39. Immunopathology (HT)

Question 1

Name 6 ways in which the immune system can go wrong and cause disease.

Answer 1

1. Autoimmunity
2. Transplant / transfusion rejection
3. Leukaemia and lymphoma
4. Immunodeficiency
5. Septic shock / sepsis / failure of ‘tissue tolerance’
6. Immune-type hypersensitivity

Question 2

Why is the body susceptible to leukaemias and lymphomas?

Answer 2

• Generating BCR and TCR is very dangerous because the body positively encourages human genome rearrangement in somatic cells.
• This can lead to cancers.
• Example: Burkitt’s Lymphoma where the t (8;14) reciprocal chromosomal translocation brings the Ig heavy chain locus on chromosome 14 next to the c-myc oncogene on chromosome 8

Question 3

Give a summary table of the 4 main types of hypersensitivity.

Answer 3

Question 4

According to the spec, what are the 5 types of hypersensitivity called?

Answer 4

• Type 1 = Anaphylactic
• Type 2 = Cytotoxic
• Type 3 = Immune Complexes
• Type 4 = Delayed Type Hypersensitivity
• Type 5 = Stimulatory Hypersensitivity

Question 5

Describe the mechanism of Type 1 hypersensitivity.

[IMPORTANT]

Answer 5

• An allergen is presented by APCs to helper T cells, which activate B cells to produce IgE immunoglobulins against it
• IgE binds to high-affinity IgE receptors on the surfaces of mast cells, which means that these cells are now primed to react the next time the cells come into contact with the allergen
• Cross-linking of IgE on the cell surface causes rapid degranulation of histamine, proteases, heparin and chemotactic factors
• There is also synthesis and release of platelet activating factor (PAF), leukotrienes and prostaglandins
• The histamine leads to smooth muscle contraction
• Widespread activation of mast cells leads to systemic effects -> Circulatory shock, hypotension, chest tightness and, in the most severe cases, respiratory arrest and death. This is called anaphylactic shock.

Question 6

What do mast cells release?

Answer 6

• Their granules contain heparin and histamine, which are rapidly released
• They can also release leukotrienes, prostaglandins and cytokines (TNFa), but this release is slower

Question 7

In what sort of allergies are type 1 hypersensitivity reactions involved?

[IMPORTANT]

Answer 7

• Hay fever
• Asthma
• Food allergies

Question 8

Which immunoglobulins are important in type 1 hypersensitivity reactions?

Answer 8

IgE (they bind to mast cells, priming them)

Question 9

What are the effects of mast cell degranulation in the:

• GI tract
• Airways
• Blood vessels

Answer 9

Question 10

Over what time frame do type 1 hypersensitivity reactions occur?

Answer 10

Rapidly (within approximately 20 min of an insult) so they are also called ‘immediate hypersensitivity reactions’.

Question 11

To what receptors on mast cells do IgE bind? What is the effect of this?

Answer 11

FcεRI

(This denotes that it is the Fc region of IgE being bound)

The effect of this is that the mast cell becomes primed for degranulation if it encounters the appropriate antigen.

Question 12

Summarise the effects of histamine in type 1 hypersensitivity reactions.

Answer 12

• The actions of histamine depend on the site of release.
• In the airways, it induces smooth muscle contraction; in the skin, it causes the hallmark wheal and flare response.

Question 13

Give some clinical relevance for how you can find out that you have an allergy.

[EXTRA]

Answer 13

A skin prick test, also called a scratch test, checks for immediate allergic reactions to as many as 40 different substances at once.

Question 14

What are anaphylactoid reactions?

[EXTRA]

Answer 14

• Anaphylactoid reactions are anaphylaxis-like reactions that also result from mast cell degranulation and widespread histamine release.
• In these reactions the initial stimulation of mast cells does not occur through interaction of IgE with antigen.
• Mast cells are stimulated directly by anaphylactoid substances. Examples include dextran starches, fluorescein and radio-opaque contrast media.
• Anaphylactoid reactions are not induced in all individuals exposed to these compounds. Anaphylactoid reactions may be responsible for cases of severe cardiovascular collapse during anaesthesia.

Question 15

What are some immediate and long-term treatments for type 1 hypersensitivity reactions?

[IMPORTANT]

Answer 15

Immediate:

• Anti-histamines
• Adrenaline

Long-term:

• Cromoglycate
• Leukotriene receptor antagonists
• Glucocorticoids
• Anti-histamines

Question 16

Describe the mechanism of type II hypersensitivity reactions.

[IMPORTANT]

Answer 16

• Type II hypersensitivity reactions occur when IgG antibodies are produced against a non-harmful antigen.
• This can occur when self-reactive B-cells are not deleted during development or during other specific situations, such as blood transfusion.
• Binding of the IgG antibodies to native cells leads to cell destruction via:
  
  • Complement activation
  • Antibody-dependent cellular cytotoxicity (ADCC), where cytotoxic T cells kill native cells marked by antibodies
• In some cases, the antibodies may also block signal transduction if they bind at important receptors.
• This can underlie autoimmune disease, including organ specific disease and immune haemolytic anaemias.

Question 17

Give some examples of situations in which type II hypersensitivity may occur.

[IMPORTANT]

Answer 17

• Blood transfusions with ABO or rhesus group mimatches -> The recipient has (or produces) antibodies against the foreign antigens
• Hyperacute allograft rejection -> Due to existing antibodies against foreign ABO blood antigens (see transplantation flashcards)
• Haemolytic disease of the newborn -> Due to IgG antibodies that cross the placenta into the foetus and bind to RBCs, leading to anaemia.

Question 18

What is haemolytic disease of the newborn? What is the pathogenesis and how can it be prevented?

[IMPORTANT]

Answer 18

• It is a condition that develops in a foetus at or around birth, when the mother’s IgG molecules pass through the placenta and attack the foetus’
• Usually occurs when:
  
  • Rhesus D-negative mother becomes pregnant with an Rhesus D-positive child (the child having inherited the D antigen from the father). The mother’s immune response to the fetal D antigen is to form antibodies against it (anti-D).
  • Incompatibility of the ABO blood group. This happens when a mother with blood type O becomes pregnant with a fetus with a different blood type. The mother’s serum contains naturally occurring anti-A and anti-B antibodies, which can cross the placenta. This is usually less severe.
• This sensitisation of the mother’s immune system usually occurs during the first pregnancy, often when a small amount of fetal blood enters the mother’s system during labour. This usually involves mostly IgM antibodies.
• HDN occurs in the second pregnancy, when IgG are produced and can cross the placenta.

Treatment:

• Intravenous immunoglobulins
• Plasmapheresis (removal of the antibodies)
• Early delivery

Question 19

Give some clinical examples of conditions caused by type II hypersensitivity.

[EXTRA]

Answer 19

• Goodpasture’s syndrome -> Antibodies are produced against type IV collagen found on the basement membrane of the lung and glomerulus.
• Myasthenia gravis -> Antibodies are produced against the acetylcholine receptor.

Question 20

Describe the mechanism of type III hypersensitivity reactions.

[IMPORTANT]

Answer 20

• Antigen/antibody complexes (a.k.a. immune complexes) are deposited in areas of the body, leading to complement activation and inflammation.
• Normally, immune complexes are maintained as soluble immune complexes in the blood by complement proteins C2 and C4. These immune complexes bind to complement receptors on red blood cells allowing their transport to the spleen where complexes are removed and destroyed.
• However, if the production of immune complexes is greater than the clearance, this is when precipitation can occur and the hypersensitivity reaction is triggered.
• Areas affected by immune complex precipitation tend to be sites of filtration such as the glomeruli, synovium and epidermal basement membrane.

Question 21

Give some examples of conditions that are related to type III hypersensitivity.

[IMPORTANT]

Answer 21

• Systemic lupus erythematosus (SLE) -> Due to fewer complement receptors on RBCs, which means that immune complexes are cleared at a slower rate. The deposition is often renal.
• Farmer’s lung -> Due to inhaled organic dust particles that produce large amounts of immune complexes in the lungs and causing inflammation of the alveoli.
• Rheumatoid arthritis -> May include deposition of immune complexes in the joints.

Question 22

Where are immune complexes deposited in type III hypersensitivity?

Answer 22

• It may be local (e.g. Farmer’s lung) or diffuse (e.g. deposition in microvasculature).
• The glomeruli are common sites of type III hypersensitivity due to their function in filtration of plasma.

Question 23

Describe the mechanism of type IV hypersensitivity reactions.

[IMPORTANT]

Answer 23

• An antigen is taken up by local innate immune cells such as macrophages and Langerhans cells.
• These APCs activate previously sensitized? CD4+ T cells.
• These T cells tend to take on a Th1 profile and migrate to the area of high antigenic load where they release inflammatory cytokines, including IFN-γ, IL-1, IL-2 and IL-6.
• This leads to local inflammation and further immune cell migration and activation
• No B cells or antibodies are involved
• The process takes over 12 hours, so it is known as delayed type hypersensitivity (DTH)

Question 24

Why is type IV hypersensitivity delayed?

[IMPORTANT]

Answer 24

It takes time for the cells to accumulate.

Question 25

In type IV hypersensitivity, what happens if the antigen exposure is prolonged? When might this happen?

[IMPORTANT]

Answer 25

• If an antigenic challenge is prolonged, the chronic inflammatory response can result in granuloma formation characterised by multinucleate giant cells produced by the fusion of macrophages. Granulomatous reactions can take weeks to resolve.
• This can occur in pathogenic infections, such as tuberculosis, or in autoimmune conditions

Question 26

What are some conditions related to type IV hypersensitivity?

Answer 26

• Contact dermititis (inflammation of the skin after contact with a sensitizing agent)
• Type I diabetes
• Multiple sclerosis

Question 27

What is the Mantoux test and how does it work?

[IMPORTANT]

Answer 27

• It is a test for previous tuberculosis infection
• It works by intradermal administration of tuberculin (a protein derived from Mycobacterium tuberculosis)
• If the person has been exposed to the bacterium before, they will have been sensitized to it, so the sensitized T-cells are recruited to the skin site where they release lymphokines.
• These lymphokines induce induration through local vasodilatation, edema, fibrin deposition, and recruitment of other inflammatory cells to the area.
• This is a classical example of type IV hypersensitivity (delayed type hypersensitivity) and the peak is seen after more than 24 hours

Question 28

Describe the mechanism of type V hypersensitivity. Give an example of a condition where it is seen.

[IMPORTANT]

Answer 28

• It is caused by an autoantibody acting as an agonist on cell surface receptors
• Example: Grave’s Disease (hyperthyroidism).