Hypersensitivity ( 超敏反应 )

Qingqing WangInstitute of Immunology

Zhejiang University School Of Medicinewqq@zju.edu.cn

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

Robin Coombs 1921 - 2006

I 型 ---- 速发型 （ IgE ）II 型 ---- 细胞毒型（ IgG ， IgM ）III 型 ---- 免疫复和物型（ IgG ）IV 型 ---- 迟发型（ TDTH ）----------------------------------------------

Philip George Houthem Gell1914 - 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)

初次注射海葵毒素

无明显反应再次注射海葵毒素

导致狗死亡

Richet 和 Porteir 提出了过敏反应的概念，二人因此获 1913 年诺贝尔奖。

anaphylaxis

Carl Prausnitz-Giles 1876-1963

Type I hypersensitivity

Prausnitz-Kustner test --- “reagin”

1921

Kimishige Ishizaka （ 1925- ） and Teruka Ishizaka

Reagin = IgE

1966

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.

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.

II. Components involved in type I hypersensitivity

Allergen

禾本科花粉 豚草花粉

长蠕孢子格链孢子

IgE分子及其受体

H2N NH2

HOOC COOH

NH2

NH2

COOH

COOH

FcRI

NH2

NH2

NH2

COOH

FcRII

IgE 分 子 及 其 两 种 Fc 受 体

FcεRⅠ （高亲和力）： αβγγFcεRⅡ （ CD23 ）（低亲和力）

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

Mediators released by eosinophil: eosinophil cationic protein eosinophil peroxidase LTs, PAF, etc.

They express FcRI Their granulated cytoplasm contain pharmacologically active mediators

III. Pathogenic mechanisms

Th1 (IFN-, IL-12) allergen→body→B cell← Th2 (IL-4) ↓ Fc IgE→masts cell or basophils (FcRI ) ↓ Ag cross-linking IgE on FcR ↓ signal transduction occurring through the chain of FcRI ↓ 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 FcRI, 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

MediatorsThe 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 Metabolites1. cyclooxygenase products: prostaglandins

(PG) PGD22. 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 phaseThe 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 hypersensitivity- associated 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

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.

1. Systemic anaphylaxis (shock)

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.

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wqq@zju.edu.cn