17 - Hypersensitivity Flashcards by Dom Brooke

Type 1 / immediate hypersensitivity

Allergies
Caused by the release of mediators from mast cells
Depends on the production of IgE against environmental antigens and binding of IgE to mast cells in various tissues

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Type 2 hypersensitivity

Caused by antibodies directed against cell or tissue antigens

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Type 3 hypersensitivity

Caused by antibodies against soluble antigens in blood forming immune complexes
Immune complexes deposit in blood vessels in various tissues causing inflammation and tissue injury

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Type 4 hypersensitivity

T cell-mediated hypersensitivity reactions mainly due to autoimmunity and exaggerated or persistent responses to microbial or ther environmental antigens

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Atopic

People prone to type 1 hypersensitivities (high levels of IgE)

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Steps of type 1 hypersensitivity

Activation of Th2 and IL-4 secreting Tfh cells, which stimulate production of IgE
Binding of IgE to IgE specific Fc receptors of mast calls (FcεRI)
On subsequent exposure to antigen, cross linking of the bound IgE activates the mast cells to release various mediators

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Mast cell mediators in type 1 sensitivity

Immediate reaction: Rapid increase in vascular permeability and smooth muscle contraction
Late phase reaction: Recruit neutrophils and eosinophils to site of reaction

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When does immediate reaction occur

Minutes after exposure to antigen

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When does late phase reaction occur

6-24 hours after exposure to antigen

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Common types of allergies

hay fever, food allergies, asthma, and anaphylaxis.

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Activation of mast cells

Cross-linking of IgE on a mast cell by an allergen
stimulates phosphorylation of immunoreceptor tyrosine based activation motifs (ITAMs) in the signalling chains of the IgE Fc receptor (FcεRI)
Initates multiple signalling pathways

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What do signalling pathways activated by IgE cross linking stimulate

Release of mast cell granule contents (amines, proteases)
Synthesis of arachidonic acid metabolites (leukotrienes)
Synthesis of various cytokines

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Effects of release of mast cell granule contents (amines, proteases)

Vascular dilation, smooth muscle contraction
Tissue damage

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Effects of synthesis of arachidonic acid metabolites (leukotrienes)

Vascular dilation
Smooth muscle contraction

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Effects of synthesis of various cytokines

Inflammation (leukocyte recruitment)

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Anaphylaxis

Shock caused by vascular dilation and airway obstruction due to laryngeal edema

Steps of type 2 hypersensitivity

Typically IgG antibodies causing disease by binding to their target antigens in different tissue
Most often autoantibodies against self antigens
Cause disease by IOI

What does IOI stand for in antibodies causing disease

I: Inducing inflammation at site of deposition
O: Opsonising cells for phagocytosis
I: Interfering with normal cellular functions (e.g. hormone receptor signalling)

Diseases caused by type 2 hypersensitivity

Haemolytic transfusion reaction (HTR)
Haemolytic disease of the newborn
Myasthenia gravis
Graves disease

Haemolytic transfusion reaction

Blood from a type A donor is administered to a patient with type B blood
Anti-A antibodies in the recipient bind to and agglutinate the incoming donor type A red blood cells
Bound anti-A antibodies activate the classical complement cascade, resulting in destruction of the donor red blood cells

Haemolytic disease of the newborn

If an Rh− woman carries an Rh+ baby to term, the mother’s immune system can be exposed to Rh+ fetal red blood cells.
Problems occur in subsequent pregnancies if foetus is Rh+
Treated with anti-Rh antibodies which inactivate foetal Rh antigens before they stimulate immune response in mother

Myasthenia gravis

Autoantibodies against the acetylcholine receptor inhibit neuromuscular transmission, causing paralysis

Graves disease

Autoantibodies to TSH receptor stimulate receptor without hormone
Thyroid produces excessive amounts of thyroid hormones, which regulate metabolism

Steps of type 3 hypersensitivity

Antigen-antibody complexes (produced during normal immune responses), cause disease when they are formed in excessive amounts and not efficiently removed by phagocytes, and become deposited in tissues
Causes vasculitis

Vasculitis

- Immune complexes deposit in blood vessels, activating complement and binding Fc receptors on neutrophils, causing them to release damaging proteases and ROS - Leads to renal disease if occurs in kidney glomerulus

Diseases caused by type 3 hypersensitivity

- Systemic Lupus Erythematosus (SLE) - Serum sickness - Arthus reaction

SLE

- Immune complexes of anti-DNA antibodies and DNA can deposit in the blood vessels of almost any organ, causing vasculitis and impaired blood flow, leading to a multitude of different organ pathologies and symptoms - Causes by susceptibility genes and external factors (e.g. UV radiation)

Serum sickness

Can occur as a complication of any therapy involving injection of foreign proteins, such as antibodies against microbial toxins, snake venoms and T cells, that are usually made in goats or rabbits

Arthus reaction

- Formation of immune complexes at the site of antigen injection and a local vasculitis. - Vaccine recipients who have previously been vaccinated or already have antibodies against the vaccine antigen, a painful swelling that develops at the injection site

Two main mechanisms of type 4 hypersensitivity

- Inflammation may be triggered by cytokines produced by CD4 T cells, causing tissue injury by activated inflammatory cells - Direct killing of target cells mediated by CD8 CTLs

Delayed type hypersensitivity reaction in the skin

- Occurs 24 to 48 hours after an individual previously exposed to a protein antigen is challenged with the antigen - Delay due to time taken for circulating effector T lymphocytes to home to the site of antigen challenge and respond to the antigen at this site.

What are DTH reactions manifested by

- Infiltrates of T cells and blood monocytes in the tissues - Increased vascular permeability in response to cytokines - Tissue damage induced by leukocyte products, from macrophages and neutrophils (that are activated by the T cells)

Examples of diseases caused by type 4 hypersensitivity (DTH)

- Chronic inflammation and tubercular granuloma - Type 1 diabetes

Chronic inflammation and tubercular granuloma

- In TB, a T cell–mediated immune response develops against protein antigens of Mycobacterium tuberculosis - Response becomes chronic because the infection is difficult to eradicate. - The resultant granulomatous inflammation causes injury to normal tissues at the site of infection.

Tuberculin reaction

- Sensitised for DTH by infection or injection of protein antigens - Subsequent exposure to same antigen elicits the reaction (testing for IFN-gamma)

Example of tuberclulin reaction

Purified protein derivative (PPD), a protein antigen of Mycobacterium tuberculosis, elicits the tuberculin reaction when it is injected into individuals who have been exposed to M. tuberculosi

Type 1 diabetes

- Activated B cells interact with CD4+ and CD8+ T cells, as well as dendritic cells (DCs) - Antigen presentation by B cells and DCs drives the activation of β-cell-specific CD8+ T cells. - In addition, the exposure of B cells to β-cell autoantigens leads to the production of islet-targeting autoantibodies,