Flashcards in (10) Allergic Diseases Deck (126):
What is allergy/hypersensitivity?
Undesirable, damaging, discomfort-producing and sometimes fatal reactions produced by the normal immune system (directed against innocuous antigens) in a pre-sensitised (immune) host
How many immunopathological classifications are there for allergy?
4 types - Coombs and Gell 1963
type 5 - extended classification
What are the 4 types of hypersensitivity?
type 1 = anaphylactic
type 2 = cytotoxic
type 3 = immune complex
type 4 = delayed type
Which antibodies are involved in the 4 types of hypersensitivity?
type 1 = IgE
type 2 = IgG, IgM
type 3 = IgG, IgM
type 4 = none
What is the immunopathogenesis in type II cytotoxic?
IgG/IgM Ab response against combined self/foreign antigen at the cell surface - complement activation/phagocytosis/ADCC
What are the clinical features of type II cytotoxic?
- onset minutes to hours
- cell lysis and necrosis
What are the common antigens of type II cytotoxic?
What are the associated diseases of type II cytotoxic?
- erythroblastosis fetalis
- goodpasture's nephritis
What are the steps when penicillin causes a type II cytotoxic reaction to cause lysis?
- complement-coated penicillin-modified red blood cells are phagocytosed by macrophages using their complement receptors
- macrophages present peptides from the penicillin-protein conjugate and activate specific CD4 T cells to become TH2 cells
- B cells are activated by the antigen and by help from activated TH2 cells
- Plasma cells secrete penicillin-specific IgG which binds to modified red blood cells
- complement lytic pathway
What is the immunopathology in type III-immune complex reactions?
IgG/IgM Ab against soluble antigen-immune complex deposition
What are the clinical features of type III-immune complex reactions?
- onset 3-8 hours
What is the traditional cause of type III-immune complex reactions?
Mouldy hay – farmer’s lung
What disease is associated with type III-immune complex reaction?
If the site of immune-complex deposition is the blood vessel walls, what is the resulting disease?
If the site of immune-complex deposition is the renal glomeruli, what is the resulting disease?
If the site of immune-complex deposition is the joint spaces, what is the resulting disease?
If the site of immune-complex deposition is the perivascular area, what is the resulting disease?
What is arthus reaction?
The Arthus reaction is a type of local type III hypersensitivity reaction which involves the deposition of antigen/antibody complexes mainly in the vascular walls, serosa (pleura, pericardium, synovium) and glomeruli.
If the site of the immune-complex deposition is the alveolar/capillary interface, what is the resulting disease?
What is the immunopathology in type IV-delayed reactions?
Antigen specific T-cell mediated cytotoxicity
What are the clinical features of type IV-delayed reactions?
- delayed onset 48-72 hours
- erythema induration
What is the common antigen in type IV-delayed reactions?
- metals eg. Nickel
- (tuberculin reaction)
What disease is associated with type IV-delayed allergic reaction?
In type IV-delayed allergic reactions, an antigen leads to a T cell response, briefly describe the following steps
- antigen is processed by tissue macrophages and stimulates THI cells
- chemokines, cytokines and cytotoxins are released which perform different functions
In type IV-delayed allergic reactions, chemokines, cytokines and cytotoxins are released. State which and their functions
- chemokines = macrophage recruitment to the site of antigen
- IFN-y = activates macrophages increasing release of inflammatory mediators
- TNF-a and TNF-b = local tissue destruction, increased expression of adhesion molecules on local blood vessels
- IL-3/GM-CSF = monocyte production by bone marrow stem cells
Describe the stages in the development of allergy
- environment and genetics (atopy)
- barrier dysfunction
- changes in T cell sub-sets dominated by Th2
Which allergy is associated with the eyes?
Which allergy is associated with the nose?
Which allergy is associated with the mouth?
Oral allergy syndrome
Which allergy is associated with the airways?
Which allergy is associated with the skin?
Which allergy is associated with the GI tract?
How do we get allergies?
- those components of the immune system involved in responses to parasitic infection are also involved in allergic responses
- the system has developed to produce a rapid tissue-based response to re-infection
- the lack of infectious drive is a contributory factor in allergic disease
In immune response to parasitic disease, what is there increased levels of?
Increased levels of IgE
- specific to pathogen – cross-reactive
In immune responses to parasitic diseases, there is tissue inflammation with what?
- eosinophilia and mastocytosis
- basophil infiltration
What is eosinophilia?
An increase in the number of eosinophils in the blood, occurring in response to some allergens, drugs, and parasites, and in some types of leukaemia
Which cells are present in immune responses to parasitic disease?
Presence of CD4+ T cells secreting: IL4, IL5, IL13
Describe the ‘hygiene hypothesis’ in relation to parasitic disease and allergy
- stimulation by microbes is protective
- animal models – T1DM, EAE, asthma
- increased atopy (asthma) after anti-parasitic Rx
- prevention of autoimmunity (Crohn’s) by infections
- pro-biotics in pregnant women
- mechanism – Th1 Th2 deviation
What are the genetic influences on the ‘allergic’ immune response?
- polygenic disease
- cytokine gene cluster IL3, IL, IL9, IL13
- IL12R; IL4R
- IFNg; TNF
Are genetic influences of ‘allergic’ immune response sufficient for disease?
No, not sufficient for disease, only susceptibility
What defects causing an allergic response can be caused by genes?
- barrier function
- tissue response
- atopic immune responses
- environment sensing
Which genes contribute to all of asthma, atopic dermatitis and allergic rhinitis?
Which genes contribute to only allergic rhinitis?
Which gene contributes to both asthma and allergic rhinitis?
What is an allergen?
Antigens that initiate an IgE-mediated response
What does the first encounter with an allergen result in?
Innate and IgM response (you do not generate and allergic response on first encounter)
What is the conventional immune response?
- allergen requires processing
- presentation to T cells and cytokine release
- results in delineation of T-helper subsets into different types
In allergic responses, what are the early priming events?
- decreased barrier function
- allergen is passively taken in or actively taken up through barrier
- immature dendritic cell gets activated
- dendritic cell migrates and matures
- mature dendritic cell presents antigen to naive T cell in lymph node
- T cell activation
- Th2-cell development
What is a dendritic cell?
Main function is to process antigen material and present it on the cell surface to T cells
In an allergic response there is differentiation of T-helper cells. Give 4 different types of T helper cell involved
What do Treg cells do?
Regulatory T cells calm down the immune response. They cause inflammatory suppression caused by the other T helper cells
Which effector cytokines do Treg cells release?
Which effector cytokines do Th1 cells release?
Which effector cytokines do Th2 cells release?
Which effector cytokines do Th17 cells release?
How are IgE antibodies produced?
Th2 cells release IL-4 cytokines which stimulates the B cells to proliferate and produce IgE
Which cell is ultimately responsible for IgE production?
Which T cell is involved in IgE production?
Which cytokines is involved in IgE production?
How do IgE antibodies go on to produce an allergic response? (type I allergic response)
- IgE binds to the Fc receptor on sensitised mast cells
- mast cells activation and degranulation
- release of mediators which cause the symptoms
Which parts of the body are affected by the vasoactive amines/lipid mediators/chemokines/cytokines released by mast cells and basophils?
- smooth muscle
- blood vessels
- sensory nerve endings
What is the immunopathogenesis in IgE mediated allergic response?
IgE antibody mediated mast cell and basophil degranulation - release of pre-formed and de novo synthesised inflammatory mediators
What are the clinical features of IgE mediated allergic response?
- fast onset (15-30 minutes)
- wheal and flare
(unlikely to be this allergy if presents the day after)
What are the two types of response in IgE mediated allergic responses?
1. initial response/immediate phase
2. late-phase reaction
What is involved in the initial response in IgE mediated allergic responses?
- degranulation of mast cells and basophils
- granule contents = histamine, proteases, chemotactic factors
What is involved in the late-phase reaction in IgE-mediated allergic responses?
- secondary mediators
- leukotrienes and prostaglandins
- central role for Th2 T cell
What is the role of the Th2 T cell?
- multiple cytokine release
- innate inflammatory response (macrophages etc)
- drive for immunoglobin production (support for B cells)
What are the 3 conditions in the atopic triad?
Which of the atopic triad are type I hypersensitivity?
Which of the atopic triad are type IV hypersensitivity?
What are the symptoms of allergic rhinitis caused by mast cells in the nasal mucosa and airway epithelium?
- nasal congestion (oedema, mucus, nasal polyps)
- nasal inflammation
- tonsillar and adenoidal enlargement
What are the symptoms of asthma caused by mast cells in the airway epithelium and lungs?
- airway inflammation (oedema, mucus)
- airway constriction and hyper-reactivity
What are the two types of rhinitis?
What are the two types of allergic rhinitis?
What allergens can cause rhinits?
- house dust mite
- animal danders
What are the symptoms of rhinitis?
- blocked nose
- runny nose
- often with eye symptoms
What is the treatment for rhinitis?
- nasal steroids
What is asthma a disease of?
Inflammation and hyper-reactivity of the small airways
Which allergens cause asthma?
- aero-allergic stimuli in childhood (airborne allergens)
- house dust mite - key pathogenic importance
What are the immediate symptoms of asthma due to?
What is damage to the airways in asthma caused by?
Late phase reaction
Damaged airways in asthma are hyper-reactive to what?
Non-allergic stimuli eg. fumes
What is the basic difference between asthma and rhinitis?
Rhinitis = upper airways
Asthma = lower airways
What is the pathogenesis in asthma? (describe the inflammatory cascade in allergic asthma)
- antigen-presenting cell
- Th2 cell
- IL-4 and IL-3 to B cell plasma cell
- IL-5 to eosinophil
- B cell plasma cells produces IgE
- IgE to mast cells and basophils
- mast cells, basophils and eosinophils cause release of histamine, leukotrienes, prostaglandins, cytokines, basic proteins and enzymes
- allergic asthma
What are the two major types of dermatitis?
- contact (allergic/non-allergic)
What is atopic dermatitis also known as?
How would a patient with atopic dermatitis present?
- intense itching
- cracking of skin
What is a major trigger in atopic dermatitis?
House dust mite
What is the treatment for atopic dermatitis?
- topical steroids
Which cytokine mediator causes the scratch/pruritus in atopic dermatitis?
IL-31 directly causes scratch
How is there a viscous circle in atopic dermatitis?
Barrier disruption leads to development of Th2 then IgE and also T cell-derived itch mediator: IL-31
This causes pruritus/scratch
The scratching causes further barrier disruption and therefore more IL-31 and more scratching
What is anaphylaxis?
An acute, potentially life-threatening, IgE-mediated systemic hypersensitivity reaction
What are the 3 classifications of anaphylaxis?
- 1 (mild)
- 2 (moderate)
- 3 (severe)
What are some symptoms of type 1 (mild) anaphylaxis?
- abdominal pain
- nausea and vomiting
- runny nose and sneezing
- throat tightness
- mild wheezing
- tachycardia (>15 beats per min)
- increased anxiety
What are some symptoms of type 2 (moderate) anaphylaxis?
- severe abdominal pain
- moderate dyspnoea
- tachycardia (>15 beats per min)
- feel of pending life-threatening event
What are some symptoms of type 3 (severe) anaphylaxis?
- profuse diarrhoea and loss of bowel control
- severe wheezing
What are the methods of diagnosis of allergy?
- specific IgE (>0.35 KuA/L)
- skin prick test (>3mm wheal)
- intra-dermal test
- oral challenge test
- basophil activation test
- component resolved diagnostics
What is the gold standard test in allergy diagnosis?
Oral challenge test
eg. feed peanut and see what happens (quick onset)
Why is history important in allergy diagnosis?
Temporal relationship between exposure and symptoms is relevant
Type 1 = symptoms are short-lived
How do you measure IgE in allergy diagnosis?
BUT can have positive test and be clinically tolerant
How is a skin prick test carried out in allergy diagnosis?
negative control = drop of saline solution on skin
positive control = drop of histamine on skin
then eg. drop of grass pollen on skin
and see if you have a reaction
What happens in chronic spontaneous urticaria?
Random rashes for no reason
How does the basophil activation test work in allergy diagnosis?
Certain substances (makers) inside the basophil cell either come out of the cell or increase in number when the cell is activated
eg. CD63 comes out of the cell
What are the advantages and disadvantages of the specific IgE test in allergy diagnosis?
Advantage = safe (just a blood test)
Disadvantage = false negatives and false positives
What are advantages and disadvantages of the skin prick test in allergy diagnosis?
Advantage = quick (don't have to send samples to lab) and patient satisfaction
Disadvantages = false negatives, false positives, antihistamines, slight risk
What are the symptomatic treatments for allergy?
What specific treatment is there for allergy?
Immunotherapy - modulate immune system (subcutaneous or sublingual administration)
What are the indications for immunotherapy for allergy?
- life threatening reactions to wasp and bee sting
- severe hay fever
- animal dander allergy
Immunotherapy for allergy is not helpful in which situations?
- multiple allergies
- food allergy
- allergic rashed eg. eczema, urticaria
Describe the mechanism of immunotherapy
- more Th1 and less Th2 in tissues
- decreased IgE and more of other types of antibodies (IgG, IgA) and so more competition
What are the major food allergens?
- cow's milk
- legumes (peanut, soybean, tree nuts)
- cereal grains
The major food allergens are what type of proteins?
Water-soluble glycoproteins 10-60kd
What are the clinical manifestations of food allergy?
- oral symptoms
Respiratory (upper and lower)
- role of food in atopic dermatitis is unclear
Food allergy can be of which 3 types?
- non-IgE mediated
What are some examples of causative agents of IgE mediated type I drug allergy?
- B-lactam antibiotics
- platinum-based chemotherapeutics
- perioperative agents
What are the clinical manifestations of IgE mediated type I drug allergy?
What are some examples of causative agents of cytotoxic type II drug allergy?
What are the clinical manifestations of cytotoxic type II drug allergy?
- haemolytic anaemia
What are some examples of causative agents of immune complex type III drug allergy?
What are the clinical manifestations of immune complex type III drug allergy?
- serum sickness
What are some examples causative agents of delayed type type IV drug allergy?
- sulfonamide antibiotics
What are the clinical manifestations of delayed type type IV drug allergy?
- contact dermatitis
What are the response times in the 4 different types of hypersensitivity?
type I anaphylactic = 15-30 minutes
type II cytotoxic = minutes-hours
type III immune complex = 3-8 hours
type IV = 48-72 hours
What is the appearance of the 4 different types of hypersensitivity?
type I anaphylactic = wheal and flare
type II cytotoxic = lysis and necrosis
type III immune complex = erythema, oedema, necrosis
type IV delayed type = erythema induration
What is the histology of the 4 different types of hypersensitivity?
type I anaphylactic = basophils and eosinophils
type II cytotoxic = antibody and complement
type III immune complex = complement and neutrophils
type IV delayed type = monocytes and lymphocytes