Lecture 13 - Immunology Hypersensitivity

Question 1

Type I hypersensitivity

Answer 1

• Immediate hypersensitivity
• Involves IgE (antigen binding to IgE crosslinks induces release of mediators&raquo_space; causing hypersensitivity)
• Involves mast cells
• Occurs within 30 min
• E.g. hay fever, asthma

Question 2

Type II hypersensitivity

Answer 2

• Antibody mediated hypersensitivity
• Involves IgG and IgM
• Involves phagocytosis, NK cells and neutrophils migrating to the site of infection, complement
• Occurs within hours
• E.g. ABO transfusion reaction

Question 3

Type III hypersensitivity

Answer 3

• Immune complex mediated hypersensitivity
• Involves IgG, IgM, CD8 and CD4
• Involves complement
• E.g. Farmer’s lung

Question 4

Type IV hypersensitivity

Answer 4

• T cell mediated hypersensitivity
• Involves CD4 (T helper cells) and CD8 (cytotoxic T cells), no antibodies involved
• Involves activation of WBCs
• Occurs within weeks
• E.g. poison ivy

Question 5

Role of eosinophils

Answer 5

• Migrate into tissues during
  inflammation
• Production stimulated by IL-3 & IL-5
  from Th2 cells & mast cells
• Activated by cytokines & chemokines

Question 6

Role of mast cells

Answer 6

• Long lived in tissues
• Granules contain mediators
• Bind IgE on FceRI -> activation
• Also activated by C3a and C5a, and some drugs (e.g. opiates)

Question 7

Symptoms of anaphylaxis

Answer 7

• Urticaria (rash/skin eruption characterised by hives)
• Angio-oedema/swelling of deep layers of skin
• Throat swelling
• Wheeze
• Dizziness, collapse
• Vomiting, diarrhea

Question 8

Atopic dermatitis/eczema

Answer 8

• Itchy, dry skin
• Breakdown of skin barrier
• Early age of onset, often infancy
• Personal or family history of allergic disease
• Infections -> worse symptoms

Question 9

How immediate hypersensitivity works

Answer 9

• First exposure to allergen
• Activation of TH2 cells and stimulation of IgE class switching in B cells
• Production of IgE
• Binding of IgE to FcεRI on mast cells
• Repeated exposure to allergen
• Activation of mast cells; release of mediators (vasoactive amines, lipid mediators)
• Immediate hypersensitivity reaction

Question 10

Possible theories of why allergies are becoming more common

Answer 10

• Theory 1: Th2 responses have evolved to control parasites, so with our parasite infections Th2 cytokines “look for” another job and cause allergy… but treatment to remove parasites increased allergies
• Theory 2: bacterial infections skew immune responses to Th1
• Theory 3: all infections induce IL-10, TGFb &/or Treg…which depress allergies

Question 11

Mediating tolerance to allergens

Answer 11

• Foxp3+ Treg cells mediate
  tolerance to allergens through
  diverse suppressive mechanisms

Including:
• T-cell cytolysis through a
granzyme-dependent mechanism

• IL-2 deprivation

• production of IL-10, IL-35 & TGF-β
able to block proliferation of effector T cells

• Down-modulation of APCs
through LAG-3–MHC class II &
CTLA-4–CD80/CD86 interactions

Question 12

How Treg cells regulation Th2 and IgE production in allergies

Answer 12

• GITR stimulation of Treg cells increased their suppressive functions, leading to blockade of naive CD4+ T cell conversion into allergen-specific TH2 T cells.
• Treg cells are also able to control B cells and block IgE production through a direct CTLA-4 and cell contact–dependent mechanism and through production of cytokines, such as IL-10

Question 13

Pathogenic TH2 and food allergies

Answer 13

• Pathogenic “TH2 cell–like” Treg cell reprogramming in patients with food allergy.
• Food allergy is characterized by a decreased induction of allergen-specific iTreg cells at the intestinal mucosa.
• Induced allergen-specific Treg cells in patients with food allergy are prone to
  acquire a “TH2-like” phenotype with increased IL-4 secretion.
• They cannot control the effector
  TH2 cell immune response and mast cell expansion, perpetuating the allergic phenotype.

Question 14

Pathogenic “TH17 cell–like” Treg cell reprogramming by the IL-4Rα Q576R allele.

Answer 14

• Human IL-4Rα Q576R increases asthma severity. Signaling through the IL-4Rα Q576R allele on iTreg cells induces dual activation of STAT6 and STAT3, through an autocrine IL-6 production loop
• IL-6–STAT3 axis promotes pathogenic “TH17 cell–like” Treg cell reprogramming,
  resulting in RORγt expression and IL-17 secretion by the reprogrammed Treg.

Question 15

Microbiota

Answer 15

• immune cell interactions shape oral tolerance and hence food allergies
• Metabolites (eg: short chain fatty acids) produced by bacterial fermentation of dietary fibers promote the proliferation and de novo induction of iTreg cells
• Clostridial bacterial species promote the production of IL-22 by RORγt innate lymphoid cells, reinforcing oral tolerance by decreasing gut permeability and oral allergen uptake.…this includes RORγt–expressing iTreg cells

Question 16

Strategies for the drug treatment of allergy

Answer 16

• Corticosteroids down-regulate
  inflammation
• Cromoglycate may stabilise mast cells
• Monoclonal antibodies can prevent IgE binding to mast cells
• Adrenaline and b2 adrenergic agonists can inhibit effects of mast cell mediator
• Leukotriene and histamine receptors can be blocked