17. atopy, allergy and delayed type hypersensitivity

Question 1

allergen definition

Answer 1

substance to which IgE antibodies may be produced

Question 2

early phase allergic reaction

Answer 2

in allergic individuals, allergen exposure lead to rapid development of symptoms (seconds-minutes)
allergens bind to IgE antibodies on mast cells and basophils

Question 3

IgE ligation in allergy

Answer 3

IgE binds specific allergen
cross-linking of IgE by allergen beads to clustering of receptors
intracellular portion of receptor becomes phosphorylates
intracellular cascade leads to cell activation
mast cells degranulate - release histamine, tryptase and other preformed mediators

Question 4

leukotrienes

Answer 4

delayed mediators
similar pharmacological effect to histamine
phospholipase A2 from mast cell activation starts pathway
derived from arachidonic acid

Question 5

pharmacological effects of mast cell mediators and leukotrienes

Answer 5

skin - wheal and flare
nose - discharge, sneezing
eyes - conjunctivitis
lungs - wheeze

Question 6

mast cell activation and granule release - GI tract

Answer 6

increased fluid secretion
increased peristalsis
expulsion on gastrointestinal tract contents (diarrhoea, vomiting)

Question 7

mast cell activation and granule release - airways

Answer 7

decreased diameter
increased mucus secretion
congestion and blockage of airways (wheezing, coughing, phlegm)
swelling and mucus secretion in nasal passages

Question 8

mast cell activation and granule release - blood vessels

Answer 8

increased blood flow
increased permeability
increased fluid in tissues - increased flow of lymph to lymph nodes, increased cells and protein in tissues
increased effector response in tissues

Question 9

allergen sources

Answer 9

almost always otherwise innocuous environmental proteins

pollen, house dust mite faeces, stinging insect venom

Question 10

general characteristics of allergens

Answer 10

proteins (minor exceptions) - only protein can produce T/B cell response
physical properties favour transition across mucus membrane (soluble, low molecular weight)
biologically active (often enzymes)
moderate homology with self-proteins

Question 11

clinical allergy syndromes: anaphylaxis

Answer 11

generalised allergic reaction
systemic release of histamine
causes generalised vasodilation and fluid loss from circulation into tissues
foods, drugs and insect venom = most common in UK

Question 12

anaphylaxis symptoms

Answer 12

hives, angioedema
vomiting, diarrhoea, laryngeal oedema, bronchoconstriction
vasodilatation, hypotension

Question 13

anaphylaxis cardinal features

Answer 13

typical symptoms
multi-system and dramatic
rapidly follows exposure to allergen
tends to improve quickly thereafter

Question 14

clinical allergy syndromes: oral allergy syndrome

Answer 14

most common type of food allergy in the UK
IgE against pollen proteins cross-reacts with homologous proteins in plant-derived food
oral itching on exposure to raw fruit, nuts and vegetables
UK - pollen mainly birch, food mainly Rosaceae fruits

Question 15

clinical allergy syndromes: airway disease

Answer 15

rhinitis - sneezing, rhinorrhoea, blockage (type 1 allergy)
lower airway obstruction - wheeze (type 1 allergy)
allergens may be seasonal (pollens) or episodic (animal dander)
when symptoms are chronic, inflammation becomes established - cannot be explained by mast cell degranulation

Question 16

immunological tightrope

Answer 16

self vs non self
dangerous infection vs commensal organisms
environmental allergens, food/pollen
activation for defence vs tolerance to prevent autoimmune and inflammatory diseases

Question 17

origins of allergic disease

Answer 17

allergic/atopic math - progression of disease observed from infancy
eczema, food allergy, rhinitis, asthma
most children outgrow eczema and many food allergies
rhinitis/asthma may or may not be outgrown
allergic disease may present de novo in adults

Question 18

chronic allergic inflammation: asthma

Answer 18

ongoing symptoms
most patients are sensitised to variety of airborne allergens
biopsy shows inflammatory infiltrate and airway changes (remodelling - thickened basement membrane, smooth muscle hyperplasia)
early allergic reaction phase does not provide good explanation by itself

Question 19

late phase allergic reaction

Answer 19

early phase reaction is followed some hours later by a late phase reaction
biopsy of let tase shows infiltration with inflammatory cells
CD4 T cells, eosinophils, mast cells in particular
some insight into chronic allergic inflammation

Question 20

T cell subsets (CD4)

Answer 20

Th1 - releases IFN gamma
Th2 - releases IL-4,-5,-9,-13
Th17- releases IL-17
Treg - releases IL-10, contact dependent mechanisms

Question 21

Th2 hypothesis

Answer 21

Th2 responses to allergens consistently associated with allergic disease
biopsies of allergic inflammation are rich in T cells expressing Th2 cytokines

Question 22

why might Th2 be important in allergy?

Answer 22

IL-4 required for B cell class switching to IgE
IL-4 and IL-13 promotes mucus hypersecretion
IL-5 required for eosinophil survival
IL-9 recruits mast cells

Question 23

asthma acute responses

Answer 23

inflammatory mediators cause increased mucus secretion and smith muscle contraction - leads too airway obstruction
cells are recruited from the circulation

Question 24

asthma chronic responses

Answer 24

caused by cytokines and eosinophil products

Question 25

genetics

Answer 25

childhood allergy strongly predicted by parent with allergy | numerous genetic risk factors identified

Question 26

hygiene hypothesis

Answer 26

low hygiene levels, high pathogen load and helminth infection = immunity skewed to Th1, Treg cells induced high hygiene levels, low pathogen load, no helminth infection = immunity skewed to Th2, reduced production of Treg cells

Question 27

detection of allergen specific IgE in vivo

Answer 27

skin prick testing allergen extract applied as drops top layers of epidermis punctured with lan net wheal and flare response within 15 mins = positive result needs interpretation in clinical context

Question 28

detection of allergen specific IgE in vitro

Answer 28

usually ELISA purified allergen, stuck, incubated with sera IgE antibodies in sera binds to allergen immobilised IgE antibodies detected with detection antibody

Question 29

allergy treatment

Answer 29

``` symptom relievers drugs acting on early phase mediators corticosteroids monoclonal antibodies immunotherapy ```

Question 30

allergy symptom relievers

Answer 30

``` nasal decongestants - eg. oxymetazoline - alpha 1 adrenoreceptors - cause vasoconstriction - short term b2 agonists - eg salbutamol - act on lung adrenoreceptors - cause smooth muscle relaxation adrenaline - systemic adrenergic effects - oppose vasodilation and bronchconstriction ```

Question 31

drugs acting on early phase mediators

Answer 31

mast cell stabilisers H1 antihistamines leukotriene receptor antagonists

Question 32

mast cell stabilisers

Answer 32

``` eg sodium cromoglycate reduce mast cell degranulation (unknown mechanism) topical only short half life main benefit = steroid free ```

Question 33

H1 antihistamines

Answer 33

inverse agonists at H1 histamine receptor best used before exposure to allergen 1st generation: clorpheniramine (sedation, drug interactions) 2nd generation: cerizine, loratadine (minimal/no sedation)

Question 34

leukotriene receptor antagonists

Answer 34

only UK drug = montelukast effective in reducing early allergic responses inferior to H1 antihistamines beneficial in chronic asthma

Question 35

corticosteroids

Answer 35

reduce immune activation alter gene expression in T cells, B cells, and cells of the innate immune system onset of action is delayed

Question 36

omalizumab

Answer 36

monoclonal antibody directed against IgE used for atopic asthma

Question 37

allergen specific immunotherapy

Answer 37

allergen doses administered by subcutaneous injection long term protection mainly venom allergy and rhinitis

Question 38

immunotherapy immunological effects

Answer 38

``` induce Treg cell responses to allergens reduce Th2 responses induce allergen-specific IgG antibodies reduction in mast cell responsiveness reduce allergen-specific IgE levels ```

Question 39

delayed type hypersensitivity

Answer 39

mediated by antigen specific effector T cells

Question 40

antigen specific definition

Answer 40

implies that a specific antigen stimulus is required, chichis them processed and presented to relevant T cells responsible for reaction

Question 41

effector T cell definition

Answer 41

T cells that have previously met antigen, and are 'primed' to produce a rapid and robust response

Question 42

contact dermatitis - sensitisation

Answer 42

molecules react with self proteins to create protein-hapten complexes complexes are picked up by Langerhans cells which migrate to lymph nodes Langerhans cells process and present antigen on MHC class II in some individuals, complexes are recognised as foreign activated T cells migrate to the dermis

Question 43

hapten

Answer 43

small molecule that cannot individually invoke an immune response, but can bind to protein to alter its immunogenicity

Question 44

contact dermatitis - elicitation

Answer 44

chemokines recruit macrophages Th1 cells secrete IFN gamma (increases expression of vascular adhesion molecules, activates macrophages) TNF alpha/beta stimulates local inflammation

Question 45

poison ivy

Answer 45

poison ivy lipid can cross skin and modify intracellular proteins proteins are processed and presented on MHC class I to T cells causes contact dermatitis not everyone is susceptible

Question 46

patch testing for contact dermatitis

Answer 46

antigen impregnated patch placed on back nickel, chrome, epoxy resin etc read after 2 days