Hypersensitivity & Allergy Flashcards
• Explain Appropriate Immune Tolerance
Can occur to SELF & FOREIGN harmless proteins - involves:
• antigen recognition
• generation of T-reg cells
• regulatory (blocking) Ab production (IgG4)
Antigen recognition in absence of “danger” = immune tolerance
Broadly, give the classifications of Hypersensitivity Reactions
Classified by Gell & Coomb:
o Type 1
• Immediate Hypersensitivity (allergic)
o Type 2
• Ab-dependent Cytotoxicity
o Type 3
• Immune Complez Mediated
o Type 4
• Delayed Cell Mediated
Explain against what are hypersensitivity reactions responding to?
Hypersensitivity reactions occurs when responses are mounted against:
Harmless foreign antigens
• e.g. pollen
Auto-antigens
• e.g. Auto-immune
Allo-antigens
• e.g. transfusion reactions
Allo-antigens are antigens present in only SOME individuals (i.e. ABO blood groups).
Note – many diseases involve a mixture of the different types of hypersensitivity reactions
What is Type 1 hypersensitivity mediated by and examples?
Mediated by:
IgE
Example: • Anaphylaxis • Asthma • Rhinitis • Food Allergy
Explain how Type 1 hypersensitivity comes about
1st exposure:
• SENSITISATION rather than tolerance
• IgE AB production = binds to mast cells and basophils
2nd exposure:
• MORE IgE produced
• antigens crosslink IgE on mast cells and basophils = degranulation = release of inflammatory mediators
What is Type II hypersensitivity mediated by and what does clinical presentation depend on?
Mediated by:
• Abs responding to cell-surface OR matrix-bound antigen (INSOLUBLE)
Clinical Presentation depends on TARGET TISSUE
Give examples of Clinical presentations in Type II Hypersensitivity
Organ-specific AI diseases - reactions associated with Abs directed against:
- Anti-ACh R AB –> Myasthenia gravis
- Anti-glomerular basement membrane AB –> Glomerulonephritis
- Anti-epithelial cell cement protein AB –> Pemphigus vulgaris
- Intrinsic factor blocking AB –> Pernicious anaemia
AI cytopaenias – AB-mediated blood cell destruction:
- Haemolytic anaemia.
- Thrombocytopaenia.
- Neutropenia
What tests can you carry out for Type II Hypersensitivity to test for specific Abs?
(1) Immunofluorescence
(2) ELISA
• e.g. anti-CCP (Cyclic-Citrullinated Peptide) Abs for RA
What is Type III hypersensitivity mediated by and what does this result in?
Mediated by:
• antigen-Ab complexes
Abs respond to SOLUBLE antigens
• these can NOT traverse vessel walls very easily
SO
• are DEPOSITED in various TISSUES
Explain what the deposition of the antigen-Ab complexes in the various tissues leads to in Type III Hypersensitivity
Leads to:
• complement activation
&
• cell recruitment
Leads to activation of cascades such as clotting & leads to tissue damage:
• e.g. SLE
• e.g. Vasculitis (in kidneys, skin, joints, lungs)
What is Type IV hypersensitivity mediated by and examples?
Mediated:
• T-cells
Examples: • Chronic GRAFT rejection • Chronic graft rejection • Graft-versus-Host disease (GVHD) • Coeliac disease • Contact hypersensitivity • Allergic inflammation – asthma, rhinitis, eczema
Explain the mechanisms of Type IV Hypersensitivity Responses
Three main Varieties:
• Th1 - produces lots of GAMMA-IFN (activates macrophages - producing TNF-a which causes tissue damage)
- Cytotoxic
- Th2 - releases IL-4/5/13 (allergic inflammation)
Mechanisms:
• transient or persistent antigen presence = T-cell activation of macrophages & CTLs = TNF-a damage
Nickel and hypersensitivity?
Nickel can cause a Type IV Hypersensitivity
• CONTACT HYPERSENSITIVITY
What causes inflammation?
CYTOKINES released by the immune cells leads to features of inflammation
Cytokines which INCREASE PERMEABILITY include:
• C3a, C5a
• histamine
• leukotrienes
Other cytokines involved:
• IL-1/2/6
• TNF
• IFN-gamma
Also brought about by CHEMOKINES which mediate cell-trafficking:
• neutrophils, macrophages, lymphocytes & mast cells undego chemotaxis & active cells
• IL-8
• IP-10
Define Atopy
Form of Allergy
Hereditary/constitutional tendency to develop hypersensitivity reactions
• e.g. hay fever, allergic asthma, atopic eczema
Severity varies:
• Mild - occasional symptoms
• Severe - chronic asthma
• Life threatening - anaphylaxis
What are the broad Risk Factors for Allergies?
(1) Genetic
(2) Envrionmental
Explain the Genetic Risk Factor for Allergies
Genetic – 80% of atopies have a family history:
• Polygenic
50-100 genes are associated with asthma and atopy
IL-4 gene cluster – Chr5
• linked to raised IgE, asthma and atopy.
Chr11q IgE Receptor
• genes linked to atopy and asthma.
Genes linked to eczema (filaggrin) and asthma (IL-33, ORMDL3).
Explain the Envrionmental Risk Factor for Allergies
Age
• increases in infancy to a peak in teens and then drops into adulthood.
Gender
• more common in males (childhood) and females (adulthood).
Family size
• more common in small families.
Infections
• lends to early life protection from infections
Animals
• early exposure protects against them
Diet
• breast feeding, anti-oxidants and fatty acids protects against atopy.
What are some types of inflammation in allergy and the associated hypersensitivity reaction?
T1-hypersensitivity (IgE-mediated):
• Anaphylaxis
• Urticaria
• Angioedema
T2-hypersensitivity (IgG-mediated):
• Idiopathic/chronic urticaria
Mixed T1 (IgE), T4 (chronic inflammation) hypersensitivity:
• Asthma
• Rhinitis
• Eczema
What does Expression of Disease require?
Requires:
• development of sensitisation to allergens INSTEAD of tolerance (1o response - usually in early life)
• further allergen exposure to produce disease (memory response - any time after sensitisation)
Explain the Expression of Disease in Atopic Airway Diseases - FIRST STEP?
SENSITISATION!
APC presents the allergen to the naïve T-cell which then becomes: • Th1 cell (produce IFN-g). • Th2 cell (lead to activation of B-cells). • Treg cells (if presented with a harmless antigen).
Explain the Expression of Disease in Atopic Airway Diseases - SECOND STEP?
SUBSEQUENT EXPOSURE!
APC presents the allergen to the Th2 memory cells which leads to: • Degranulation of eosinophils via IL-5. • Production of IgE plasma cells via IL-4, IL-13.
IgE then mobile onto the surface of mast cells and degranulate the mast cells.
• mediators released inc. histamine, cytokines, leukotrienes, PGs
Main Allergic Cell Mediators?
Eosinophils
Neutrophils
Mast Cells
Explain Eosinophils as Allergic Cell Mediators
o 2-5% of blood leukocytes.
o Present in the blood but most are in the tissue
o Recruited during allergic inflammation.
o Generated from bone marrow.
o Have polymorphic nuclei – bi-lobed.
o Have large granules full of toxic proteins.
Explain Neutrophils as Allergic Cell Mediators
Important in
• virus induced
• severe & atopic asthma
o 55-70% of blood leukocytes.
o Multi-lobed nuclei with digestive enzyme granules.
Synthesise: • oxidant radicals • cytokines and • leukotrienes
Explain Mast Cells as Allergic Cell Mediators
Tissue resident cells.
IgE receptors on the cell surface:
• cross-linking with IgEs leads to release of inflammatory mediators:
Pre-formed:
• Histamine.
• Cytokines.
• Toxic proteins.
Newly synthesised:
• Leukotrienes.
• Prostaglandins.
o Leads to ACUTE inflammation.
Explain Acute Asthma
Asthma is a mixture of T1 and T4 hypersensitivities:
• Mast cell activation & degranulation releases histamines, prostaglandins and leukotrienes = narrowing airway
Airway narrowing caused by:
Vascular leakage – airway wall oedema.
Mucus secretion – fills lumen.
Smooth muscle contraction.
o There is a two-phase response to single allergen challenges with an early and then late response.
Explain Chronic Asthma
o Airway wall is grossly thickened with a narrow lumen.
o Cellular infiltrations of Th2 lymphocytes and eosinophils.
o Smooth muscle (SMC) hypertrophy.
o Mucus plugging.
o Epithelial shedding.
o Sub-epithelial Fibrosis
Important clinical features of Asthma?
•
o Reversible airway obstruction
• = chronic episodic wheeze
o Bronchial hyperresponsiveness
o Cough, dyspnoea, chest tightness
o mucus production
o responds to treatment, BUT has spontaneous variation
o a REDUCED PEF and VEF.
What are the symptoms of Allergic Rhinitis
Seasonal
• e.g. hay fever
Perennial
• e.g. perennial allergic rhinitis (house mites etc.)
Symptoms: • sneezing • rhinorrhoea • itchy nose & eyes • nasal blockade • sinusitis • loss of smell/taste
Explain Allergic Eczema
Chronic itchy skin rash
• found in flexures of the arm & legs
Can lead to house dust mite (HDM) sesitisation & dry cracked skin
• HDMs through cracked skin
It is complicated by bacterial & viral infections
Explain what type of allergy food allergies are, the common ones and the reaction types you can get
Type I Hypersensitivity Reaction
Common food allergies change with age:
• Infancy (3yo) – eggs and cow’s milk.
• Children/adults – peanuts, shellfish, nits, fruits, cereals, soya.
Reaction types:
• Mild – itchy lips and mouth, angioedema, urticaria.
• Severe – nausea, abdominal pain, diarrhoea, anaphylaxis.
General information regarding anaphylaxis
A severe generalised allergic reaction:
Uncommon but are potentially fatal.
Caused by generalised degranulation of IgE-sensitised mast cells.
Symptoms of anaphylaxis?
o Itchiness at mouth. o Wheeze/chest tightness. o Diarrhoea & vomiting. o Swelling if lips & throat o Fainting/collapse. o Death.
What systems can be affected in anaphylaxis?
o CVS
– vasodilation, CVS collapse
o Respiratory
– bronchospasm, laryngeal oedema.
o Skin
– vasodilation, erythema, urticaria, angioedema.
o GI
– vomiting and diarrhoea.
What investigations and diagnosis can be done to detect allergies?
o Skin prick testing. o RAST – blood specific IgE ABs in blood. o Measure total IgE. o Careful history. o Lung functions (asthma).
What is the treatment in place for Anaphylaxis?•
Emergency:
• epi-pen & anaphylaxis kit
– anti-histamine (mild), steroids, adrenaline (severe)
Prevention: • avoidance • emergency kits to hand • inform • medicalert bracelet.
Treatment for Allergic Rhinitis?
o Anti-histamines.
o Nasal steroid therapy.
o Cromoglycate – for children in the eyes.
Treatment for Eczema?
o Emollients – maintains moisture of skin
• reinforces barrier function
o Topical steroid cream.
If either Allergic Rhinitis or Eczema is severe, what can be given?
Anti-IgE
Anti-IL4/13
Anti-IL5
mAbs!!
Treatment for Astham?
Astham: 4 Steps:
- Short-acting beta2 agonist drugs
• SALBUTAMOL - Inhaled steroids (low-moderate dose):
(a) Beclomethasone /Budesonide
(b) Fluticasone.
- Add further therapy:
(a) Long-acting beta2 agonist (bronchodilators) OR a leukotriene antagonist.
(b) High dose inhaled steroids.
- Add courses of oral steroids.
(a) Prednisolone.
(b) Anti-IgE, anti-IL-4/13, anti-IL-5 mAb.
Explain how Immunotherapy works for Allergies and Asthma
Effective for SINGLE ANTIGEN hypersensitivities
• induces tolerance by exposure to very small amounts of purified antigens
• e.g. venom allergy, pollens, HDM
Given SUBCUTANEOUSLY
• 3 years needed
• weekly/monthly 2hr clinic visits
Can also recieve it SUBLINGUALLY
• can be taken at home
• 2-3years is enough
