Hypersensitivity & Allergy

Question 1

What is hypersensitivity?

Answer 1

• when the immune response occurs in an exaggerated or inappropriate form causing tissue damage
• 4 different types (I-IV)

Question 2

Type I Hypersensitivity

Answer 2

• initial exposure to allergen produces IgE response
• Mast cells bind to IgE via FcℰRI Fc receptor
• IgE binds to antigen or allergen
  
  • IgE cross-linking on mast cells
  • mast cell degranulation
  • release of mediators
• brings about immediate hypersensitivity or atopic disease

e.g.

• allergic rhinitis
• asthma
• eczema
• food allergy

Question 3

Eczema

Answer 3

• Th2 cells cytokines - TNF, IL-4
• Treatment - corticosteroids
  
  • inhibit cytokine synthesis - cyclosporin
• also known as atopic dermatitis

Question 4

IgE

Answer 4

• triggers mast cell degranulation onto surface of intestinal parasites
• produced by B cells and plasma cells in response to antigenic stimulus
• driven by Th - dependant
  
  • cytokines play role in the switch
  • IL-4 promotes switch from IgG4 to IgE
• Presence of IL-4 and IL-13 induce ab class switching from other isotopes to IgE
• normally 0.001% of total serum Ig

Question 5

IgE receptor binding

Answer 5

• IgE binds to FCℰRI receptors - high levels present on mast cells and basophils
• Affinity fo IgE and its receptor is 2x higher than IgG and its receptor (FcyR)
• only a few FCℰRI receptors need to be cross-linked by IgE binding to trigger mast cell degranulation

Question 6

Properties of allergens

Answer 6

• mainly proteins - water soluble
• low to medium MW (10-14 kDa)
• glycosylated
• diverse functions - enzymatic
• triggers immediate hypersensitivity

Question 7

Allergens

Answer 7

• Antigens that trigger hypersensitive type I reaction
• dust mite, grass

Question 8

Mast Cells

Answer 8

• 2 types: mucosal & connective
• mucosal infiltrate nasal epi
  
  • hay fever patients during pollen season
  • broncho-alveolar fluid from lungs of asthmatics
• mediators cause
  
  • vasodilation
  • broncoconstriction

Question 9

IgE ½ life

Answer 9

• IgE in serum - less than 2 days
• IgE bound to mast cells - ~ 10 days

Question 10

Types if reaction associated with asthma

Answer 10

• 70% of asthma cases associated with IgE-mediated reactions

Question 11

Asthma

Answer 11

• biphasic response
• sodium cromoglycate (SCG) - prevents mast cell degranulation

Question 12

Asthma Treatment

Answer 12

• Ventolin inhalers
  
  • active ingredient - salbutamol
  • used to treat bronchospasm - the sudden constriction of bronchiole muscles
  • β2 agonist - β-blockers bind to β2r - blocks binding of epinephrine and norepinephrine to their receptors
  • causes muscles to relax - airways opened

Question 13

New Asthma Treatments

Answer 13

• immunotherapy with allergen extracts - desensitisation
• humanised monoclonal anti-IgE ab

Ongoing clinical trials

• recombinant soluble IL-4r
• anti-IL-4 and IL-13 mabs

Question 14

Desensitization

Answer 14

• establish antigen
• regular injection over period of months
• dose progressively increases
• use of small peptides (~20 AA)
• some danger of anaphylactic shock
• gradual change from IgE to IgG

Question 15

Th1 vs Th2

Answer 15

• Th1 - produced by normal individuals - IgG or IgA response to antigen
• Th2 - produced by individuals that suffer from allergies - Il-4 response promoting IgE production to allergen

Question 16

Humanized monoclonal anti-IgE ab

Answer 16

• omaslizumab
• used to treat moderate to severe asthma and chronic hives
• serum range (30 - 700)
• subcutaneous administration
• binds to FcℰRI recognition site on IgE
• removes free IgE from circulation

Question 17

Man targeting IL-4

Answer 17

• IL-4 plays important role in IgE amplification and histamine-induced vascular endothelium dysfunction, vasodilation and anaphylaxis
• Dupilumab
  
  • mAb blocking Il-4 activity (and IL-3 as they share same receptor - IL-4a)
• used for severe to moderate Eczema
• also FDA approved as an odd on maintenance treatment for moderate to severe eosinophilic asthma (6 to 11 yrs)

Question 18

Food Allergies

Answer 18

• non-allergic food hypersensitivity - lactose intolerance (decreased expression of lactase)
• IgE-mediated food allergy - peanut, latex
• Non IgE mediated food allergy - Coeliac disease (MHC II alleles DP2/DQ8)

Question 19

Oral Tolerance in GIT

Answer 19

• state of local and systemic immune unresponsiveness induced by oral administration of innocuous antigens such as food proteins

Question 20

Immune inductive sites in GIT

Answer 20

• peyers patches
• mesenteric lymph nodes
• lamina propria

Question 21

Largest immune system in body

Answer 21

Gut associated lymphoid tissue (GALT)

Question 22

GALT

Answer 22

• must be able to digest dietary antigens as to not result in untoward immune reactions
• protect organism from pathogens
• tolerogenic environment

Question 23

GUT tolerance

Answer 23

• attenuated GIT response to microbes - no systemic response
• high doses of orally fed food antigens promote clonal deletion of T and B cells and anergy
• DCs - important role in inducing unresponsiveness
• CD103 DCs - drive differentiation of immunosuppressive T-reg cells
• breakdown of this control - hypersensitivity occurs - chronic GIT inflamm

Question 24

Common reg pathway for induction of mucosal tolerance and IgA production

Answer 24

• antigens captures in lamina propria and PPs
• carried to mesenteric lymph nodes by CD103 DCs
• stimulates Treg cell response
• release of immunosuppressive cytokines
  
  • IL-10
  • IL-4
  • TGFβ
• suppressor of T cells
  
  • Th1
  • Th2
• increase in differentiation of B cells towards pIgA production

Question 25

Peanut Allergy

Answer 25

• Peanut allergen powder (Palforzia)
• children (4 to 17 yrs)
• child given small amounts of powder over several months - doses gradually increased