hypersensitivity ( 超敏反应 ) jianzhong chen institute of immunology zhejiang university school...

Hypersensitivity ( 超敏反应 )

Jianzhong ChenInstitute of Immunology

Zhejiang University School Of Medicinechenjianzhong@zju.edu.cn

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 FcR.

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

A 型血抗原

A 型血输入 B 型血体内B 型血体内存在抗 A 抗体

补体

抗原抗体反应

输血

活化

血细胞溶解

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.

Human antibody-mediated diseases

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 ↓FcRactivation of complement plat. and basophils ↓ C3a, C5a →mast cell → release of vasoactive amines ↓ basophils ③ Neutrophils vasodilation ↓ lysosomal edema enzymes→damage the tissue

aggravate

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。

C3aC5a

肥大细胞 血小板

补体

抗体 抗原内皮细胞

复合物

血管活性胺

C5a

中性粒细胞

血小板凝聚

免疫复合物沉淀

趋化

活性酶

微血栓形成

基底膜

血管壁

1 2

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和物，沉积于肾小球基底膜处

Human immune complex disease

4. Rheumatoid arthritis

Rheumatoid factor (RF): an immunoglobulin (mainly IgM but also IgG and IgA) with antibody specificity for the Fc portion of IgG.

The joint synovial fluid contains IC consisting of RF-IgG-complement.

Many patients with rheumatoid arthritis also have antinuclear antibodies.

5. Systemic lupus erythematosus (SLE)

antinuclear antibodies hypergammaglobulinemia

自身抗体与可溶性自身抗原形成免疫复和物，沉积于皮下、关节和肾小球基底膜等处。

RA ， SLE

SLE

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 killing target cells ↓ by the release of inducing the inflammatory perforin and granzymesresponse or by the FasL-Fas

pathway(primarily M and T cells)

Mechanisms of T cell-mediated tissue injury

II. Clinical diseases

1. Infectious DTH In the infective process, intracellular

parasitical bacteria (Mycobacterium tuberculosis, Mycobacterium leprae, Brucella), viruses and fungi cause T cell-mediated immune responses, which are referred to as infectious delayed type hypersensitivity.

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)

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.

接触橡胶接触羽毛

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.

T cell-mediated diseases

Comparison of 4 types of hypersensitivity

Thanks for your attention!