Lecture 9: Hypersensitivity and chronic inflammation

Question 1

How do hypersensitivities occur?

Answer 1

When the immune system responds to foreign antigens but in too vigorous a manner

Question 2

How many classifications of hypersensitivities are there?

Answer 2

4 (I, II, III, IV)

Question 3

What type of response of allergy?

Answer 3

Predominantly a type I response but sometimes type III or IV

Question 4

How does chronic inflammation occur?

Answer 4

when immune system responds to foreign antigens but is not turned off properly

Question 5

What is autoimmunity?

Answer 5

where the immune system inappropriately attacks self-antigens

Question 6

What is a type I hypersensitivity reaction and what are the main mediators of this reaction?

Answer 6

Type I (allergy and atopy)
- B-cell class switch to produce IgE antibodies in response to cytokine signalling - these IgE antibodies bind to antigen via variable region and to FcεRI or FcεRII of immune cells via their constant region
- mediators = IgE resulting in degranulation of mast cells, basophils (and eosinophils to a lesser extent)

Question 7

What is the difference between FcεRI and FcεRII?

Answer 7

FcεRI has high affinity for the Fc region of IgE antibodies and is found on mast cells and basophils responsible mainly for Type I reactions
- also found on eosinophils = contribute to allergy, stimulated by cytokine and chemokines released by mast cells
- also found on dendritic cells and macrophages to internalise the IgE-antigen complex and present antigen to stimulate TH2 responses

FcεRII has lower affinity for IgE antibodies and is expressed by B cells, macrophages, and epithelial cells
- it functions in antigen presentation but not involved in allergy

Question 8

What are the properties of IgE antibodies?

Answer 8

• IgE isotype has the lowest abundance in vivo and is tightly regulated - low steady-state level
• serum half-life is shorter than all Ig isotypes
  -low steady-state level and the transient nature of IgE responses may help to minimise cross-reactivity that may trigger an allergic reaction
• IgE bound to cell surface receptors can persist for a long time - act as a waiting trigger (held on the surface of mast cells - antibodies ready to be complexed)

Question 9

What type of infections is IgE particularly beneficial in fighting?

Answer 9

parasitic infections (worms)

Question 10

What is an atopic individual?

Answer 10

someone who has a predisposition (due to both genetic and environmental factors) to make IgE antibodies in response to common environmental antigens that most people are tolerant to, not just parasitic worms

Question 11

Describe substances that are allergens?
(what are they mostly and what antigen properties do they typically have)

Answer 11

Most are proteins or glycoproteins but many are proteases

Their antigens are multivalent

Question 12

Give four examples of allergens

Answer 12

Plant pollens - grass
Drugs - penicillin
Foods - nuts, eggs
Insects - venoms, dust mites

Question 13

what are the common types of allergy?

Answer 13

hay fever (sneezing, runny nose etc)
asthma (constriction of the airways)
dermatitis (skin rashes and itching)
food allergies

Question 14

What is anaphylactic shock?

Answer 14

a strong systemic effect that can be fatal
- occurs when an allergen is introduced into the bloodstream
- symptoms include difficulty breathing, low blood pressure, contraction of smooth muscles and bronchiolar constriction leading to asphyxiation

Question 15

What is the mechanism of Type I hypersensitivity (primary and secondary exposure)?

Answer 15

Primary exposure stimulates a TH2 response that produce cytokines IL-4 and IL-13 that drives class switching to produce IgE antibodies and plasma cells.
- sensitisation of mast cells in which the IgE antibodies bind via Fc region to FcεRI

Secondary exposure cross-linkage reaction of antibodies = signalling via ITAMs results in degranulation and release of active mediators

Question 16

What are primary mediators of Type I hypersensitivity and give 3 examples?

Answer 16

Primary mediators: substances released from intracellular granules by degranulation with direct effects

Examples:
1. Histamine released from granules
2. Eosinophil chemotactic factor (ECF-A) released from granules to recruit additional effectors
3. Neutrophil chemotactic factor (NCF-A) released from granules to recruit additional effectors

Question 17

How does the primary mediator histamine work in a type I hypersensitivity reaction?

Answer 17

Histamine acts rapidly by binding to histamine receptors on various cells and tissues causing:
- contraction of intestinal and bronchial smooth muscle
- increased vascular permeability and vasodilation
- increased mucous secretion

Question 18

What are secondary mediators of Type I hypersensitivity and give 3 examples?

Answer 18

Secondary mediators: substances synthesised or released from membranes following stimulation

Examples:
1. Platelet-activating factor (PAF)
2. Leukotrienes
3. Prostaglandins
4. Bradykinins
–> all cause further increase in vascular permeability and smooth muscle contraction
5. range of cytokines and chemokines that increase inflammation and IgE production by B-cells

Question 19

What characterises chronic type I hypersensitivity?

Answer 19

extravasation of basophils, which stimulates other cells, such as stromal fibroblasts to release cytokines and chemokines, attracting in other immune cells/granulocytes and contributing to chronic inflammation

Question 20

What environmental factors can contribute to an atopic individual?

Answer 20

Exposure to pathogen and diet

Question 21

How are allergies diagnosed?

Answer 21

Skin prick test
- introduction of small quantities of allergen into skin
- look for local mast cell degranulation resulting in swelling/redness at site of skin prick

Question 22

What are the positive and negative controls used in skin prick tests?

Answer 22

Positive = histamine
Negative = saline

Question 23

How can allergies be treated?

Answer 23

Hyposensitisation, which increases IgG responses and inhibits IgE

Pharmacological inhibitors including antihistamines, leukotreine inhibitors and corticosteroids

Question 24

How does hyposensitisation treatment work?

Answer 24

Administration of small repeated low/increasing doses of an allergen can be used to treat allergy in the long term by:
1. Increasing immune tolerance via immunosuppressive cytokines TGF-beta and IL-10 inducing Treg cells
2. generation of IgG4 antibodies that compete with IgE or reduce FcεRI signalling by clustering with inhibitory FcγRII receptors.

Question 25

How can they ‘Hygiene hypothesis’ explain the rise in allergy and autoimmunity?

Answer 25

as a result of decreased exposure to some pathogens and potential allergens during early life, normal regulated maturation of the immune system does not occur resulting in increased reactivity to non-infectious environmental antigens and increased allergic and autoimmune disease

Question 26

True or False: Type I hypersensitivity is driven by polarised TH2 type responses?

Answer 26

True

Question 27

How can they ‘Diet (microbiome) hypothesis’ explain the rise in allergy?

Answer 27

Maternal diet can influence the immune response of the breastfed child to dietary and environmental antigens as breast milk contains both food allergens and aeroallergens
- such exposure favours the induction of oral tolerance to these antigens and helps prevent development of allergies in the offspring

secondary metabolites produced by processing of solid foods by the commensal flora regulate immune homeostasis through various receptors - changes in flora result in different metabolites produced and change antigens

Question 28

What causes Type II hypersensitivities?

Answer 28

IgG and IgM antibodies binding to an antigen on red blood cells and inducing cell destruction by recruitment of complement or ADCC by NK cells and granulocytes

Question 29

What are the three main situations where Type II hypersensitivities occur?

Answer 29

1. Blood transfusion reactions
2. Haemolytic disease of the newborn
3. Haemolytic anaemia

Question 30

What antigen is expressed by all four blood groups?

Answer 30

the H antigen

Question 31

How does blood group A differ from blood group B in terms of antigens?

Answer 31

Both express the H antigen but blood group A expresses an additional N-acetyl galactosamine residue and B expresses an additional galactose residue

Question 32

Why doe people of one blood group develop antibodies against the other?

Answer 32

The blood group antigens are carbohydrates and are similar to the surface carbohydrates found on gut bacteria so people develop antibodies against these gut bacteria carbohydrates (if they are not expressed themselves)

Question 33

Which blood group are universal recipients?

Answer 33

AB

Question 34

Which blood group are universal donors?

Answer 34

O

Question 35

What is haemolytic disease of the newborn?

Answer 35

If an Rh- mother is pregnant with a Rh+ for first time, during birth, exposure to umbilical cord blood produces antibodies in mother against the Rh antigen

In subsequent pregnancies with an Rh+ child, these antibodies are able to cross the placenta and bind to the red blood cells of the foetus’ red blood cells

Question 36

What is haemolytic anaemia?

Answer 36

Occurs when certain antibiotics non-specifically bind to the surface of red blood cells and are perceived as foreign antigens
If the drug is administered continually/repeated, the antibodies produced can cause haemolysis

Question 37

What causes Type III hypersensitivities?

Answer 37

caused by immune complexes of antibody and antigen when they cannot be cleared by phagocytes due to structure of the antigen or disorders in phagocytic machinery - big complexes cannot be cleared by phagocytes and can become stuck in blood vessels (Capillary beds)

un-cleared immune complexes can cause degranulation of mast cells and inflammation (due to complement activation)
- can be deposited in tissues and capillary beds where they induce more innate immune activity, blood vessel inflammation and tissue damage

Question 38

Give 3 examples of situations in which Type III hypersensitivity reactions (immune complex reactions) can occur

Answer 38

• Serum sickness from the passive immunisation with horse serum to treat diphtheria or snake bite (due to different Fc regions, the antibodies are not cleared in the same way as effectively)
• Immunotherapy using monoclonal antibodies (similar situation to serum sickness) - Genetically engineered to be more human now
• Infections - meningitis, hepatitis, malaria, trypanosomiasis

Question 39

What is a localised Type III hypersensitivity reaction and give two examples of situations in which this may occur?

Answer 39

Localised Type III reaction are called Arthus reactions - characterised by swelling and bleeding

Examples:
Insect bites, Farmer’s lung (fungal spores in hay), Pigeon Fancier’s disease (inhaled dried faeces)

Question 40

What type of response occurs in Type IV hypersensitivity reactions and what is the mechanism of this?

Answer 40

Type of response:
Delayed-type hypersensitivity (DTH) response

Mechanism:
- First contact with bacteria promotes a TH1 type response (sensitisation of TH1 cells upon first exposure)
- Re-exposure stimulates TH1 cytokine release and inflammation due to activation and recruitment of macrophages, symptoms occurring 2-4 days later (delay)

Question 41

Give two examples of pathogens that can induce DTH responses?

Answer 41

• measles (virus)
• Mycobacterium tuberculosis (reaction to the tuberculin - DTH responsible for granulomas associated with tuberculosis)
• Leishmania (protozoan)
• Listeria (bacterium)

Question 42

Define chronic inflammation

Answer 42

Pathological condition characterised by persistent, increased expression of inflammatory cytokines.

Question 43

Does chronic inflammation have infectious or non-infectious origins?

Answer 43

Both
- can be caused by an infection that is not fully resolved
- can be caused by chronic tissue damage brought about by wounds, tumours, autoimmune disease or organ disease

Question 44

What is recognised as one of the most common causes of chronic inflammation?

Answer 44

Obesity (adipose tissue is a source of pro-inflammatory cytokines such as IL-1 and TNF-alpha)

Question 45

How can chronic inflammation have implications on organ dysfunction and tumour development?

Answer 45

Chronic inflammation produces cytokines that can induce tissue scarring (resulting in organ dysfunction) and cytokines that can induce proliferation and angiogenesis (which promotes tumour development)