Hypersensitivity - Part 1 Flashcards
What is the consequence of immune recognition?
Intended destruction of the antigen and incidental tissue damage
What is hypersensitivity?
Any inappropriate or excessive immune response that results in bystander damage to the self
What is the definition of an allergy?
Immune response are induced against innocuous exogenous antigens
Antigen specific IgE or sensitized T cells play a definite role
What is the definition of autoimmunity?
Harmful response directed against self-antigens
This can result in damage - autoimmune disease
What are the antibody mediated hypersensitivity types?
Type 1 - immediate hypersensitivity (IgE mediated)
Type 2 - antibody mediated cell damage
Type 3 - immune complex mediated
Type 5 - variant of II where antibodies can stimulate a function (Graves disease)
What is the cell mediated hypersensitivity type?
Type 4 - T-cell mediated
What are the 3 phases in pathophysiology for type 1 allergy?
Sensitisation, reaction + early-phase and reaction + delayed phase
Describe sensitisation
In some people, allergen exposure produces a strong T-cell response
Antigen presenting cells present the antigen to T-cells that produce cytokines IL-4 and IL-13
These activate B-cells which secrete IgE - binds to mast cells (sensitising them to allergy)
Describe house dust mite allergy
HDM allergens are gut derived proteins, largely located in the faecal pellets
Highest exposure is on public transport and lowest overnight in bed
What are the allergens in cats and dogs?
Cats - found in saliva and sebaceous glands of cat’s skin, particularly head region
Dog - hair, dander, saliva and urine
What is the protein involved in peanut allergy?
Ara h2 - very stable protein
Ara h8 - cross reactivity with other food and not very stable
What makes certain people more susceptible to an allergy?
Atopy, age (children), male, small family size, reduced microbial burden in developed countries, smoking, high levels of antigen exposure and dietary factors
Describe atopy
Genetic predisposition to produce IgE antibody in response to environmental allergens
Increases risk of developing asthma, eczema, allergic dermatitis and allergic rhinitis
Describe early phase of allergy
Mast cell degranulation occurs on subsequent exposure to the allergen due to specific IgE antibody-antigen interaction
Results in cascade of biochemical events defined as early allergic reaction - peaks at 20-30 mins
What is mast cell degranulation?
Mast cell has IgE pre-attached to FcR1
Allergen cross-linking
Causes activation and degranulation with diverse mediators
What are the results of mediator release in early phase?
Histamine, chemokines, leukotrienes and prostaglandins
Causes increased vascular permeability, vasodilation and bronchial constriction
Histamine gives triple vascular response - response of Lewis
Describe late phase in allergy
Broader cell-based cascade occurs at the same time, which commences about 2hrs after exposure and continues over several days
Can become chronic
What are the investigations used for allergic disease?
Skin prick test, specific IgE tests, component resolved diagnostics, challenge tests, mast cell tryptase and non-specific markers for atopic state (total IgE and eosinophil count)
What does a positive skin prick test show?
Gives wheal and flare - oedema and erythema
Bigger reaction then more severe the allergy
What are the pros and cons of skin prick tests?
Pros - inexpensive, immediate results and wide range of allergies available
Cons - need to avoid antihistamines, need interpretation and difficult if eczema
What are the pros and cons of IgE blood test?
Pros - not affected by drugs or skin, safe and quantitative results
Cons - limited no. of tests, requires specialist equipment and delay in results turnover
Describe component resolved diagnostics
Identification of specific component responsible for allergic sensitization can help guide clinicians stratifying patients as high or low risk to systemic reaction
What is the management for allergic disease?
Symptoms - antihistamines, disease specific management (asthma) and allergen immunotherapy
Prevention - leukotriene receptor antagonist, corticosteroids, mast cell stabilisers, biologics and allergen immunotherapy
What are some examples of antihistamines?
Diphenhydramine, chlorpheniramine, hydroxyzine and promethazine
What are the actions of corticosteroids?
Decrease cytokine mediators, leak and mucus secretion, and increase B2 receptor cytokines
Decrease number of inflammatory cells, cytokines and increase mast cells + dendritic cells
What is the function of cromoglycate?
Stabilises the mast cell membrane inhibiting release of vasoactive mediators
Effective prophylactic agent in asthma + allergic rhinitis
No role in acute attacks
Describe allergen immunotherapy (AIT)
Desensitisation or hypo-sensitisation treatment
Involves sequential administration of escalating amounts of dilute allergen over prolonged period of time
Need high potency and good adherence
What are the most common causes of extreme type 1 reaction (systemic allergy or anaphylaxis)
Bee or wasp stings
Food
Latex rubber
Drugs
What is the treatment of anaphylaxis?
Give IM adrenaline
Establish airway, give high flow O2 and apply monitoring
If no response then repeat IM adrenaline and IV fluid bolus
IV fluid challenge - use crystalloid
What are anaphylactoid reactions?
Anaphylactoid reaction - no prior sensitisation required
Mast cell basophil releases histamine, prostaglandin, leukotrienes, proteases and proteoglycans
Not IgE mediated
What is the treatment and management for anaphylactoid reactions?
Same as anaphylaxis
Management - distinguish it between anaphylaxis
What is the pathophysiology of type 2 hypersensitivity reaction?
Antibodies bind to the cell-surface antigens
Results in activation of complement (cell lysis and opsonisation) and opsonisation (anti-body mediated phagocytosis)
What are the functions of the antibody?
Opsonisation, complement activation, toxin neutralisation, antibody dependant cell mediated cytotoxicity and direct antimicrobial acitivity
What are the effects of complement activation?
Chemotaxis - stimulates migration of macrophages and neutrophils to site of inflammation
Solubilization of immune complexes
Direct killing of encapsulated bacteria
Opsonisation - enhances phagocytosis by macrophages and neutrophils
Describe antibody dependant cell mediated cytotoxicity (ADCC)
Antibodies bind to receptors on target cell surface
Effector cell Fc-receptors recognise cell bound antibodies
Effector cell lyses target cell
Target cell death
Describe phagocytosis in type 2 hypersensitivity
IgG or IgM antibodies on the cell surface antigen act as opsonin for phagocytes
This results in cell death through phagocytosis by macrophages
What are examples of type 2 hypersensitivity reaction?
Autoimmune haemolytic anaemia, transfusion reactions, myasthenia gravis, idiopathic thrombocytopenic purpura, good pastures syndrome and Grave’s disease (considered sometime sad type V)
Describe an ABO transfusion reaction
Patient has anti-B antibodies and antigen A and donor has B antigens
Complement mediated lysis followed by haemolysis of transfused cells
Fever, rigors, increased HR + BR, fall in BP, headaches, chest pain and dizziness
What is the aim of type 2 hypersensitivity reaction management?
Aim to remove pathogenic antibody
Plasmapheresis
Immunosuppression
Describe the pathophysiology of type 3 hypersensitivity reactions
1 - formation of antigen/ antibody complexes (when ratio is equal large complexes form)
2 - immune complex deposition in small vessels
3 - inflammation from complement activation and infiltration of macrophages
How is type 3 hypersensitivity reactions classified?
Localised and generalised
Describe a localised type 3 hypersensitivity reaction
Ex. Pigeon fancier’s lung
Results in wheezing 4-8hrs after exposure to antigen
Dry cough, pyrexia and breathlessness
Acute hypersensitivity pnuemonitis
Describe generalised type 3 hypersensitivity reaction
Ex. SLE
Immune complexes are deposited in small vessels in skin, joints and kidneys
Causes small vessel inflammation
Vasculitis purpura and arthralgias
How is type 3 hypersensitivity reactions diagnosed?
Detection of relevant antibodies - in blood
Detection of immune complexes - identified in affected tissues
Surrogate marker - consumption of complement factors
Describe the pathophysiology of type 4 hypersensitivity reactions
Can take 2-3 days to develop - mediated by T-cells
T-cells become sensitised to the antigen - subsequent exposure - activation of previously sensitised T-cells - recruitment of macrophages, lymphocytes + neutrophils - release of proteolytic enzymes + persistent inflammation
What are Haptens?
Small molecules that elicit an immune response only when attached to large carrier such as a protein
Hapten carrier conjugate induces the immune response
Describe nickel hypersensitivity
Infiltration of activated T cells into subcutaneous tissue - CD4+ cells and CD8+ cell-mediated direct cell killing
Recruitment of macrophages - collection of macrophages and lymphocytes is a granuloma
Symptoms 1-2 days after exposure, itch and rash
What are the types of eczema?
Abnormal immune response - contact allergic and atopic
Abnormal barrier function of skin - contact irritant and atopic
How is type 4 hypersensitivity reactions diagnosed?
Patch testing
Exposure to antigen and biopsy
