Week 11 Flashcards
What are type B adverse drug reactions known as?
Idiosyncratic
What are type A adverse drug reactions?
They are predictable and dose dependent, they are more common, there is a low mortality rate and managing this just requires a lower dose.
What are type B adverse drug reactions?
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.
What is the HLA Locus?
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
What are HLA molecules used for?
- Present a wide variety of “self” and “non-self” peptides
- Antigen presentation
How would you classify specific HLA regions?
Chromosome region, the gene, the allele group and the specific HLA allele. For example HLA-DRB1*13:01
What is the allele group?
group of alleles that share the same serotype detected by one antibody
What is antigen presentation used for?
A vital immune process, essential for T cell immune response triggering.
What do T cells do after recognising foreign antigens?
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)
What is an antigen?
Intracellular (viruses, some bacteria etc), exogenous pathogen
What does MHCI present antigens to?
Cytotoxic CD8+ T-cells
Intracellular antigens
What does MHCII present antigens to?
CD4+ helper T-cells
Extracellular antigens
How does MHC class 1 antigen process and present antigens?
- 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
What is abacavir?
Is a prodrug used in HIV treatment
How does abacavir work?
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.
Which allele is associated to abacvir hypersensitivity?
HLA-B*57:01 allele is associated with an increased risk of hypersensitivity reaction
The HLA-B has many different variation, why is this important in the immune system?
It allows the immune system to respond to a wide range of foreign invaders.
How are the polymorphisms written in the HLA gene?
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
What are the hypotheses of involvement of HLA ligand behind the hypersensitivity reactions from abacavir?
((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
Why are cells tolerant to ‘self’ peptides?
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.
What happens normally if they cell recognises some ‘self’ peptides?
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.
How do HLA-B*57:01 alleles differ in their peptide binding/specificity?
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.
What happens with Abacavir and HLA-B57*01?
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.
How does abacavir cause a hypersensitivity reaction in HLA*57:01 carriers?
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.
Why might ‘self’ peptide be recognised as foreign by the CD8+ memory T cells?
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.
Why does abacavir not bind to the HLA-B*57:02 and 03?
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.
What percent of individuals with the HLA-B*57:01 allele will develop hypersensitivity to abacavir?
45%
How common is HLA-B*57:01 in the different populations?
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
What are the CPIC guidelines for abacavir?
Screening should be performed in all abacavir-native individuals, and abacavir is not recommended in individuals who are HLA-B*57:01 positive.
What does abacavir change?
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.
What is the chemical group of abacavir that interacts with HLA-B*57:01, how could this be a target for improvement?
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.
What is depersonalising therapy?
When you change the therapy to make it completely accessible to all individual no matter what polymorphic DNA they have.
What is Carbamazepine?
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.
What is Carbamazepine hypersensitivity?
Cultaneous adverse drug reactions, of which most are mild, but cause considerable discomfort leads to discontinuation of therapy.
What are the serious effects of Carbamazepine hypersensitivity?
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.
What are the two alleles associated with carbamazepine hypersensitivity?
HLA-A*31:01 and
HLA-B*15:02
What is the mechanism of carbamazepine hypersensitivity?
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.
In what population is the HLA-B*15:02 allele most common?
South East Asia
Not usually seen in caucasians or Japanese individuals
How is HLA-A*31:01 spread over the populations?
Quite evenly distributed over all the populations.
What are the CPIC guidelines for Carbamazepine?
At risk poulations should be screened in the presence of HLA-B*15:02 allele prior to starting the therapy.
What are the guidelines for Carbamazepine in Canada?
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.
