Hypersensitivity reactions (asthma and allergy)

Question 1

Define Hypersensitivity

Answer 1

An inappropriate immune response to non-infectious antigens that results in tissue damage and disease

Question 2

What are the 4 types of hypersensitivity?

Answer 2

1. Type 1: immediate hypersensitivity
2. Type 2: cytotoxic hypersensitivity
3. Type 3: serum sickness and Arthus reaction
4. Type 4: delayed-type hypersensitivity, contact dermatitis

Question 3

Describe what causes immediate hypersensitivity?

How do we diagnose a patient with hypersensitivity?

Answer 3

• Results from interaction from specific IgE and specific allergen
• Generally, have mast cells in your skin or circulation, which are armed with specific IgE
• when this IgE recognises specific allergens to which it comes in contact with, and this allergen cross links the IgE, you get activation of mast cells and an acute type 1 hypersensitivity reaction
• This is typical of the early phase of allergic rhinitis, asthma, anaphylaxis
• Diagnose patients using a skin test
• Put specific allergens on the skin  prick through them with a lancent
• Wait 15 minutes to see if someone has a reaction to the presence of the allergen, indicating they have specific ige and are allergically sensitised to that particular allergen
• Activation of the mast cells  releases inflammatory mediators  get a wheal at the site of the prick indicating that you are atopic to that allergen

Question 4

Describe what causes cytotoxic hypersensitivity

Answer 4

• Involves IgG antibodies directed at cell-surface receptors
• These antibodies disrupt the normal functions of the receptor by either:
o Uncontrollable activation or blocking receptor function
o e.g. Taking penicillin  attaches to RBCs immune response may recognise this as a new antigen  cause disease – this is type 2 HS
o In this you have IgG

Penicillin RBC complex is recognised as foreign  immune system responds by developing IgG  this binds to the RBCs with penicillin on the surface  this is recognised by the immune system and the RBC is filtered in the spleen and destroyed causing a hemolytic anemia

Question 5

Give examples of a cytotoxic hypersensivity reaction

Answer 5

• Grave’s disease
• Thyrotoxicosis in which an antibody recognises the receptor to which TSH binds to induce production of thyroxine from thyroid gland, can cause excess production of thyroxine leading to thyrotoxicosis
• Antibodies block or destroy nicotinic acetylcholine receptor at the junction between the nerve and muscle
• Form of paralysis in which your immune response reacts to the ACh receptor on the neuromuscular junction and blocks synaptic transmission causing a form of paralysis
• Caused by rhesus incompatibility - if you have a rhesus negative mother and a rhesus positive baby, during the first pregnancy its fine
• At the time of birth, when the placenta separates from uterus, you get mixing of fetal blood into the maternal circulation and this can sensitise the mother to the rhesus antigen
• In a subsequent pregnancy, she may be sensitised and her antibodies which she developed to rhesus may cross the placenta and act against the RBS of the rhesus positive fetus causing a hemolytic anemia

Question 6

Describe Type III: Serum sickness/Arthus reaction

Answer 6

1. This is when specific antibody, IgG, reacts with soluble antigen in excess such as at the site of a vaccination
2. inject vaccine into arm  have a lot of specific antigen there  can get immune complexes formed and these are formed through complement fixation  leading to inflammation at the site of where immune complexes are causing disease
3. Immune complex forms  macrophages recognise the Fc receptor on the IgG
4. The localised reaction is typically called Arthus – e.g. Arthus following tetanus vaccine
5. More systemic are called serum sickness

Question 7

What causes Arthus reaction following diptheria/tetanus vaccination?

Answer 7

• Activate mast cells to release inflammatory mediators.
• Inflammatory cells invade the site, and blood vessel permeability and blood flow are increased.
• Platelets also accumulate, leading to occlusion of the small blood vessels, haemorrhage, and the appearance of purpura.

Question 8

What is serum sickness caused by?

What can cause it?

Answer 8

• Caused by large intravenous doses of soluble antigens (e.g. Drugs)
• IgG antibodies produced form small immune complexes with the antigen in excess.
• Immune complexes deposited in tissues e.g. Blood vessel walls.
• Tissue damage is caused by complement activation and the subsequent inflammatory responses
• Snake bite
• Bitten by a snake, want anti venom (made by injecting horses with small amounts of venom over long periods of time and use Ig from horse to inject someone)
• If inject anti venom can cause severe reactions as it’s from a horse, can cause serum sickness reaction depending on where immune complexes are deposited

Question 9

How can farmers hay cause a Serum sickness/Arthus reaction?

Answer 9

• Farmers who have hay, can become sensitised to molds in the hay and they can get inhaled and form immune complexes in the lung
• Causes localised inflammation in the lung and after repeated exposure over many years, can get severe pathology

Th2 CD4+ T-cell activates B cell, releases antibodies in alveoli to form immune complex with antigen, leading to cell accumulation, inflammation and fibrosis.

Question 10

What causes Hypersensitivity pneumonitis?

Describe the histology of it?

Answer 10

dust, bacteria, fungi, etc. Farmer’s lung is usually in response to a mould called thermophilic actinomycosis. Pigeon breeder’s lung- bird proteins inhaled.

Histology- interstitial pneumonitis with non-caseating granulomas. Interstitial fibrosis, honeycombing and obliterative bronchiolitis and intra-alveolar infiltrate.

Question 11

What determines delivery determine the pathology observed in type III hypersensitivity reactions?

Answer 11

Antigen dose and route of delivery determine the pathology observed in type III hypersensitivity reactions

Question 12

What causes Type IV: Delayed-type hypersensitivity?

Answer 12

• Have 2 forms of Type IV
o TH1 – associated with strong cell mediated reactions such a tuberculin
o TH2 – associated with allergic reactions
• Type 2 – TH2 cells produce TH2 cytokines in the presence of a specific antigen and these TH2 cytokines are typically IL4 IL5 IL13 etc and activate eosinophils and other immune effect cells
• Classically delayed hyper sensitivity is a TH1 reaction associated
o With TH1 cytokines such as interferon gamma in which macrophages are activated  causing a localised reaction where the antigens are associated with the release of specific cytokine and chemokines etc

Question 13

Describe the time course of delayed (Type IV) hypersensitivity

Answer 13

Antigen injected into subcutaneous tissue and processed by local APC. TH1 effector cell recognises antigen and releases cytokines that act on vascular endothelium. Recruitment of phagocytes and plasma to site of antigen injection causes visible lesion.

Question 14

What does the Mantoux test for?

Answer 14

• Tuberculin injected in skin if you have T helper cells in skin which recognise the tuberculin get a localised inflammatory reaction with recruitment of other inflammatory cells
• Get localised inflammation at the site of injection and this takes 1-3 day for cells to develop
• With tuberculin reaction you have an inter dermal injection and then you are asked to come back after 2-3 days to measure size of reaction to check if exposed to TB

Question 15

Have a look at summary tables

Answer 15

On image

Question 16

What is Production of allergen-specific IgE defined as?

Answer 16

Defined as “disease following a response by the immune system to an otherwise innocuous antigen”

Question 17

What is IgE?

Answer 17

• First line of defence against worms
• Binds FcεR1 receptor on mast cells
• Pre-arms mast cells to react when in the presence of antigen
• To get an allergic response, the mast cells have to be coated or pre armed with IgE and then when exposed to specific allergen to which IgE recognises, you can get activation of mast cells

Question 18

How does an allergen result in the production of IgE from B cells?

Answer 18

• Get exposed to allergen  APCs (dendritic cells) pick up the allergen  present it to various immune cells
• Depending on type of signals they get, T cells produced can be:
• TH2 (associated with allergy)
• TH1 (associated with inflammation)
• In allergy, TH2cell produces IL4 and IL13 which are important for B cells to produce IgE
• When sensitise to pollen, on our 1st exposure, breathe it  TH2 cells educate B cells in the presence of cytokines like IL4 to make IgE  this IgE coats the surface of mast cells
• So when we are re-exposed, we can react to the allergen with an allergic response

Question 19

What causes Allergic Sensitisation?

Answer 19

• Exposure to Allergen is critical, this includes: – Nature of the allergen
• Dosage of Allergen (high vs. low)
• Timing
• Location of Priming
• Role of pro-allergic dendritic cells and cytokines
• Genetic predisposition to Allergy
• Some allergen exposure can cause tolerance
• Signals received by T cells determine how they respond, certain signals induce allergic response and make T cells à TH2

Question 20

Give some common allergens

Answer 20

• House dust mite, pollens, cockroach.
• Allergens are named systematically- after source organism and order discovered.
• Possible that all allergens have common functionality- e.g. all are proteases.
• Allergens normally received in small doses. High dose exposure may lead to tolerance.

Question 21

Describe the genetics of allergys

Answer 21

No single gene explains- polygenic.
Gene and environment contribute.
Filaggrin is important gene in atopic dermatitis- links skin integrity and allergy. When it is defective, atopic dermatitis is greater due to access for allergens.

Question 22

What Makes Dendritic Cell Pro-Allergic?

Answer 22

• Not Known but One Candidate Protein is TSLP This may switch DC to a ‘pro- allergic’ state (TSLP= Thymic stromal lymphopoietin).
• Skin and the underlying epidermis and dermis
• We have Langerhans cell which are dendritic cells (APCs) and when skin is damaged  signals are released  may induce an allergic response
• Various cytokines and molecules are important like TSLP
• Langerhans cells from skin pick up antigens in an environment where you have signals with lots of TSLP  go to the lymph nodes and educate the lymphocytes that pass through the lymph nodes to be more allergic

Question 23

How allergic immune response happens?

Answer 23

• We become sensitised so we inhale allergen
• Individuals with genetic susceptibility, the interaction between the immune cells induces a TH2 response in which IL4 is produced  causes B cells to make IgE
• IgE lines the surface of mast cells, when we get re-exposed to allergen  mast cells are ready to react to cause inflammation

Question 24

What do mast cells contain and release

Describe the early and late phases of mast cell activation

Answer 24

• Resting mast cell contains granules containing histamine and other inflammatory mediators. It is allergen specific.
• Activates- multivalent, specific antigen cross-links bound IgE antibody, causing release of granule contents.
• Early phase produces- histamine (vascular permeability and causes smooth muscle contraction), leukotrienes (vascular permeability, smooth muscle contraction and stimulates mucus secretion) and prostaglandins (chemoattractant for T cell, eosinophils and basophils).
• Late phase- cytokines- IL-4/13 (promote Th2 and IgE) and TNF-a (promotes tissue inflammation).
• GI- increased fluid secretion and peristalsis- expulsion of contents.
• Airways- decreased diameter and increased mucus secretion- congestion/blockage of airways (wheezing, coughing, phlegm) and swelling and mucus secretion in nasal passages.
• Blood vessels- increased blood flow and permeability- increased fluid in tissues, causing increased flow of lymph nodes. Increased cells/protein in tissues, increased effector response in tissues.

Question 25

What is an early and late phase allergic response?

Answer 25

• Allergic responses have an early and late phase
• Early is mediated by mast cells
• Late is mediated by T cells

Question 26

Where are eosinophils located, recruited to and express?

What are the 2 effector functions of them?

Answer 26

Located in tissues, recruited to sites of allergic reactions, express PceR1 upon activation.

Two effector functions of eosinophils- to release highly toxic granule proteins and free radicals upon activation to kill microorganisms/parasites and cause tissue damage in allergic reaction and to synthesise and release prostaglandins, leukotrienes and cytokines in order to amplify the inflammatory response by activating epithelial cells and recruiting leukocytes.

Question 27

Describe the Late phase IgE-mediated allergic response:

Answer 27

• Continued synthesis and release of inflammatory mediators
• Chronic allergic inflammation caused by Th2 cells i.e. a type IV hypersensitivity reaction
• The late phase of allergic response is T cell mediated
• Mostly consisting of allergen specific Th2 cells
• These cells recruit other cells by cytokine release
• Potentiate further responses

Question 28

What is asthma?

Give some examples of atopic and non-atopic

Answer 28

•	“A State of reversible bronchial hyper-reactivity resulting from a persistent inflammatory process in response to a number of stimuli in a genetically susceptible individual”.
•	Atopic and Non-Atopic
•	Non Atopic includes 
o	Occupational
o	Exercise induced
o	Nocturnal Asthma
o	Post-bronchiolitic Wheeze

Question 29

What are the characteristics of asthma?

Answer 29

•	Episodes of wheezy breathing • narrowing of the airways
•	Rapid changes in airway
•	Obstruction 
•	Severity varies
o	Slight wheeziness to asthma attack
•	Common allergens causing asthma include
o	Pollen
o	Hdm
o	Plants
o	Some foods

Question 30

Describe the acute and chronic asthmatic response

Answer 30

Acute response:
• Occurs within seconds of allergen exposure
• Results in airway obstruction and breathing difficulties
• Caused by allergen-induced mast cell degranulation in the submucosa of the airways

Chronic response
• Chronic inflammation of the airways
• Caused by activation of eosinophils, neutrophils, T cells and other leukocytes
• Mediators released by these cells cause airway remodelling, permanent narrowing of the airways, and further tissue damage

• Normal airway –
o Smooth muscle on the outside
o Has a mucus layer and mucosa
• During acute episode of asthma
o The muscles constrict and we get more mucus secretion both of which together act to decrease the diameter of lumen of airway to cause wheezing
• In chronic asthma
o Lot of mucus production and airways may become blocked with mucus and we get chronic inflammatory response in the airways with more permanent changes like fibrosis

Question 31

How can asthma be treated?

What effector pathways can be blocked and what medications can be given?

Answer 31

• Blocking effector pathways- inhibit mediators for specific receptors (antihistamine blocks H1 receptor), inhibits mast cell degranulation (mast cell stabilizer- chromoglycate), inhibits synthesis of specific mediators (lipoxygenase inhibitors).
• Steroids- act directly on DNA to increase transcription of anti-inflammatory mediators (IL-10) and decrease transcription of pro-inflammatory mediators (prednisolone).
• Bronchodilators- reverse acute effect on airways (B2 agonist salbutamaol).
• Immunotherapy- reverse sensitisation to allergen through tolerising exposure.

Blockage of effector pathways:
• Inhibit effects of mediators on specific receptors
• Anti-histamine (block the histamine H1 receptor)
• Inhibit mast cell degranulation
• Mast cell stabiliser (e.g. Chromoglycate)
• Inhibit synthesis of specific mediators
• Lipoxygenase inhibitors (e.g montelukast)