Hypersensitivity

Question 1

Some features of antibodies (GAMED)

Answer 1

IgG3 potently activates complement and Fc receptor mediated phagocytosis
IgA can cross mucosal epithelium
IgE can induce mast cell degranulation.

Question 2

Main differences between CD4+and CD8+ T cells

Answer 2

CD4+ activated macrophages , B cells and other cells while CD8+ cells kill infected ‘target cell’s’and act in macrophage activation

Question 3

What is Type 1 Hypersensitivity

Answer 3

Immediate/anaphylactic hypersensitivity. Allergic reactions that is provoked by interaction with allergen , examples include asthma, allergic rhinitis and atopic dermatitis.

Question 4

Antibodies included in Type 1 hypersensitivity

Answer 4

Antigen specific IgE antibodies ( non allergic, e.g. in response to parasitic infections or very potent venoms).

With allergens : antibodies against common multivalent environmen

Question 5

Common allergens

Answer 5

Foods ( peanuts), plants( Timothy grass and birch trees) , animal dander( cats and dogs), drugs ( penicillin and sulphonamides) and insect products ( bee venom, house dust, mites)

Question 6

How does the initial sensitisation of the immune response to allergens occur

Answer 6

1. Generation of type 2 helper (Th2) CD4 T cells and B cell helper follicular CD4 T cells
   
   2. Produce type 2 cytokines IL-4 and IL-13
   3. Act on B cells => promote B cell to switch from IgM to producing antigen specific IgE ( IgE is rarely found in circulation)

Question 7

What happens when the IgE ( after it has been sensitised by one allergen) comes into contact with allergen ( again)

Answer 7

1. IgE rapidly bound to the surface of innate immune cells, esp mast cells and basophils. These granulocytic cells express a high affinity IgE receptor, Fc epsilon receptor I (FcεRI).

If an allergen is encountered by cell bound IgE
1.Rapid crosslinking and degranulation of the mast cell or basophil.

The end product of these reactions is the release of histamine, a host of cytokines that can recruit other cells and promote further Th2 differentiation, and highly active smooth muscle contracting molecules such as leukotrienes and prostaglandins.

Question 8

Early phase response on Type 1

Answer 8

Theearly phase, a result of bioactive small molecules produced directly by mast cells, occurs within minutes of allergen exposure.

Question 9

Later response of Type 1 hypersensitivity

Answer 9

• Alater response, often seen within a few hours is the result of the recruitment of early inflammatory cells such as neutrophils.

Question 10

Third phase of Type 1 hypersensitivity

Answer 10

• A third phase, orlate response, is often peaks 3-4 days after exposure where high frequencies of eosinophils are recruited and Th2 cells are present

Question 11

What is type 2 hypersensitivity

Answer 11

known as antibody-mediated cytotoxic hypersensitivity, involves the destruction of cells by IgG or IgM antibody bound to antigens present on the surface of the cells.

Question 12

Examples of type 2 hypersensitivity

Answer 12

Mismatched blood transfusion which results in the destruction of rbc, inflammation and tissue damage

• haemolytic disease of newborns ( mismatch of RhD alleles)
• immune 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

Type 2 sensitisation can involve either

Answer 13

• Exposure to a foreign antigen (for example some drugs can bind to the surface of cells in the blood), or non-self antigens (blood transfusions or organ transplants)
  
  • Aberrant response to a self-antigen resulting in IgGs or IgMs that recognise cell surface structures.

Question 14

How can the antibodies involved in Type 2 sensitisation result in diseases

Answer 14

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 15

How does the complement cascade work

Answer 15

a complex process by which antibody on the surface of cells is recognised by the complement components, ultimately leading to the formation of the membrane attack complex (MAC) in the surface of the cell, and cell death due to loss of osmotic integrity.

Activation of the classical complement pathway also however results in inflammation, opsonisation and recruitment and activation of immune cells.

Question 16

What is the classical pathway

Answer 16

Antigen-antibody immune complexes

Question 17

What is the lectin pathway

Answer 17

PAMP recognition by lectins

Question 18

What is the alternative pathway

Answer 18

Spontaneous hydrolysis of pathogenic surfaces

Question 19

Antibody dependent cell-mediated cytotoxicity ( ADCC)

Answer 19

InADCCantibody-antigen complexes on the surface of cells are bound by Fc receptors (which bind the constant (Fc), not antigen specific, tail regions of IgM and IgG antibodies) expressed by cells such as granulocytes and NK cells lead to directed lysis of the target cell, but also the release of inflammatory mediators, chemokines and cytokines.

Question 20

How does type 2 hypersensitivity result in multiple mechanisms of tissue injury .

Answer 20

local or systemic inflammation, cell depletion leading to a loss of function or imbalance in organ function.

Question 21

How does type 3 hypersensitivity work

Answer 21

known as immune complex driven disease.Immune complexesare non-cell bound antigen-antibody complexes which are normally cleared through the activity of the immune system.

If immune complexes cannot be efficiently cleared they end up being deposited in the blood vessel walls and tissues, promoting inflammation and tissue damage.

Question 22

Symptoms of type 3 hypersensitivity

Answer 22

• Fever, rashes, joint pain
  
  • Protein in the urine
  • Vasculitis if deposited in blood vessels
  • Glomerulonephritis if in the kidneys
  • Arthritis if in the joints.

This can happen if the complexes are the result of antibodies reacting against self-antigens such as nuclear DNA.

Question 23

Examples of auto immune diseases involving type 3 hypersensitivity

Answer 23

• Rheumatoid arthritis
  
  • Multiple sclerosis (MS)
  • Systemic lupus erythematosus (SLE)- in SLE patients develop IgGs against DNA or nucleoproteins (proteins present in the nucleus of cells) which form persistent immune-complex deposits and a variety of pathologies.

Question 24

Examples of type 3 hypersensitivity that involves foreign antigens ( instead of autoimmune disorders)

Answer 24

• Persistent infections such as hepatitis virus infections can result in immune complex deposition
  
  • Exposure to freely circulating foreign antigens such as drugs.
    ○ Serum sickness:
    § Person is bitten by a snake => given anti-serum (antibodies specific to the snake venom proteins) to neutralise the snake venom.
    § These are foreign proteins, and while they neutralize the venom our bodies will react against them to produce antibodies that recognise the anti-venom antibodies.
    § First exposure => process may take several weeks so not a problem as anti-sera and the snake venom will be long cleared.
    § If however the person gets bitten by a snake again, these antibodies will rapidly recognise the anti-serum and drive rapid inflammation; another good reason to avoid venomous snakes.

Question 25

Type 4 hypersensitivity

Answer 25

other known as delayed-type or T cell mediated hypersensitivity, is primarily initiated by T cells.

Question 26

Sensitisation of type 4 hypersensitivity

Answer 26

antigen is presented to naïve T cells by antigen presenting dendritic cells => leads to generation of antigen specific memory T cells; like other forms of sensitization it takes several weeks.

Question 27

What happens during the subsequent exposure in Type 4 hypersensitivity

Answer 27

On a subsequent exposure these memory T respond promoting inflammation at the site of exposure. However because the memory T cell response is slightly slower than antibody mediated memory there is often a delay between exposure and response, with peak responses often seen 2-3 days after inflammation (T cell response requires recruitment and expansion)

Question 28

Example of Type 4 hypersensitivity

Answer 28

The most common example is contact dermatitis caused by exposure to poison ivy, where a small molecule called urushiol, drives a T helper 1 response (but due to its small nature rarely results in antibody production).

On re-exposure these 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.

Other examples include nickel salts or hair dyes which can drive Th1 based inflammation or other intracellular pathogens like measles and tuberculosis

Question 29

How does tuberculin skin test work

Answer 29

measures previous exposure to tuberculosis bacteria by injection of small amounts of M. tb protein into the skin, is a type IV hypersensitivity reaction.

Question 30

Asthma and type 4 hypersensitivity

Answer 30

allergens can cause overreaction of T helper 2 cells => produce soluble mediators => promote bronchoconstriction. In many diseases more than one hypersensitivity reaction can take place.

Question 31

Transplant cells and hypersensitivity

Answer 31

While CD8 T cells can lead to inflammation and rejection of a tissue graft by directly killing transplanted cells.