1 - Hypersensitivity and Allergy Flashcards
When do appropriate immune responses occur?
Appropriate immune responses occur to foreign harmful agents such as:
- viruses
- bacteria
- fungi
- parasites
Required to eliminate pathogens
May be concomitant tissue damage as a side effect, but as long as pathogen is eliminated quickly will be minimal and repaired easily
Involves antigen recognition by cells of the immune system and antibody production
When do hypersensitivity reactions occur?
Hypersensitivity Reactions occur when immune responses are mounted against:
- Harmless foreign antigens
- allergy
- contact hypersensitivity
- Autoantigens (self antigens)
- autoimmune diseases
- Alloantigens (foreign antigens)
- serum sickness
- transfusion reactions
- graft rejection
How are hypersensitivity reactions classified?
Classified by Gell & Coombs:-
- Type I : Immediate Hypersensitivity
- Type II : Antibody-dependent Cytotoxicity
- Type III : Immune Complex Mediated
- Type IV : Delayed Cell Mediated
Each involves distinct parts of the immune system reacting
NOTE: many diseases involve a mixture of types
What hypersensitivity conditions are classified as Type 1?
Anaphylaxis
Asthma
Rhinitis
- Seasonal
- Perennial (year-round)
Food Allergy
What events lead to a Type 1 hypersensitivity reaction?
STEP 1: PRIMARY Antigen Exposure
- Sensitisation not tolerance
- In allergy, you develop sensitisation
- If no allergy, you develop tolerance
- IgE antibody production
- IgE binds to Mast Cells & Basophils
STEP 2: SECONDARY Antigen Exposure
- More IgE Ab produced
- Antigen cross-links IgE on Mast Cells/Basophils
- Degranulation
- Allergic reaction ensues
What does the clinical presentation of Type 2 hypersensitivity depend on?
Clinical presentation depends on target tissue
What conditions are classified as Type 2 hypersensitivity?
Organ-specific autoimmune diseases
- Myasthenia gravis (Anti-acetylcholine R Ab)
- Glomerulonephritis (Anti-glomerular basement membrane Ab)
- Pemphigus vulgaris (Anti-epithelial cell cement protein Ab)
- Pernicious anaemia (Intrinsic factor blocking Abs)
Autoimmune cytopenias (Ab mediated blood cell destruction)
- Haemolytic anaemia
- Thrombocytopenia
- Neutropenia
How do you test for Type 2 hypersensitivity?
Type 2 = Antibody-Dependent Hypersensitivity
Test for specific autoantibodies
- Immunofluorescence
- ELISA e.g. anti-CCP (Cyclic Citrullinated Peptide Abs for Rheumatoid Arthritis)
What is Type 3 Hypersensitivity?
TYPE 3 = Immune Complex Mediated Hypersensitivity
- Formation of Antigen-Antibody complexes (immune complexes) in blood
- Complex deposition in blood vessels/tissue
- Complement & cell activation in site where complexes have been deposited
- Activation of other cascades egclotting
- Tissue damage (vasculitis)
- Systemic lupus erythematosus (SLE)
- Vasculitides (Poly Arthritis Nodosum, many different types)
In what conditions do you get Type 4 Hypersensitivity responses?
TYPE 4 = DELAYED HYPERSENSITIVITY RESPONSES
Th1 Mediated
- Chronic graft rejection
- GVHD
- Coeliac disease
- Contact hypersensitivity (on the skin)
- Many autoimmune diseases….
Th2 Mediated
- Asthma
- Rhinitis
- Eczema
What is the mechanism behind Type 4 Hypersensitvity responses?
THREE MAIN VARIETIES OF THESE RESPONSES
- Th1
- Cytotoxic
- Th2
MECHANISMS
Th1 Mechanism
Antigen taking up by Antigen-Presenting Cell
Presented to Th1 cell
Produces lots of IFN-γ
This leads to:
- Macrophage activation and then TNF production
- Activates fibroblasts, leading to angiogenesis and fibrosis
- Leads to IL-2 production which activates CTLs which produce proteins perforin which kills cells
General Mechanism
Transient/Persistent Ag
T cell activation of macrophages, CTLs
Much of tissue damage dependent upon TNF and CTLs
What is Type 4 Hypersensitivity?
Delayed Hypersensitivity Responses
Give an example of a Type 4 Delayed-Type Cell-Mediated Hypersensitivity response
Nickel
- Contact Hypersensitivity
Summarise the different forms of hypersensitivity reactions
What are the features of inflammation?
IMMUNE CELL
- recruitment to sites of injury/infection
- activation
INFLAMMATORY MEDIATORS
- complement
- cytokines
- etc.
Features of Inflammation
Vasodilatation (increased blood flow)
Increased vascular permeability
Inflammatory mediators and cytokines
Inflammatory cells and tissue damage
What are the signs of inflammation?
Redness
Heat
Swelling
Pain
What occurs in inflammation?
Immune cell recruitment to sites of injury and/or infection
Immune cell activation
Inflammatory mediators also have a role e.g. complement, cytokines etc.
What cytokines are pro-inflammatory?
- IL-1
- IL-6
- IL-2
- TNF
- IFN-γ
What chemokines are involved in attracting inflammatory cells?
- IL-8/CXCL8
- IP-10/CXCL10
What caused increased vascular permeability in inflammation?
Caused by:
- C3a
- C5a
- Histamine
- Leukotrienes
By what mechanisms do inflammatory cells infilitrate tissues?
Cell Trafficking (Chemotaxis)
- Neutrophils
- Macrophages
- Lymphocytes
- Mast Cells
Cell Activation
List some common allergens
Animal fur
Pollen
House dust mites
What is atopic?
Denoting a form of allergy in which a hypersensitivity reaction such as eczema or asthma may occur in a part of the body not in contact with the allergen.
Outline the prevalence of atopy in UK
Prevalence of atopy is 50% in young adults in UK
Explain how the severity of atopy can differ
SEVERITY CAN VARY
Mild
- e.g. occasional symptoms
Severe
- e.g. chronic asthma
Life-Threatening
- e.g. life threatening anaphylaxis
What are the overall risk factors for allergy?
Genetic
Environmental
Outline genetic risk factors that can cause allergies
80% of atopics have a family history
Polygenic
- 50-100 genes liked to ashtma/atopy
- genes of IL-4 gene cluster (chromosome 5) linked to raised IgE, asthma, atopy
- genes on chromosome 11q (IgE receptor) linked to atopy and asthma
- genes liked to structural cells linked to eczema (flaggrin) and asthma (IL-33, ORMDL3, CDHR3)
Outline environmental risk factors that can cause allergies
AGE
- increases from infancy
- rare in infancy
- peaks in teens
- reduces in adulthood
GENDER
- asthma more common in males in childhood and females in adults
FAMILY SIZE
- more common in small families
- only child has higher risk of allergy/asthma
INFECTIONS
- early life infections are protective
ANIMALS
- early exposure is protective
- children that grow up on farms have very low incidence of allergies
DIET
- breast-feeding = protective
- anti-oxidants = protective
- fatty acids = protective
What is happening to the prevalence of allergies in the UK?
Allergies are increasing in the UK
- asthma, hayfever and eczema have all increased
- believed to be due to environmental changes
- especially, decreased infectious disease incidence
What are the types of inflammation in allergy?
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 does expression of atopy 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)
DIAGRAM:
Lumen of the airway depicted
Smooth muscle cells lining airway
Dendritic cells just under surface of epithelium
- Sample allergens using their processes
- Process allergen
- Present peptides from allergen
Presented to naive T cells
Tolerance: Becomes Treg cell
Autoimmunity: Th1 response
Allergy (Sensitisation): Th2 response
Th2 response (Allergy)
Th2 cells proliferate
Cytokines IL-4 and IL-13
These cytokines tell B cells to produce IgE instead of IgG
IgE is specific to the peptide allergen
IgE binds to plasma cells
More IgE producion
Subsequent Exposure
IgE already being produced and present on mast cells
Intake of allergen
Allergen peptide presented by dendritic cells
T cells become Th2
More IL-4 and IL-13
More IgE
IL-5 also produced which leads to eosinophil recruitment and activation
Eosinophils produce mediators of inflammation
This combines with mast cell response which is degranulation and inflammatory mediator recruitment
Expression of allergic disease
SENSITISATION NOT TOLERANCE
What are eosinophils?
0-5% of blood leukocytes
Present in blood, most reside in tissues
Recruited during allergic inflammation
Generated from bone marrow
Nucleus
- two lobes
Contain large granules
- toxic proteins
Lead to tissue damage
What are mast cells?
Tissue resident cells
IgE receptors on cell surface
Crosslinking of IgEs leads to:
Multiple granules in cytoplasm
- Mediator release
- Pre-formed:
- histamine
- cytokines
- toxic proteins
- Newly synthesized:
- leukotrienes
- prostaglandins
- Pre-formed:
What are neutrophils?
Important especially in:
- virus induced asthma
- severe asthma
- atopic eczema
55-70% of blood leukocytes
Polymorphonuclearcells (PMNs)
- nucleus contains several lobes
Granules contain
- digestive enzymes
Also synthesize
- oxidant radicals
- cytokines
- leukotrienes
What is the immunopathogenesis of asthma?
Acute inflammation of the airways
- Mast Cell Activation and Degranulation
- Pre-stored mediators
- histamine
- Newly synthesised mediators
- prostaglandins
- leukotrienes
- Acute airway narrowing
- Airway wall oedema
Outline the two-phase response to single allergen challenge
Initially, PEF is still lower than average due to pre-exisiting condition (e.g. asthma)
Pathogen inhalation
Acute rapid response due to:
- Mast cell activation
- Degranulation
- Mediators:
- Prostaglandins
- Histamine
- Leukotrienes
- These cause airway narrowing due to:
- Mucus
- Smooth muscle
- Oedema
This recovers fairly rapidly within an hour
Then there’s another late response without inhalation of the allergen as a cell-mediated response
- Lymphocyte driven inflammation
- Eosinophil driven inflammation
Occurs 2-8 hours after a single large-dose inhalation
What are the important clinical features of asthma?
Reversible generalised airway obstruction
- chronic episodic wheeze
Bronchial hyperresponsiveness
- bronchial irritability
Cough
Mucus production
Breathlessness
Chest tightness
Response to treatment
Spontaneous variation
- due to variation in allergen exposure
Reduced and variable peak flow (PEF)
Outline the daily PEF of a person with poorly controllled asthma
Use inhaler in order to increase PEF
Exercise decreases PEF
PEF decreases during sleep normally due to house dust-mites
What can cause allergic rhinitis?
SEASONAL
- hay-fever (grass, tree pollens)
PERENNIAL (year-round)
- perennial allergic rhinitis (HDM, pets)
What are the symptoms of allergic rhinitis?
Sneezing
Rhinorrhoea
Itchy nose
Itchy eyes
Nasal blockage
Sinusitis
Loss of smell/taste
What is allergic eczema?
Chronic itchy skin rash
- Common in flexures of arms and legs
House dust-mite sensitisation
- HDMs can enter dry cracked skin so this makes it worse
- HDM sensitisation and dry cracked skin
Complicated by bacterial and (rarely) viral infections (early childhood, herpes simplex)
50% clears by 7 years
90% by adulthood
What percentage of allergic eczema cases are cleared by the age of 7 and what percentage by adulthood?
50% cleared by 7 years old
90% cleared by adulthood
What forms of food allergy most commonly affect infants and children/adults?
INFANTS (3 YEARS)
- eggs
- cows milk
CHILDREN/ADULTS
- peanuts
- nuts
- shell-fish
- fruits
- cereals
- soya
What are the symptoms of mild food allergies?
Itchy lips
Mouth
Angiodema
Urticaria (generalised all over body)
What are the symptoms of severe food allergies?
Nausea
Abdominal Pain
Diarrhoea
Collapse
Wheeze
Anaphylaxis
What is anaphylaxis?
Severe generalised allergic reaction
Uncommon
Potentially fatal
What causes anaphylaxis biologically?
Generalised degranulation of IgE sensitised mast cells
What are the symptoms of anaphylaxis?
Itchiness around:
- mouth
- pharynx
- lips
Swelling of:
- lips
- throat
- other parts of body
Wheeze
Chest tightness
Dyspnoea
Faintness
Collapse
Diarrhoea
Vomiting
Death (if severe and untreated)
What is the effect of anaphylaxis on different body systems?
CARDIOVASCULAR
- vasodilatation
- cardiovascular collapse
RESPIRATORY
- bronchospasm
- laryngeal oedema
SKIN
- vasodilatation
- erythema
- urticaria
- angioedema
GI
- vomiting
- diarrhoea
How are allergies investigated and diagnosed?
Careful history is essential
Skin-prick testing
- Wheel of 3mm is diagnostic of allergy
- Flare surrounds the wheel
RAST (blood specific IgE):
- Total IgE - not very specific
- Lung function (asthma)
How do you treat anaphylaxis?
EMERGENCY TREATMENT
EpiPen and Anaphylaxis Kit
- antihistamine
- steroid
- adrenaline (epinephrine)
Then seek immediated medical aid
How do you prevent anaphylaxis?
Avoidance of known allergen
Always carry a kit and EpiPen
Inform immediate family and caregivers
Wear a MedicAlert bracelet
How do you treat rhinitis and eczema?
ALLERGIC RHINITIS
- anti-histamines (sneezing, itching, rhinorrhea)
- nasal steroid spray (nasal blockage)
- cromoglycate (children, eyes)
ECZEMA
- emollients (keep skin barrier healthy without cracking so HDMs can’t enter)
- topical steroid cream
IF SEVERE:
- anti-IgE
- anti-IL-4
- anti-IL-13
- anti-IL-5 mAb
These are very effective, however they are also very expensive. Therefore, they are restricted to severe disease.
Outline asthma treatment
STEP 1
Use short-acting β2 agonist drugs as required by inhalation
- Salbutamol
STEP 2
Inhaled steroid low-moderate dose
- Beclomethasone/Budesonide (50-800μg per day)
- Flucticasone (50-400μg per day)
STEP 3
Add further therapy
- Long-acting bronchodilators, leukotriene antagonist
- High dose inhaled steroids - up to 2mg per day via a spacer
STEP 4
Add course of oral steroids, SLIT, azithromycin
- Prednisolone - 30mg daily for 7-14 days
- Anti-IgE, Anti-IL-5, Anti-IL-4/-13 monoclonal Abs
What is immunotherapy effective for?
Effective for single antigen hypersensitivities
- Venom allergy - bee or wasp stings
- Pollens
- HDM
This is done via subcutenous injection
Build it up from low dose to high dose
Helps to build tolerance
Need to do the subcutaneous version it for 3 years to build good tolerance
Antigen used is purified
What is SCIT?
Subcutaneous Immunotherapy (SCIT)
- 3 years needed
- weekly/monthly 2 hour clinic visits
- still relatively expensive
What is SLIT?
Sublingual Immunotherapy (SLIT)
- Can be taken at home
- 3 years needed
When does appropriate immune tolerance occur?
Appropriate immune tolerance occurs to self, and to foreign harmless proteins:
- food
- pollens
- other plant proteins
- animal proteins
- commensal bacteria
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 kinds of responses would someone with asthma undergo daily?
Mixture of early Type 1 response and ongoing late, cell-mediated response at the same time
What are the features of asthma?
Chronic inflammation of the airways
Cellular infiltrate
- Th2 lymphocytes, eosinophils
Smooth muscle hypertrophy
Mucus plugging
Epithelial shedding
Sub-epithelial fibrosis
This is all in addition to ongoing acute inflammation features
What is rhinorrhea?
Runny nose
Nasal cavities filled with mucus
