Immunopathology - Allergy & Hypersensitivity

Question 1

What are the four types of hypersensitivites?

Answer 1

• type I - immediate hypersensitivity
  
  • type II - antibody mediated
  • type III - immune complex
  • type IV - delayed type hypersensitivity

Question 2

What is allergy?

Answer 2

An immune mediated inflammatory response to common environmental allergens that are otherwise harmless

Question 3

What is atopy?

Answer 3

A person who has high levels of circulating IgE, elevated numbers of eosinophils in circulation and in the tissues and large numbers of Th2 T cells secreting IL-4

Question 4

What are the features of type I immediate hypersensitivity?

Answer 4

Inflammatory response to antigens mediated by IgE, involves a sensitisation followed by a response which is either local or systemic. The response has both an immediate and a late phase.

Question 5

What are the 6 contributors to the allergic mechanism?

Answer 5

allergens, Th2 cells, IgE, FcepsilonR1 receptor, mast cells, eosinophils

Question 6

What is the allergen associated with dust mites?

Answer 6

The der p 1 enzyme in dust mite faeces

Question 7

What are the common features of allergens?

Answer 7

Stable, highly soluble in bodily fluids, introduced in very low doses, often are enzymes

Question 8

What happens in the sensitisation?

Answer 8

The APC takes up the allergen and presents it to the T cell with the cytokine IL-4 to create Th2 cell. The Th2 cell interacts with B cells to induce proliferation and isotype switching to IgE which leads to IgE secretion. The IgE binds to mast cells via the FcepsilonR

Question 9

Where does the cytokine IL-4 come from to induce Th2 differentiation?

Answer 9

Dendritic cells don’t produce IL-4 but do produce IL-33. Basophils are activated to secrete IL-4 either by the IL-33 secreted by DCs or by direct activation from the allergen. This either happens in combination with a dendritic cell acting as the APC or the basophil can act as an APC on its own. (Graphic)

Question 10

What happens in the effector phase?

Answer 10

The allergen binds to the IgE antibody bound to the mast cell to cause cross linking of the receptor which induces release of granules - this is the immediate response. It also induces the synthesis and secretion of lipid mediators - also the immediate response. It also induces the the synthesis and secretion of cytokines- this is the slow response.

Question 11

What do the granules of mast cells contain?

Answer 11

histamine, heparin, tryptase, chymase, TNFalpha

Question 12

What are the lipid mediators?

Answer 12

Prostaglandins and leukotrienes

Question 13

What are the cytokines?

Answer 13

IL-3, IL-4, IL-13, IL-5 and TNF alpha

Question 14

What are the symptoms of the immediate phase?

Answer 14

Wheal and flare due to blood vessel dilation and leakage

Question 15

What are the symptoms of the late phase?

Answer 15

Hard lump due to cellular infiltration and smooth muscle contraction

Question 16

What is the allergic response in the GI tract?

Answer 16

fluid secretion and peristalsis - leads to diarrhoea and vomiting

Question 17

What is the allergic response in the skin?

Answer 17

fluid secretion and vasodilation - leads to swelling, itching and urticaria

Question 18

What is the allergic reaction in the airways?

Answer 18

bronchoconstriction and mucous secretion - leads to nasal blockage, phlegm, coughing, asthma

Question 19

What is the allergic reaction in the blood vessels?

Answer 19

Increased blood flow and permeability leads to anaphylactic shock

Question 20

What is the role of eosinophils in allergic response?

Answer 20

Eosinophils produce toxic intermediates from their granules which causes tissue damage and remodelling and produce chemical mediators to activate epithelial cells and recruit inflammatory cells

Question 21

What leads to the increased production of eosinophils?

Answer 21

IL-5 secreted from Th2

Question 22

What brings epithelial cells to the site?

Answer 22

CC chemokines from epithelial cells

Question 23

What causes the increased sensitivity of eosinophils?

Answer 23

Increased number of FCepsilonR1 receptors on surface after activation

Question 24

What is used for symptomatic treatment of allergy?

Answer 24

adrenaline for anaphylaxis, beta adrenoceptor agonists for asthma, antihistamines, coritcosteroids

Question 25

What is involved in immunotherapy/desensitisation?

Answer 25

Administration of increasing doses of allergen under the skin - induces switching of Th2 to Th1, stimulation of apoptosis of T cells, increased production of Treg, decreased allergen induced proliferation

Question 26

What is delayed type IV hypersensitivity?

Answer 26

persistent antigenic stimulation resulting in increased Th1 activity as well as CD8 T cells and macrophages

Question 27

What happens in sensitisation in type IV hypersensitivity?

Answer 27

Antigen uptake by APC, APC secretes IL-12 to differntiate T cell to Th1 - antigen persists at the site so Th1 cells persist and accumulate at the site

Question 28

What cytokine does Th1 secrete?

Answer 28

IFN gamma

Question 29

What is the role of IFN gamma?

Answer 29

Induces macrophage release of inflammatory mediators

Question 30

What is the result of release of TNFalpha?

Answer 30

Tissue destruction and adhesion molecules on local blood vessels

Question 31

What is the result of release of IL-3

Answer 31

monocyte production in the bone marrow

Question 32

What are the 3 kinds of type IV hypersensitivity?

Answer 32

contact sensitivity, mycobacterium tuberculosis, coeliac disease

Question 33

What is an example of contact hypersensitivity?

Answer 33

Poison ivy

Question 34

What is the mechanism contact hypersensitivity?

Answer 34

A sensitisation phase involves the antigen presenting to the T cell via a DC, activating T cells which migrate to the site. The response phase involves re-exposure to the antigen which activates effector memory T cells and central memory T cells which leads to a production of interferon gamma, activation of macrophages and excessive inflammation

Question 35

What is the mechanism of type IV hypersensitivity due to mycobacterium tuberculosis?

Answer 35

The pathogen can survive in macrophages due to its thick waxy walls. Infection stimulates production of Th1 cells which activates macrophages. The delayed type hypersensitivity restricts the growth of the pathogen - however in a small number of individuals it results in an interruption of respiratory function. Macrophages and dendritic cells present the antigen to T cells which activates CD8 and Th1 cells. CD8 and Th1 cells migrate to site and secrete IFNgamma to active macrophages. Macrophage activation results in production of CXCL8, IL-1, TNFalpha which results in endothelial activation (all), phagocyte and lymphocyte migration (all), fever (IL-1), weight loss (TNF-alpha), granuloma formation (TNF-alpha). Granuloma can lead to impaired oxygen exchange.

Question 36

What is the mantoux test?

Answer 36

A test for exposure (not immunity) to M. tuberculosis. Proteins from the organism are induced under the skin an if proteins interact with memory T cells then confirms exposure. Detect memory T cells with a hard lump present after 48-72 hours.

Question 37

What is the HLA gene for patients with celiac disease?

Answer 37

DQ2 or DQ8

Question 38

What is the mechanism for celiac disease?

Answer 38

Gliadin (a protein component of gluten) is made up largely of glutamine and proline. Tissue transglutaminase 2 deamidates the glutamine to glutamate. The glutamate allows the gliadin to bind to HLA DQ2 or DQ8. Presents to T cells and activates Th1 cells. Th1 cells produce cytokines which damage villi. This is a type IV hypersensitivity.