MHC Genetics and Disease Flashcards
What is the MHC?
MAJOR HISTOCOMPATIBILITY COMPLEX
What is the HLA?
Human Leukocyte Antigen Complex
Where is the MHC?
Located on Chromosome 6
What does the MHC consist of?
Transmembrane glycoproteins
What is the main role of the HMC?
Present antigens on the cell surface
What genes code for the MHC?
Highly polymorphic genes
How is the MHC inherited?
As haplotypes from parents.
What does the MHC locus contain?
2 types of highly polymorphic genes Class I and II
What is the difference between class i and class ii MHC?
Different but homologous
Different tissue distribution
Where are the glycoproteins expressed for class 1 of MHC?
All nucleated cells
What is the structure of MHC class 1?
MHC-encoded α-chain of 45kDa
α-chain anchored to the cell membrane
What elements are associated with the MHC Class 1 but are not covalently bonded?
β2-microglobulin, 12kDa, non-MHC encoded, non-transmembrane.
How is the shape of MHC class 1 formed?
Peptide antigen in a groove formed from a pair of α-helicies on a floor of anti-parallel β-strands
Where are the glycoproteins of MHC class 2 expressed?
Glycoprotein expression restricted to APCs
What is APCs?
Macrophages
Dendritic cells
B cells
How heavy is the alpha chain of the class 2 MHC?
34kDa
How heavy is the beta chain of the class 2 MHC?
29kDa
What is the structure of MHC class 2?
Both α and β chains anchored to the cell membrane
Peptide antigen in a groove formed from a pair of a-helicies on a floor of anti-parallel b strands
When was a full MHC sequence complete?
1999
Where do the polymorphisms occur on MHC?
Binding cleft
What is the peptide binding cleft?
Highly specialised grooves for antigen presentation, form
stable complexes with antigens
What size peptides do class 1 MHC accommodate for?
8-10
What size peptides do class 1 MHC accommodate for?
13-18
Which if the MHC classes binding cleft has an open structure?
Class 2
What does MHC bind to?
Antigen fragments produced by infected cells
Fragments from the proteolysis of foreign material.
How does the MHC interact with T cells?
MHC moves to surface to present antigen for T cell recognition.
What happens when antigens presented on surface aren’t MHC bound?
T cell won’t recognise it
Which T cell type does class 1 MHC interact with?
CD8 t cell
Which T cell type does class 2 MHC interact with?
CD4 t cell
Which MHC class deals with the endogenous pathway?
1
Which MHC class deals with the exogenous pathway?
2
What are the 2 laws of inheritance the MHC follows?
Polygeny
Polymorphism
What does it mean that the MHC is polygenic?
Codominance, combination of α and β for MHCII and from both parents
What does it mean that the MHC is polymorphic?
Have changes to the peptide binding groove.
Does the MHC change over time?
The type and variant MHC molecules do not vary in the lifetime of the individual
What are the variations in class 1 MHC?
A B and C
What are the variations in class 2 MHC?
DP DQ and DR, but each can be alpha and beta so 6.
Which gene can be had more than one of?
DR beta
What does it mean if when an individual is heterozygous MHC?
The more variety the more antigens presented.
What about cleft polymorphisms in MHC suggest the presence of polymorphism?
Replacement substitutions (non-synonymous) occur at a greater rate than silent substitutions.
What is the effect of MHC on disease susceptibility?
Certain MHC alleles can increase susceptibility to disease
Certain MHC alleles can be protective in relation to disease
What is the problem with studying MHC disease Loci?
High gene density
Extreme polymorphism
Strong linkage disequilibrium of MHC
Which makes it hard to study individual loci.
Which gene in the MHC was found to be associated with Ankylosing Spondylitis?
HLA-B*27
What is Ankylosing Spondylosis?
AS is a heritable chronic disease; form of inflammatory arthritis frequently affecting the spine?
Which gene of the MHC is associated with type 1 diabetes?
HLA-DR-DQ haplotype
Why is this HLA coded gene linked to diabetes 1?
Due to specific amino acid at position 57 of the HLA-DQ β chain
What kinds of drugs do MHC bind?
Small molecules drugs
Why is MHC binding drugs a problem?
Can pose a risk and cause adverse reactions
What is AHS?
ABACAVIR HYPERSENSITIVITY
What is Abacavir?
Anti-retroviral used to treat HIV-1
What percentage of patients have AHS?
5-8%
How was AHS avoided?
The implementation of HLA-B*57:01 screening prior
What underpins selection at the MHC?
- Parasite-mediated selection and MHC evolution
- MHC-dependent sexual selection
What is parasite-mediated selection for a rare allele advantage ?
New allele, then MHC advantage allele increases selection will favour pathogenic strains that are not recognised by this allele and than this pathogen will increase in frequency until recognised by a new novel MHC allele.
What is parasite-mediated selection for a heterozygous advantage?
Immune competence could be
substantially enhanced by heterozygosity at MHC loci, as
heterozygotes recognise a wider variety of antigens derived from
multiple pathogens.
What is sexual selection?
The advantage that certain individuals have over other individuals of the same sex and species, in exclusive relation to reproduction.
What are the 2 mechanisms of sexual selection?
Male competition (intrasexual selection)
Female choice (intersexual selection)
What is female choice?
To evolve it must confer a benefit in terms of reproductive success.
What are the 2 benefits of female choice?
1)Females directly improve their own RS due to choice (fecundity).
2) Genetic benefits for offspring: females improve the RS of their offspring
What is Zahavi’s handicap principle?
The handicap is costly therefore the individual must be of sufficient quality to afford such as costly handicap.
Why are humans a bad example of sexual selection?
Too complex, with too many developed background requirements for mates along with genetics.
What is the consequence of MHC similarity?
Lower successful birth rate.
