1. Hypersensitivity and allergy Flashcards
What is an appropriate immune response?
Appropriate immune responses occur to foreign harmful agents such as viruses, bacteria, fungi and parasites
Involves antigen recognition by cells of the immune system and antibody production
What is appropriate immune tolerance? What does it involve?
Appropriate immune tolerance occurs to self, and to foreign harmless proteins such as food, pollens, other plant proteins, animal proteins, commensal bacteria
It involves antigen recognition and generation of regulatory T cells and regulatory (blocking) antibody (IgG4) production
What causes an appropriate immune response and what causes appropriate immune tolerance?
Antigen recognition in context of “danger” signals leads to immune reactivity, absence of “danger” to tolerance
When do hypersensitivity reaction occur?
Hypersensitivity reactions occur when immune responses are mounted against:
Harmless foreign antigens (allergy, contact hypersensitivity)
Autoantigens (autoimmune disease)
Alloantigens (serum sickness, transfusion reactions, graft rejection)
NOTE: alloantigen = an antigen present only in some individuals (e.g. of a particular blood group) and capable of inducing the production of an alloantibody in people that lack it
How are the different hypersensitivity reactions classified?
Type 1 - Immediate hypersensitivity
Type 2 - Antibody-dependent cytotoxicity
Type 3 - Immune complex mediated
Type 4 - Delayed celll mediated
Give examples of type 1 hypersensitivity reactions (immediate hypersensitivity)
Anaphylaxis
Asthma
Rhinitis – seasonal (pollen proteins) and perennial (all year round such as cats)
Food allergy
Give examples of some diseases that can be caused by type 2 hypersensitivity (antibody dependent hypersensitivity)
Organ specific autoimmune diseases: Myasthenia gravis (anti-acetylcholine receptor antibodies are formed causing muscle weakness) Glomerulonephritis (anti-glomerular basement membrane antibody which causes kidney inflammation) Pemphigus vulgaris (anti-epithelial cell cement protein antibody causes blistering of the skin) Pernicious anaemia (intrinsic factor blocking antibodies so vit B12 can't be absorbed)
Autoimmune cytopenias (antibody mediated blood cell destruction)
Haemolytic anaemia
Thrombocytopenia
Neutropenia
How would you test for specific antibodies? Give examples of conditions that can be caused by specific antibodies
Test for specific antibodies:
Immunofluorescence
ELISA (e.g. anti-CCP antibodies in rheumatoid arthritis)
Pemphigus vulgaris - due to autoimmune attack of an antibody that cements epithelial cells together
Bullous pemphigoid - another blistering skin disorder (antibodies are against basement membrane proteins) so the blisters tend to be a bit more robust because they are due to a deeper inflammation in the skin than pemphigus
What happens in Type 3 (Immune Complex Mediated) hypersensitivity? Give examples
Formation of antigen-antibody complexes in the blood
They can’t get through the small blood vessels very easily
These complexes become deposited in various tissues
It leads to complement activation and cell recruitment/activation
Activation of other cascades e.g. clotting
Tissue damage
Examples:
SLE (systemic lupus erytematosus)
Vasculitides (polyarteritis nodosa, many different types)
NOTE: vasculitides = plural of vasculitis
Most common sites of vasculitis: renal (glomerulonephritis), skin, joints and lung
What are some common diseases associatesd with type 4 delayed hypersensitivity?
Chronic graft rejection Graft-versus-host disease (GVHD) Coeliac disease Contact hypersensitivity Many others: asthma, rhinitis, eczema (these are Th2 mediated)
How are Th1 cells involved in type 4 delayed hypersensitivity responses?
Th1 - characterised by producing lots of gamma-interferon
Th1 is important in most hypersensitivity reactions:
An antigen is taken up by an APC and is taken up by a Th1 lymphocyte
This produces lots of interferon gamma which causes macrophage activation and the production of tumour necrosis factor (TNF) from the macrophage
Th1 also activates fibroblasts leading to angiogenesis and fibrosis
Th1 also causes IL-2 production which activates cytotoxic T cells (which damage/kill cells through producing perforin)
How are Th2 cells involved in type 4 delayed hypersensitivity responses?
Th2 releases:
IL-4
IL-5
IL-13
Th2 mediates allergic inflammation e.g. asthma, rhinitis and eczema
What are the mechanisms involved in delayed hypersensitivity responses?
Mechanisms involve either a transient antigen presence or a persistent antigen
T cells are activated (T helper cells 1 and 2)
T cells then activate macrophages and cytotoxic T cells
Much of the tissue damage is dependent upon TNF-alpha, hence why neutralising TNF-alpha has marked clinical benefits
What are the features of inflammation?
Vasodilation, increased blood flow
Increased vascular permeability
Inflammatory mediators and cytokines
Tissue damage
What are the signs of inflammation?
Redness
Heat
Swelling
Pain
What is the increased vascular permeability in inflammation caused by?
Complement activation such as C3a, C5a and also by histamine and leukotriene release
What are the cytokines involved in inflammation
IL-1 IL-2 IL-6 TNF IFN-gamma
What are chemokines and which ones are involved in inflammation
Cytokines that attract inflammatory cells
IL-8/CXCL8 and IP-10/CXCL10 are involved in inflammation
What are the major cell types involved in inflammation?
Neutrophils, macrophages, lymphocytes and mast cells recruited
What is atopy?
Atopy - a form of allergy in which there is a hereditary of constitutional tendency to develop hypersensitivity reactions (e.g. hay fever, allergic asthma, atopic eczema) in response to allergens (atopens). Individuals with this predisposition - and conditions provoked in them by contact with allergens - are described as atopic.
Atopy is very COMMON - about 50% in young adults in the UK
How are genes involved in atopy?
About 80% of atopics have a family history
The genetic component is polygenic
50-100 genes associated with asthma/atopy
Which genes are involved in atopy?
Genes of the IL-4 gene cluster (Chr 5) linked to raised IgE, asthma and atopy – this gene codes for IL4, IL5 and IL13 which are important cytokines involved in creating Th2 responses
Genes on chromosome 11q (IgE receptor) are linked to atopy and asthma
Genes linked to structural cells are linked to eczema (filaggrin) and asthma (IL-33, ORMDL3)
What are the environmental risk factors of atopy
Age - increases from infancy, peaks in teens, and reduces in adulthood
Gender - asthma is more common in:
Males - in childhood
Females - in adults
Family size - more common in small families
Infections - early life infections protect
Animals - early exposure protects
Diet - breast feeding, anti-oxidants and fatty acids protect
What are the different diseases that are related to the different types of hypersensitivity?
Anaphylaxis, urticaria, angioedema
Type 1 hypersensitivity (IgE mediated)
Idiopathic/chronic urticaria
Type 2 hypersensitivity (IgG mediated)
Asthma, rhinitis, eczema:
Mixed inflammation
Type 1 hypersensitivity (IgE mediated)
Type 4 hypersensitivity (chronic inflammation)
What is required in order for a disease to be expressed?
Development of sensitisation to allergens to sensitise instead of develop tolerance (primary response - usually early in life)
Exposure to produce disease (memory response - any time after first exposure)
How are T cells initially activated in atopic airway disease?
Under the epithelial surface there are dendritic cells that sample the allergens and present its peptides to T cells
The T cells are naïve before they have seen the antigen – they are unsure if they are tolerant or will be sensitised to the allergen
What happens to T cells in atopic airway disease after they have been activated?
Once the CD4+ T cells are activated by an antigen presenting cell, they then become specific to the presented antigen
They could become Th1 (producing IFN-gamma)
They could become Th2 cells that leads to the activation of B cells. Th2 cells proliferate upon the presentation of the allergen and cause the production of the cytokines IL4 and IL13.
These cytokines tell the B cells to produce IgE instead of IgG which will increase the immune response
If the T cell was presented with a harmless antigen, they can become regulatory T cells
What happens if there is subsequent exposure to the allergen?
The allergens are presented by APCs to the memory Th2 cells
These then cause degranulation of eosinophils by releasing IL-5
Th2 cells also release IL-4 and IL-13, which stimulate the production of IgE by plasma cells
The IgE then becomes mobilised onto the surface of mast cells
The antigens then cross-link with the IgE on the surface of the mast cells and cause mast cell degranulation
There is a massive release of inflammatory mediators, which gives rise to the effects seen in an allergic reaction
Outline the characteristics of eosinophils
0-5% of blood leukocytes
Present in the blood, but more reside in tissues
Recruited during allergic inflammation
Generated from bone marrow
Polymorphous nucleus - TWO lobes
Contains large granules full of toxic proteins
Leads to tissue damage
Outline the characteristics of mast cells
Tissue resident cells
Single lobes nucleus
Many granules int heir cytoplasm containing mediators of inflammation
They have IgE receptors on their cell surface
Crosslinking of IgE leads to mediator release
What are the different types of mediators released by mast cells? Give examples
Preformed mediators:
Histamine
Cytokines
Toxic proteins
Newly synthesised mediators:
Leukotrienes
Prostaglandins
Outline the characteristics of neutrophils
Important in virus induced asthma, severe asthma and atopic eczema
55-60% of blood leukocytes
Multilobed nucleus
Granules contain digestive enzymes
Neutrophils also synthesise:
Oxidant radicals
Cytokines
Leukotrienes
What type of hypersensitivity can asthma be classed as?
Type 1 + type 4
What is the mechanism behind an asthma attack?
Mast cell activation and degranulation releases histamines (pre-stored mediators) and prostaglandins and leukotrienes (newly synthesised mediators)
These lead to acute airway narrowing
What is airway narrowing in asthma caused by?
Vascular leakage leading to airway wall oedema
Mucus secretion fills up the lumen
Smooth muscle contraction around the bronchi
What features can be seen in chronic asthma?
The lumen of the airway is very narrow and the airway wall is grossly thickened
There will be cellular infiltration - Th2 lymphocytes and eosinophils
Smooth muscle hypertrophy
Mucus plugging causes a blockage of the airway
Epithelial shedding due to damage from CTL
Sub-epithelial fibrosis (if the inflammation has persisted for a long time)
What are the clinical features of asthma?
Reversible generalised airway obstruction - causes chronic episodic wheeze
Bronchial hyperresponsiveness (they are much more sensitive to bronchial irritants)
Cough
Mucus production
Breathlessness
Chest tightness
Responsive to treatment
Spontaneous variation
Reduced and variable peak expiratory flow (PEF)
What are the two kinds of allergic rhinitis?
Seasonal - e.g. hay fever (grass and tree pollens)
Perennial - perennial allergic rhinitis (e.g. house dust mites, animal allergens)
What are the symptoms of allergic rhinitis?
Sneezing
Rhinorrhoea (runny nose)
Itchy nose and eyes
Nasal blockage, sinusitis, loss of smell/taste
What are the characteristics and symptoms of allergic eczema?
Chronic itchy skin rash
Most commonly found in the flexures of the arms and legs
This can lead to house dust mite sensitisation - the house dust mite proteins can get through the dry, cracked skin much more easily than through healthy moist skin
Allergic eczema is complicated by bacterial and (rarely) viral infections (e.g. HSV)
50% clears by 7 years
90% cleared by adulthood
What type of a hypersensitivity reaction can a food allergy be classed as?
Type 1 (IgE mediated) hypersensitivity
How do food allergies change with age?
Infancy - 3 years:
Eggs
Cow’s milk
Children/adults: Peanuts Shellfish Nuts Fruits Cereals Soya
What are the symptoms of a food allergy?
Mild reaction:
Itchy lips and mouth
Angioedema
Urticaria
Severe reaction: Nausea Abdominal pain Diarrhoea Anaphylaxis
What is analphylaxis and what is it caused by?
Anaphylaxis = severe generalised allergic reaction
Anaphylaxis is uncommon and potentially fatal
There is generalised degranulation of IgE sensitised mast cells
What are the symptoms of anaphylaxis?
Itchiness around mouth, pharynx and lips
Swelling of the lips, throat and other parts of the body
Wheeze, chest tightness and dyspnoea
Faintness, collapse
Diarrhoea and vomiting
DEATH if severe and untreated
What are the systems involved in anaphylaxis?
Cardiovascular - vasodilation, cardiovascular collapse
Respiratory - bronchospasm, laryngeal oedema
Skin - vasodilation, erythema, urticaria, angioedema
GI - vomiting and diarrhoea
What are some methods of investigating and diagnosing an allergy?
Careful history is essential – this makes any food allergies obvious
Skin prick testing - solutions of allergen are placed on the skin and the skin is picked. There is a raised red area if the person is allergic (a wheel of 3mm is diagnostic of allergy)
RAST (radioallergosorbent test) - tests for the amount of specific IgE antibodies in the blood. Put different allergens on the sample and the one that binds to the IgE is causing the allergy
Measure total IgE
Lung function (in asthma)
How would you treat anaphylaxis
EpiPen and anaphylaxis kit
Emergency treatment if mild = antihistamine (this can be backed up with a steroid injection)
Emergency treatment if SEVERE = ADRENALINE
How would you try and prevent an anaphylactic reaction?
Avoidance of the known allergen
Always carry an anaphylaxis kit and EpiPen
Inform immediate family and caregivers
Wear a MedicAlert bracelet
What is used in the treatment of allergic rhinitis?
Anti-histamines (will help the sneezing, itching and rhinorrhoea)
Nasal steroid therapy (nasal decongestant) - needed if there is cell mediated inflammation instead of Th1 mediated as this does not involve histamine
Cromoglycate (in children, eyes) - inhibits mast cell degranulation
What is used in the treatment of asthma?
Emollients (maintain the moisture in skin thus reinforcing its barrier function)
Topic steroid cream
What has newly been used to treat severe allergic airway inflammation?
Monoclonal antibodies that target the mediators involved in the reactions:
Anti-IgE mAb
Anti-IL4/13 mAb
Anti-IL5 mAb
What are the different steps that are involved in the treatment of asthma?
STEP 1
Short-acting beta-2 agonist by inhalation
Example: SALBUTAMOL (the blue inhaler)
STEP 2
Inhaled steroid low-moderate dose – mainly an anti-inflammatory treatment
Beclomethasone/Budesonide (50-800 mg/day)
Fluticasone
STEP 3
Add further therapy
Add long-acting beta-2 agonist or a leukotriene antagonist
High dose inhaled steroids - up to 2 mg/day via a spacer
STEP 4
Add courses of oral steroids and azithromycin (an antibiotic)
Prednisolone 30 mg/day for 7-14 days
Anti-IgE, Anti-IL4/13, Anti-IL5 mAbs
What is immunotherapy? Give examples
Make people develop tolerance by exposing them to small amounts of the allergen that they are allergic to and then slowly build this up to higher doses. Your immune system will think the allergen is harmless and stop reacting
Effective for single antigen hypersensitivities
E.g. venom allergies (bee or wasp stings), pollens, house dust mites
The antigen used is purified
Subcutaneous immunotherapy (SCIT) - 3 years needed (weekly/monthly 2 hr clinic visits)
Sublingual immunotherapy (SLIT) - can be taken at home, 2-3 years enough
