TYPE III & IV HYPERSENSITIVITY REACTION 1 Hypersensitivity reaction.

TYPE III & IV HYPERSENSITIVITY REACTION

1Hypersensitivity reaction

Outline

Introduction. Type III hypersensitivity reaction.

- General mechanisem of action

1-Systemic Immune Complex Disease

2-Local Immune Complex Disease

- Summary TypeVI hypersensitivity reaction.

- Variants of type IV hypersensitivity reactions

- Mechanisem of action

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Hypersensitivity reaction

Type III hypersensitivity reaction

Sensitization phase

• IgM and IgG bind to soluble Ag which lead to immune comlex formation

• Soluble Ag-Ab complex that are large in size are cleared from circulation by phagocyte cell (liver and spleen)

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However

Circulation Ag-Ab immune complexe formed in excess (chronic infection) and are Small in size

escape clearance

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Title

Larger aggregates fix complement and are readily cleared from the circulation by the mononuclear phagocytic system. The small complexes that form at antigen excess, however, tend to deposit in blood vessel walls. There they can ligate Fc receptors on leukocytes, leading to leukocyte activation and tissue injury.

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Effectors phase

They are then deposited in capillary walls either: Locally at site Ag entry Systematically in blood vessels and various tissue.

Ag-Ab complex stimulate complement activation causing tissue damage (Type III)

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Factors that determine whether immune complex formation will lead to tissue deposition and disease:

*Size of immune complexes and functional status of the mononuclear phagocyte system

1. large complexes in antibody excess are rapidly removed from circulation by mononuclear phagocyte system (harmless)

2.Pathogenic complexes are small or intermediate (formed in antigen excess), which bind less avidly to phagocytic cells circulate longer

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Antigen-Antibody complex

Complement activation

Attract polymorphs

Rlease of proteolyt

ic enzyme

Macrophage activation

Release TNF-α ,IL1

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Immune complex-mediated diseases can be

generalized immune complexes are formed in circulation and deposited in many organs

localized deposited to particular organs, such as kidney (glomerulonephritis), joints (arthritis), or small blood vessels of skin

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Systemic Immune Complex Disease

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Pathogenesis of systemic immune complex disease divided into three phases:

1.) formation of antigen-antibody complexes in circulation

- initiated by introduction of an antigen, a protein, and interaction with immunocompetent cells formation of antibodies which are secreted into blood they react with antigen still present in the circulation to form antigen-antibody complexes

2.) deposition of the immune complexes in various tissues

3.) an inflammatory reaction at the sites of immune complex deposition

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Type III hypersensitivity reactionSystemic Immune Complex Disease

Two types of antigens cause immune complex –mediated injury

1) antigen may be exogenous (foreign protein, bacterium, or virus)

2) individual can produce antibody against self-components (endogenous antigens); antigen compounds of one’s own cells/tissues such as nuclear antigens, immunoglobulin or tumour antigens.

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Systemic Immune Complex Disease

serum sickness

- patients with diphtheria infection treated with serum from horses immunized with diphtheria toxin

- patients develop arthritis, skin rash, fever

- patients made antibodies to horse serum proteins antibodies formed complexes with injected proteins, and disease was due to antibodies or immune complexes

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hypersensitivity Reactions Type IV

(T-Cell Mediated)

Type IV hypersensitivity Reactions (T-Cell Mediated)

It is also known as cell mediated or delayed type hypersensitivity.

Type IV hypersensitivity reactions are mediated by immune cells

(T cell), not antibodies that develops in response to antigen

challenge in a previously sensitized individual.

In contrast with immediate hypersensitivity, the DTH reaction is

delayed for 48-72 hours, which is the time it takes for effector T

cells to be recruited to the site of antigen challenge and to be

activated to secrete cytokines.

The delayed hypersensitivity reactions lesions mainly

contain monocytes and T cells

Type IV hypersensitivity Reactions

Two types of T cell reactions are capable of causing tissue injury and disease:

(1) Cytokine-mediated inflammation:

-In which the cytokines are produced mainly by CD4+ T cells .

-CD4+ T cells of the TH1 and TH17 subsets secrete cytokines, which recruit and activate other cells, especially macrophages, and these are the major effector cells of injury.

(2) Direct cell cytotoxicity:

-Mediated by CD8+ T cells

-In which cytotoxic CD8+ T cells are responsible for tissue damage.


1) Cytokine-mediated inflammation :

1-Naive CD4+ T lymphocytes recognize peptide antigens of self or microbial

proteins in association with class II MHC molecules on the surface of

DCs or macrophages that have processed the antigens.

2-Then CD4+ T cells are activated and differentiate into TH1 and TH17

effector cells.

(If the DCs produce IL-12, the naive T cells differentiate into effector cells of

the TH1 type, If the APCs produce IL-1, IL-6, or IL-23 instead of IL-12,

the CD4+ cells develop into TH17 effectors)


3-Subsequent exposure to the antigen the previously generated effector

cells are recruited to the site of antigen exposure and results in the

secretion of cytokines.

4-The TH1 cells secrete IFN-γ, which is the most potent macrophage-

activating cytokine known.

5-Macrophages produce substances that cause tissue damage and

promote fibrosis, and TH17 secrete IL-17 and other cytokines recruit

leukocytes especially macrophages , thus promoting inflammation.

Cytokine-mediated inflammation


2)T cell–mediated cytotoxicity :

1- CD8+ CTLs specific for an antigen recognize cells expressing the target antigen and kill these cells.

2- Class I MHC molecules bind to intracellular peptide antigens and present the peptides to CD8+ T

lymphocytes, stimulating the differentiation of these T cells into effector cells called CTLs.

3-The principal mechanism of killing by CTLs is dependent on the perforin–granzyme system.

4-These enzymes induce apoptotic death of the target cells.

5-CD8+ T cells may also secrete IFN-γ and contribute to cytokine-mediated inflammation, but less so

than CD4+ cells

T cell–mediated cytotoxicity

T cell–mediated cytotoxicity

Sensitization phase


Cont. phases : 2- Effector phase:This occurs following re-exposure to antigen and activation of the memory Th1 cells IFN γ, from activated Th1 cells, promotes differentiation of monocytes tomacrophages, and activates mature macrophages to kill intracellular organisms. In addition, activated macrophages secrete products including IL-1and TNF, that stimulate processes producing inflammatory mediators thatcause bystander tissue injury.

Effector phase:

IFNγ, secreted byactivated Th1 cells, is a potent activator of tissue macrophages

Activated macrophages secrete cytokines (e.g., IL-1 and TNF) andchemokines that activate adhesion molecules on the endotheliumand circulating leukocytes

Neutrophils phagocytose antigen and secrete inflammatory mediators that cause local tissue damage


Examples :

1. Contact hypersensitivity2. Granulomatous hypersensitivity3. The tuberculin test

Contact Hypersensitivity

is usually caused by haptens that combine with proteins (particularly the amino acid lysine) in the skin of some people to produce an immune response . Reactions to poison ivy , cosmetics, and the metals in jewelry (especially nickel ) are familiar examples of these allergies.

Contact Hypersensitivity

Granulomatous hypersensitivity

It usually results from the persistence within macrophages ofintracellular microorganisms, which are able to resist macrophage killing or particles that the cell is unable to destroy.

This leads to chronic stimulation of T cells and the release of cytokines. The process results in the formation of epithelioid cell granulomas with a central collection of epithelioid cells,giant cells and macrophages surrounded by lymphocytes.

Granulomas occur with chronic infections such as tuberculosisor with foreign particulate agents such as talc and silica .

Granulomatous hypersensitivity

The tuberculin test

The test is used to determine whether an individual has been infected with the causative agent of tuberculosis, Mycobacterium tuberculosis. (A previously infected individual would harbor reactive T cells in the blood.)

The Mechanism of Tuberculin Test

small amounts of protein extracted from the mycobacterium are injected into the skin.

If reactive T cells are presentredness and swelling appear at the injection site 24-72 hours

If a tissue sample is examined, it will show: **infiltration by lymphocytes and monocytes,

**increased fluid between the fibrous structures of the skin ,

**some cell death

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TYPE III & IV HYPERSENSITIVITY REACTION 1 Hypersensitivity reaction.

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TYPE III & IV HYPERSENSITIVITY REACTION 1 Hypersensitivity reaction.