Lecture 23 - Allergies II Flashcards
Compare the following in the two phases of allergic reactions:
• Onset
• Due to…
• Brings about…
- Immediate reaction
• Seconds to minutes
• Due to release of pre-formed mediators in mast cell granules (histamine, tryptase)
• Short lived (histamine rapidly removed from system)
• Brings about:
- Vascular leakage (increased permeability and dilation)
- (Transient) bronchoconstriction
- Gastric hyper motility
2. Late phase reaction • Hours (peaks after 8-12 hours) • Due to de novo generation of cytokines & arachidonic acid metabolites • Brings about: - Sustained bronchoconstriction - Sustained vascular leakage - Inflammatory cell infiltration
List examples of different manifestations of atopy
Food allergy
Cutaneous allergy
Respiratory allergic responses
Describe the prevalence of various forms of atopy in different age groups
0-4 yrs:
• Highest rates of eczema and food allergy
3-8:
• Highest rates of asthma
11+:
• Highest rates of allergic rhinitis
Allergic asthma, eczema and food allergy tend to resolve after the first decade of life
Allergic rhinitis is far less common in the first decade of life
Describe the generation of cutaneous reactions
- Allergen introduced to skin
- IgE cross linking on mast cells
- Immediate reaction (wheal and flare)
• Blood vessels dilate → rubor, engorgement of RBCs
• Increased vascular permeability → tumour (tissue oedema) - Late phase response: (4-6 hrs)
• Extensive inflammatory cell infiltrate → induration
List two cutaneous reactions
Urticaria
Eczema
Describe the pathogenesis of urticaria
What mediates this reaction?
- Ingestion of allergen
- Allergen absorbed into bloodstream
- Allergen circulates to skin
- IgE cross linking on mast cells in skin
→ degranulation, histamine release - Patchy, but widespread wheals on skin
Predominantly mediated by histamine
Describe the pathogenesis of eczema
What mediates this reaction?
Chronic inflammatory response to allergen in skin
Pathogenesis:
• Similar to allergic asthma in airways:
→ Fibrosis, tissue remodelling
Predominantly mediated by cytokines
Compare the factors that mediate urticaria and eczema
Urticaria: histamine
Eczema: cytokines
What is the inherited component of eczema?
Filaggrin deficiency linked to eczema
Filaggrin: protein that maintains skin integrity
List the various responses that can occur in food allergy
What determines which happens?
Response depends on which mast cells are activated
Urticaria
• Skin mast cells activated
Vomiting / diarrhoea
• Gastric mucosal mast cells activated
Systemic anaphylaxis
• Widespread connective tissue and mucosal mast cells activated
List the various respiratory allergic responses
Allergic rhinitis
Allergic asthma
Describe the pathogenesis of allergic rhinitis
What are the symptoms?
How can it be treated?
(aka hay fever)
- Allergen introduced into upper airways
- Crosslinking of IgE on mast cells beneath nasal epithelium → degranulation
- Immediate phase response
Symptoms: • Sneezing • Itching • Local oedema • Mucus secretion
Therapy:
• Anti-histamines
Describe the pathogenesis of allergic asthma
- Allergen introduced into lower airways
- Allergen cross linking on IgE bound to mast cells under bronchial epithelium → degranulation
- Immediate phase response:
• Immediate bronchoconstriction
• Immediate mucus secretion - Late phase response:
• Inflammatory cell infiltrate (eosinophils)
• Subepithelial collagen deposition
• Persistent bronchoconstriction
• Epithelial damage
• Goblet cell metaplasia
• Mucus gland hyperplasia
• Bronchial smooth muscle hypertrophy - Tissue remodelling and fibrosis
Why must one specify ‘allergic’ asthma?
Because asthma can be induced by a number of triggers: • Cold • Stress • Exercise • Drugs etc.
Describe the role of leukotrienes in the allergic response
Newly synthesised (thus part of the late phase response)
Bind to receptors on:
• Endothelium → vascular leakage
• Bronchial smooth muscle → sustained bronchoconstriction
How are allergies treated?
Specify which reactions the drugs are used for
- Adrenaline
• Anaphylaxis, asthma
• e.g. Epipen - Anti-histamines
• Allergic rhinits, urticaria
• Block histamine receptors, preventing oedema and itching
• e.g. Telfast
3. Inhaled β2-ADR agonists • Asthma • LABA = controller • SABA = reliever • Results in relaxation of bronchial smooth muscle • e.g. Ventolin (albuterol)
- Leukotriene receptor antagonists
• Allergic rhinitis, asthma
• Bind and block receptors on smooth muscle and endothelium
• e.g. Singulair - Corticosteroids
• Asthma and eczema
a. Topical: inhaled, creams
b. Systemic: IV or ingested
• = preventers
• Stop the underlying chronic inflammation
• MOA: prevents the transcription of cytokines
What are the drawbacks of corticosteroid use?
- Broad immunosuppression: susceptibility to infection
- Stunts growth, bone demineralisation
- Cushingoid features
- Skin thinning
• Efficacy wanes over time
Describe allergy immunotherapy
What is the proposed mechanism?
What are the risks?
This is the only therapy to target the underlying cause of the allergy
Approach:
• Individual exposed to very low doses of allergen over a period of time
• Subcutaneous injection
• Individual is able to experience allergen whilst still undergoing the therapy
Mechanism:
• Th2 → Th1 skewing, IgE → IgG4
• Development of Tregs (IL-10 and TGF-β) (most important thing that’s happening)
• Loss of IL-4,5
Risks:
• Chance of severe reaction (anaphylaxis)
Novel approach: sublingual administration (SLIT)
• Need greater doses of allergen
• Decreased risk of severe reactions
• Can be administered at home
Which cytokine is most important for eosinophil recruitment and activation?
What is the source of the cytokine in allergy?
IL-5
Mast cells synthesise IL-5 once activated by IgE cross linking
Describe pharmacological immunotherapy for allergy
- Omalizumab
• Anti-Fc mAb
• Reduces circulating IgE
• Also reduces expression of FceRI - Mepolizumab
• Anti-IL5 mAb
• Highly effective in severe eosinophilic asthma (10% of asthma sufferers)
• Reduces eosinophil recruitment
Describe the hygiene hypothesis
In early life, Th2 responses predominate
Non-pathogenic infections early in life help to establish Th1 predominance later in life
These early infections induce IL-10, TGF-β and Tregs, which help prevent atopy
What is the effect of early parasitic infections?
Decreases risk of atopy
What is the effect of early RSV infection?
Early RSV infection increases risk of asthma:
• IL-4 cytokine bias
• Timing of exposure?
Indicate a time frame for DTH reactions
24-48 hours
What things can induce DTH responses?
Intradermal injection of antigens
• e.g. insect venom
Microbial infection
Contact sensitivity
• e.g. Poison ivy pentadecacatechol, Nickel salts
• Ag absorbed through the skin
Which cells mediate DTH?
T cells, not pre-formed Abs (as in allergy)
- Th1 are usually activated
- CTLs can also be activated
• Macrophages are generally the ultimate effector cell
Describe the generation of a DTH response
A. Sensitisation
- Antigen encountered for the first time (usually through skin)
- Ag taken up by local APCs (Langerhans cells), which then migrate to LNs
- Ag presented to T cells in LN
- T cells become activated and stimulated to go down Th1 pathway
- Th1 traffic back to the site of Ag encounter and remove the causative agent
- High levels of memory T cells remain in circulation (and skin: tissue resident memory cells)
B. Re-challenge / Elicitation
- Antigen is encountered again
- Memory T cells are reactivated
- T cells produce cytokines: IFN-γ, TNF
- Keratinocytes become activated and release cytokines and chemokines
- Activation of vascular endothelium → inflammatory cell (PMN) recruitment
- Induration
C. Resolution:
• Elimination of the infection / antigen
What is the function of PGE?
Where does it come from?
Inhibits the immune response
It is produced by macrophages
Outline the inflammatory mediators released by Th1, and their function in DTH reactions
IFN-γ, TNF and Lymphotoxin • ↑ vascular adhesion molecules • Macrophage activation (IFN-γ) • Increased vascular permeability → leakage of plasma fibrinogen → tissue damage
Chemokines:
• Lymphocyte and monocyte migration to site
IL-3, GM-CSF:
• Stimulation of monocytes in BM, and recruitment to site
What is contact hypersensitivity?
Give examples of things that can cause it
An allergic reaction caused by DTH
Small molecules that are able to penetrate the skin modify self proteins to form neo-antigens
The immune system has not been tolerised against these new Ags
DTH is induced, results as an eczema-like appearance
Agents:
• Nickel salts
• Chemicals in dyes and drugs
• Pentadecacatechol in poison ivy
List instances in which chronic DTH occurs
This happens when the Ag can not be eliminated for various reasons
- Intracellular bacterial infections that resist killing mechanisms
• M. tuberculosis
• M. leprae - Non-degradable particulate agents
• Talc
• Silica
After several weeks, the inflammatory response has cause significant tissue damage, and fibrosis occurs
Describe the role of macrophages in chronic DTH
Macrophages are recruited in great numbers, but fail to eliminate the causative agent
Macrophages chronically stimulate Th1 cells, which produce many cytokines, including IFN-γ which in turn stimulates macrophages
Vicious cycle
Formation of granuloma:
• Multinucleated Giant cells (from macrophage fusion)
• Ring of activated macrophages and Th1
• Often with necrotic core (caseous necrosis)
• Fibrosis
List diseases that are caused by DTH
What is the causative agent for each?
Describe the pathology in each instance
- Tuberculosis
• M. tuberculosis
• Granulomas in lung
• Chronic inflammation - Leprosy
• M. leprae
• Granuloma formation
• Chronic inflammation - Sarcoidosis
• Unknown, environmental irritant
• Lung, skin, eye granulomas
• Fibrosis - Crohn’s disase
• Commensal flora, ?
• Inflammation of ileum and colon
• Granulomas in bowel
What is responsible for the wheal and the flare in immediate hypersensitivity reactions?
Wheal: Oedema and vasodilation at site of challenge
Flare: vasodilation at edge of lesion
What does the drug in Epipen bring about?
Epinephrine
- Reforms the tight junctions of the bronchial epithelium
- Bronchodilator (acts of β2 adrenoceptors)
- Accelerates heart rate (acts on β1 adrenoceptors in heart)
• Also ‘stabilise’ mast cells, preventing degranulation
List pharmacological agents that act on the following: • Histamine • Leukotrienes • Bronchoconstriction • Mast cell degranulation • Cytokine production • Eosinophil activation
Histamine:
• Anti-histamines, e.g. Telfast
Leukotrienes:
• Leukotriene receptor antagonists
• e.g. Singulair
Bronchoconstriction:
• β2-adrenoceptor agonists (Ventolin)
Mast cell degranulation:
• Adrenaline: mast cell stabiliser
• Omalizumab: anti-IgE mAb
Cytokine production:
• Corticosteroids
Eosinophil activation:
• Mepolizumab
For which types of reactions are anti-histamines used?
Allergic rhinitis
Urticaria
For which types of reactions are leukotriene inhibitors used?
Asthma
also allergic rhinitis
What is SLIT?
Sublingual immunotherapy
Desensitisation using sublingual administration of allergen
How does concentration of IgE affect FceRI expression?
The more IgE present, the greater the expression of FceRI
This is why there is down-regulation of FceR when Omalizumab is used (removes IgE from system)
What is the major immunological change occurring in immunotherapy of allergic disease?
Induction of Tregs
Also, skewing from IgE -> IgG4
Why is mepolizumab particularly effective in severe eosinophilic asthma?
In severe eosinophilic asthma, the eosinophils are causing most of the pathology
IL-5 is released by both Th2 and Mast cells, bringing about:
• Stimulation and activation of eosinophils
This monoclonal antibody removes the IL-5 from the system, thus inhibiting eosinophil recruitment and activation
Describe how Th1 adjuvants could be used as a novel therapy for asthma
Approach:
• Immunisation with allergen + cytokine that skews to Th1 phenotype (IL-12)
Rationale:
• This would induce Th1 responses specific for the allergen, and balance out the harmful Th2 responses
Describe the novel therapeutic approach of injection of allergen peptides
What are the advantages and disadvantages of this approach?
Approach:
• Peptides from the allergen are injected
• This induces anergy
Benefits:
• Peptide can not cross link IgE on mast cells, thus there is no risk of anaphylaxis, as in immunotherapy (injection of entire allergen)
Disadvantages:
• Causative allergenic peptide differs between individuals
• This peptide will be different for each individual, and thus is more difficult than simple injection of entire allergen
• Would need to HLA typing to be able to determine which peptides are being presented in this individual
Which hypothesis for allergy is favoured nowadays?
Counter-regulation hypothesis
• All types of infections in early life induce Treg responses
• This protects from atopy
Compare the symptoms during the primary and secondary exposure to antigen that elicits DTH responses
Primary exposure: no symptoms
Elicitation: DTH response
• Induration etc.
Describe the mantoux test
Test to determine is an individual has been previously exposed to, or is immunised against M. tuberculosis
- Primary exposure:
• Could be immunisation
• Could be infection
Tuberculin test:
2. Tuberculin injected subcutaneously
• Tubuerculin is a protein from M. tuberculosis
If there has been prior exposure:
- Activation of memory T cells specific for tuberculin
- Migration to site of injection
- Release of cytokines etc.
• Tissue damage
• Inflammatory cell recruitment
• Vasodilation - Induration visible, site of lesion measured
Compare DTH to pathogens and innocuous agents
Pathogens: • Not allergy • e.g. Tuberculin / Mantoux test • Tubercolosis • Leprosy
Allergy: • Directed against self antigens / modified self antigens Examples: • Contact dermatitis: - Nickel salts - Dyes - Pentadecacatechol in poison ivy
Which cells predominantly mediate DTH?
CD4 T cells
• Nickel contact hypersensitivity
However, CD8 T cells can also mediate DTH reactions
• e.g. Poison ivy contact hypersensitivity
Describe how poison ivy causes DTH
- Exposure to poison ivy
- Pentadecacatechol is lipid soluble, cross cell membrane
- Inside the cell, pentadecacatechol modifies self peptides
- Neo-self Ags are presented in the context of MHC I by APCs
- Activation of CD8 T cells against this new self antigen
- CTLs kill cells at the site of contact with poison ivy that are expressing the altered self proteins
• Perforin/granzyme dependent
Compare chronic DTH reactions with others
Chronic DTH: • Causative antigen can not be removed Examples: • Crohn's disease • Tuberculosis • Leprosy • Sarcoidosis • Non-degradable particulate antigens (silica, talc)
Acute DTH: • Causative antigen can be eliminated Examples: • Poison ivy contact hypersensitivity • Poison ivy is avoided in future
