17 - Hypersensitivity

Question 1

Type 1 / immediate hypersensitivity

Answer 1

• 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

Question 2

Type 2 hypersensitivity

Answer 2

Caused by antibodies directed against cell or tissue antigens

Question 3

Type 3 hypersensitivity

Answer 3

• 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

Question 4

Type 4 hypersensitivity

Answer 4

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

Question 5

Atopic

Answer 5

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

Question 6

Steps of type 1 hypersensitivity

Answer 6

• 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

Question 7

Mast cell mediators in type 1 sensitivity

Answer 7

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

Question 8

When does immediate reaction occur

Answer 8

Minutes after exposure to antigen

Question 9

When does late phase reaction occur

Answer 9

6-24 hours after exposure to antigen

Question 10

Common types of allergies

Answer 10

hay fever, food allergies, asthma, and anaphylaxis.

Question 11

Activation of mast cells

Answer 11

• 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

Question 12

What do signalling pathways activated by IgE cross linking stimulate

Answer 12

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

Question 13

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

Answer 13

• Vascular dilation, smooth muscle contraction
• Tissue damage

Question 14

Effects of synthesis of arachidonic acid metabolites (leukotrienes)

Answer 14

• Vascular dilation
• Smooth muscle contraction

Question 15

Effects of synthesis of various cytokines

Answer 15

Inflammation (leukocyte recruitment)

Question 16

Anaphylaxis

Answer 16

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

Question 17

Steps of type 2 hypersensitivity

Answer 17

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

Question 18

What does IOI stand for in antibodies causing disease

Answer 18

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

Question 19

Diseases caused by type 2 hypersensitivity

Answer 19

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

Question 20

Haemolytic transfusion reaction

Answer 20

• 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

Question 21

Haemolytic disease of the newborn

Answer 21

• 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

Question 22

Myasthenia gravis

Answer 22

Autoantibodies against the acetylcholine receptor inhibit neuromuscular transmission, causing paralysis

Question 23

Graves disease

Answer 23

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

Question 24

Steps of type 3 hypersensitivity

Answer 24

• 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

Question 25

Vasculitis

Answer 25

- 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

Question 26

Diseases caused by type 3 hypersensitivity

Answer 26

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

Question 27

SLE

Answer 27

- 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)

Question 28

Serum sickness

Answer 28

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

Question 29

Arthus reaction

Answer 29

- 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

Question 30

Two main mechanisms of type 4 hypersensitivity

Answer 30

- 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

Question 31

Delayed type hypersensitivity reaction in the skin

Answer 31

- 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.

Question 32

What are DTH reactions manifested by

Answer 32

- 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)

Question 33

Examples of diseases caused by type 4 hypersensitivity (DTH)

Answer 33

- Chronic inflammation and tubercular granuloma - Type 1 diabetes

Question 34

Chronic inflammation and tubercular granuloma

Answer 34

- 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.

Question 35

Tuberculin reaction

Answer 35

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

Question 36

Example of tuberclulin reaction

Answer 36

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

Question 37

Type 1 diabetes

Answer 37

- 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,