Week 11

Question 1

What are type B adverse drug reactions known as?

Answer 1

Idiosyncratic

Question 2

What are type A adverse drug reactions?

Answer 2

They are predictable and dose dependent, they are more common, there is a low mortality rate and managing this just requires a lower dose.

Question 3

What are type B adverse drug reactions?

Answer 3

They are not predictable based off drug structure and not dose dependent, and they rarely occur, so are not likely to be picked up until the drug is licenced, there is a high mortality rate and the management would be to discontinue therapy.

Question 4

What is the HLA Locus?

Answer 4

It a small region of the short arm of chromosome 6, which has the Class I (A, B,C) , II (DP, DM, DO, DQ, DR) and III genes

Question 5

What are HLA molecules used for?

Answer 5

• Present a wide variety of “self” and “non-self” peptides

- Antigen presentation

Question 6

How would you classify specific HLA regions?

Answer 6

Chromosome region, the gene, the allele group and the specific HLA allele. For example HLA-DRB1*13:01

Question 7

What is the allele group?

Answer 7

group of alleles that share the same serotype detected by one antibody

Question 8

What is antigen presentation used for?

Answer 8

A vital immune process, essential for T cell immune response triggering.

Question 9

What do T cells do after recognising foreign antigens?

Answer 9

Destroy the foreign antigens only when they are in the form of short polypeptides on the cell surface, that have been presented by the antigen presenting cells (MHCI or II)

Question 10

What is an antigen?

Answer 10

Intracellular (viruses, some bacteria etc), exogenous pathogen

Question 11

What does MHCI present antigens to?

Answer 11

Cytotoxic CD8+ T-cells

Intracellular antigens

Question 12

What does MHCII present antigens to?

Answer 12

CD4+ helper T-cells

Extracellular antigens

Question 13

How does MHC class 1 antigen process and present antigens?

Answer 13

• Virus infects the cell
• Viral proteins synthesised and degraded in cytosol
• Peptide fragments bind to MHC Class I in the ER
• MHC travels to the cell surface
• Cytotoxic T cell kills cell

Question 14

What is abacavir?

Answer 14

Is a prodrug used in HIV treatment

Question 15

How does abacavir work?

Answer 15

Once activated acts as a reverse transcriptase inhibitor (Carbovir), when viruses are replicating in the cell, carbovir is incorporated into the viral genome, HIV replication is terminated.

Question 16

Which allele is associated to abacvir hypersensitivity?

Answer 16

HLA-B*57:01 allele is associated with an increased risk of hypersensitivity reaction

Question 17

The HLA-B has many different variation, why is this important in the immune system?

Answer 17

It allows the immune system to respond to a wide range of foreign invaders.

Question 18

How are the polymorphisms written in the HLA gene?

Answer 18

Thousands of versions of HLA-B genes are known of which are given a particular number and categorised together, e.g. HLA-B57:01, HLA-B57:02, HLA-B*57:03

Question 19

What are the hypotheses of involvement of HLA ligand behind the hypersensitivity reactions from abacavir?

Answer 19

((pro)happen hypothesis) - A ligand that is uniquely presented by HLA allele is modified by the drug.
(p-i concept)
- The HLA molecule itself is modified by the drug in a region exposed to the TCR
(altered self-repertoire hypothesis)
Favoured
- The binding specificity of the HLA molecule is altered by the presence of the drug, resulting in presentation of other ligands such as peptide B

Question 20

Why are cells tolerant to ‘self’ peptides?

Answer 20

So there would have been a negative selection, so that ‘self’ peptides which bind to the E.g HLA-B*57:01 protein, there would not be a reaction too.

Question 21

What happens normally if they cell recognises some ‘self’ peptides?

Answer 21

Peptide antigens are generated, and then imported in the ER, where they bind to newly synthesised HLA-B*57 molecules that are exported to the cell surface via the Golgi body. At the cell surface complex is presented by CD8+ cytotoxic T-cells. Nothing will happen if they are ‘self’ protein as they have gone through negative selection.

Question 22

How do HLA-B*57:01 alleles differ in their peptide binding/specificity?

Answer 22

HLA-B*57:01 molecules preferentially bind peptides with A, S or T at position 2, while W, Y or F is preferred at C-terminus position 9.

Question 23

What happens with Abacavir and HLA-B57*01?

Answer 23

Abacavir can binds to a site in the peptide binding cleft of the HLA-B*57:01 molecules at aspartate at position 114 and serine at position 116.
Changes peptide specificity at position 9 to leucine and isoleucine (was Tryptophan, tyrosine and Phenylalanine previously), expressing different peptides to the cell surface.

Question 24

How does abacavir cause a hypersensitivity reaction in HLA*57:01 carriers?

Answer 24

Abacavir causes an altered peptide repertoire to be presented.
Derived from ‘self’ proteins but were NOT involved in establishing self tolerance as they don’t usually bind HLA-B*57:01.
Recognition of of these ‘self’ peptides by circulating CD8+ cytotoxic T cells precipitates an autoimmune reaction. Resulting in attack of healthy cells and overproduction of pro-inflammatory cytokines, such as IFN-gamma and TNF-alpha.

Question 25

Why might ‘self’ peptide be recognised as foreign by the CD8+ memory T cells?

Answer 25

any self peptide, which, sue to its lack of HLA-B*57:01 binding, has not been involved in the establishing self-tolerance, but becomes presented in the presence of abacavir will become recognised as foreign by pre-existing CD8+ memory T cells.

Question 26

Why does abacavir not bind to the HLA-B*57:02 and 03?

Answer 26

Because abacavir binds to specific 114 aspartate and 116 serine, which is not present in the other HLA-B*57:02 and 03 and doesn’t bind to these amino acids.

Question 27

What percent of individuals with the HLA-B*57:01 allele will develop hypersensitivity to abacavir?

Answer 27

45%

Question 28

How common is HLA-B*57:01 in the different populations?

Answer 28

7% European populations
3% in African Americans
Absent in homogenous South Asian, African and Japanese populations
Up to 20% in Northern Thai and Indian populations

Question 29

What are the CPIC guidelines for abacavir?

Answer 29

Screening should be performed in all abacavir-native individuals, and abacavir is not recommended in individuals who are HLA-B*57:01 positive.

Question 30

What does abacavir change?

Answer 30

Abacavir binds in the peptide binding cleft on HLA-B*57, causing a change in displayed peptides on the cell surface meaning they are displayed as foreign.

Question 31

What is the chemical group of abacavir that interacts with HLA-B*57:01, how could this be a target for improvement?

Answer 31

6-aminocyclopropyl group, could this group be replaced with another group so it does not bind to the HLA-B*57:01, which still doesn’t activate T-cells and antiviral activity needs to be maintained still stops replication of HIV genetic material.

Question 32

What is depersonalising therapy?

Answer 32

When you change the therapy to make it completely accessible to all individual no matter what polymorphic DNA they have.

Question 33

What is Carbamazepine?

Answer 33

Is a tricyclic compound, which blocks voltage-dependent sodium channels in the inactivated state, leaving fewer of the channels available to open. Which inhibits the rapid and repetitive generation of action potentials, treats Epilepsy, Trigeminal neuralgia and Bipolar disorder.

Question 34

What is Carbamazepine hypersensitivity?

Answer 34

Cultaneous adverse drug reactions, of which most are mild, but cause considerable discomfort leads to discontinuation of therapy.

Question 35

What are the serious effects of Carbamazepine hypersensitivity?

Answer 35

Stevens-Johnson syndrome (SJS)
Toxic Epidermal necrolysis (TEN)
Both life threatening conditions characterised by lesions of the skin (detachment of epidermis) and mucous membranes eroding. High mortality rate of 10% SJS and 50% of TEN.

Question 36

What are the two alleles associated with carbamazepine hypersensitivity?

Answer 36

HLA-A*31:01 and

HLA-B*15:02

Question 37

What is the mechanism of carbamazepine hypersensitivity?

Answer 37

There is the self-repertoire hypothesis like abacavir. Research suggests carbamazepine binds to the HLA-B*15:02 molecule at a secondary anchor site underneath the residues of the presented peptide, changing the peptide on the surface.

Question 38

In what population is the HLA-B*15:02 allele most common?

Answer 38

South East Asia

Not usually seen in caucasians or Japanese individuals

Question 39

How is HLA-A*31:01 spread over the populations?

Answer 39

Quite evenly distributed over all the populations.

Question 40

What are the CPIC guidelines for Carbamazepine?

Answer 40

At risk poulations should be screened in the presence of HLA-B*15:02 allele prior to starting the therapy.

Question 41

What are the guidelines for Carbamazepine in Canada?

Answer 41

Testing for the HLA-B15:02 is beneficial in populations where its most common, However, it should be completed in all patients, irrespective of their ancestors, as the safest option.
And testing everyone for HLA-A31:01 is recommended.