L55: Hypersensitivity Reactions

Question 1

4 types of hypersensitivity reactions

Answer 1

Type I - immediate
mediator: IgE
effector: Mast cell degranulation
speed: immediate

Type II - antibody-mediated
mediator: IgG / IgM + complement
effector: cytotoxicity to own cell
speed: fast

Type III - immune complex mediated
mediator: Ag/Ab immune complex
effector: inflammation
speed: slow

Type IV - delayed (T-cell mediated)
mediator: Th1 (IFNγ)
effector: chronic inflammation, tissue damage, granuloma
speed: delayed

Question 2

Helper T cell subset and functions

Answer 2

Th1: IFNγ, IL-12
Th2: IL-4, IL-13
Treg: IL-10
Th17: IL-17a

Question 3

Nature of hypersensitivity

Answer 3

1. Antigen driven
2. Normal but exaggerated magnitude and inappropriate response
3. Host tissue damage
4. Life-threatening

Question 4

Type I hypersensitivity

Answer 4

Allergic rhinitis, allergic asthma

Mediator: IgE (normal protective response against helminthic infection)

Effector: Mast cells:
- granules containing histamines, proteases, heparin, serotonin
- high affinity for Fc of IgE
- found in tissues exposed to environment (mucosal surface)
- Allergen bind to IgE on mast cell surface
- IgE receptor cross linking —> ↑ intracellular Ca —> Intracellular signaling pathway

1. Mast cell degranulation
   —> preformed granules: histamine, heparin, protease
2. Arachidonic acid enzymatic pathway activation
   —> lipid mediators: prostaglandins, leukotriene, bradykinin
3. Transcriptional activation of cytokine genes
   —> cytokine release (TNF, IL1, IL8)

Histamine: vasodilation, ↑ permeability, smooth muscle contraction, mucus secretion
Protease: tissue damage
Prostaglandin: vasodilation, smooth muscle contraction
Leukotriene: smooth muscle contraction, ↑ permeability
Cytokine: induce inflammation, leukocyte recruitment (Eosinophil)

Physiological changes:
1. Smooth muscle contraction —> bronchoconstriction
2. Vasodilation and ↑ permeability —> angioedema, hives / flushing, itching
3. Mucus secretion —> watery eyes, rhinitis
4. Sensory neural stimulation —> coughing, sneezing

Th2 response: (Dendritic cell —> Th2 —> B cell IgE —> Mast cell)
Sensitisation phase: Dendritic cells prime Th2 development
—> Th2 cytokines (IL4) —> B cell producing IgE (specific to allergen)
—> IgE captured by mast cells with Fc receptor —> mast cells sensitised

Activation phase: re-exposure —> rapid degranulation —> type I reaction

Question 5

Anaphylaxis

Answer 5

Severe form of type I
- fatal
- bee stings / food
- systemic reaction with short time
***- histamine release in multiple tissue
- extensive vasodilation —> edema in tissue —> low BP (shock)
- laryngeal oedema —> airway obstruction
- bronchoconstriction —> SOB
- coronary spasm —> cardiac arrest

Treatment: injectable epinephrine: vasoconstriction —> ↓ swelling + ↓ loss of fluid

Question 6

Genetic susceptibility and Allergy test for Type 1 hypersensitivity

Answer 6

Genetic susceptibility:
- significantly high IgE level —> susceptible to Th2 response
- environmental factors
- hygiene hypothesis

Allergy test:
1. Skin test (Patch, Prick, Intradermal)
2. Blood test (ELISA —> presence of allergen specific IgE antibody)

Question 7

Treatment options for type I hypersensitivity

Answer 7

1. Avoidance
2. Drugs
   - Antihistamines: H1/H2 blockers
   - Corticosteroid: immune suppression
   - Cromolyn sodium: prevent mast cell degranulation
   - Salbutamol, epinephrine, isoproterenol (beta-agonist)
3. De-sensitisation
   - immunisation with small and increasing amount of allergen over long period of time
   - develop allergen-specific IgG for antigen competition
   - develop allergen-specific Treg for suppressing T cell response

Question 8

Type II hypersensitivity

Answer 8

Antibody mediated cytotoxicity against self-tissue/cells

Mediator: IgM / IgG + complement

Effector: Cytotoxicity to normal cell

• IgM / IgG bind to antigen —> Ag/Ab complex —> Complement activation (classical pathway) —> MAC —> cytotoxicity

Example:
1. Incompatible blood type
Anti-B antibody bind to B antigen —> complement-mediated lysis of RBC

2. Haemolytic disease of newborn
   IgG bind to Rh antigen —> complement activation + Fc-mediated phagocytosis + ADCC —> anaemia
3. Myasthenia gravis
   Autoantibodies against acetylcholine receptor —> block neurotransmitter signalling at NMJ —> muscle weakness

Question 9

Type III hypersensitivity

Answer 9

Mediator: Ag/Ab immune complexes

Effector: Immune complex mediated inflammatory responses

Deposit in vessels in joints, kidneys, skin etc.
- Activate 1. Complement 2. Neutrophil 3. Macrophage 4. Platelet
- Complement: inflammation + chemotaxis —> neutrophil —> ROS —> more inflammation + injury
- Opsonisation and phagocytosis
- Platelet aggregation —> thrombus
—> systemic vasculitis and inflammation

Example:
1. Serum sickness
- proteins in non-human anti-serum —> fever, vasculitis, arthritis, nephritis (usually transient)

2. Systemic lupus erythematosus (SLE)
   - female prevalence, loss of tolerance to self-antigen —> anti-nuclear auto-Ab —> immune complexes mediated tissue/inflammation

Question 10

Type IV hypersensitivity

Answer 10

Delayed type: 1-2 days after antigen exposure

Mediator: T helper cell (Th1): IFNγ, IL-12 (Major effector mechanism against facultative intracellular pathogens)

Effector: Cell-mediated inflammatory response + macrophage + CD8 T cell

1. Sensitisation phase:
   APC (dendritic cells / Langerhans cells) —> CD4 T helper —> Th1
2. Effector phase:
   Sensitised Th1 —> IFNγ, IL-12
   —> activate macrophage + CD8 T cell
   —> ↑ Class II MHC, TNF receptor, oxygen radicals, Nitric oxide

Example:
1. Allergic contact dermatitis (poison ivy, latex)
Re-exposure —> rapid recruitment of macrophage + CD8
—> inflammatory infiltration + local oedema + erythema

2. Granulomatous hypersensitivity (Tuberculosis)
   - Granuloma: Caseous necrosis (with persistent pathogen) surrounded by Epitheloid macrophage, Langhans giant cells, T Lymphocytes (Th1), Fibroblast

• Dendritic cell carry Mtb antigen + IL-12 production —> activate Th1 —> IFNγ
  —> activate macrophage —> cannot kill mycobacteria and contain the infection
  —> Infected macrophage continue to present Mtb antigen to Th1 —> IFNγ
  —> activate macrophage —> infected macrophage
  —> chronic inflammation (vicious cycle)
  —> granuloma formation
  —> Chronic localised delayed-type hypersensitivity / Cell-mediated inflammation

Other example: Leprosy, Sarcoidosis, Crohn’s disease