Allergy

Question 1

what is the body’s response to allergens/worms

Answer 1

Allergens trigger signalling cytokines to signal ILC2 innate lymphocytes which signal 1)th2 cells which signal b cells to produce IgE 2) Eosinophils to eliminate worms etc 3) mucous secretions

Question 2

where are innate lymphoid cells found

Answer 2

mucosal barriers which lack antigen specific receptors e.g. skin, resp tract

Question 3

what do innate lymphoid cells respond to

Answer 3

inflammatory cytokines e.g. IL-23, TSLP, il-25, il-1 AND il-12

Question 4

What do innate lymhpoid cells secrete

Answer 4

secrete IL-4, IL-5, IL-9, IL-13 and amphiregulin (AREG)
Secretion of type 2 cytokines by ILC2 implicated in allergic asthma, allergic rhinitis AD, food allergy and eosinophilic oesophagitis
Amphiregulin paly an important role in epithelial barrier repair in skin and respiratory tract
In allergic disease overcome steady state inhibition exerted by tissue CD4 T regulatory cells

Question 5

what are CD4 Th2 cells

Answer 5

Distinct CD4 T subset characterised by expression of the lineage determining transcription factor GATA-3 and the signal transduction protein STAT-6

Question 6

what are the signature cytokines of CD4 Th2 cells

Answer 6

Signature cytokines are IL-4, IL-5, IL-13
Helps B cells to produce IgE (IL-4)
Expands and activate eosinophils (IL-5)
Stimulate mucous secretion (IL-13)

Question 7

what do eosinophils do

Answer 7

Host defence against parasites, bacteria and viruses

Eliminate pathogens by secretion of cytotoxic granules, RNAase proteins and extracellular traps

IL-5 is the key cytokine in the development and expansion of eosinophils

Implicated in late stage tissue damage in atopic dermatitis, asthma, eosinophilic oesophagitis, and granulomatous disease

Question 8

what 2 things does IgE bind to

Answer 8

IgE binds to high affinity receptor (FcR1) on mast cells, basophils, eosinophils and DC

IgE also binds to ‘low affinity’ (FcR2) receptor on above cells as well as B cells, respiratory and gastrointestinal epithelial cells

Question 9

what is the function of Ig E

Answer 9

IgE function
Protection against helminth and parasitic infection

IgE induces mast and basophil degranulation associated with immediate hypersensitivity (allergic) reactions

Question 10

what are the 2 mast cell subtypes

Answer 10

2 main subtype in human: MC (Tryptase T) skin and MC (Chymotryptase CT) in airways

Question 11

what are the 2 receptors which trigger mast cell degranulation

Answer 11

Mast cells degranulation triggered by 1) IgE/IgG receptors which respond to antibody-antigen cross linking and 2) G-protein-coupled receptors which are ligands for soluble mediators (complement and drugs)

Question 12

what does mast cell degranulation lead to

Answer 12

Release of pre-formed inflammatory mediators from granules (histamine)

Release and synthesis of lipid mediators (leukotrienes, prostaglandins)

Synthesis of pro-inflammatory cytokines
Mast cell degranulation leads to
Recruitment of soluble proteins and inflammatory cells to site of infection

Increase in rate of lymphatic flow back to regional lymph nodes

Smooth muscle contraction in lungs and gut (may help to expel pathogens) and activation of sensory neurons (itch, sneeze)

Question 13

what factors promote IgE production

Answer 13

Antigen dose

Length of exposure

Physical properties of allergen
Source 
Small water soluble proteins
Carbohydrate 
Resistance to heat, digestive enzymes

Route of exposure

Question 14

how are allergies developed

Answer 14

Defects in skin epithelial barrier (atopic dermatitis) are a significant risk factor for development of IgE antibodies.

Stressed or damage epithelial cells secrete IL-25, IL-33, GM-CSF and TSLP which act on tissue immune cells (DC, basophils, type 2 innate lymphoid cells) and neurons to induce Th2 cells immune responses (IL-4, IL-5, IL-9, IL-13)

IL-4 plays a crucial role in development of Th2 immune responses and is only induced following peptide-MHC presentation to naïve/memory Th2 cells

Question 15

what occurs after crosslinking of IgE on mast cell and basophil surface

Answer 15

Rapid onset of symptoms within 4 hours caused by release of inflammatory mediators following allergen cross linking of IgE on surface of mast cells and basophils

Delayed symptoms result from CD4T2 cell (IL-4, IL-5, IL-13) immune responses and eosinophil related tissue damage

Th2 cytokines secreted by tissue lymphocytes act on effector cells (eosinophils, basophils, epithelial cells, B cells, sensory neurons endothelium and smooth muscle cells) to eliminate and expel pathogens allergens, and repair tissue damage

Question 16

how is allergy diagnosed

Answer 16

History is the key to diagnosis

Examination

Allergen specific IgE (Sensitisation) Tests
Skin prick and intradermal test
IgE blood tests

Functional allergen tests

In vitro tests
Basophil activation
Serial mast cell tryptase

Ex vitro tests
Open or blinded allergen challenge

Question 17

clinical features of IgE allergic response

Answer 17

Skin: angioedema (swelling of lips, tongues, eyelids) , urticaria ( wheals or ‘hives’), flushing and itch

Respiratory tract: cough, SOB wheeze, sneezing, nasal congestion and clear discharge, red itch watery eyes

Gastrointestinal tract: nausea, vomiting and diarrhoea

Blood vessels and Brain: symptoms of hypotension (faint, dizzy, blackout) and a sense of impending doom

Question 18

how does skin prick test work

Answer 18

Expose patient to standardised solution of allergen extract through a skin prick to the forearm.

Use standard skin test solutions and positive control (histamine) and negative control (diluent)

Measure local wheal and flare response to controls and allergens

IgE crosslinking on skin mast cells, leading to degranulation and release of histamine and other inflammatory mediators
A positive test is indicated by a wheal ≥ 3mm greater than the negative control.

Question 19

how do intradermal tests work

Answer 19

Application of positive, negative controls and allergens into the skin

Moe sensitive but less specific than SPT

Best used to follow up negative venom and drug allergy test (better than blood tests)

Can be used if SPT to allergen is negative but convincing history

Labour intensive, greater risks of anaphylaxis

Question 20

indication for blood sensitisation tests

Answer 20

No access to SPT and/or IDT

Patients who can’t stop anti-histamines

Patients with a history of dermatographism, extensive eczema

Patient with a history of anaphylaxis

Decision on who needs food challenge

Prediction for resolution of egg, milk, wheat allergy

Monitor response to anti-IgE therapy

Question 21

what is mast cell tryptase used for

Answer 21

Tryptase: pre-formed protein found in mast cell granules

Systemic degranulation of mast cells during anaphylaxis results in increase in serum tryptase

Peak concentration at 1-2 hours; returns to baseline by 6-12 hours

Failure to return to baseline after anaphylaxis may be indicative of systemic mastocytosis

Useful if diagnosis of anaphylaxis is not clear (hypotension + rash during anaesthesia)

Reduced sensitivity for food induced anaphylaxis