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
