glomerular capillaries is
approximately four times that of most other capillaries.
II. Clinical diseases
1. Arthus reaction
An animal is immunized repeatedly until it has
appreciable levels of serum Ab (mainly IgG).
Following subcutaneous or intradermal
injection of the antigen a reaction develops at
the injection site, sometimes with marked
edema and hemorrhage.
Nicolas Arthus 1862-1945
Arthus’s reaction
（1903）
经抗原反复免疫之后,注射抗原的皮下出现局部红肿、出血
和坏死等剧烈炎症反应。
基底膜
1
2
内皮细胞
抗原
抗体
复合物
免疫复合物沉淀
中性粒细胞
补体
C3a
C5a
血小板
血小板凝聚
C5a
肥大细胞
微血栓形成
血管活性胺
血管壁
趋化
2. Serum sickness
Serum sickness is a complication of
serum therapy, in which massive doses
of anti-serum are given in conditions
such as snake bite.
Serum sickness（血清病）
Clemens Pirquet 1874-1929
3. Postinfectious glomerulonephritis
常见于A族溶血性链球菌感染后2-3周。抗体与链球菌可溶性
抗原形成复合物，沉积于肾小球基底膜处
Pathologic features of antibody-mediated glomerulonephritis
Human immune complex disease
4. Systemic lupus erythematosus (SLE)
 antinuclear antibodies
 hypergammaglobulinemia
SLE
自身抗体与可溶性自身抗原形成免疫复合物，
沉积于皮下、关节和肾小球基底膜等处。
SLE
Mechanisms of T cell–mediated diseases
Type IV hypersensitivity
(Delayed type hypersensitivity)
 Delayed type hypersensitivity is initiated
by sensitized T cells reacting with specific
antigens. The reactions are manifest as
inflammation at the site of antigen
exposure, which usually peaks 24-72
hours after exposure.
 This reaction is independent of antibody
and complement.
I. Pathogenic mechanisms
Ag-MHC
Antigen→APC→T cells
co-stimulating factors
↓
sensitized T cell
↓
effector and memory cells
↓
↓
CD4+T cell (Th1 type) CD8+T cell (CTL)
↓
release of cytokines
↓
inducing the inflammatory
response
(primarily M and T cells)
↓
killing target cells
by the release of
perforin and granzymes
or by the FasL-Fas pathway

II. Clinical diseases
1. Infectious DTH
In the infective process, intracellular
parasitical bacteria (Mycobacterium
tuberculosis, Mycobacterium leprae,
Brucella), viruses and fungi cause T cellmediated immune responses, which are
referred to as infectious delayed type
hypersensitivity.
Granulomatous inflammation
结核菌素试验
Tuberculin-type hypersensitivity
The tuberculin skin test (OT) reaction principally involves M
tuberculin→body→T cells are activated
↓
IFN-→M→TNF, IL-1
↓
endothelial cells in dermal blood vessels
↓express
CAM: E-selectin, ICAM-1, VCAM-1
↓
recruiting monocytes and T cells
(Monocytes constitute 80-90% of
the total cellular infiltrate)
DTH reaction
Tuberculin-like delayed type hypersensitivity
reaction are used practically in two ways.
1) To confirm past infection with M. tuberculosis,
but not necessarily active disease.
2) To be a general measure of cell-mediated
immunity.
2. Contact dermatitis
 Langerhans cells and keratinocytes acting as
APCs have key roles in contact hypersensitivity.
 Keratinocytes produce a range of cytokines.
 A contact hypersensitivity reaction has two
stages: sensitization and elicitation.
Sensitization produces a population of memory T
cells and elicitation involves recruitment of CD4+
lymphocytes and macrophages.
接触羽毛
接触橡胶
 Many important sensitizing allergens are
organic chemicals, and some are metals
such as nickel, chromate. It is assumed
that they function as haptens.
 When allergen again penetrates the skin,
these memory cells rapidly evolve into
effectors that mediate a delayed-type
hypersensitivity reaction at the site of
penetration.
Comparison of 4 types of hypersensitivity
References
(1) Abul K. Abbas, Andrew H. Lichtman, Shiv Pillai. Cellular
and molecular immunology. Elsevier Saunders
publishing. 2011 (7th edition）chapter 18, 19
(2)《医学免疫学》（第6版），曹雪涛，人民卫生出版社，2013
（第17章）
(3) Kenneth M. Murphy. Janeway's Immunobiology.
Garland Science. 2012 (8th edition)
Thanks for your attention!
 Thank you very much for your support and
cooperation
 If you have any question and suggestion,
please feel free to contact me:
[email protected]