Hypersensitivity and Allergy Flashcards
what is the appropriate immune reaction against harmful foreign agents?
recognition, production and removal:
- involves the recognition of antigens by immune cells
- production of antibody
- eventual removal (of pathogens)
possible concomitant tissue damage to remove the pathogen but it can be repaired so we cool
what is the appropriate immune response to self and foreign harmless proteins?
what is produced to mediate this response?
tolerance to self and foreign harmless proteins like food
this involves generation of TReg cells and regulatory (blocking) antibody production (IgG4) for their recognition
– antigen recognition in the absence of danger leads to immune tolerance.
what are the two types of immune responses in the context of a danger signal?
1) reaction in the presence of danger signal
2) tolerance in the absence of danger signal (most)
what type of Ig is the regulatory Ig?
IgG4
what are the types of hypersensitivity reactions?
type 1-4 type 1: immediate hypersensitivity type 2: antibody dependant cytotoxicity type 3: immune complex mediated type 4: delayed cell mediated
many diseases involve a mix of the different hypersensitivity reactions
what 3 things are hypersensitivity reactions mounted against?
Harmless foreign antigens. E.G. pollen.
Auto-antigens (Auto-immune)
Allo-antigens (Transfusion reactions)
allo-antigens are present only in some individuals like ABO groups
what are the reactions that comes under type 1 hypersensitivity reactions?
Type 1 Immediate Hypersensitivity: o Anaphylaxis. o Asthma. o Rhinitis – seasonal and perennial (all year round) o Food allergies.
IgE involved
what are the two exposures that occur to causes type 1?
what occurs in them?
1st exposure – sensitisation, not tolerance.
- IgE AB production which binds to mast cells and basophils.
2nd exposure – more IgE produced
- antigens crosslink IgE on mast cells and basophils leading to degranulation and release of inflammatory mediators.
2nd one is worse
what does type 2 presentation depend on?
Anti-body (AB) Dependant Hypersensitivity is dependent on the target tissue i.e. organ specific
IgG involved
name the targets of the antibodies produced in: Myasthenia gravis Glomerulonephritis Pemphigus vulgaris Pernicious anaemia
o Myasthenia gravis–> Anti-ACh R AB.
o Glomerulonephritis –> Anti-glomerular basement membrane AB.
o Pemphigus vulgaris –> Anti-epithelial cadherin protein AB.
nb bullous pemphigoid is against basement protein
o Pernicious anaemia–> Intrinsic factor blocking AB.
name the AI cytopenias by AB-mediated blood cell destruction (type 2)
o Haemolytic anaemia.
o Thrombocytopaenia.
o Neutropenia.
NB type 2 targets organs or cell types
how can you test for specific antibodies involved in type 2 reaction?
o Immunofluorescence.
o ELISA
– e.g. anti-cyclic citrullinated peptide ABs (ACPA) in RA.
what occurs in type 3 reaction to eventually lead to tissue damage?
immune complex mediated
- the formation of antigen-AB complex
- this deposits in tissues
- leads to activation of complement
- recruitment of inflammatory cells and their activation
- cascades like clotting are activated
- results in tissue damage
what are the particular sites ,that tissue damage arises in,due to the deposition of immune complexes (type 3)?
vasculitis in kidneys, skin, joints and lungs
vasculitis is blood vessel destruction due to inflammation
E.g. SLE, vasculitides (plural vasculitis).
IgG involved (transferable to placenta)
give examples of disease with type 4 reactions
o Chronic graft rejection. o Graft-versus-Host disease (GVHD). o Coeliac disease. o Contact hypersensitivity. these are all Th1 mediated
o Others – asthma, rhinitis, eczema (Th2 mediated)
what are the mediators of type 4 reaction?
1) Th1–> IFNgamma, IL-2, FGF
FGF to stimulate fibroblasts (angiogenesis and fibrosis)
IFN to stimulate macrophages (release TNFalpha)
2) CTL
TNF and CTL make most damage
3) Th2–> IL-4,5,13 (allergic inflammation)
what are the different immune reactants involved the different hypersensitivity reactions?
type1- IgE
type2- IgG
type3- IgG
type4- Th1, Th2, CTL i.e. T cell mediated
what is the mechanism in type 4 reaction to cause tissue damage?
Transient or persistent antigen presence
- -> T-cell activation of macrophages, CTLs
- -> TNF-a damage
what are the solubilities of the antigens involved in the different types of hypersensitivity ?
type 1- soluble antigen
type 2- insoluble cell or matrix associated antigen
or cell surface receptor
type 3- soluble antigen
type 4- soluble antigen or cell-associated antigen
what are the features of inflammation?
o Vasodilation (Rubor-redness)
o Increased vascular permeability (Calor-heat)
o Inflammatory mediators and cytokine (Tumour-swelling)
o Inflammatory cells and tissue damage (Dolor-pain)
what cells does inflammation involve?
immune cells and cytokines
what effect do cytokines have?
name cytokines and chemokines involved in inflammation
increased vascular permeability
cytokines: IL-1, IL-2, IL-6, TNFalpha and IFNgamma
chemokines: IL-8 (CXCL8), IP-10 (CXCL10).
what are the cells that make the cellular infiltrate in inflammation?
Neutrophils, macrophages, lymphocytes and mast cells undergo chemotaxis and activate cells.
what are the cytokines that mediate the increase in vascular permeability?
C3a, C5a, histamine, leukotrienes
what is atopy?
a form of allergy in which there is a hereditary tendency to develop hypersensitivities.
Atopy is very common – 50% of young adults.
Severity ranges from mild to severe to life threatening
what are the genetic risk factors in allergy?
namely asthma, eczema and general atopy
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)
- asthma (IL-33, ORMDL3).
what are the environmental risk factor in allergy?
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. Animals – early exposure protects. Diet – breast feeding, anti-oxidants and fatty acids protects against atopy.
what are the genes involved in allergy pathology?
IL-4 gene cluster
Chr11q IgE Receptor –
eczema (filaggrin) and asthma (IL-33, ORMDL3).
what are the types of inflammation, according to the antibody that mediated it, in allergy?
- IgE mediated (Type 1 HYPr)
- IgG mediated (Type 2 HYPr)
- mixed inflammation (Type 1 and Type 4- chronic)
what are the inflammatory reactions in IgE mediated inflammation? i.e. type 2
Anaphylaxis
urticaria
angioedema
what are the inflammatory reactions in IgG mediated inflammation?
Idiopathic/chronic urticaria
examples of allergy with mixed hypersensitivities?
Asthma
rhinitis
eczema
type 1 and type 4
what is required for the expression of allergy?
Expression of disease requires development of sensitisation (not tolerance) at an atopic site i.e. vulnerable and then subsequent exposure
what occurs in sensitisation in atopic airway disease?
APC presents the allergen to the naïve T-cell which then becomes:
o Th1 cell (produce IFN-g).
o Th2 cell (lead to activation of B-cells).
o Treg cells (if presented with a harmless antigen).
what happens in the subsequent exposure in atopic airway disease? (2nd step)
APC presents the allergen to the Th2 memory cells which leads to:
o Degranulation of eosinophils via IL-5.
o Production of IgE plasma cells via IL-4, IL-13.
IgE then mobile onto the surface of mast cells and degranulate the mast cells.
describe eosinophils
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.
describe neutrophils
o Important in virus induced, severe and atopic asthma.
o 55-70% of blood leukocytes.
o Multi-lobed nuclei with digestive enzyme granules.
o Synthesise – oxidant radicals, cytokines and leukotrienes.
describe mast cells
what receptors do they have on the surface?
what do these cells cause?
o Tissue resident cells.
o IgE receptors on the cell surface (enable type 1 HySenR)
o Cross-linking with IgEs leads to release of inflammatory mediators
o Leads to acute inflammation.
what are the inflammatory mediators released as a result of cross linking go IgE in mast cells?
preformed and newly synthesised mediators
Pre-formed: • Histamine. • Cytokines. • Toxic proteins. Newly synthesised: • Leukotrienes. • Prostaglandins.
These lead to acute inflammation
which hypersensitivities is asthma a mix of?
how does peak expiratory rate change in asthma?
type 1 and type 4 hypersensitivities
there is an early response where Peak Expiratory Rate falls rapidly and then a late response where the fall is gradual
what do mast cells release to cause the airways to narrow in asthma?
Mast cell activation and degranulation releases histamines, prostaglandins (namely PGD2) and leukotrienes –>narrowing airway.
what is the mechanism in airway narrowing in asthma?
Vascular leakage – airway wall oedema. Mucus secretion – fills lumen. Smooth muscle contraction.
what are the pathological features in chronic asthma?
o Airway wall is grossly thickened with a narrow lumen.
o Cellular infiltrations of Th2 lymphocytes and eosinophils.
o Smooth muscle hypertrophy.
o Mucus plugging.
o Epithelial shedding.
o Sub-epithelial fibrosis
what are the clinically important features of asthma?
o Reversible airway obstruction –>chronic episodic wheeze.
o Bronchial hyperresponsiveness.
o Cough, mucus production, dyspnoea, chest tightness, responds to treatment, has spontaneous variation and a reduced PEF and VEF.
what are the two forms of rhinitis?
Seasonal – e.g. hay fever.
Perennial (long term)– e.g. perennial allergic rhinitis (house mites etc.).
what are the symptoms of rhinitis?
sneezing rhinorrhoea itchy nose & eyes nasal blockade sinusitis loss of smell/taste.
what are the features of allergic eczema?
Chronic itchy skin rash.
Found in the flexures of the arm and legs.
Can lead to house dust mite (HDM) sensitisation and dry cracked skin (HDMs through the cracked skin)
AE is complicated by bacterial and viral infections.
50% clear in 7 years and 90% clear by adulthood.
what type of hypersensitivity reaction is food allergy?
type 1
what are some common food allergies in infancy and children/adults?
o Infancy (3yo) – eggs and cow’s milk. o Children/adults – peanuts, shellfish, nuts, fruits, cereals, soya.
what are the mild and severe reactions in food allergy?
o Mild – itchy lips and mouth, angioedema, urticaria.
o Severe – nausea, abdominal pain, diarrhoea, anaphylaxis.
what does anaphylaxis mean?
a severe generalised allergic reaction, potentially fatal but uncommon, caused by generalised degranulation of IgE-sensitised mast cells
what are the symptoms of anaphylaxis?
- Itchiness at mouth
- Wheeze/chest tightness
- Diarrhoea & vomiting.
- Swelling of lips and throat
- Fainting/collapse
what systems can be affected by anaphylaxis?
o CVS – vasodilation, CVS collapse. o Respiratory – bronchospasm, laryngeal oedema. o Skin – vasodilation, erythema, urticaria, angioedema. o GI – vomiting and diarrhoea.
what are the investigations done to find allergies?
o Careful history. o Skin prick testing. o RAST – blood specific IgE ABs in blood. o Measure total IgE. o Lung functions (asthma).
what is the emergency treatment for anaphylaxis?
epi-pen and anaphylaxis kit – anti-histamine, steroids, adrenaline
what is the prophylaxis for anaphylaxis?
1) prevention:
- inform
- medicalert bracelet
- avoidance
2) emergency: emergency kits to hand
- anti-histamine
- steroids
- adrenaline
what is used to treat allergic rhinitis?
o Anti-histamines.
o Nasal steroid therapy.
o Cromoglycate – for children in the eyes.
what is used to treat eczema?
o Emollients – maintains moisture of skin.
o Topical steroid cream.
what is used as treatment if rhinitis and eczema are severe?
target their mediators:
anti-IgE, anti-IL-4/13, anti-IL-5 mAb.
what is the asthma treatment over time?
- Short-acting beta 2 agonist drugs
– salbutamol for mild asthma - Inhaled steroids (low-moderate dose):
- Beclomethasone/Budesonide.
- Fluticasone. - Add further therapy:
- Long-acting beta2 agonist or a leukotriene antagonist.
- High dose inhaled steroids. - Add courses of oral steroids.
- Prednisolone.
- Anti-IgE, anti-IL-4/13, anti-IL-5 mAb.
- SLIT and SCIT immunotherapy
- SLIT (2-3yrs course)
- SCIT (3 yr course weekly visits)
what hypersensitivity is immunotherapy useful for?
consider the antigen
single antigen hypersensitivities e.g. bee sting, pollens
What is the defect in eczema?
filaggrin
