Transcript 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
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
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
FceRI
NH2
NH2
FceRII
 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 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 FceRI
Their granulated cytoplasm
contain pharmacologically
active mediators
Mediators released by eosinophil:
eosinophil cationic protein
eosinophil peroxidase
LTs, PAF, etc.
III. Pathogenic mechanisms
Th1 (IFN-, IL-12)
 allergen→body→B cell← Th2 (IL-4)
↓ Fc
IgE→masts cell or basophils
(FceRI )
↓
Ag cross-linking IgE on FceR
↓
signal transduction occurring
through the  chain of FceRI
↓
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
Biochemical events in
mast cell activation.
Cross-linking of IgE on a
mast cell by an allergen
initiates multiple signaling
pathways from the
signaling chains of the
FceRI, including the
phosphorylation of ITAMs.
These signaling pathways
stimulate the release of
mast cell granule contents
(amines, proteases), the
synthesis of arachidonic
acid metabolites (PG, LT),
and the synthesis of
various cytokines.
IgE Antibody Binds To
Mast Cells & Basophils
To Arm Them For
Mediator Release
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.
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.
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
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.
• 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
 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.
Thanks for your attention!
 Thank you very much for your support and
cooperation in my teaching
 If you have any question and suggestion,
please feel free to contact me:
[email protected]