1. Hypersensitivity and allergy Flashcards
What are alloantigens?
- Antigen present only in some individuals
- Capable of inducing the production of an alloantibody in people that lack it
- e.g. blood group antigens
What are the 4 types of hypersensitivity?
- Type I - immediate hypersensitivity
- Type II - antibody-dependent cytotoxicity
- Type III - immune complex mediated
- Type IV - delayed cell mediated
Give examples of type I hypersensitivity
- Anaphylaxis
- Asthma
- Rhinitis
- Food allergy
Outline the mechanism of type I hypersensitivity
- 1st antigen exposure - sensitisation
- IgE production
- IgE binds to mast cells + basophils
- 2nd antigen exposure
- More IgE produced
- Antigen cross-links IgE on mast cells + basophils
- Degranulation and release of inflammatory mediators
What happens in type II hypersensitivity?
- The antibodies produced by an immune response binds to antigens on the patient’s own cell surfaces
- B cell proliferation
- IgG and IgM bind - classical complement
Give examples of organ-specific autoimmune diseases (type II hypersensitivity) and the antibodies they involve
- Myasthenia gravis - anti-acetylcholine receptor antibodies (muscles become weak)
- Glomerulonephritis - anti-glomerular BM antibodies (cause of kidney disease)
- Pemphigus vulgaris - anti-epithelial cell cement protein antibodies (blistering skin condition)
- Pernicious anaemia - intrinsic factor blocking antibodies (prevents vit. b12 absorption)
Give examples of autoimmune cytopenias (antibody-mediated blood cell destruction) (type II hypersensitivity)
- Haemolytic anaemia - red cells
- Thrombocytopenia - platelets
- Neutropenia - neutrophils
What is bullous pemphigoid?
- Blistering skin disorder
- Antibodies against BM proteins
- More robust blisters than pemphigus due to deeper inflammation in the skin
How can you test for specific antibodies?
- Immunofluorescence
* ELISA
Outline the progression of a type III hypersensitivity response
- Excess antigen
- Formation of antigen-antibody complex in the blood
- Can’t get through small blood vessels easily - complexes deposit in the vessels and tissues
- Leads to complement activation and cell recruitment
- Activation of other cascades e.g. clotting
- Tissue damage - inflammation of blood vessels (vasculitis)
Give an example of a type III hypersensitivity autoimmune disease
Systemic lupus erythematosus (SLE)
Given an example of a vasculitis disorder
Polyarteritis nodosa - systemic necrotising vasculitis
What are the most common sites of vasculitis?
- Renal (glomerulonephritis)
- Skin
- Joints
- Lungs
Give examples of type IV hypersensitivity reactions/disorders
Th1
• Chronic graft rejections
• Coeliac disease
• Contact hypersensitivity
Th2 (all others are Th1)
• Asthma
• Rhinitis
• Eczema
What does a Th1 type IV hypersensitivity reaction mainly involve?
Production of lots of gamma-interferon by Th1
Which cytokines does Th2 release in type IV hypersensitivity?
- IL-4
- IL-5
- IL-13
What cells can T helper cells activate in type IV?
- Macrophages
* Cytotoxic T lymphocytes
Do type IV hypersensitivity reactions depend on a transient antigen presence or a persistant antigen?
Both
What is a lot of tissue damage in type IV dependent on?
TNF-alpha
What is asthma caused by (in terms of Ig and immune cells)?
- IgE binding to mast cells
* Induction of T cells producing Th2 type cytokines
What are the features of inflammation?
- Vasodilation
- Increased vascular permeability
- Inflammatory mediators + cytokines
- Inflammatory cells + tissue damage
What are the signs of inflammation?
- Redness
- Swelling
- Heat
- Pain
What causes increased vascular permeability in inflammation?
- C3a
- C5a
- Histamine
- Leukotrienes
Which cytokines are released during inflammation?
- IL-1
- IL-6
- IL-2
- TNF
- IFN-γ
Which chemokines are released during inflammation and what do they do?
- IL-8/CXCL8 - attracts neutrophils
* IP-10/CXCL10 - attracts lymphocytes
What is atopy?
- Form of allergy
- Hereditary or constitutional tendency to develop hypersensitivity reactions in response to allergens (atopens)
- e.g. allergic asthma, hay fever, atopic eczema
How common is atopy?
Very - 50% of young adults in the UK
Give examples of the varieties of atopy
- Mild occasional symptoms
- Severe chronic asthma
- Life threatening asthma
Give examples of some genetic risk factors to atopy
(genetic component is polygenic)
• IL-4 gene cluster (Chr5) linked to raised IgE, asthma and atopy
• Chromosome 11q genes (IgE receptor) linked to asthma and atopy
• Structural cell genes linked to eczema (filagrin) and asthma (IL-33)
How does the risk of atopy change with age?
- Increases from infancy
- Peaks in teens
- Reduces in adulthood
How does gender influence asthma (atopy)?
- More common in males in childhood
* More common in females in adults
How is the risk of atopy different depending on family size?
More common in small families
How does early life exposure to infections and animals affect atopy?
Protects from reactions
What type of hypersensitivity is anaphylaxis, urticaria and angioedema?
Type I
What type of hypersensitivity idiopathic/chronic urticaria?
Type II
What type of hypersensitivity asthma, rhinitis and eczema?
- Type I
* Type IV
When an APC activates the CD4+ T cells, they become specific and can become…
- Th1 (producing IFN-gamma)
- Th2 (leads to B cell activation)
- Treg (if harmless antigen)
What happens when the allergens are presented by APCs to the memory Th2 cells?
- Th2 releases IL-5
- This causes the degranulation of eosinophils
- Th2 also releases IL-4 and IL-13
- This stimulates the production of IgE by plasma cells
- IgE then becomes mobilised onto the surface of mast cells
- Antigens then cross-link with IgE and cause degranulation of mast cells
- Massive release of inflammatory mediators - allergic reaction
How many nucleus lobes do eosinophils have?
2
What are in the large granules in eosinophils?
Toxic proteins
What are the pre-formed and newly synthesised mediators in mast cells?
Pre-formed
• histamine
• cytokines
• toxic proteins
Newly synthesised
• leukotrienes
• prostaglandins
What allergies/hypersensitivies are neutrophils important in?
- Virus induced asthma
- Severe asthma
- Atopic eczema
What do neutrophil granules contain?
Digestive enzymes
What 3 processes cause airway narrowing in asthma?
- Vascular leakage leading to airway wall oedema
- Mucus secretion
- Smooth muscle contraction around the bronchi
There is cellular infiltration of which cells in chronic asthma?
Th2 and eosinophils
What happens to the epithelium in chronic asthma?
- Epithelial shedding
* Sub-epithelial fibrosis
What are some of the clinical features of asthma?
- Reversible generalised airway obstruction - chronic episodic wheeze
- Bronchial hyper-responsiveness
- Cough, mucus, breathlessness, chest tightness
- Spontaneous variation
- Response to treatment
- Reduced and variable peak expiratory flow (PEF)
What are the 2 types of allergic rhinitis and give an example of each?
- Seasonal e.g. hay fever
* Perennial (long lasting) e.g. animal allergens
What are the symptoms of allergic rhinitis?
- Sneezing
- Rhinorrhoea
- Itchy nose and eyes
- Nasal blockage, sinusitis, loss of smell/taste
What is allergic eczema?
- Chronic itchy skin rash
* Most common in the flexures of the arms and legs
What is the relation between allergic eczema and house dust mites?
House dust mite proteins can get through the dry, cracked skin => sensitisation
What can cause allergic eczema complications?
Bacterial and (rarely) viral infections e.g. HSV
When does allergic eczema usually clear?
- 50% by 7 years
* 90% by adulthood
What are the mild and severe allergic reactions to food?
Mild
• itchy lips and mouth
• angioedema
• urticaria
Severe • Nausea • Abdominal pain • Diarrhoea • Anaphylaxis
What is anaphylaxis and what are the symptoms?
Severe generalised allergic reaction - degranulation of IgE sensitised mast cells
• itchiness around mouth, pharynx and lips
• swelling of lips, throat, etc.
• wheeze, chest tightness and dyspnoea
• faintness
• diarrhoea and vomiting
• death if severe/untreated
What are the systemic effects in anaphylaxis
- CV - vasodilation, collapse
- Resp - bronchospam, laryngeal oedema
- Skin - vasodilation, erythema, urticaria, angioedema
- GI - vomiting and diarrhoea
How can allergies be investigated and diagnosed?
- Careful history
- Skin prick testing
- RAST (radio-allergosorbent test) - IgE blood test
- Measure total IgE
- Lung function (for asthma)
What is the emergency treatment for anaphylaxis?
- EpiPen and anaphylaxis kit
- Antihistamine (if mild)
- Adrenaline (if severe)
How can anaphylaxis be prevented (+ safety precautions)?
- Avoidance of known allergen
- Always carry an EpiPen and anaphylaxis kit
- Inform immediate family and caregivers
- Wear medicalert bracelet
What is the treatment for allergic rhinitis?
- Anti-histamines
- Nasal steroid therapy
- Cromoglycate (eye drops)
What is the treatment for eczema?
- Emollients
* Topical steroid cream
What is the treatment for allergic rhinitis/eczema if severe?
- Anti-IgE mAb
- Anti-IL4/13 mAb
- Anti-IL5 mAb
What is the treatment for asthma (4 steps)?
1) Short-acting beta-2 agonist by inhalation e.g. salbutamol
2) Inhaled steroid low-moderate dose e.g. beclomethasone, fluticasone
3) Add long-acting beta-2 agonist or leukotriene antagonist, or high dose inhaled steroids
4) Add courses of oral steroids and/or monoclonal antibodies
What is immunotherapy and when is it effective?
- Make people develop tolerance by exposing them to small amounts of the allergen
- Effective for single antigen hypersensitivities
- e.g. bee stings, pollens etc.
What are 2 types of immunotherapy?
- Subcutaneous immunotherapy (SCIT) - weekly/monthly 2hr clinic visits, 3 years
- Sublingual immunotherapy (SLIT) - can be taken at home, 2-3 years
