Hypersensitivity and Allergy Flashcards
What is immune tolerance
Appropriate immune tolerance occurs to self, and to foreign harmless proteins:
Food, pollens, other plant proteins, animal proteins, commensal bacteria
What does immune tolerance involve
Involves antigen recognition and generation of regulatory T cells and regulatory (blocking) antibody (IgG4) production
Antigen recognition in context of “danger” signals leads to immune reactivity, absence of “danger” to tolerance
What can hypersensitivity reactions be a response to
Harmless foreign antigens (allergy, contact hypersensitivity)
Autoantigens (autoimmune diseases)
Alloantigens (graft rejection)
What are the types of hypersensitivity reactions
Type I : Immediate Hypersensitivity
Type II : Antibody-dependent Cytotoxicity
Type III : Immune Complex Mediated
Type IV : Delayed Cell Mediated
Give examples of type I (immediate) hypersensitivity
Anaphylaxis
Asthma
Rhinitis (seasonal, perennial)
Food Allergy
What occurs on first antigen exposure for immediate hypersensitivity
Sensitisation not tolerance
IgE antibody production
IgE binds to Mast Cells and Basophils
What occurs on second antigen exposure for immediate hypersensitivity
More IgE Ab produced
Antigen cross-links between IgE on Mast Cells/Basophils
Degranulation and mediator release
What are the autoantibody targets for the following type II hypersensitivity diseases: myasthenia graves, pemphigus vulgarisms, glomerulonephritis and pernicious anaemia
Myasthenia gravis: postsynaptic nicotinic acetylcholine receptor at neuromuscular junctions
Pemphigus vulgaris: desmoglein (links keratinocyte desmosomes to the basement membrane)
Glomerulonephritis: glomerular basement membrane
Pernicious anaemia: intrinsic factor
Give examples of autoimmune cytopenias
Haemolytic anaemia
Thrombocytopenia
Neutropenia
What are the tests done for type II hypersensitivity and give an example
Immunofluorescence or ELISA
e.g. ELISA for anti-CCP (cyclic citrullinated peptide) antibodies for rheumatoid arthritis.
Describe what occurs in type III (immune complex mediated) hypersensitivity
- Formation of Antigen-Antibody complexes in blood
- Deposition in blood vessels/tissue
- Complement + cell activation
- Activation of other cascades eg clotting
- Tissue damage (vasculitis)
Give examples of vasculitis and tissue damage from type III hypersensitivity
Systemic lupus erythematosus (SLE or lupus)
Vasculitides (which also cause systemic inflammation, such as polyarteritis nodosum).
What may cause type IV (delayed) hypersensitivity reactions
Chronic graft rejection GVHD Coeliac disease Contact hypersensitivity Many autoimmune diseases (asthma, rhinitis, eczema)
What is GVHD
graft vs host disease
a bone marrow transplant’s immune cell products rejecting their new host’s other tissues
Which hypersensitivity reaction type is the most common
Type IV
Describe the role of Th1 in type IV hypersensitivity reactions
- Antigens are presented Th1
- Th1 produces interferon-γ (IFN-γ)
- IFN-γ activates macrophages to produce lots of TNF-α.
- Th1s also produce IL-2, which stimulates CD8+ CTLs.
If the resulting inflammation is chronic, fibroblast growth factor (FGF) is also made by the Th1s, leading to fibrosis and angiogenesis.
Describe the role of Th2 and CTL in type IV hypersensitivity reactions
Th2 - Involved in allergic responses, in chronic asthma and hayfever.
CTL - Kill virally infected cells.
What occurs in inflammation
immune cell recruitment to the sites of injury/infection and subsequent activation
Inflammatory mediators include complement, cytokines etc.
What are the features of inflammation
Vasodilatation, increased blood flow
Increased vascular permeability
Inflammatory mediators + cytokines
Inflammatory cells + tissue damage
What are the signs of inflammation
Redness
Heat
Swelling
Pain
What are the types of inflammation in allergy
Type I - Anaphylaxis, angioedema, urticaria - IgE mediated
Type II - Urticaria (chronic or idiopathic) - IgG mediated
Type I + IV (mixed) - asthma, hay fever, eczema
What does expression of disease require
Development of sensitisation to allergens instead of tolerance (primary response - usually in early life)
Further allergen exposure to produce disease (memory response - any time after sensitisation)
Describe the process of sensitisation in atopic airway disease
- Protein antigen (inhaled) is taken up by endogenous cell
- Dendritic cells process the allergen into peptides
- Presentation of peptides to Cd4+ t cells
- Th1, Treg, Th2 activation
- Th2, once sensitised, produce IL-4 and IL-13
- B cell proliferation and differentiation
- IgE production from plasma cells
Describe what occurs in subsequent exposure from sensitisation in atopic airway disease
- Dendritic cells take up antigen
- Antigen processed into peptides
- Presentation to memory Th2 cells
- Production of IL-4, IL-5 and IL-13
IL-4, IL-13 = B-cells product IgE
IL-5 = Eosinophil recruitment and activation - Mast cells and T-cell mediated activation
What process in memory cell generation is blocked in atopy
when an allergen is presented to a naïve T cell, regulatory T cells stop memory generation via IL-10. This is blocked in atopy, hence sensitisation proceeds fully.
Describe eosinophils (proportion, location, recruitment, production, microscopic structure)
2-5% of circulating WBCs
More are in tissues than in the bloodstream
Recruited during allergic inflammation
Generated in bone marrow
Two-lobed nucleus
Contain large granules of toxic proteins which can lead to tissue damage
Describe mast cells (location, receptors)
Only reside in tissues
Have IgE as receptors on their cell membrane
Crosslinking of IgE as antigen binds causes release of mediators:
Which mediators are released on crosslinking of IgE on mast cells
Pre-formed: histamine, cytokines, toxic proteins
Newly synthesised: leukotrienes, prostaglandins
Which immune cells are important in asthma and atopic eczema
neutrophils
What does chronic inflammation in asthma involve
Cellular infiltrate of Th2 cells and eosinophils Mucus plugging Smooth muscle hypertrophy Epithelial shedding Sub-epithelial fibrosis
What is asthma (in reference to the lungs) and what does it lead to
reversible generalised airway obstruction, leading to a chronic episodic wheeze.
The bronchi are hyperresponsive and irritable.
It leads to cough, mucus production, and breathlessness.
What can treatment of asthma involve
inhaled β2-adrenoceptor agonists (salbutamol)
Short acting and/or longer-acting inhaled steroids
Oral steroids
Leukotriene antagonists
Anti-IgE monoclonal antibodies.
What is hay fever
Hayfever is seasonal allergic rhinitis. If year-round, it is called perennial allergic rhinitis instead. Perennial allergic rhinitis is not due to pollen, but other allergens such as animal fur or dust mites.
What can treatment of hay fever involve
Antihistamines to combat sneezing, itching, and rhinorrhoea
Nasal steroid spray for the blockage
Cromoglycate can help children’s eyes.
What is eczema (where is it common, what does it result in, age of presentation and clearance)
A chronic itchy rash on the skin. Most common at the knee and elbow flexures
It results in dry, cracked skin and can be complicated by infections (majority bacterial, sometimes HSV).
It is generally a disease of childhood, as 50% of cases clear by age 7 and 90% by adulthood.
What can treatment of eczema involve
Topical steroid cream and emollients (moisturisers)
What symptoms does a mild food allergy cause
itchy mouth and lips, angioedema, and urticaria.
What symptoms does a severe food allergy cause
nausea, abdominal pain, diarrhoea, and in the worst cases anaphylaxis.
What can treatment of food allergy involve
Avoidance
Anaphylaxis:
Adrenaline
Antihistamines
Steroids
How are allergies tested for
Careful histories
Skin prick testing
Radioallergosorbent test (RAST), which checks for specific IgE antibodies in the blood
Total IgE levels
Lung function tests (for asthma)
What is immunotherapy useful for
Single antigen hypersensitivities (bee/wasp venom, pollen, dust mites).
What are the types of immunotherapy for hypersensitivity
Subcutaneous immunotherapy - requires 3 years of regular clinic attendance for injections
Sublingual immunotherapy - can be done at home with pills
