Hypersensitivity

Question 1

Describe the structure of the different antibody classes

Answer 1

IgG, IgD and IgE all form a Y shape with variable region joined to constant region via a hinge region. IgA also forms a Y shape however constant regions of two antibodies are joined by a J chain forming a dimer. IgM is a pentamer with adjacent antibodies joined by disulphide bonds and one J chain.

Question 2

Describe the functions of IgG antibodies

Answer 2

IgG1 antibodies potently bind to Fc receptors on phagocytes. Moderate activity in activating complement pathway and crossing placenta. IgG2 shows minimal activity with all activities of IgG1. IgG3 potently activates the classic complement pathway and binds to Fc receptor on phagocytes with moderate activity in crossing placenta. IgG4 cannot activate CCP but carries out moderate activity of other two functions.

Question 3

Describe the functions of IgA antibodies

Answer 3

Mucosal transport - two isotypes IgA1 and 2.

Question 4

Describe the function of IgM antibodies

Answer 4

Responsible mainly for activating classical complement pathway but have moderate activity involved in mucosal transport and are present on mature B cell membranes.

Question 5

Describe the function of IgE antibodies

Answer 5

Induce mast cell degranulation

Question 6

Describe the function of IgD antibodies

Answer 6

Present on membrane of mature B cells

Question 7

What is the CD4 T-cell responses to an APC?

Answer 7

Naive CD4 T-cells recognise antigen from the APC and are activated through autocrine function as they produce IL-2 which then binds to IL-2R on the same cell, stimulating clonal expansion supported by cytokines produced from other cellular sources. It then differentiates in the lymphoid tissue to produce effector CD4+ T-cell, responsible for activation of machrophages, B-cells and other cells. Memory cells are also produced.

Question 8

What is the CD8 T-cell response to an APC?

Answer 8

Naive CD8+ T-cell recognises antigen by binding to APC and is activated through autocrine function by IL-2 binding to IL-2R. Undergoes clonal expansion supported by cytokines produced from other cellular sources. It then differentiates in the lymphoid tissue to produce effector CD8+ T-cell, responsible for killing of infected target cells and macrophage activation.

Question 9

What are the different types of T-cells and their functions?

Answer 9

Treg cells are responsible for regulation and suppression of immune and inflammatory responses. TH17 cells are responsible for inflammation. TH2 cells are responsible for allergic and anti-helminth responses. TFH cells are responsible for B cell help in germinal centres. TH1 cells are responsible for cell-mediated immunity, macrophage activation and inflammation.

Question 10

What is type 1 hypersensitivity?

Answer 10

Allergic reaction provoked by re-exposure to a specific type of antigen referred to as an allergen. Most diseases thought of as allergic are likely to be a result of a type I hypersensitivity reaction including asthma, allergic rhinitis and atopic dermatitis.

Question 11

What is the response to type 1 hypersensitivity mediated by?

Answer 11

Mediated by antigen-specific IgE antibodies. Non-allergic => predominantly only make IgE in response to parasitic infections or very potent venoms. With allergies => antibodies against common multivalent environmental antigens (antigen has multiple sites at which an antibody can attach/antigen can be produced) - these antigens have become known as allergens

Question 12

What are common allergens?

Answer 12

1. Foods (e.g. peanuts)
2. Plants (e.g. timothy grass, birch trees)
3. Animal dander (e.g. cats, dogs)
4. Drugs (e.g. penicillin, sulphonamides)
5. Insect products (e.g. bee venom, house dust mites)

Question 13

How does the initial sensitization reaction occur in type 1 hypersensitivity?

Answer 13

The initial sensitization of the immune response to allergens that causes IgE production is complex with factors in genetics, age and the environment all involved. The end result, however, is

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
4. IgE rapidly binds 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)

Question 14

What happens when allergen is re-encountered in T1H?

Answer 14

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.

In the primary response, histamine and heparin causes increased vascular permeability and smooth muscle contractions. ECF-A and NCF-A cause eosinophil chemotaxis and neutrophil chemotaxis.

Question 15

What happens in the secondary reaction to T1H?

Answer 15

The early phase, a result of bioactive small molecules produced directly by mast cells, occurs within minutes of allergen exposure. A later response, often seen within a few hours is the result of the recruitment of early inflammatory cells such as neutrophils. A third phase, or late response, often peaks 3-4 days after exposure where high frequencies of eosinophils are recruited and Th2 cells are present

Leukotrienes are responsible for increased vascular permeability and increased pulmonary smooth muscle contractions. Prostaglandins do the same as well as vasodilation and platelet aggregation.

Question 16

What is type 2 hypersensitivity?

Answer 16

Type II hypersensitivity, 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 17

What is an example of TH2?

Answer 17

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 18

What conditions are caused by TH2?

Answer 18

1. Haemolytic disease of newborns, where maternal antibodies can cross the placenta and destroy foetal red blood cells if the foetus and the mother have mismatched Rh D alleles.
2. Immune thrombocytopenia, where antibodies develop against platelet surface proteins
3. Graves disease where patients develop thyroid stimulating antibodies that bind the thyrotropin receptor resulting in secretion of thyroid hormones.

Question 19

How can TH2 sensitization occur?

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. Aberrant response to a self-antigen resulting in IgGs or IgMs that recognise cell surface structures.

Question 20

How can antibodies cause disease in TH2?

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 the complement cascade?

Answer 21

The complement cascade 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, opsonization, recruitment and activation of immune cells.

Question 23

What is antibody dependant cell-mediated cytotoxicity?

Answer 23

In ADCC antibody-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 24

What are the mechanisms of tissue injury in TH2?

Answer 24

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

Question 25

What is type 3 hypersensitivity?

Answer 25

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

Question 26

What are the symptoms of a TH3 reaction?

Answer 26

If immune complexes cannot be efficiently cleared they end up being deposited in the blood vessel walls and tissues, promoting inflammation and tissue damage. This can lead to symptoms such as:
Fever, rashes, joint pain
Protein in the urine
Vasculitis if deposited in blood vessels Glomerulonephritis if in the kidneys
Arthritis if in the joints.

Question 27

What are examples of diseases involving type 3 reactions?

Answer 27

1. Rheumatoid arthritis
2. Multiple sclerosis (MS)
3. 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 28

What are examples of diseases caused by foreign antigens that involve a TH3 reaction?

Answer 28

Persistent infections such as hepatitis virus infections can result in immune complex deposition. Exposure to freely circulating foreign antigens such as drugs such as in serum sickness.

Question 29

What is serum sickness?

Answer 29

1. Person is bitten by a snake => given anti-serum (antibodies specific to the snake venom proteins) to neutralise the snake venom.
2. 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.
3. First exposure => process may take several weeks so not a problem as anti-sera and the snake venom will be long cleared.
4. 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 30

What is type 4 hypersensitivity?

Answer 30

Type IV hypersensitivity (delayed-type or T cell mediated hypersensitivity) is primarily initiated by T cells.

Sensitization phase needs to occur where antigen is presented to naïve T cells by antigen presenting dendritic cells => leads to generation of antigen specific memory T cells which takes several weeks.

When re-exposed, 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 31

What condition is an example of TH4 reaction?

Answer 31

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.

Question 32

What can cause a TH4 response and how can it be tested?

Answer 32

Other contact antigens such as nickel salts or hair dyes can also drive Th1 based inflammation, as can many intracellular pathogens such measles virus and Mycobacterium tuberculosis. Indeed the 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 33

Which cells can be involved in causing a TH4 response?

Answer 33

Type IV reactions are not limited to memory Th1 cell responses however, with any memory T cell capable of driving an immune overreaction. For instance in asthma, allergens can cause overreaction of T helper 2 cells => produce soluble mediators => promote bronchoconstriction. While CD8 T cells can lead to inflammation and rejection of a tissue graft by directly killing transplanted cells.