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Type III & IV hypersensitivity reaction 1Hypersensitivity reaction1OutlineIntroduction.Type III hypersensitivity reaction. - General mechanisem of action 1-Systemic Immune Complex Disease 2-Local Immune Complex Disease - SummaryTypeVI hypersensitivity reaction. - Variants of type IV hypersensitivity reactions - Mechanisem of action

2Hypersensitivity reaction2Type III hypersensitivity reactionSensitization 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)3Hypersensitivity reaction3 However

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

4Hypersensitivity reactionType III hypersensitivity reactionThese circulating complexes can then become deposited on tissues. Tissue deposition may lead to reaction with complement, causing tissue damage. this type of hypersensitivity develops as a result of systematic exposure to an antigen and is dependent on i) the type of antigen and antibody and ii) the size of the resulting complex .More specifically, complexes that are too small remain in circulation; complexes too large are removed by the glomerulus; intermediate complexes may become lodged in the glomerulus leading to kidney damage.4TitleLarger 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.

5Hypersensitivity reaction5Effectors 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)6Hypersensitivity reactionType III hypersensitivity reactionType III hypersensitivity occurs as a result of immune complex deposition. Immune complexes are antigen - antibody complexes. They usually form when antigen is produced in excess of antibody. They may be localised to the site of antigen production or they may be found in the circulation.

6 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 large complexes in antibody excess are rapidly removed from circulation by mononuclear phagocyte system (harmless)Pathogenic complexes are small or intermediate (formed in antigen excess), which bind less avidly to phagocytic cells circulate longer

7Hypersensitivity reactionType III hypersensitivity reaction7 8Hypersensitivity reactionType III hypersensitivity reactionImmune complexes are formed during many immune responses and represent a normal mechanism of antigen removal; some are just pathogenic

8Immune 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 skin9Hypersensitivity reactionType III hypersensitivity reaction9 Systemic Immune Complex Disease10Hypersensitivity reactionType III hypersensitivity reaction10Pathogenesis 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 complexes2.) deposition of the immune complexes in various tissues3.) an inflammatory reaction at the sites of immune complex deposition

11Hypersensitivity reactionType III hypersensitivity reactionSystemic Immune Complex Disease11 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 ones own cells/tissues such as nuclear antigens, immunoglobulin or tumour antigens.

12Hypersensitivity reactionType III hypersensitivity reaction12Systemic 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 13Hypersensitivity reactionType III hypersensitivity reactionacute serum sicknessis prototype of systemic immune complex disease


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 antibodiesthat 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 ReactionsTwo 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.

Type IV hypersensitivity ReactionsCytokine-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)

Type IV hypersensitivity Reactions3-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-, 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

Type IV hypersensitivity Reactions2)T cellmediated 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 perforingranzyme system.4-These enzymes induce apoptotic death of the target cells.5-CD8+ T cells may also secrete IFN- and contribute to cytokine-mediated inflammation, but less so than CD4+ cells

T cellmediated cytotoxicity

T cellmediated cytotoxicity

Sensitization phase

Type IV hypersensitivity ReactionsCont. phases : 2- Effector phase:This occurs following re-exposure to antigen and activation of the memory Th1 cells IFN , 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:

IFN, secreted byactivated Th1 cells, is a potent activator of tissue macrophagesActivated 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

Type IV hypersensitivity ReactionsExamples :

Contact hypersensitivityGranulomatous hypersensitivityThe tuberculin test

Contact Hypersensitivityis 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 hypersensitivityIt 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 ofepithelioid cell granulomaswith 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 testThe 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

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