Hypersensitivity

Question 1

What is Hypersensitivity?

Answer 1

Immunologically driven:

• host tissue-damaging process.
• tissue-irritating process.

Question 2

Features of the innate immune system (IIS)

Answer 2

• First lines of defence, general, rapid response;
• Complement system.
• Granulocytes:
  
  • Neutrophils, basophils, eosinophils, mast cells, NKs.
• Macrophages, dendritic cells
• Antigen Presenting Cells:
  
  • Macrophages, dendritic cells, follicular DCs and B cells.

Question 3

Features of the adaptive immune system (AIS)

Answer 3

• Directed by the innate immune cells, antigen-specific, memory, late response;
• T and B cells.
• Antibodies: ImmunogIobulins (Ig):
  
  • IgA, IgG, IgM, IgE, IgD.

Question 4

What is type 1 hypersensitivity?

Answer 4

(A) Immediate Hypersensitivity:

• (Allergy-Anaphylaxis and Atopy):

Non-microbial environmental antigens that are innocuous (should not illicit an immune response).

Response within minutes.

Mediated by IgE-mast cells.

Question 5

What is type 2 hypersensitivity?

Answer 5

(B) Antibody Mediated:

• IgM, IgG antiBodies against cell surface/extracellular matrix.
• Complement-mediated.

Question 6

What is type 3 hypersensitivity?

Answer 6

(C) Immune Complex Mediated:

• Soluble immune complexes Antigen-IgM or Antigen-IgG.
• Complement-mediated.

Question 7

What is type 4 hypersensitivity?

Answer 7

(D) Cell Mediated (Delayed):

• CD4 and CD8 cells.
• Cell killing and cytokine-mediated inflammation.
• 24-48h.

Question 8

What is the mechanism behing type 1 hypersensitivity?

Answer 8

Antigen presenting cell (dendritic cell/macrophage) finds an antigen (Ag).

• Presents Ag to the T cell which activates it into a Th2 phenotype.
  
  • Releases cytokines: IL-4 and IL-13.
    
    • These cytokines induce B cells to produce IgE.
      
      • IgE binds to the surface of mast cells (sensitised) (primed).

Once the antigen returns, it crosslinks with the antibodies on the mast cell and causes degranulation.

IL-5 activates Eosinophils.

Question 9

What triggers degranulation of mast cells?

Answer 9

Crosslinking of two adjacent antibodies by an antigen.

Question 10

What storage granule compounds are released from mast cells?

What do they do?

Answer 10

Histamine:

• Increased vascular permeability.
• Smooth muscle contraction.
  
  • (can cause asthma this way)

Tryptase:

• Tissue remodelling.
• Increased mucus secretion.

Question 11

What are the three mediators made by de novo synthesis in mast cells?

And what do they do?

Answer 11

de novo synthesis = needs activation to be produced.

Prostaglandins (PGD₂):

• Increased vascular permeability.

Leukotrienes:

• Smooth muscle contraction.
• Bronchoconstriction.

Cytokines:

• Vasodilation systemic anaphylaxis.

Question 12

What are some main characteristics of allergens?

And some exampled of some.

Answer 12

Individuals are repeatedly exposed to them.

They do not induce macrophages/dendritic cells-typical responses driving Th1/Th17.

• (like microbes do).

Inhaled:

• Pollens, spores, dander, dustmite.

Ingested:

• Peanut, egg, fruits, sesame.

Venoms:

• Bee, wasp stings and bites (Hymenoptera)

Drugs:

• Antibiotics, chemotherapeutics.

Question 13

What type of asthma is the allergic type?

Answer 13

Immediate asthma.

Question 14

Give examples of allergic mediators and the body systems/tissues they affect.

Answer 14

Question 15

How can we diagnose hypersensitivity (allergies)?

Answer 15

Symptoms (rapid onset):

• Lung – asthma, wheezing.
• Nose – rhinitis, sneezing, runny nose.
• Eye – conjunctivitis.
• Skin – atopic dermatitis.
• Gut – food allergy.

All about mucosal tissues!

Skin prick test > 3mm wheal (swelling).

Laboratory tests:

• Total IgE (>100 IU/mL).
• Specific IgE (against a certain antigen) (e.g. RAST).

Question 16

What is wheal and flare?

(what mediator is it caused by?)

Answer 16

Vasodilation and vascular leak.

• Leakage of plasma and protein (edema).
• Vasodilation and congestion.

Caused by histamine.

Question 17

What are the mechanisms behind Type II hypersensitivity?

Answer 17

Binding of antibodies to antigens on cells / antigens on tissues;

• Activate complement and recruit immune cells.

Question 18

What are the mechanisms behind Type III hypersensitivity?

Answer 18

Binding of Ab to Ag (self or foreign):

• Soluble complexes not cleared.
• Accumulation of antibody-antigen complex which drives the damage.

Activation of complement, recruitment of neutrophils and macrophages.

• Pathologic features reflect the site of deposition;
  
  • Multiple tissues.

Question 19

What are the mechanisms behind Type IV hypersensitivity?

Answer 19

Delayed inflammation:

• 24-48h after Ag challenge (instead of mins).

Antibody-independent.

• Main drivers are the CD4 and CD8 cells.

Question 20

What are some well-known conditions resulting from type IV hypersensitivity?

Answer 20

Cytokine-mediated inflammation:

• Inflammatory bowel disease:
  
  • Th₁/Th₁₇ = Crohn’s Disease.
  • Th₂ = Ulcerative Collitis.

T Cell-mediated cytotoxicity:

• Type 1 diabetes - destruction of islet cells.

Question 21

Which two types of hypersensitivity are related to asthma?

Answer 21

Types I and IV.

Type I:

• Immediate Hypersensitivity,
  
  • (Allergy-Anaphylaxis and Atopy)

Type IV:

• Cell Mediated (Delayed):
  
  • CD4 and CD8 cells.
  • Cell killing and cytokine-mediated inflammation.
  • 24-48h.

Question 22

How does asthma differ from COPD in terms of symptom timing?

Answer 22

Asthma has symptoms that vary over time and in intensity, together with variable expiratory airflow limitation.

• Variable nature is how it differs from COPD.
  
  • i.e. reversible.

Question 23

What is the pathology of asthma with regards to inflammation?

Answer 23

Inflammatory infiltrate:

• Inflammatory cell recruitment.
  
  • More Th2 cells, mast cells & eosinophils.

Mucosal oedema:

• Bronchial microvascular leak.

Mucus hypersecretion:

• Blockage of airways by mucus plugs.

Bronchial smooth muscle contraction:

• Action of inflammatory mediators.

Question 24

What is the pathology of asthma with regards to remodelling?

Answer 24

Epithelial cell damage:

• ‘leaky’ epithelium.

Reticular basement membrane thickening.

Airway smooth muscle thickening.

Submucosal mucus gland hypertrophy.