L17:. Atopy, allergy and dth 1 (Theme 1) Flashcards
(24 cards)
what is the early phase allergic reaction
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
what is the basic mechanism of the early phase
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
what are leukotrienes
The leukotrienes produced have similar pharmacological effects to histamine
study slide 8 for the specific flow chart
what are the pharmacological effects of mast cell mediators and leukotrienes
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
give examples of allergens
pollen
house dust and mite faeces
stinging insect venom
they consist of innocuous environmental proteins
what are the general characteristic and meaning of allergens
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
what is anaphylaxis
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
what is oral allergy syndrome
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
clinical allergy syndromes: airway disease
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
what does the immunological tightrope consist of
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
what is allergic or atopic march
= progression of disease observed from infancy
what are origins of allergic disease
Eczema - food allergy - rhinitis - asthma
explain the chronic allergic inflammation :Asthma
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
what does the late phase reaction consist of
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
what are the different types of T cells from a NAIVE CD4 cell
TH1- IFN-g
TH2- IL-4,5,9 &13
TH17-IL-17
TREG- IL-10, contact dependent mechanism
where does TH2 affect
infiltration in an asthmatic lung
alder allergy associated with TH2
what is the TH2 hypothesis
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
what is the acute response to the chronic allergic disease of asthma
- Inflammatory mediators cause increased mucus secretion and smooth muscle contraction leading to airway obstruction
- recruitment of cells from the circulation
what is the chronic response to the chronic allergic disease
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
how does genetic aetiology of genetics
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
factors of the hygiene hypothesis
- 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
what is the hygiene hypothesis
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
what was the LEAP study
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
what occurs if exposure is from the gut compared to skin
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
