type iii and iv hypersensitivity

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 1/30

Type III and IVhypersensitivity

Yingping Xu

Yingpxu@126.com 

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 2/30

1. Characteristics

2. Mechanism of type III hepersensitivity

3. Common disease of type III hepersensitivity

Type III hypersensitivity

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 3/30

  1、characteristics

(immune complex hypersensitivity)

Large amounts of circulating antigen can form immune complexes

which are not easily cleared by phagocytic cells

Free Ag + Primed Ab middle immune complex

Deposit in tissue or blood vessel wall

Inflammation

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 4/30

2、Mechanism of type III hypersensitivity

Formation of the intermediate immune complex

Deposition of the intermediate immune complex

Tissue injury by the immune complex

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 5/30

  When the complexes are deposited in tissue very near the

site of Ag entry, a localized reaction develops.

When the complexes are formed in blood, a reaction candevelop wherever the complexes are deposited.

the complex deposition is frequently observed

on the blood-vessel walls

in the synovial membrane of joints

on the glomerular basement membrane of kidney

on the choroid plexus of brain

These deposition of these complexes initiates a reaction that

result in the following mechanisms to hurt tissues.

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 6/30

(1)Recruitment of neutrophi ls  to the site

tissure is injuryed as consequence of granular release from neutrophils.

(2) To activate complement systems array  of effector molecules

such as C3a, C4a, C5a (anaphylatoxin) cause mast-cell degranulation and

consequent increase in local valcular permeability.

such as C3a, C5a, and C5b67 are also chemotactic factors for neutrophils.

(3) Much of tissue damage in type I I I hypersensitivity stems from

release of Lytic enzymes by neutrophi ls  as they attempt to phagocytose IC.

IC

C3b

neutrophil

CR1

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 7/30

However, the complexes are deposited on the basement-membrane

Surface, phagocytosis is impeded to ingest the adhering IC.

(4) Fur ther activation of MAC  can also contribute to the destruction

of tissue.

(5) I n addition, the activation of complement can induce aggregation

of platelets, and the resulting release of clotting factors can lead to

Fromation of microthrombi.

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 8/30

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 9/30

3. common disease of type III hypersensitivity 

(1). Local immune complex disease

Arthus reaction ：  Experimental local anaphylaxic reaction,

 Necrotic vasculitis and Ulcer

Human local reaction(Arthus-like reaction):

insulin-dependent diabetes mellitus (IDDM)

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 10/30

Vascular endothelial cell

(1)  Anaphylatoxin-mediated

activation of mast cells to

degranulation

(2) Chemotactic neutrophils to

the site of tissue 

(3) To release of Lytic enzymes of

neutrophils

Mechanism of type I I I hypersensitivity

Immune complex

 Intradermally or subcutanenously

Edema and erythema at the site of

protein I njection or insect-bite.

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 11/30

(2). Acute systemic immune complex disease

serum sickness: (To inject more  antitoxin for the first time) 

Anti-serum Ab+Ag systemic tissue injury,fever, arthritis, skin rash 

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 12/30

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 13/30

 A Dominant Role for Mast Cell Fc Receptors in the Arthus Reaction:

Sylvestre et al, 1996,

Immunity 5:387

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 14/30

A: Control -/-; B: Control +/+; C: Control W/Wv; D: W/Wv 

reconstituted with -/- mast cells or E: +/+ mast cells

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 15/30

Acute immune complex glomerulonephritis and

choroidmeningitis : 

Streptococcus infection

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 16/30

(3). Chronic immune complex disease SLE (systemic lupus erythematosus)

Rheumatoid arthritis ：RF+IgG Deposit on synovial membrane

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 17/30

  Type IV hypersensitivity 

(delayed type-hypersensitivity)

1、characteristics of type IV hepersensitivity

2、 mechanism of type IV hepersensitivity

3、

common diseases of type IV hepersensitivity

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 18/30

Type IV hypersensitivity definition:

Some subpopulations of activated Th cells encounter certaintypes of Ags, they secrete cytokines that induce a localized

inflammatory reaction.

The reaction is characterized by large influxes of nonspecific

inflammatory cells, in particular, macrophages.

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 19/30

1. Characteristics

Interaction of primed T cells and associated antigen

Infiltration of Mononuclear Cells, especially macrophage

induce inflammatory response

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 20/30

2. Mechanism of type IV hypersensitivity 

(1) Formation of effector and memory T cells (sensitization phase) 

(2) Inflammation and cytotoxicity caused by effector T cells

(effector phase)

Inflammation and tissue injury mediated by CD4+Th1 

Release chemokines and cytokines

Immune injury mainly caused by infiltration of mononuclear cells and

lymphocytes

Cytotoxicity of CD8+CTL

 perforin and granzymes

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 21/30

The development of the DTH response begins with the initial sensiti zation phase

Of 1-2 weeks after primary contact with an antigen . 

A DTH ll d t b t ti l f 24h

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 22/30

Recruit and activate

Macrophage and other

non-specif ic immune cells

A DTH response normally does not become apparent unti l an average of 24h

after the second contact with the antigen, the response generally peaks 48-72h

after the second contact . The delayed onset of this response ref lects the

time required for the cytokines to induce localized inf luxes of macrophages and

their activation

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 23/30

Cytokines elarated by Th1 cells induce blood monocytes to

adhere to vascular endothelial cel ls and migrate from the blood

into sur rounding tissues. Dur ing the process, the monocytes

differentiate into activated macrophages. 

On the one hand  , activated macrophages exhibit increased levels

of phagocytosis and increased ability to kill microorganisms

through different cytotoxic mediators.

On the other hand, the heightened phagocytic activity and the

buildup of lytic enzymes from macrophages in the area of infectionlead to nonspecific destruction cells.

Double-edged nature

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 24/30

In some cases, especially if the Ag is not easily cleared, a prolonged DTH response

Can itself become destructive to the host as the intense inflammatory response

Develops into a visible granulomatous reaction.

A granuloma develops when continuousactivation of macrophages induces them

to adhere closely each other, assuming

an epithelioid shape and fusing to form

multinucleated giant cells. These cells

displace normal tissue cells, forming palpable nodules, and release high

concentration of lytic enzymes which

destroy surrounding tissue.

 A prolonged DTH response can lead to formation of a

 granuloma, a nodule-l ike mass . Lytic enzymes released from

activated macrophages in a granuloma can cause extensive

tissue damage.

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 25/30

Antigen T cell

(CD4+,CD8+)

Secondary

contact

Induce

Primed T cell

CD4+ 

T cell

CD8+ 

T cell

Release 

Cytokines

IL-2

TNF- 

INF-TF

MCF

MIF

MAF

SRF

Directly kill target cells

Infiltration of

monocyte and Mf

Proliferation of T cell

Exudation and edema

Cytotoxicity 

Inflammation characterized by infiltration of Mf  , monocyte,

And tissue injury

Mechanism of type IV hypersensitivity

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 26/30

MCF:

Macrophage chemotactic factor

MIF:

Macrophage inhibitory factor

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 27/30

3. Common disease of type IV hypersensitivity

(1) Infectious delayed type hypersensitivity

OT( Old Tuberculin ) test or PPD( purified protein derivative)The characteristics of Tuberculin Test

①   Maximum at 48-72 hours

②   Inflitration of lesion with mononuclear cells

③   First described as a reaction to the lipoprotein

antigen of tubercle bacillus

④   Responsible for lesions associated with bacterial allergy

⑤   cavitation, caseation, general toxemia seen in TB

⑥  May progress to granulomatous reaction

in unresolved infection

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 28/30

Epitheloid Cell Granuloma Formation

• Large flattened cells with increased endoplasmic reticulum

• Multinucleate giant cells with little ER

•

May see necrosis• Damage due to killer T-cells recognizing antigen-coated

macrophages, cytokine-activated macrophages

• Attempt by the body to wall-off site of persistent infection

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 29/30

Granuloma Formation

8/13/2019 Type III and IV Hypersensitivity

http://slidepdf.com/reader/full/type-iii-and-iv-hypersensitivity 30/30

(2) Contact dermatitis :

Paint, drug

red rash, papula, water blister, dermatitis