Type I-IV hypersensitivity mechanisms

Question 1

What is the Gell-Coombs classification of hypersensitivity?

Answer 1

• Type I - immediate
• Type II - antibody dependent (cytotoxic type & anti-receptor type (sometimes considered Type V))
• Type III - immune complex
• Type IV - cell-mediated / delayed type hypersensitivity (DTH)

Question 2

What type of antigens (allergens) are involved in type I (immediate) hypersensitivity?

Answer 2

Generally ubiquitous environmental substances to which only genetically susceptible individuals react inappropriately
(eg house dust mite allergen, food allergen)

Question 3

What kind of response is seen with type I (immediate) hypersensitivity?

Answer 3

Cellular & tissue changes
Clinical signs of allergic (hypersensitivity) disease
eg/ asthma

Question 4

What causes type I (immediate) hypersensitivity?

Answer 4

-Repeated exposure to antigen or allergen over time
-Allergens may be derived from grass, pollen, house dust mites, animal dander, food, bee venom etc
-Allergic reactions generally occur when sensitisation to an allergen occurs > development of allergen (specific IgE)

Question 5

How does stage 1 sensitisation seen with type I (immediate) hypersensitivity occur?

Answer 5

1. Dendritic cell captures allergen & becomes activated > processed & presented by MHCII
2. Dendritic cell migrates to local lymphoid tissue & triggers a T cell response (Th2)
3. Th2 response provides B cell help (IL-4, 9, 13)
4. Allergen specific B cells are activated > result in plasma cells that produce allergen specific IgE

Question 6

What are some characteristics of IgE?

Answer 6

-Serum concentration is very low
-Produced in small quantities
-Short half life (2 days)
-Mostly found bound to high affinity Fc𝛆RI on mast cells & basophils
-Fc𝛆RI receptors are usually saturated with IgE despite low concentration of IgE in serum (high affinity)

Question 7

What is stage II hypersensitivity of Type I (immediate) hypersensitivity?

Answer 7

Subsequent exposure to the same allergen will cross-link IgE, which is bound to mast cells, resulting in mast cell degranulation & a Type I hypersensitivity reaction

Question 8

What is the process of stage II hypersensitivity of Type I (immediate) hypersensitivity?

Answer 8

1. Allergen cross-links IgE bound to Fc𝛆RI
2. Intracellular signalling pathway leads to degranulation of mast cells
   3a. Immediate response - bronchoconstriction, vasodilation, pruritus (itching) (5-60 mins)
   3b. Late phase recruitment eosinophils & macrophages (4-24hrs)

Question 9

What are the 2 types of Type I hypersensitivity disease?

Answer 9

LOCALISED:
-cutaneous (eg flea allergy, insect bite)
-respiratory (eg asthma)
-intestinal (eg food allergy)

SYSTEMIC:
-anaphylaxis (eg bee sting, penicillin reaction)
-bronchoconstriction, laryngeal oedema, vasodilation
-severe & life threatening

Question 10

How is Type I hypersensitivity regulated?

Answer 10

IgE production
Eosinophil attraction
Mast cell attraction

Question 11

What are the 2 causes of Type II hypersensitivity?

Answer 11

1. Antibody-mediated cytotoxicity
2. Anti-receptor antibodies

Question 12

What is the mechanism of antibody-mediated cytotoxicity?

Answer 12

-FcR (receptor) effector cells (eg phagocyte) recognises target cells (eg pathogen)
-Opsonisation = antibodies binding to antigens on target cell surface increases efficiency of phagocytosis
-Complement mediated lysis of target cell
-Antibody dependent cytotoxicity (ADCC) mediated by Natural Killer cells

Question 13

What are the 2 reactions/diseases that are a result of Type II hypersensitivity?

Answer 13

Blood transfusion reactions
Antibody-mediated autoimmune diseases

Question 14

What happens if a type DEA1- dog is transfused with DEA1+ blood twice?

Answer 14

-After the first transfusion, the dog with make an anti-DEA1 antibody > induced alloantibody
-If a 2nd transfusion of DEA1+ blood is given, then the anti-DEA1+ antibody will bind to the DEA1+ RBCs > mediates cytotoxicity (eg type II hypersensitivity)

Question 15

Why is Grave’s disease a type II hypersensitivity disease?

Answer 15

-Produces receptor stimulating antibodies (‘anti-TSHR antibodies)
-Cause prolonged stimulation of the thyroid gland
-Excess thyroid hormone secreted
-Increased metabolic rate

Question 16

Why is Myasthenia Gravis disease a type II hypersensitivity disease?

Answer 16

-Disease of the neuromuscular junction of humans, dogs & cats
-Produces receptor blocking antibodies
-Blocking antibodies specific against AchR > Ach can’t bind
-Causes muscular weakness & excessive fatigue

Question 17

What is another name for Type III hypersensitivity?

Answer 17

Immune complex hypersensitivity

Question 18

What are the 2 causes of Type III hypersensitivity?

Answer 18

1. Antigen excess
2. Antibody excess

Question 19

How does antibody excess cause Type III hypersensitivity?

Answer 19

Sensitisation, which leads to an excessive IgG response
After an individual has become sensitised, then subsequent local exposure to allergen will result in:
-local immune complex formation (Ag & Ab)
-triggers local inflammatory response
-the ‘Arthus Reaction’

Question 20

Where is the most common place for Type III hypersensitivity caused by antibody excess, to occur?

Answer 20

Respiratory tract

Question 21

What are the consequences of immune complex (IC) formation?

Answer 21

-Complement activation
-Mast cell degranulation
-Chemotaxis + leucocyte recruitment + IL-1, TNF = inflammation
-Vasodilation, oedema , platelet aggregation, microthrombi

Question 22

How does antigen excess cause Type III hypersensitivity?

Answer 22

-Sensitisation leads to circulating antibody
-Exposure to high concentration antigen (antigen excess)
-Results in the formation of small soluble immune complexes which are found in the blood & circulate around the body, resulting in systemic disease

Question 23

How does immune complex (IC) deposition in blood vessels result in complement activation & vasculitis?

Answer 23

Complement activation leads to neutrophil degranulation, platelet aggregation & basophil release
Platelet aggregation creates microthrombi > blood vessel occlusion & ischemic necrosis
Results in vasodilation & inflammation of the blood vessel wall (“vasculitis”)

Question 24

What are some sites of localisation of circulating immune complexes?

Answer 24

IC deposition occurs at certain predilection sites - small bore capillaries with a turbulent blood flow
Sites:
-renal glomeruli
-uveal tract of the eye
-skin at the junction between the epidermis & dermis
-synovium of joints

Question 25

What factors determine IC deposition?

Answer 25

-Size of complex
-If IC clearance mechanisms are overwhelmed
-Nature of antigen
-Nature of antibody
-More likely to deposit at sites of high blood pressure & turbulent blood flow (eg renal glomeruli)
-Damage to blood vessel walls (endothelial lesions)

Question 26

What does feline immune complex glomerulonephritis cause?

Answer 26

A protein loosing nephropathy

Question 27

What are some characteristics of Type IV hypersensitivity?

Answer 27

-Involves mononuclear cells & cytokines
-Delayed onset 24-72hrs
-Delayed type hypersensitivity (DTH)

Question 28

Describe the process of Type IV hypersensitivity?

Answer 28

1. Antigen presenting cell (APC)
2. Sensitised memory Th1 cells reacts to antigen
3. Th1 produces IFN-𝞬 which causes adhesion molecule expression + causes production of macrophages, Th1, CD8, NK cells
4. Macrophages produce IL-1, TNF, IL-6

Question 29

Name 2 examples fo hypersensitivity mechanisms evolved for immunological benefit

Answer 29

Type I mechanism anti-parasitic
Type IV mechanism tuberculosis