Hypersensitivity Reactions

Question 1

define hypersensitivity

Answer 1

inappropriate immune response to non-infectious/otherwise benign antigens, resulting in tissue damage and disease

Question 2

4 types of hypersensitivity - name them

Answer 2

type 1 - immediate hypersensitivity

type 2 - cytotoxic hypersensitivity

type 3 - serum sickness and Arthus reaction

type 4 - delayed type hypersensitivity, contact dermatitis

Question 3

Type I : Immediate hypersensitivity (allergy)

Answer 3

This type results from being exposed to allergens in the environment, and the host generates an immune response characterised by IgE antibody production

The IgE antibodies attach to mast cells, and when an antigen is present, the IgE will cross link the antigen, activating the mast cell and causing it to release mediators - cause inflammation

an example is asthma or system anaphylaxis

-system anaphylaxis is a more exaggurated allergic response, fluid leaks into tissues causing oedema - this can restrict the airways and lead to death

Question 4

how can you induce an immediate hypersensitivity reaction (type 1)?

Answer 4

• injecting allergens into the skin
• scratching the surface of the skin with an allergen

If you have mast cells in your tissue carrying that specific IgE, the IgE will be cross linked, the mast cells will be activated and will release lots of inflammatory mediators

Results in plasma leakage into surrounding tissues causing a wheal, and vasodilation causing a flare response

this forms the basis of an allergen test:

scratch the surface of the skin with an allergen, wait 10 mins
– a wheal formation is indication you have IgE’s made against that allergen

Question 5

Type II: cytotoxic hypersensitivity

Answer 5

respond to altered components of human cells, not something from the environment

IgG binds to “foreign antigen” on RBC or platelets - this antigen is a drug (eg. penicillin) and the immune system recognises it as a new allergen

drug now coated in IgG, activates cell containing the IgG receptor - mast cell and complement activation, resulting in inflammation. Antibody-bound cells are cleared by macrophages and complement.

Special case: slightly different in the sense that you stimulate antibodies that stimulate or block receptors
Eg. myasthesia gravis, graves disease (thyroxin release, HDN)

Question 6

example of type II: Grave’s disease

Answer 6

thyroxin usually binds to TSH receptors on the pit gland - negative feedback mechanism

here, an immune response is made against the TSH receptors, blocking them and causing excess thyroxin levels in the blood with no negative feedback - thryotoxicosis

Question 7

example of type II: Myasthenia gravis

Answer 7

NMJ with a synapse, Nerve is activated and releases Ach which stimulates post synaptic receptors on the muscle cell causing muscle contraction

here an immune response is made against post synaptic receptors - receptors blocked by antibodies causing nerve paralysis.

Question 8

example of Type II: Hemolytic disease of the newborn

Answer 8

RhD is a blood group antigen on the surface of red cells

RhD negative mother has a RhD positive foetus - rupture of the embryonic chorion during delivery releases red cells into maternal circulation, and immune response (antibodies) made against the RhD antigen

The first child is ok, but the second pregnancy is the issue.

The antibodies that were stimulated in the first pregnancy can cross the placenta and attack the red cells causing anaemia and death in the child.

Question 9

Type III: Serum sickness/Arthus reaction

Answer 9

IgG and precense of a soluble antigen, e.g. diphtheria toxoid

IgG and soluble antigen form immune complexes which are cleared by phagocytes.

serum sickness, arthus reaction, farmers lung

Question 10

Arthus reaction (type III)

Answer 10

Mast cell activation means inflammatory mediator release - inflammatory cells invade the site of infection, and blood vessel permeability and blood flow are increased.

Platelets accumulate, leading to occlusion of the small blood vessels, hemorrhage, and purpura.

Question 11

Serum sickness (type III)

Answer 11

• caused by large intravenous doses of soluble antigens (e.g. drugs) or following antivenom (serum from horse to treat snakebite)
• IgG antibodies produced form small immune complexes with the antigen in excess, and these complexes are deposited in tissues e.g. blood vessel walls.
• tissue damage due to complement activation and inflammatory responses

Question 12

what determines type III hypersensitivity reaction pathology?

Answer 12

Antigen dose and route of delivery

Question 13

Type IV: Delayed-type hypersensitivity

Answer 13

2 scenarios: TH1 and TH2 specific

• Mantoux test
• poison ivy

1. antigen stimulates TH1 to produce IFN gamma and IL-12, stimulating macrophages to release chemokines/cytotoxins/cytokines which recruit immune cells to the site of infection, granuloma occurs - 2-3 days to form
   - Tuberculin reaction
   - Tuberculoid leprosy, strong TH1 immune response to the presence of TB
2. TH2 produces IL-4, IL-5, important in IgE production and activating eosinophils and recruiting them to the site of infection
   - Allergic contact dermatitis (eg Nickel)

Question 14

What is IgE?

Answer 14

First line of defence against worms

Binds FcεR1 receptor on mast cells, coating them and pre-arming them to react in the presence of antigen

diff in structure compared to IgG because it has 1 extra domain in the heavy chain

Question 15

Allergen-specific IgE Production

Answer 15

First exposure to pollen activates immune response

APC (DC’s) pick up the pollen and take it to local lymph nodes to activate immune cells

Th2 cells release IL4 which induces B cells to produce IgE. IGE is released into circulation and binds to mast cells, ready for the next exposure to the allergen - when we are exposed to the same allergen again, we get activation of mast cells and hay fever

Question 16

Filaggrin and Atopic Dermatitis

Answer 16

People who lack the fillaggrin gene - their skin is far less of an effective barrier to the environment and things can cross the skin more easily, so the allergic immune response is more likely to be stimulated.

Question 17

What Makes Dendritic Cell Pro-Allergic?

Answer 17

One Candidate Protein is TSLP, may switch DC to a ‘pro-allergic’ state

(TSLP= Thymic stromal lymphopoietin)

Question 18

Mast cell activation

Answer 18

A resting mast cell is full of dense granules which contain inflammatory mediators eg. histamine

IgE cross links and actviates the mast cell, which then releases all its mediators, and it has a different structure

Question 19

2 phases to the allergic response?

Answer 19

early and late

Early is mediated by mast cells
Late is mediated by T cells

Question 20

Early and late phase allergic response

Answer 20

Exposure to the allergen causes activation of mast cells and release of mediators - immediate response, lasts a few years

When the allergen dose and level of activation is quite high, we can get a late phase response due to recruitment of other immune cells such as T cells to the site, causing a later allergic response

• associated with more diffuse inflammation and oedema

Question 21

The immune response to allergens

Answer 21

allergen exposure, DC presents APC to T cells - TH2 cells

TH2 cells release IL-4 and IL-13, which activate B cells to produce IgE which binds to mast cells producing ACUTE allergic reactions (wheezing, sneezing, conjunctivitis)

IL-4 also activates mast cells to produce histamines and cytokines which cause chronic allergic reactions (further wheezing, sustaining nose blockage, eczema)

IL-5 activates eosinophils which reduce cytokines that contribute to chronic allergic reactions

chronic means they release mediators over a longer period of time

Question 22

Effector mediators produced by mast cells

Answer 22

EARLY PHASE

• histamine and leukotrienes to cause SM contraction and increase vascular permeability
• prostaglandins are chemoattractants for T cells

LATE PHASE
-cytokines, IL-4, IL-13 (promote TH2 and IgE) and TNF-alpha (tissue inflammation)

mast cells cause wheezing due to increased mucus secretion and decreased airway diameter

diarrhoea and vomiittng due to increased peristalsis and fluid secretion

Question 23

Eosinophils

Answer 23

located in the tissues, recruited to the sites of allergic reactions and express FcεRI upon activation

The two effector functions of eosinophils:
1. Release highly toxic granule proteins and free radicals when activated, killing microbes and causing tissue damage in allergic reactions.

2. Synthesis and release of prostaglandins, leukotrienes and cytokines to amplify the inflammatory response by activating epithelial cells and recruiting leukocytes.

Question 24

what is a late phase response dependent on?

Answer 24

allergen dose
-more allergen you are exposed to, the more likely it is that you will have a late phase response

Mostly consisting of allergen specific Th2 cells which recruit other cells via cytokines

Question 25

before individuals can react to an antigen what has to happen?

Answer 25

must be sensitised to an allergen before they can react

• sensitisation requires presentation of allergen to Th2 CD4 T cells by DC and the priming of Cognate B cells to produce IgE
• reaction – IgE on mast cells cross-linked by cognate antigen leading to inflammation

Question 26

Asthma

Answer 26

reversible bronchial hyper-reactivity resulting from a persistent inflammatory process

Atopic (allergic) and Non-Atopic
Non Atopic includes
Occupational
Exercise induced
Nocturnal Asthma
Post-bronchiolitic Wheeze

Question 27

characteristics of Allergic Asthma

Answer 27

• episodes of wheezy breathing
• narrowing of the airways
• rapid changes in airway obstruction
• severity varies - slight wheeziness to asthma attack

common allergens causing asthma include:
pollen, plants, some foods

Question 28

allergic asthma - acute and chronic response

Answer 28

Acute response:

• occurs within seconds of allergen exposure, inflammatory mediators cause increase mucus secretion and SM contraction, leading to airway obstruction and breathing difficulties
• recruitment of cells from circulation
• caused by allergen-induced mast cell degranulation in the submucosa of the airways

Chronic:
- chronic inflammation of the
airways cause by eosinophils, neutrophils and T cells activation
- mediators released by these cells cause fibrosis and airway remodelling, permanent airway narrowing and further tissue damage

Question 29

Treatment of allergy in the clinic

Answer 29

Blockage of effector pathways:

inhibit effects of mediators on specific receptors
anti-histamine (block the histamine H1 receptor)

inhibit mast cell degranulation
mast cell stabilizer (e.g. chromoglycate)

 inhibit synthesis of specific mediators
 lipoxygenase inhibitors (e.g montelukast)

Steroids – Act directly on DNA to increase transcription of anti-inflammatory mediators (e.g. IL-10) and decrease transcription of pro-inflammatory mediators (e.g prednisolone)

Bronchodilators – Reverse acute effect of allergy on airways (e.g B2 agonist salbutamol)

Immunotherapy – Reverses the sensitisation to allergen by means of tolerising exposure