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MIIM30003 - Medical & Applied Immunology > Lecture 22 - Allergies I > Flashcards

Lecture 22 - Allergies I Flashcards

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USMLE® Step 1 flashcards
1
Q

Outline the various ways that the immune system can be dysregulated, and the conditions that can result

A

Hyporesponsiveness:
• Tumours
• Persistent infection
• Opportunistic infection

Hyperresponsiveness:
• Hypersensitivity
• Autoimmunity

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2
Q

What are hypersensitivity reactions?

A

Aberrant, excessive or uncontrolled immune reactions

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3
Q

Outline the Gel and Cooms classification of hypersensitivities

A
  1. Type I
    • IgE mediated
    • Immediate hypersensitivity
  2. Type II
    • Ab mediated
    • Ab binding to self-Ags (cell surface or matrix)
  3. Type III
    • Immune complex mediated
    • Improper clearance and deposition
  4. Type IV
    • DTH
    • T cell mediated
    • e.g. contact hypersensitivity
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4
Q

Outline the various responses in type I hypersensitivity

A

Local (common):
• Rhinitis
• Asthma
• Conjunctivitis

System (rare):
• Anaphylaxis

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5
Q

Outline the generation of the type I hypersensitivity reaction

A
  1. 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

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6
Q

Define atopy

List the important features

A

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
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7
Q

List some allergic diseases

A

Asthma
Allergic rhinitis
Food allergy
Urticaria

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8
Q

Describe the clinical tests for type I atopy

A
  1. Skin prick test
    • Introduces allergen into skin
    • Look for wheal-and-flare response
  2. Radioallergosorbent (RAST)
    • Checks for presence of IgE against known Ags
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9
Q

Describe experimental data that links IgE to allergy

A

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

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10
Q

Outline the genetic and environmental factors that contribute to allergic disease

A 
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

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11
Q

Describe the risk factor of family history in allergic disease

A

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

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12
Q

Describe the features of allergens

List a few

A
  • 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
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13
Q

Describe the role of basophils in development of type I hypersensitivity

How has this proposed role changed over time?

A

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.

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14
Q

Describe determination of ‘helper’ T cell phenotype

A

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
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15
Q

Describe how isotype switching is controlled by helper T cells

A

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

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16
Q

Describe the structure of FcεRI

A

Three subunits: α β γ

α:
• Large extracellular domain
• Binds Fc region of IgE

β:
• ITAM
• Four TM domains

γ:
• Two per receptor
• ITAM

17
Q

Where is FcεRI expressed?

A

Granulocytes:
• Mast cells (constitutive)
• Basophils (constitutive)
• Eosinophils (induced by IL-5)

18
Q

Describe the important features of FcεRI

What does it ‘do’?

A

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

19
Q

Describe the important features of mast cells:
• Location
• Structural features

A

Location:
• Under epithelial surfaces
• Near blood vessels

Structural features:
• FcεRI constitutively expressed
• Pre-formed granules in cytoplasm

20
Q

Describe some experimental evidence for mast cell participation in allergic responses

A

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

21
Q

List the contents of the pre-formed granules in mast cells

Describe what each brings about

A 
Biogenic amines:
 • Histamine
→ Increased vascular permeability; vascular leakage
→ Intestinal hyper motility
→ Bronchoconstriction

Proteases:
• Tryptase
→ Tissue damage

22
Q

Compare the effect of pre-formed and newly formed mediators released by mast cells upon activation

A

Pre-formed:
• Bring about immediate reaction
• Vascular / smooth muscle response

Newly synthesised:
• Bring about late phase reaction

23
Q

List the newly synthesised mediators released by mast cells upon activation

Describe what each brings about

A 
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

24
Q

Describe the role of eosinophils in the allergic response

What activates them?

What is their effector function?

A

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

25
Q

Why is there eosinophilia in allergic disease?

Describe the ways that eosinophil responses become dysregulated

A

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)

26
Q

Describe the response in various tissues around the body during an allergic reaction

A

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

27
Q

What determines the course of the allergic response?

Compare these factors in systemic and local reactions

A

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

28
Q

When does a hypersensitivity reaction occur?

A

Upon secondary encounter of an antigen

Primary encounter is sensitisation

29
Q

What is type I hypersensitivity also known as?

A

Immediate hypersensitivity

30
Q

What is thought to be the reason why allergens are typically experienced at very low doses?

A

The introduction of these allergens at very low doses is thought to favour the Th2 responses

31
Q

Which is the key effector cell in allergic reactions?

A

Mast cells

32
Q

Compare the cytokines that drive class switching to IgG2a and IgE

A

IgG2a: IL-2, IFN-γ
IgE: IL-4, IL-13

33
Q

On which cells is FceRI constitutively expressed?

A

Constitutive expression:
• Mast cells
• Basophils

Induced expression (IL-5)
 • Eosinophils
34
Q

What is the implication of the very high affinity of FceRI for IgE?

A

Levels of free IgE in the system is very low

all bound by the receptors

35
Q

Compare the duration of activity of histamine and leukotrienes after mast cell degranulation

A

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

36
Q

Which molecules do eosinophils produce that mediate the allergic reaction?

A

(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

MIIM30003 - Medical & Applied Immunology (30 decks)

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