Hypersensitivity - Part 1

Question 1

What is the consequence of immune recognition?

Answer 1

Intended destruction of the antigen and incidental tissue damage

Question 2

What is hypersensitivity?

Answer 2

Any inappropriate or excessive immune response that results in bystander damage to the self

Question 3

What is the definition of an allergy?

Answer 3

Immune response are induced against innocuous exogenous antigens
Antigen specific IgE or sensitized T cells play a definite role

Question 4

What is the definition of autoimmunity?

Answer 4

Harmful response directed against self-antigens
This can result in damage - autoimmune disease

Question 5

What are the antibody mediated hypersensitivity types?

Answer 5

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)

Question 6

What is the cell mediated hypersensitivity type?

Answer 6

Type 4 - T-cell mediated

Question 7

What are the 3 phases in pathophysiology for type 1 allergy?

Answer 7

Sensitisation, reaction + early-phase and reaction + delayed phase

Question 8

Describe sensitisation

Answer 8

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)

Question 9

Describe house dust mite allergy

Answer 9

HDM allergens are gut derived proteins, largely located in the faecal pellets
Highest exposure is on public transport and lowest overnight in bed

Question 10

What are the allergens in cats and dogs?

Answer 10

Cats - found in saliva and sebaceous glands of cat’s skin, particularly head region
Dog - hair, dander, saliva and urine

Question 11

What is the protein involved in peanut allergy?

Answer 11

Ara h2 - very stable protein
Ara h8 - cross reactivity with other food and not very stable

Question 12

What makes certain people more susceptible to an allergy?

Answer 12

Atopy, age (children), male, small family size, reduced microbial burden in developed countries, smoking, high levels of antigen exposure and dietary factors

Question 13

Describe atopy

Answer 13

Genetic predisposition to produce IgE antibody in response to environmental allergens
Increases risk of developing asthma, eczema, allergic dermatitis and allergic rhinitis

Question 14

Describe early phase of allergy

Answer 14

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

Question 15

What is mast cell degranulation?

Answer 15

Mast cell has IgE pre-attached to FcR1
Allergen cross-linking
Causes activation and degranulation with diverse mediators

Question 16

What are the results of mediator release in early phase?

Answer 16

Histamine, chemokines, leukotrienes and prostaglandins
Causes increased vascular permeability, vasodilation and bronchial constriction
Histamine gives triple vascular response - response of Lewis

Question 17

Describe late phase in allergy

Answer 17

Broader cell-based cascade occurs at the same time, which commences about 2hrs after exposure and continues over several days
Can become chronic

Question 18

What are the investigations used for allergic disease?

Answer 18

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)

Question 19

What does a positive skin prick test show?

Answer 19

Gives wheal and flare - oedema and erythema
Bigger reaction then more severe the allergy

Question 20

What are the pros and cons of skin prick tests?

Answer 20

Pros - inexpensive, immediate results and wide range of allergies available
Cons - need to avoid antihistamines, need interpretation and difficult if eczema

Question 21

What are the pros and cons of IgE blood test?

Answer 21

Pros - not affected by drugs or skin, safe and quantitative results
Cons - limited no. of tests, requires specialist equipment and delay in results turnover

Question 22

Describe component resolved diagnostics

Answer 22

Identification of specific component responsible for allergic sensitization can help guide clinicians stratifying patients as high or low risk to systemic reaction

Question 23

What is the management for allergic disease?

Answer 23

Symptoms - antihistamines, disease specific management (asthma) and allergen immunotherapy
Prevention - leukotriene receptor antagonist, corticosteroids, mast cell stabilisers, biologics and allergen immunotherapy

Question 24

What are some examples of antihistamines?

Answer 24

Diphenhydramine, chlorpheniramine, hydroxyzine and promethazine

Question 25

What are the actions of corticosteroids?

Answer 25

Decrease cytokine mediators, leak and mucus secretion, and increase B2 receptor cytokines Decrease number of inflammatory cells, cytokines and increase mast cells + dendritic cells

Question 26

What is the function of cromoglycate?

Answer 26

Stabilises the mast cell membrane inhibiting release of vasoactive mediators Effective prophylactic agent in asthma + allergic rhinitis No role in acute attacks

Question 27

Describe allergen immunotherapy (AIT)

Answer 27

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

Question 28

What are the most common causes of extreme type 1 reaction (systemic allergy or anaphylaxis)

Answer 28

Bee or wasp stings Food Latex rubber Drugs

Question 29

What is the treatment of anaphylaxis?

Answer 29

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

Question 30

What are anaphylactoid reactions?

Answer 30

Anaphylactoid reaction - no prior sensitisation required Mast cell basophil releases histamine, prostaglandin, leukotrienes, proteases and proteoglycans Not IgE mediated

Question 31

What is the treatment and management for anaphylactoid reactions?

Answer 31

Same as anaphylaxis Management - distinguish it between anaphylaxis

Question 32

What is the pathophysiology of type 2 hypersensitivity reaction?

Answer 32

Antibodies bind to the cell-surface antigens Results in activation of complement (cell lysis and opsonisation) and opsonisation (anti-body mediated phagocytosis)

Question 33

What are the functions of the antibody?

Answer 33

Opsonisation, complement activation, toxin neutralisation, antibody dependant cell mediated cytotoxicity and direct antimicrobial acitivity

Question 34

What are the effects of complement activation?

Answer 34

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

Question 35

Describe antibody dependant cell mediated cytotoxicity (ADCC)

Answer 35

Antibodies bind to receptors on target cell surface Effector cell Fc-receptors recognise cell bound antibodies Effector cell lyses target cell Target cell death

Question 36

Describe phagocytosis in type 2 hypersensitivity

Answer 36

IgG or IgM antibodies on the cell surface antigen act as opsonin for phagocytes This results in cell death through phagocytosis by macrophages

Question 37

What are examples of type 2 hypersensitivity reaction?

Answer 37

Autoimmune haemolytic anaemia, transfusion reactions, myasthenia gravis, idiopathic thrombocytopenic purpura, good pastures syndrome and Grave's disease (considered sometime sad type V)

Question 38

Describe an ABO transfusion reaction

Answer 38

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

Question 39

What is the aim of type 2 hypersensitivity reaction management?

Answer 39

Aim to remove pathogenic antibody Plasmapheresis Immunosuppression

Question 40

Describe the pathophysiology of type 3 hypersensitivity reactions

Answer 40

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

Question 41

How is type 3 hypersensitivity reactions classified?

Answer 41

Localised and generalised

Question 42

Describe a localised type 3 hypersensitivity reaction

Answer 42

Ex. Pigeon fancier's lung Results in wheezing 4-8hrs after exposure to antigen Dry cough, pyrexia and breathlessness Acute hypersensitivity pnuemonitis

Question 43

Describe generalised type 3 hypersensitivity reaction

Answer 43

Ex. SLE Immune complexes are deposited in small vessels in skin, joints and kidneys Causes small vessel inflammation Vasculitis purpura and arthralgias

Question 44

How is type 3 hypersensitivity reactions diagnosed?

Answer 44

Detection of relevant antibodies - in blood Detection of immune complexes - identified in affected tissues Surrogate marker - consumption of complement factors

Question 45

Describe the pathophysiology of type 4 hypersensitivity reactions

Answer 45

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

Question 46

What are Haptens?

Answer 46

Small molecules that elicit an immune response only when attached to large carrier such as a protein Hapten carrier conjugate induces the immune response

Question 47

Describe nickel hypersensitivity

Answer 47

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

Question 48

What are the types of eczema?

Answer 48

Abnormal immune response - contact allergic and atopic Abnormal barrier function of skin - contact irritant and atopic

Question 49

How is type 4 hypersensitivity reactions diagnosed?

Answer 49

Patch testing Exposure to antigen and biopsy