Allergic Disease Flashcards
What is the definition of an allergic reaction?
An undesirable, damaging, discomfort-producing and sometimes fatal reaction produced by the normal immune system directed against innocuous antigens in a pre-sensitised (immune host)
What is meant by “innocuous antigens” and “pre-sensitised host”?
Innocuous antigens:
- this is an antigen that is not usually harmful
Pre-sensitised host:
- the host has had prior exposure to the innocuous antigen
What are the 4 types of hypersensitivity?
Type I - anaphylactic
Type II - cytotoxic
Type III - immune complex
Type IV - delayed type
Types I, II and III are mediated by antibodies
Type IV is a mediated by cells
What are the characteristics of a type I (anaphylactic) allergic reaction?
What are the characteristics of a type II (cytotoxic) reaction?
What are the characteristics of a type III (immune complex) reaction?
What are the characteristics of a type IV (delayed type) reaction?
What is the immunopathogenesis of a type II (cytotoxic) reaction?
- It is an IgG/IgM antibody response against combined self/foreign antigen at the cell surface
- the antigens are on the cell surface
- this leads to complement activation/phagocytosis/ADCC
What are the clinical features and common antigens associated with a type II cytotoxic allergic reaction?
Clinical features:
- onset of minutes to hours
- cell lysis and necrosis
Common antigens:
- penicillin
What diseases are associated with a type II hypersensitivity reaction?
- Erythroblastosis fetalis
- goodpasture’s nephritis
How does haemolytic disease of the newborn work?
- IgG molecules produced by the mother pass through the placenta
- Some antibodies attack antigens on the surface of red blood cells in the foetal circulation
- The foetus then develops reticulocytosis and anaemia
- Many erythroblasts are present in the fetal blood
What is the immunopathology of type III hypersensitivity reactions like?
IgG/IgM antibodies against soluble antigens
this leads to immune complex deposition in the skin, kidneys and joints
What are the clinical features and associated diseases of Type III hypersensitivity reactions?
Clinical features:
- onset of 3 - 8 hours
- vasculitis
Associated diseases:
- the traditional cause is serum sickness
- SLE
What is meant by serum sickness?
A reaction to proteins in antiserum derived from a non-human animal source occurring 5-10 days after exposure
The immune system mistakes the proteins for harmful antigens
the body produces antibodies which combine with the proteins to form immune complexes
What happens to the immune complexes after they have formed?
The complexes precipitate and enter the walls of blood vessels to activate the complement cascade
they initiate an inflammatory response
What are the typical symptoms of serum sickness?
rashes
itching
joint pain (arthralgia), especially finger and toe joints
fever, as high as 40 °C and usually appears before rash
lymphadenopathy (swelling of lymph nodes), particularly near the site of injection, head and neck
malaise
hypotension (decreased blood pressure)
splenomegaly (enlarged spleen)
glomerulonephritis
protein in the urine
blood in the urine
shock
Complete the table with the route of antiserum administration and the site of immune complex deposition
What is the immunopathology and clinical features of a type IV hypersensitivity reaction?
Immunopathology:
- antigen specific T-cell mediated cytotoxicity
Clinical features:
- delayed onset of 48-72 hours
- erythema and induration
What are the common causes and associated diseases associated with Type IV hypersensitivity?
Common causes:
- metals e.g. nickel
- tuberculin reaction
Associated diseases:
- contact dermatitis
What is the mechanism behind a Type IV hypersensitivity reaction?
- CD4+ Th1 cells recognise foreign antigen in a complex with the MHC class II on the surface of APCs
- The T cells are drivers of pathology that secrete chemokines and cytokines that cause damage
What cytokines and chemokines are secreted as part of the Type IV delayed response?
- Macrophages secrete IL-12, which stimulates the proliferation of further Th1 cells
- T cells secrete Il-2 and IFN-gamma, which induces further release of other Th1 cytokines
- Activated CD8+ T cells destroy target cells on contact, whilst activated macrophages produce hydrolytic enzymes
What is the end result of the type IV hypersensitivity reaction?
Overreaction of helper T cells and overproduction of cytokines damages tissues, causes inflammation and cell death
Why do people get allergies?
- The components of the immune system involved in allergic responses are primarily involved in responses to parasitic infection
- the immune system has evolved to generate a rapid tissue-based response to reinfection
- the lack of infectious drive is also a contributatory factor
What characteristics of the immune response to parasitic disease is the same in an allergic reaction?
Increased levels of IgE:
- both total and cross-reactive (specific to pathogen)
Tissue inflammation with:
- eosinophils and mast cells
- basophil infiltration
Presence of CD4+ T cells secreting:
- IL4, IL5 and IL13
What is meant by the ‘hygiene hypothesis’?
Immune stimulation by microbes protects against allergies
If the immune system is not fighting against bacteria, it turns to fight against the harmless antigens
A pathogen-free environment leads to increased incidence of disease
What is the mechanism behind the hygiene hypothesis?
- There is deviation from a Th1 response to a Th2 response
- there is lack of antigenic competition from infections, which leads to immune regulation
What is meant by the genetic influences on the allergic immune response?
What is significant about the genetic component?
Only involves polygenic diseases
cytokine gene cluster IL3, 5, 9, 13
IL12R, IL4R
FceRI
IFN-gamma and TNF
These are NOT sufficient for disease, only susceptibility
What are the 4 groups of susceptibility genes for allergic diseases?
- Environment sensing genes
- Atopic immune responses
- Tissue response genes
- Barrier function genes
What is meant by ‘environment setting’ genes?
They encode molecules that directly modulate the effect of environmental risk factors for allergic disease
e.g. Modulate the effect of exposures involving tobacco smoke and air pollution on asthma susceptibility
What is meant by barrier function genes?
They tend to be expressed in the epithelium
they affect epithelial and dermal barrier function, allowing the allergen to enter the body more easily
What is meant by the genes that regulate atopic inflammation?
They regulate Th1/Th2 differentiation and effector function
they regulate atopic sensitisation
What is meant by ‘atopy’?
personal and/or familial tendency to become sensitised and produce IgE antibodies in response to ordinary exposure to allergens, usually proteins
What is meant by tissue response genes?
Genes that modulate the consequences of chronic inflammation
What are the stages involved in development of allergy?
What is meant by ‘sensitisation’?
The process by which a person’s body becomes sensitive to a particular allergen
someone must have encountered an antigen at least once before in order to become allergic to it
What are the stages in the conventional immune response?
- Antigen requires processing
- Presentation to T cells and cytokine release
- This results in delineation of T-helper subsets into different types
What is different about an alllergic response compared to the conventional immune response?
- Antigens initiate an IgE-mediated response
- First encounter results in innate and IgM response
What are the stages of IgE production shown in the diagram?
- Allergen is recognised by B cell and Th2 cell
- Th2 cell produces IL-4, which causes the B cells to proliferate
- B cells differentiate into plasma cells and produce antibodies
What must happen in order for the allergen to enter the bloodstream?
The barrier function must be disrupted due to inflammation or genetic defect
the allergen then enters regional lymph nodes where it is presented to T cells via an APC
What cytokines determine what type of T cell the naive CD4+ T cell will differentiate into?
What effector cytokines are produced by the different types of T cell?
What are the 3 main roles of the Th2 T cell?
- Multiple cytokine release
- Part of the innate inflammatory response
- Drive for immunoglobulin production
What are the stages involved in the Type I allergic response?
- Allergen is recognised by both the B and T cell
- IL-4 produced by T cell signals to the B cell to proliferate, differentiate into plasma cells and produce antibodies
- IgE antibodies attach to mast cells
- The allergen crosslinks antibodies on the surface of the sensitised mast cell
- This causes degranulation of the mast cell and release of vasoactive amines
What is the immunopathogenesis of the IgE mediated allergic response?
- IgE mediated mast cell and basophil degranulation
- leads to the release of preformed and de novo synthesised inflammatory mediators
What are the clinical features of the IgE mediated allergic response and late phase response?
Clinical features:
- fast onset (15-30 mins)
- wheal and flare
Late phase response:
- involves eosinophils
- central role for Th2 T cell
What are the main primary mediators of the IgE mediated allergic reaction?
- Histamine
- Proteases
- Chemotactic factors
these primary mediators are involved in the initial response
What are the main secondary mediators involved in the IgE-mediated allergic reaction?
- Leukotrienes
- Prostaglandin D2
these secondary mediators are involved in the late phase reaction
What is meant by anaphylaxis?
serious allergic reaction that is rapid in onset and may cause death
What are the 3 ways to define anaphylaxis?
Definition 1:
- sudden onset of illness with involvement of the skin, mucosal tissue or both
- and at least one of:
- Sudden respiratory symptoms
- sudden reduced BP or symptoms of end-organ dysfunction
Definition 2:
- two or more of the following that occur suddenly after exposure to a likely allergen:
- sudden skin or mucosal symptoms and signs
- sudden respiratory symptoms
- sudden reduced BP or symptoms of end organ dysfunction
- sudden gastrointestinal symptoms
Definition 3:
- reduced BP after exposure to a known allergen for that patient
What is meant by the atopic triad?
- Asthma
- Rhinitis
- Eczema
What are the typical symptoms of allergic rhinitis and asthma?
Allergic rhinitis:
- nasal congestion
- nasal inflammation
- tonsillar and adenoidal enlargement
Asthma:
- airway inflammation
- airway constriction and hyperreactivity
- obstructive sleep apnoea
- decreased nasopharyngeal area
What are the typical symptoms of rhinitis?
- Blocked/runny/itchy nose
- Sneezing
- Conjunctivitis symptoms - itching/burning/watering eyes
Complete the diagram demonstrating the 2 types of rhinitis?
What are the characteristics of asthma?
What is significant about asthma in childhood?
It is a disease of inflammation and hyper-reactivity of the small airways
in childhood, aero-allergic stimuli such as the house dust-mite are of pathogenic importance
there is more of an allergic component in childhood asthma
What causes symptoms and airway damage in asthma?
Immediate symptoms are IgE-mediated
Damage to the airways is due to the late phase response
Damage airways are hyper-reactive to non-allergic stimuli e.g. fumes
What is involved in the pathogenesis of asthma?
Complete the diagram of dermatitis classification
What are the clinical features of dermatitis?
Intense itching, blistering/weeping, cracking of skin
house dust mite is a major trigger in atopic disease
What is the treatment for rhinitis?
Antihistamines and intranasal steroids
What is the treatment for dermatitis?
Topical steroids and moisturisers
What is meant by pruitis?
What is its role in the allergy?
An unpleasant sensation of the skin which provokes the urge to scratch
itching increases barrier disruption, allowing the allergen to get into the body
What is a ‘hapten’?
a small molecule which, when combined with a larger carrier such as a protein, can elicit the production of antibodies which bind specifically to it
What tests are used in the diagnosis of an allergy?
- Specific IgE
- Skin prick test
- Intra-dermal test
- Graded challenge test
- Basophil activation test
- Component resolved diagnostics
What is meant by the specific IgE measurement?
Measure the amount of IgE in the blood
>0.35 KuA/L is a positive result
a negative test doesn’t always exclude allergy as the IgE antibodies can be stuck to the surface of cells and not in the bloodstream
What is meant by the skin prick test?
Drops of allergens are placed on the skin and then the skin surface is scratched
histamine is a positive control as it will generate a response
saline is used as a negative control (as some patients have sensitive skin)
a lancet is used to scratch the skin and see if one of the allergens causes a reaction
What is a positive skin prick test result?
Wheal and erythema
wheal is a small lump and it is positive test if it is more than 2mm larger than the negative control
What is the intra-dermal test?
A tiny amount of allergen is injected into the skin and a pen line is drawn around the site of injection
after 10-15 mins, note the size of the site of injection
if the size increases by 3mm or more then the test is positive
What is meant by the basophil activation test?
A blood sample is taken and antigen is added externally
if a specific antibody is stuck on the basophil, molecules project out onto the surface from below
What are advantages and disadvantages of specific IgE testing?
Advantages:
- very safe
Disadvantages:
- false negatives if antigens are on cell surface and not in blood stream
- and false positives in asthma and eczema patients with high levels of IgE
What are the positives and negatives of a skin prick test?
Positives:
- quick
- patient satisfaction
Negatives:
- false negatives if patients are taking anti-histamines
- false positives in patients with sensitive skin
- slight risk of triggering reaction
What are the treatments for allergic reactions?
Antihistamines, steroids, adrenaline
or
subcutaenous/sublingual immunotherapy
What are the indications for use of immunotherapy?
- Life threatening reactions to wasp and bee stings
- severe hay fever
- animal dander allergy
It is not useful in:
- multiple allergies
- food allergy
- eczema
- spontaenous urticaria
Why is immunotherapy used?
It improves quality of life of treated individuals and has been shown to reduce both symptoms of allergy and medication use
How does immunotherapy work?
- It modifies cellular and humoral responses to allergens
- Ratio of Th1 cytokines to Th2 cytokines is increased
- Regulatory T cells are induced
This works for around 5-8 years and then the patient develops the allergy again
What is the difference between food intolerance and food allergy?
Food intolerance:
- this is NOT related to IgE mediated reactions
- it includes things like palpitations due to caffeine intake and lactose intolerance due to absent enzymes
Food allergy:
- this involves both IgE and non-IgE mediated reactions
Complete the table for food allergy and intolerances
What are the 6 major food allergens?
They are water soluble glycoproteins 10-60 kd
- Cow’s milk
- Egg
- Legumes - peanut, soybean, tree nuts
- Fish
- Crustaceans/molluscs
- Cereal grains
What are the 3 systems affected by adverse reactions to food?
Gastrointestinal:
- vomiting, diarrhoea and oral symptoms
Respiratory (upper and lower):
- rhinitis, bronchospasm
Cutaneous:
- urticaria, angioedema
- role of food in atopic dermatitis unclear
anaphylaxis
How are reactions to drugs tested for?
IgE mediated reactions are the only ones that can be tested for
Penicillin can cause all 4 types of hypersensitivity reactions
What aspects should be considered in taking a history for drug allergy?
- Indication for the drug
- Detailed description of the reaction
- Time between drug intake and onset of symptoms
- Number of doses taken before onset
- Aware of pharmacological effects and non-immunological ADR
What are the stages in management of drug allergy?
- Intradermal testing
- Graded challenge
- Desensitisation
