Hypersensitivity

Question 1

What are the 5 different types of antibody classes?

Answer 1

IgG
IgD
IgE 
IgA (dimer)
IgM (pentamer)

Question 2

Why is it important to have different secreted antibody classes (isotypes)?

Answer 2

Their different structures result in different binding capacities
e.g. IgG3 potently activates complement and Fc receptor mediated phagocytosis, while IgA can cross mucosal epithelium and IgE can induce mast cell degranulation

Question 3

What are the key features of the T cell immune response?

Answer 3

Naive T cell encounters antigen, which activates it
Causes rapid proliferation - clonal expansion
Results in both effector cells and memory cells

Question 4

What are some hypersensitivity reactions that can occur within an individual?

Answer 4

Harmless foreign antigens (i.e. allergy, contact hypersensitivity)
Autoantigens (i.e. autoimmune disease)
Alloantigens - an antigen present only in some individuals (e.g. of a particular blood group) and capable of inducing the production of an alloantibody in people that lack it(i.e. serum sickness, transfusion reactions, graft rejection)

Question 5

What are the 4 types of hypersensitivity reactions and what is required to trigger them (briefly)?

Answer 5

1. Type I - Immediate hypersensitivity
2. Type II - Antibody-dependent cytotoxicity
3. Type III - Immune complex mediated
4. Type IV - Delayed cell mediated
   Types 1-3 - depend on the interaction of antigen with antibody
   Type 4 - involves T cell recognition and because of the longer time scale, it is referred to as ‘Delayed type hypersensitivity’

Question 6

What are the triggers of Type I and which class of antibodies is involved?

Answer 6

An allergic reaction provoked by re-exposure to a specific type of antigen referred to as an allergen
Involves IgE
Normally, people only make an IgE response to parasitic infections / potent venoms
Individuals with allergies produce antibodies against common multivalent, environmental antigens (antigen with multiple sites) - these antigens are known as allergens

Question 7

Examples of Type I hypersensitivity?

Answer 7

Anaphylaxis  
Asthma 
Drugs - e.g. penicillin, sulphonamides
Food allergy - e.g. peanuts
Rhinitis - seasonal and perennial :
Plants (e.g. timothy grass, birch trees), animal dander (e.g. cats, dogs) and insect products (e.g. bee venom, house dust mites)

Question 8

What is the mechanism for Type 1 hypersensitivity?

Answer 8

Type 1 sensitivity requires re-exposure:
During the 1st exposure: initial sensitisation of immune system to allergens
Cause IgE production - type 2 helper CD4 T cells and B cell helper follicular CD4 T cells bind and are activated, which produce the type 2 cytokines IL-4 and IL-13, these act on B cells and promote B cells to divide to plasma cells that produce antigen specific IgE
IgE binds to mast cells and basophils, which then express a high affinity IgE receptor
During the 2nd exposure: More IgE antibody produced
Antigen cross-links IgE on the mast cells and basophils
This leads to degranulation and release of inflammatory mediators e.g. histamine, heparin etc. - causing increased vascular permeability and smooth muscle contraction

Question 9

What are the inflammatory response ‘phases’ in type I?

Answer 9

Early phase - small molecules produced directly by mast cells, occurs within minutes of allergen exposure
Later response - within a few hours is the result of the recruitment of early inflammatory cells such as neutrophils
Third phase - 3-4 days after exposure where high frequencies of eosinophils are recruited

Question 10

How to test for Type I hypersensitivity (AKA allergies)?

Answer 10

Skin prick test - exposing the skin to small amounts of allergen, if there is inflammation, most likely they have an allergy

Question 11

What are the triggers of Type II and which class of antibodies is involved?

Answer 11

Sensitisation can involve either exposure to a foreign antigen (e.g. some drugs can bind to the surface of cells in the blood, or non-self antigens blood transfusions or organ transplants) or the response to a self-antigen
Involves IgG or IgM that bind to antigens present on the surface of the cells (causing destruction)

Question 12

Examples of Type II hypersensitivity?

Answer 12

Mismatched blood transfusion - antibodies cause immune induced destruction of those red blood cell, inflammation and tissue damage
HDN (haemolytic disease of newborns) - anti-D antibodies of mother can destroy Rh D positive blood of the foetus / newborn
Thrombocytopenia - antibodies develop against platelet surface proteins
Graves disease - patients develop thyroid stimulating antibodies that bind the thyrotropin receptor resulting in secretion of thyroid hormones

Question 13

What are the 3 different mechanisms by which these antibodies cause Type II hypersensitivity?

Answer 13

1. Anti-receptor activity – blocking or activating its function
2. Antibody dependent cell-mediated cytotoxicity (abbreviated to ADCC)
3. Classical activation of the complement cascade

Question 14

What is the complement cascade/ activation for Type II?

Answer 14

Complex process - antibody on cell surface recognised by complement components
Ultimately leads to the formation of the membrane attack complex (MAC) on the cell surface, and cell death due to loss of osmotic integrity
Also results in inflammation, opsonisation (targeted for destruction by phagocyte) and recruitment and activation of immune cells

Question 15

What is the ADCC mechanism for Type II?

Answer 15

Antibody-antigen complexes on the surface of cells are bound by Fc receptors expressed by cells e.g. granulocytes and NK cells, leading to directed lysis of the target cell, but also the release of inflammatory mediators, chemokines and cytokine

Question 16

What are the triggers of Type III and what type of molecule is involved?

Answer 16

Immune complexes - non-cell bound antigen-antibody complexes
Normally, these are efficiently cleared out of the blood, however, inefficiency can lead to immune complex deposits in body tissues, causing imflammation and tissue damage
This can lead to symptoms such as fever, rashes, joint pain or protein in the urine
Can be from self cells (autoimmune) or foreign antigens
There are no specific class of antibodies involved

Question 17

Examples of Type III hypersensitivity?

Answer 17

Vasculitis if deposited in blood vessels
Glomerulonephritis if in the kidneys
Arthritis if in the joints
Responsible for many autoimmune diseases: e.g. rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus (SLE)
Serum sickness - Body recognises the anti-venom antibodies given to patients with snake bites as foreign, hence developing antibodies against the anti-venom antibodies. If the person is bitten again and given the same anti-venom, their body’s antibodies / immune response destroys the anti-venom, causing rapid inflammation

Question 18

What is the mechanism for Type III hypersensitivity?

Answer 18

Same immunological processes as in inflammation - complement activation and cell recruitment/activation
Activation of other cascades e.g. clotting

Question 19

What are the triggers of Type IV and which type of immune cell is involved?

Answer 19

Primarily initiated by T cells
Like the others, also involved re-exposure
During the 1st exposure:
Sensitisation phase - immune system encounters antigen and is expressed by antigen presenting dendritic cells, activating naive T cells (e.g. Th 1, Th 2 etc.) to activate macrophages and cytotoxic T cells which mediate direct cellular damage; and to produce memory T cells
During the 2nd exposure:
Memory T cells respond promoting inflammation at the site of exposure, however, 2-3 days lag for peak inflammation response

Question 20

Examples of Type IV hypersensitivity?

Answer 20

Contact dermatitis - exposure to poison ivy (urushiol drives Th 1 response)
Chronic graft rejection
Graft-versus-host disease (GVHD) - seen following bone marrow transplant in immune compromised patients - i.e. graft begins to kill the host cells
Coeliac disease
Contact hypersensitivity
Many others: asthma, rhinitis, eczema
Other contact antigens such as nickel salts or hair dyes

Question 21

Why is antibody production rare for Type IV hypersensitivity?

Answer 21

Usually, small nature of molecule rarely results in antibody production

Question 22

What is the mechanism of Type IV hypersensitivity?

Answer 22

Molecules drive Th1 based inflammation (although any memory T cell capable of driving an immune overreaction e.g. Th 2 in asthma)
Memory cells produce cytokines such as IFN-gamma which promote the pro-inflammatory activation of macrophages resulting in swelling and oedema, and the formation of blister like lesions