Allergy Flashcards
what is the body’s response to allergens/worms
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
where are innate lymphoid cells found
mucosal barriers which lack antigen specific receptors e.g. skin, resp tract
what do innate lymphoid cells respond to
inflammatory cytokines e.g. IL-23, TSLP, il-25, il-1 AND il-12
What do innate lymhpoid cells secrete
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
what are CD4 Th2 cells
Distinct CD4 T subset characterised by expression of the lineage determining transcription factor GATA-3 and the signal transduction protein STAT-6
what are the signature cytokines of CD4 Th2 cells
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)
what do eosinophils do
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
what 2 things does IgE bind to
IgE binds to high affinity receptor (FcR1) on mast cells, basophils, eosinophils and DC
IgE also binds to ‘low affinity’ (FcR2) receptor on above cells as well as B cells, respiratory and gastrointestinal epithelial cells
what is the function of Ig E
IgE function
Protection against helminth and parasitic infection
IgE induces mast and basophil degranulation associated with immediate hypersensitivity (allergic) reactions
what are the 2 mast cell subtypes
2 main subtype in human: MC (Tryptase T) skin and MC (Chymotryptase CT) in airways
what are the 2 receptors which trigger mast cell degranulation
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)
what does mast cell degranulation lead to
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)
what factors promote IgE production
Antigen dose
Length of exposure
Physical properties of allergen Source Small water soluble proteins Carbohydrate Resistance to heat, digestive enzymes
Route of exposure
how are allergies developed
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
what occurs after crosslinking of IgE on mast cell and basophil surface
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
how is allergy diagnosed
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
clinical features of IgE allergic response
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
how does skin prick test work
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.
how do intradermal tests work
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
indication for blood sensitisation tests
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
what is mast cell tryptase used for
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
