Lecture 22 - Allergies I Flashcards
Outline the various ways that the immune system can be dysregulated, and the conditions that can result
Hyporesponsiveness:
• Tumours
• Persistent infection
• Opportunistic infection
Hyperresponsiveness:
• Hypersensitivity
• Autoimmunity
What are hypersensitivity reactions?
Aberrant, excessive or uncontrolled immune reactions
Outline the Gel and Cooms classification of hypersensitivities
- Type I
• IgE mediated
• Immediate hypersensitivity - Type II
• Ab mediated
• Ab binding to self-Ags (cell surface or matrix) - Type III
• Immune complex mediated
• Improper clearance and deposition - Type IV
• DTH
• T cell mediated
• e.g. contact hypersensitivity
Outline the various responses in type I hypersensitivity
Local (common):
• Rhinitis
• Asthma
• Conjunctivitis
System (rare):
• Anaphylaxis
Outline the generation of the type I hypersensitivity reaction
- Sensitisation / primary allergen exposure
• Allergen crosses epithelium and stimulates Th2 cells
• IgE against allergen produced and binds to mast cells (FcεRI) located under the epithelium
2. Re-exposure • Allergen cross epithelium and cross links IgE bound by FcεRI receptors on Mast cells • Mast cells become activated: • Degranulation • Metabolism of membrane phospholipids → Immediate hypersensitivity reaction
• Cytokine secretion
→ Late phase reaction
Define atopy
List the important features
Enhanced tendency to launch IgE responses against innocuous environmental antigens
- High levels of IgE (in serum)
- Eosinophilia
- Preponderance of Th2
- More susceptible to allergic disease
List some allergic diseases
Asthma
Allergic rhinitis
Food allergy
Urticaria
Describe the clinical tests for type I atopy
- Skin prick test
• Introduces allergen into skin
• Look for wheal-and-flare response - Radioallergosorbent (RAST)
• Checks for presence of IgE against known Ags
Describe experimental data that links IgE to allergy
Allergic disease in general:
• 80% of individuals with severe allergic disease have raised serum IgE
• 60% with mild allergic disease have raised IgE
• Very high levels of serum IgE in individuals with eczema
Outline the genetic and environmental factors that contribute to allergic disease
Genetic: Evidence: family history is risk factor for allergic disease • MHC II • FcεRI β chain • IL-4, 5, & 9 gene cluster • TIM gene family
Environmental:
• Exposure to allergens
• Early childhood exposure to infection
• Pollution
Describe the risk factor of family history in allergic disease
50% risk of atopy in child of two parents with history of allergy
30% risk when one parent has history of allergy
18% risk when neither parent has history of allergy
Describe the features of allergens
List a few
- Dust mites
- Cat dander
- Pollens
Features: • Individuals repeatedly exposed by mucosal route • Highly soluble in bodily fluids • Inhaled allergens: carried by small particles • Ingested allergens: degrade slowly • Introduced at very low doses • Stable • Often enzymes
Describe the role of basophils in development of type I hypersensitivity
How has this proposed role changed over time?
Original model:
– Basophil as accessory cell –
• Basophils migrate to the LNs with DCs
• Basophils involved in stimulation of Th0 cell differentiation into Th2 by providing IL-4
• DCs are doing the Ag presentation to the naïve T cells in the LNs
DCs are not stimulated by allergens, and thus cannot produce the correct cytokines for naïve T cell activation and skewing to Th2 phenotype
The problem was that DCs are not generally stimulated by ‘allergen’ antigens, they are more stimulated by microbial Ags
Updated model (2009):
– Basophil as APC –
• Basophils present the allergen Ag to naïve T cells in LNs, as well as provide the adequate cytokines (IL-4) for skewing to Th2 phenotype
• (Presentation in context of MHC II)
2013:
Human basophils are unable to act as APCs, as they lack
• MHC II (HLA-DR)
• Costimulatory molecules (CD80/86)
required for Ag presentation and T cell activation
In all likelihood, the Ag presentation is performed by DCs or B cells etc.
Describe determination of ‘helper’ T cell phenotype
The cytokine environment of the newly activated CD4 T cell will determine its differentiation into the various subsets
These cytokines are released by the DCs that presented the Ag to the T cells
Th1: • DC (APC) releases IL-12/IFN-γ (signal 3) • Up-regulation of Tbet • Induction of Th1 phenotype • Secretion of IFN-γ / IL-2
Th2: • DC releases IL-4 • Up-regulation of GATA3 • Induction of the Th2 phenotype • Secretion of IL-4, 5, & 13 • IL-10 secretion by the Th2 inhibits generation of Th1 cells
Describe how isotype switching is controlled by helper T cells
Isotype switching is determined by the cytokine environment of the B cell
These cytokines are provided by ‘helper’ T cells
Th1 responses:
• Th1 release IFN-γ and IL-2
• These cytokines favour IgG2a isotype
Th2 responses:
• Th2 release IL-4 and IL-13
• IL-4, 13 favour IgE isotype
Describe the structure of FcεRI
Three subunits: α β γ
α:
• Large extracellular domain
• Binds Fc region of IgE
β:
• ITAM
• Four TM domains
γ:
• Two per receptor
• ITAM
Where is FcεRI expressed?
Granulocytes:
• Mast cells (constitutive)
• Basophils (constitutive)
• Eosinophils (induced by IL-5)
Describe the important features of FcεRI
What does it ‘do’?
Very high affinity for IgE (thus most IgE is bound)
Cross linking triggers activation of cell
• Degranulation
• Metabolism of membrane phospholipids to generate inflammatory lipid mediators
• Transcription of cytokines and chemokines
Describe the important features of mast cells:
• Location
• Structural features
Location:
• Under epithelial surfaces
• Near blood vessels
Structural features:
• FcεRI constitutively expressed
• Pre-formed granules in cytoplasm
Describe some experimental evidence for mast cell participation in allergic responses
Mice lacking signalling molecules that are important in the maturation and activation of mast cells
• PI-3K
• NDRG1
These mice show:
• Severely attenuated allergic responses
• Protection from anaphylaxis
List the contents of the pre-formed granules in mast cells
Describe what each brings about
Biogenic amines: • Histamine → Increased vascular permeability; vascular leakage → Intestinal hyper motility → Bronchoconstriction
Proteases:
• Tryptase
→ Tissue damage
Compare the effect of pre-formed and newly formed mediators released by mast cells upon activation
Pre-formed:
• Bring about immediate reaction
• Vascular / smooth muscle response
Newly synthesised:
• Bring about late phase reaction
List the newly synthesised mediators released by mast cells upon activation
Describe what each brings about
Lipid mediators: • Leukotrienes • Prostaglandins • PAF → Bronchoconstriction → Vascular leakage → Gastric hyper motility
Cytokines:
• IL-4 → Propagation of Th2 response
• IL-5 → Eosinophil maturation and activation
• TNF → Endothelial activation, inflammatory cell infiltration
Describe the role of eosinophils in the allergic response
What activates them?
What is their effector function?
Normally:
• Present in mucosal linings
Allergic response:
• Observed only late in the allergic response “end stage effector cells”
• Maturation and infiltration stimulated by IL-5 and TNF respectively
• Degranulate, releasing toxic basic proteins and free radicals
• Produce chemical mediators for further epithelial activation and inflammatory cell recruitment
Why is there eosinophilia in allergic disease?
Describe the ways that eosinophil responses become dysregulated
Stimulation of eosinophils:
• IL-5 (secreted by mast cells upon activation as well as Th2) stimulates eosinophil development in BM
Infiltration into tissue:
• TNF recruits eosinophils from blood into the tissue
• Epithelial cells at the site of reaction produce eotaxins
Activation:
• Increased serum IgE levels, and IL-5 → Increased expression of FceRI
→ Decreased threshold of activation
• FcεRI up-regulated in response to IL-5 (from Th2 and mast cells)
Describe the response in various tissues around the body during an allergic reaction
Vasculature:
• Vasodilation → low BP
• Increased permeability → tissue oedema and cell infiltration
Lungs:
• Bronchoconstriction
• Mucous hyper secretion → coughing, wheezing
GIT:
• Hyper motility
• Increased fluid secretion → diarrhoea
What determines the course of the allergic response?
Compare these factors in systemic and local reactions
Dose and site of antigen delivery
Dose:
• High dose: more likely to disseminate systemically
• Low dose: more likely to remain localised
Site:
• Bloodstream → systemic reaction
• Subcutaneous → localised reaction
Systemic reactions:
• Intravenous, high allergen exposure (e.g. ingestion)
• Allergen is widely dissemination in the bloodstream
• Systemic mast cell activation
• Drop in BP, airway obstruction, tissue oedema
→ Anaphylaxis
Local reactions:
• Subcutaneous, low dose of allergen
• Local activation of mast cells
→ Rhinitis, asthma
When does a hypersensitivity reaction occur?
Upon secondary encounter of an antigen
Primary encounter is sensitisation
What is type I hypersensitivity also known as?
Immediate hypersensitivity
What is thought to be the reason why allergens are typically experienced at very low doses?
The introduction of these allergens at very low doses is thought to favour the Th2 responses
Which is the key effector cell in allergic reactions?
Mast cells
Compare the cytokines that drive class switching to IgG2a and IgE
IgG2a: IL-2, IFN-γ
IgE: IL-4, IL-13
On which cells is FceRI constitutively expressed?
Constitutive expression:
• Mast cells
• Basophils
Induced expression (IL-5) • Eosinophils
What is the implication of the very high affinity of FceRI for IgE?
Levels of free IgE in the system is very low
all bound by the receptors
Compare the duration of activity of histamine and leukotrienes after mast cell degranulation
Histamine is rapidly taken back up after its release
Hence, the effects of histamine are short lived (not chronic)
Leukotrienes bind to different receptors and cause long term bronchoconstriction
• Thus, these are much more of a problem in the long term
• Therapeutic targeting of leukotrienes is more effective than targeting of histamine
Which molecules do eosinophils produce that mediate the allergic reaction?
(remember, eosinophils only involved in the late stages of the reaction)
Produce: • ECP: eosinophil cationic protein • MBP: major basic protein • Free radicals • Chemical factors that lead to epithelial activation and inflammatory cell infiltration
