L17:. Atopy, allergy and dth 1 (Theme 1)

Question 1

what is the early phase allergic reaction

Answer 1

In allergic individuals, exposure to allergens* leads to the rapid development of symptoms

This reaction develops within seconds or minutes of exposure and results from the binding of allergens to pre-formed IgE antibodies on the surface of mast cells and basophils

Question 2

what is the basic mechanism of the early phase

Answer 2

it includes the release of IGE and the mast cells receptors

they have high affinity IGE receptors

IgE binds its specific allergen

Cross-linking of IgE antibodies by allergen leads to clustering of FcεR1 receptors

The intracellular portion of the receptor becomes phosphorylated

The resulting intracellular cascade leads to cellular activation

Mast cell ‘degranulates’ releasing histamine, tryptase and other pre-formed mediators

Question 3

what are leukotrienes

Answer 3

The leukotrienes produced have similar pharmacological effects to histamine

study slide 8 for the specific flow chart

Question 4

what are the pharmacological effects of mast cell mediators and leukotrienes

Answer 4

skin :wheal and flare

nose: discharge and sneezing
eyes: conjunctivitis
lung: wheezing

GI tract: increased fluid secretion and increased peristalsis- expulsion of GI tract contents -leading to diarrhoea and vomiting

Airways : decreased diameter due to more ucus secretion- congestion and blockage of airways, swelling and mucus secretion

Blood vessels: increased blood flow and permeability - increased fluid in tissues causing increased flow to lymph tissues and increased effector response

Question 5

give examples of allergens

Answer 5

pollen

house dust and mite faeces

stinging insect venom

they consist of innocuous environmental proteins

Question 6

what are the general characteristic and meaning of allergens

Answer 6

Proteins (there are a few minor exceptions)
- Only protein can produce a T cell (and therefore B cell) response

Physical properties that favour transition across mucus membranes-Need to cross mucus membranes to activate immunity. Typically soluble and low molecular weight

Biologically active, often enzymes
-Interesting, but ?important or coincidence

Have moderate homology with self-proteins
-Theory is that low homology with self-protein=wouldn’t bind to MHC; high homology=would be deleted during negative selection

Question 7

what is anaphylaxis

Answer 7

Generalised allergic’ reaction
Systemic release of histamine causes generalised vasodilatation & fluid loss from circulation to tissues
Cutaneous: hives, angioedema
Gut histamine release: vomiting, diarrhoea
Mucosal histamine release: laryngeal oedema, bronchoconstriction
Circulation: vasodilatation, hypotension

Cardinal features: typical symptoms, multi-system and dramatic, rapidly follows exposure to allergen and tends to improve fairly quickly thereafter

Question 8

what is oral allergy syndrome

Answer 8

Most common type of food allergy amongst UK adults

IgE directed against pollen proteins cross-reacts with homologous proteins in plant-derived foods

Oral itching upon exposure to raw fruit, nuts and vegetables

In UK:

Pollen = mainly birch

Food = mainly apples Rosaceae fruits

Question 9

clinical allergy syndromes: airway disease

Answer 9

Rhinitis-
Sneezing, rhinorhoea, blockage due to a type 1 allergy

Lower airway obstruction-
Wheeze due to type 1 allergy

Allergens/ symptoms may be:

• Seasonal: pollens, moulds
• Episodic: occupational, animal dander
• When symptoms are chronic, the inflammation becomes established and cannot be explained simply in terms of mast cell degranulation

Question 10

what does the immunological tightrope consist of

Answer 10

The immune system is constantly challenged with antigens & must somehow decide how to respond:

• Self antigens vs non-self
• Dangerous infections vs commensal organisms
• Environmental allergens such as foods and pollens

Activation

Required for defence against infection and cancer
&
Tolerance-
Required to prevent autoimmune and inflammatory diseases

Question 11

what is allergic or atopic march

Answer 11

= progression of disease observed from infancy

Question 12

what are origins of allergic disease

Answer 12

Eczema - food allergy - rhinitis - asthma

Question 13

explain the chronic allergic inflammation :Asthma

Answer 13

Patients with chronic asthma have on-going symptoms

Most patients are sensitised to a variety of airborne allergens

Biopsy shows inflammatory infiltrate and airway changes known as ‘re-modelling’ – thickened basement membrane and smooth muscle hyperplasia

The ‘early allergic reaction’ model does not provide a good explanation by itself

Question 14

what does the late phase reaction consist of

Answer 14

Biopsy of the late phase shows infiltration with inflammatory cells – particularly CD4 T cells, eosinophils and mast cells; provides some insight into chronic allergic inflammation, and often used as an experimental model

Question 15

what are the different types of T cells from a NAIVE CD4 cell

Answer 15

TH1- IFN-g

TH2- IL-4,5,9 &13

TH17-IL-17

TREG- IL-10, contact dependent mechanism

Question 16

where does TH2 affect

Answer 16

infiltration in an asthmatic lung

alder allergy associated with TH2

Question 17

what is the TH2 hypothesis

Answer 17

Th2 responses to allergens have been consistently associated with allergic disease

• Biopsies of allergic inflammation are rich in T cells expressing Th2 cytokines
• T cells from allergic patients stimulated with allergen in the laboratory produce Th2 cytokines

Plenty of reasons to believe that Th2 responses may be important in allergy:

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

Question 18

what is the acute response to the chronic allergic disease of asthma

Answer 18

• Inflammatory mediators cause increased mucus secretion and smooth muscle contraction leading to airway obstruction
• recruitment of cells from the circulation

Question 19

what is the chronic response to the chronic allergic disease

Answer 19

Activated Th2 cells and other inflammatory cells accumulate:

• Th2 products lead to chronic disease
• IL4: mucus hypersecretion
• IL-13: bronchial hyper-responsiveness
• IL-5: eosinophil recruitment
• IL-9: mast cell recruitment

Question 20

how does genetic aetiology of genetics

Answer 20

Childhood allergy is strongly predicted by presence of allergy in parents, but difficult to unpick relative contribution of environment

Numerous genetic risk factors identified, but none particularly compelling

Notable that the allergy epidemic has occurred too quickly to be explained entirely by genetics

Question 21

factors of the hygiene hypothesis

Answer 21

• Developing countries, large family sizes, rural homes, livestock and low antibiotic use.-associated with being non-allergic

Westernized countries, small family size, affluent, urban homes, high antibiotic use- allergic disorders

Question 22

what is the hygiene hypothesis

Answer 22

Low hygiene levels, high pathogen load, helminth infection proposed to:

• Skew immunity from Th2 to Th1
• Induce regulatory T cells

High hygiene levels, low pathogen load, absence of helminth infection proposed to:

• Skew immunity towards Th2
• Reduce production of regulatory T cells

Question 23

what was the LEAP study

Answer 23

is early exposure to peanuts protective?:

• High-risk infants recruited
• Tested for peanut allergy at baseline
• From age 6 months, randomised to either peanut avoidance or regular consumption
• Followed to age around 5

Question 24

what occurs if exposure is from the gut compared to skin

Answer 24

Gut- Increased B cells and less basophils and IGE leading to more tolerance

Skin- Skin exposure barrier defect- increased TH2 and cytokines-il-1,il-21

and innate activation by allergens