Week 2 tute - autoimmune and inflammation

Question 1

what is type I hypersensitivity also called?

Answer 1

immediate hypersensitivity

Question 2

what is type I hypersensitivity mediated by?

Answer 2

IgE antibodies attached to mast cells or basophils

Question 3

how long after exposure does type I hypersensitivity occur?

Answer 3

within 30 minutes of exposure

Question 4

describe the steps of type I hypersensitivity

Answer 4

• Sensitisation: TH2 releases interleukins in the prescence of Ag to cause B cells to make a new kind of Ab (IgE) for that Ag. New Abs bind to FcERI on mast cells (or basophils)
• Activation: next time IgE encounters Ag, Ag induces crosslinking of IgE on mast cell/basophil. Degranulation of mast/basophils releases vasoactive mediators
• Effector step: Pharmacological effect (vasodilation, oedema, brochoconstriction) and chemotaxis resulting in further inflammation (mainly from eosinophils)

Question 5

what is type II also known as?

Answer 5

Cytolytic or Cytotoxic

Question 6

which antibodies is type II hypersensitivity mediated by?

Answer 6

IgG or IgM antibodies binding to antigens on cell surfaces

Question 7

describe the steps of type II sensitivity

Answer 7

• IgG or IgM antibodies binding to antigens on cell surfaces
• activating the complement cascade
• cell destruction

Question 8

which immunoglobulin/antigen complexes is type III hypersensitivity mediated by?

Answer 8

Ag-IgM or Ag-IgG complexes

Question 9

how long after exposure does type III hypersensitivity occur?

Answer 9

within hours of challenge with antigen

Question 10

describe the steps of type III hypersensitivity

Answer 10

• antigen binds to immunoglobulin
• Ag-IgM or Ag-IgG complexes activate complement
• granulocytes (e.g. neutrophils) are attracted to the site of activation
• damage is caused by the release of lytic enzymes.

Question 11

what is type IV hypersensitivity also known as?

Answer 11

delayed-type hypersensitivity

Question 12

which cell is type IV (Delayed-type hypersensitivity) mediated by?

Answer 12

Th1 cells

Question 13

which 2 cells are involved in type IV (Delayed-type hypersensitivity)?

Answer 13

cytotoxic T cells (CD8+) and Th1 cells (CD4+)

Question 14

which antibodies are involved in type IV hypersensitivity?

Answer 14

there is no antibody involvement in type IV, you muggle

Question 15

describe the steps of type IV hypersensitivity

Answer 15

• antigen causes Th1 cells to release cytokines
• accumulation & activation of macrophages and activation of cytotoxic T cells which mediate local damage

Question 16

how long after exposure does type IV reaction occur?

Answer 16

days-weeks after challenge with antigen

Question 17

What % of the western world suffers from allergies?

Answer 17

20%

Question 18

What is atopy?

Answer 18

A predisposition toward developing IgE mediated hypersensitivity allergic reactions.

Question 19

IgE is important for the sensitisation stage of type I hypersensitivity, how is IgE produced and what cytokines are involved? Where is it localised?

Answer 19

Sensitization:

• Ag presenting cell (dendrocyte or macrphage) presents Ag to naive T-helper in lymph nodes
• Naive T-helper binds to Ag and costimulating factor of Ag presenting cell, in the prescnece of cytokines IL-4, IL-5 and IL-10 is “primed” and becomes a T_H2 cell
• T_H2 releases their own IL-4 and IL-13 causing B cell to undergo Ab class switching - B cell switches from producing IgM to IgE Abs. T_H2 also releases IL-5 to stimulate eosinophil maturation/activation
• IgE Abs bind to FcERI in mast cells, once mast cell is loaded with Abs it can crosslink with Ag upon next exposure and degranulate

Question 20

How does IgE contribute to the activation stage of type I hypersensitivity?

Answer 20

Post sensitisation (eg months later) IgE binds to FcERI on mast cells (and occasionally basophils). On exposure to the specific Ag that the IgE Abs have been sensitised to, Ag binding causes cross linking, resulting in degranulation and the release of histamine and other inflammatory mediators to the local tissues

Question 21

Name the inflammatory mediators released by mast cells and what are the effects of these reagents?

Answer 21

Histamine, cytokines and chemokines are released from granules, leukotrienes, protoglandins and PAF are synthesised in plamsa membrane.

1. Histamine: binds to H1 receptors cells causing vascular permeability and oedema of edothelial cells and smooth muscle contractions causing bronchoconstriction in the lungs. Binds to H2 receptors causing mucus secretion from respiratory mucosa & release of stomach acid from gut mucosa.
2. Cytokines and chemokines: IL-3, IL-4, IL-5, IL-8, IL-9, TNF-α and GM-CSF recruit inflammatory cells - neutrophils, basophils, eosinophils, macrophages and lymphocytes.
3. Leukotrienes and prostaglandins (very potent): contraction of bronchial and tracheal smooth muscle, increases vascular permeability and mucus secretion. Contributes to prolonged bronchospasm and mucus build-up in asthma.
4. Platelet activating factor (PAF): causes platelets to aggregate and release their mediators, including histamine.

Question 22

What are the differences between the early and late stages of an allergic response? What cell types & cytokines are involved in the late stage?

Answer 22

Early phase: happens within minutes, caused by direct effects on blood vessels and smooth muscle by mediators such as histamine (IgE/mast cell mediation)

Late Phase: happens 6-10 hours after initial allergic reaction and can last for days. Caused by influx of inflammatory eosinophils, neutrophils, basophils, macrophages and T_H2 cells attracted by the cytokines and chemokines secreted by mast cells.

• Eosinophils make the biggest appearance. They are attracted to IL-4 and chemokines secreted by mast cells and casued to differentiate and grow by IL-3, IL-5 (main player) & GM-CSF secreted by T_H2. Eosinophils express FcεRII for IgE and Fc receptors that bind IgG, which, when bound to the antigen cause degranualation and released inflammatory mediators (e.g. leukotrienes, major basic protein, eosinophilic cationic protein, eosinophilic peroxidase and platelet activating factor) causing extensive tissue damage (particularly to respiratory epithelium in asthma).
• Neutrophils also contribute to the late phase. They migrate in response to IL-8 (neut. chemotatic factor) from mast cells. Their surface IgG Fc receptors bind antibody coated antigen causing cell activation, phagocytosis of antibody-antigen complexes and the release of leukotrienes & lysosomal enzymes that cause tissue damage.
• Th2 lymphocytes release cytokines that cause a second wave of muscle contraction and sustained edema.

Question 23

How do mast cells contribute to an allergic reaction?

Answer 23

1. IgE binds to mast cells
2. Ag binds to IgE causing crosslinking
3. Degranulation of mast cells releases:
   - Histamine causes vasodilation/oedema and bronchoconstriction.
   - Leukotrienes and prostaglandins cause bronchoconstriction and muscous production.
   - Platelet activating factor causes platelets to aggregate and release histamine.
   - Interleukins recruit other WBCs.

Question 24

Name some diseases associated with type I hypersensitivity.

Answer 24

• asthma
• anaphylaxis
• acute urticaria (hives)
• seasonal rhinoconjunctivitis (hayfever)
• food allergy

Question 25

Explain what happens in anaphylaxis.

Answer 25

1. Allergen cross links with IgE which is bound to FcεRI on mast cell
2. Mast cell activation and degranulation releasing histamine, cytokines and chemokines and synthesis and release of prostaglandins, leukotrienes, and platelet-activating factor from the plasma membrane
3. Recruitment of TH2 lymphocytes, eosinophils, and basophils.

• Histamine causes vasodilation/oedema and bronchoconstriction.
• Leukotrienes and prostaglandins cause bronchoconstriction and muscous production (trachea and GIT).
• Platelet activating factor causes platelets to aggregate and release histamine.
• Interleukins recruit other WBCs.

Question 26

Allergy has a key role in the majority of asthma cases, but non-allergic asthma is also a possibility, explain.

Answer 26

Non-allergic asthma (not IgE-mediated) associated with exposure to air pollution, cigarette smoke, diesel particles, cold air, exercise and infection. Irritant acts on lung epithelium triggering release of IL- 33. This binds to ST2 receptors on ILC2 (type 2 innate lymphoid cells) to activate them to release IL-5, IL-13 and other type 2 cytokines resulting in inflammation plus eosinophil recruitment/degranulation.

Question 27

what type of hypersensitivity is this?

Answer 27

Type I hypersensitivity

Question 28

Match the immunoglobulin class to its main function:

A. IgD
B. IgE
C. IgM

i. agglutination, complement activation, primary B cell receptor and opsonophagocytosis
ii. activation of mast cells and eosinophils
iii. primary B cell receptor

Answer 28

A. IgD = iii. primary B cell receptor
B. IgE = ii. activation of mast cells and eosinophils
C. IgM = i. agglutination, complement activation, primary B cell receptor and opsonophagocytosis

Question 29

IgE is important for the sensitisation stage of type I hypersensitivity, how is IgE produced and what cytokines are involved? Where is it localised?

Answer 29

• Naive T cell is presented with Ag and becomes primed, under the influence of IL-4, IL-5 and IL-10 it becomes a Th2 cell
• Th2 releases IL-4, IL-5 and IL-13 causing B cells to become plasma cells, stop producing IgM and start producing IgE specific to Ag
• IgE binds to fuckery on mast cell surface, reintroduction of Ag causes crosslinking and degranulation of mast
• Occurs mostly in mucosal and epithelial tissues, in the vicinity of small blood vessels and in the subendothelial connective tissues as this is where mast cells live. Basophils also act like mast cells and can bind to Ab in the blood.