Hypersensitivity

Question 1

What is an allergen?

Answer 1

An allergic reaction provoked by re-exposure to a specific type of antigen

Question 2

What are examples of type 1 hypersensitivity?

Answer 2

asthma, allergic rhinitis and atopic dermatitis.

Question 3

What antigens are type 1 responses mediated by?

Answer 3

Antigen specific IgE antibodies

Question 4

What do non-allergic individuals predominately make IgE in response to?

Answer 4

• Parasitic infections

- V potent venoms

Question 5

What do individuals with allergies produce?

Answer 5

• antibodies against common multivalent (which means the antigen has multiple sites at which an antibody can attach or antigen can be produced) environmental antigens
• these antigens have become known as allergens, and include things such as foods (e.g. peanuts), plants (e.g. timothy grass, birch trees), animal dander (e.g. cats, dogs), drugs (e.g. penicillin, sulphonamides) and insect products (e.g. bee venom, house dust mites).

Question 6

What are prick of skin tests?

Answer 6

expose skin to small amount of allergen and look at inflamed tissue to diagnose allergy

Question 7

What is the initial sensitisation of the immune response to allergens that cause IgE production?

Answer 7

• complex

- Factors such as genetics, age environment involved

Question 8

What is the end result of sensitisation of imminent response to allergens that case IgE production?

Answer 8

1. Generation of type 2 helper CD4 T cells and B cell helper follicular CD4 T cells which produce the type 2 cytokines IL-4 and IL-13; when these act on B cells they can promote B cell to switch to producing antigen specific IgE.
2. Interestingly unlike other antibodies IgE is very rarely found in the circulation, even in allergic individuals

Question 9

What happens once IgE is production?

Answer 9

It is rapidly bound to surface of innate immune cells, especially mast cells and basophils

Question 10

What do these granulocytic cells express?

Answer 10

• a high affinity IgE receptor, Fc epsilon receptor I (FcεRI)
• If an allergen is encountered by cell bound IgE it results in rapid crosslinking and degranulation of the mast cell or basophil
• For perspective this happens much faster, and across a much broader site, even a low antigen levels, than is seen during normal inflammation based activation of mast cells (see the summary figure below and the table of mediators released).

Question 11

What is the end product of the reactions?

Answer 11

• release of histamine a host of cytokines and can recruit other cells and promote further Th2 differentiation and highly active smooth muscle contraction molecules such as leukotrienes and prostaglandins
• The variety of molecules released during type I responses results in “phases” of response

Question 12

What early phase?

Answer 12

-The early phase, a result of bioactive small molecules produced directly by mast cells, occurs within minutes of allergen exposure

Question 13

What is a later phase?

Answer 13

-A later response, often seen within a few hours is the result of the recruitment of early inflammatory cells such as neutrophils

Question 14

What is a third phase?

Answer 14

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

Question 15

What does type II hypersensitivity include?

Answer 15

-otherwise 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 16

What could mismatched blood transfusions?

Answer 16

-mismatched blood transfusion could be considered one such hypersensitivity with antibodies recognising different, non-self, carbohydrate groups of the transfused red blood cells resulting in immune induced destruction of those red blood cell, inflammation and tissue damage

Question 17

What are other examples of type II hypersensitivity?

Answer 17

-Other examples include haemolytic disease of newborns, where maternal antibodies can cross the placenta and destroy fetal red blood cells if the foetus and the mother have mismatched Rh D alleles

Question 18

What is immune thrombocytopenia disease?

Answer 18

1. Where antibodies develop against platelet surface proteins
2. Graves disease where patients develop thyroid stimulating antibodies that bind the thyrotropin receptor resulting in secretion of thyroid hormones

Question 19

What can type II sensitisation can involve?

Answer 19

1. 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)
2. The aberrant response to a self-antigen resulting in IgGs or IgMs that recognise cell surface structures

Question 20

What are the different mechanisms that antibodies cause disease?

Answer 20

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 21

What is a complement cascade?

Answer 21

-Is 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

Question 22

What does activation of the classical complement pathway cause?

Answer 22

inflammation, opsonisation and recruitment and activation of immune cells

Question 23

What happens in ADCC?

Answer 23

-In ADCC antibody-antigen complexes on the surface of cells are bound by Fc receptors (which bind the constant, 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 24

What can type II hypersensitivity result in?

Answer 24

-multiple mechanisms of tissue injury including local or systemic inflammation, cell depletion leading to a loss of function or imbalance in organ function.

Question 25

What is type III hypersensitivity sometimes known as?

Answer 25

immune complex driven disease

Question 26

What are immune complexes?

Answer 26

non-cell bound antigen-antibody complexes which are normally cleared through the activity of the immune system

Question 27

What happens if the immune complexes cannot be efficiently cleared?

Answer 27

– for example if they are the result of antibodies reacting against self-antigens such as nuclear DNA – the immune complexes end up being deposited in the blood vessel walls and tissues, promoting inflammation and tissue damage

Question 28

What symptoms does this lead to?

Answer 28

-fever, rashes, joint pain or protein in the urine: vasculitis if deposited in blood vessels, glomerulonephritis if in the kidneys or arthritis if in the joints -Many auto-immune diseases including rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus (SLE) involve type III reactions

Question 29

What happens in SLE patients?

Answer 29

-develop IgGs against DNA or proteins present in the nucleus of cells (nucleoproteins), which form persistent immune-complex deposits and a variety of pathologies

Question 30

How can type III hypersensitivity arise?

Answer 30

- While many diseases associated with type III hypersensitivity are auto-immune in origin, as with all antibody mediated diseases they can also result from encounters with foreign antigens. - For instance persistent infections such as hepatitis virus infections can result in immune complex deposition as can exposure to freely circulating foreign antigens such as drugs.

Question 31

What is a good example of type III hypersensitivity?

Answer 31

- Serum sickens - Say a person is bitten by a snake, they may be 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 - This process may take several weeks, and does not represent a problem as the 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 32

What happens in the first three types of hypersensitivity?

Answer 32

-The first 3 types of hypersensitivity all involved the generation of specific types of antibodies against antigens in different locations – resulting in inflammation

Question 33

What is type 4 hypersensitivity?

Answer 33

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

Question 34

How is type 4 sensitivity initiated?

Answer 34

1. A sensitization phase needs to occur where antigen is presented to naïve T cells by antigen presenting dendritic cells 2. This results in the generation of antigen specific memory T cells, a process that like the other forms of sensitization takes several weeks

Question 35

What happens in subsequent exposure in type 4 sensitivity?

Answer 35

1. These memory T respond promoting inflammation at the site of exposure 2. However because the memory T cell response (which requires recruitment and expansion) 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.

Question 36

What is an example of type 4 hypersensitivity?

Answer 36

1. The most common example of type IV hypersensitivity 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).

Question 37

What happens on exposure in type 4 hypersensitivity?

Answer 37

-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.

Question 38

What other contact antigens can drive Th1 based inflammation?

Answer 38

- Nickel salts, hair dyes | - intracellular pathogens such as measles virus and mycobacterium TB

Question 39

What is the skin test for TB?

Answer 39

-Positive readout of the tuberculin skin test, which 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 40

What are type iV reactions limited?

Answer 40

1. Type IV reactions are not limited to memory Th1 cell responses however, with any memory T cell capable of driving an immune overreaction 2. For instance in asthma, allergens can cause overreaction of T helper 2 cells which produce soluble mediators that that promote bronchoconstriction 3. While CD8 T cells can lead to inflammation and rejection of a tissue graft by directly killing transplanted cells. 4. In many diseases more than one type of hypersensitivity reaction may be contributing to pathology at the same times