Flashcards in HLA Immunogenetics: Strength In Numbers Deck (52):
On what chromosome are the HLA (MHC) genes located?
How many base pairs are there?
How many loci are there?
3.6 million bps
150 loci (half are immune related)
What does it mean that HLA is polygenic?
Multiple genes encode the structure
HLA-I has HLA-A, HLA-B, HLA-C loci
HLA-II has HLA-DQ(ab) HLA-DR(ab) and HLA-DP(ab)
Where is the gene encoding the HLA-I light chain located?
Where are the CD1 genes located?
B2m is on chromosome 15
CD1 is on chromosome 1
Which sub-loci of HLA-II can have 2 B loci?
HLA-DR can have two B loci and one A
(although technically the number of DQ and DP loci are also variable for B)
Where are the genes from proteins involved in the processing and presentation of antigens for HLA-I and HLA-II (like TAP and DM) located?
They are also located on chromosome 6 amongst the genes for class 2 HLA (DQ, DP, DR)
The HLA complex has loci for innate and adaptive immune functions. What are some of these loci?
1. Complement function (class III)
2. Antigen processing and presentation (TAP)
3. HLA-II antigens (DM)
4. NK receptor
5. HLA-E,F,G and MIC-A, MIC-B (non-classical class 1)
6. cytokine genes (TNF)
What is linkage disequilibrium?
non-random association of alleles at two or more loci which impact an organism's fitness
How have MHC systems evolved to deal with subversion of pathogens that have mutated to avoid HLA groove binding?
What is polygeny?
Each MHC on chromosome 6 contains multiple class 1 and class 2 genes to allow hosts to bind a larger repertoire of microbial proteins
What is meant by polymorphism?
there are multiple variants of each gene within the population (multiple alleles) at the same locus
Which loci of HLA-I is the most polymorphic?
HLA-B has the highest number of different complexes
Which loci of HLA-II is the most polymorphic (most number of alleles worldwide)?
HLA-DQ when you multiple the allelic possibilities for a and b
In addition to the incredible diversity from the polygeny and polymorphism of the MHC complex, what else contributes to the population diversity?
The HLA alleles are expressed codominantly so in heterozygotes both alleles at each locus are expressed
Why are the majority of individuals in a population heterozygous for genes encoding HLA-I and HLA-II proteins?
Because there are an enormous number of alleles for each locus (except for DRA) so there is a high likelihood that their parents had different alleles
What does it mean that HLA-II heterozygous complexes can be "cis" or "trans"?
"Cis"- ab products from polygeny
"trans" a from one chromosome binds to the b from the other 6 chromosome to form an even greater number of heterozygous combinations
What nomenclature would you use if you were referring to the HLA protein dimer in serum?
What nomenclature would you use if you were referring to the single chain gene alleles of the DNA of HLA-II?
How many known alleles are there for HLA-I loci?
How many known alleles are there for HLA-II genes?
Which is more polymorphic, HLA-II A or B?
What is a haplotype?
The combination of class I and class II alleles present on a single chromosome ("cis")
How are HLA complexes passed from parent to child?
The haplotype of class 1 and 2 genes is passed down as a single unit
Mendelian inheritance applies.
HLA matching is crucial for bone marrow transplantation. Who is the best match?
Siblings are the most compatible donors (1/4 chance they have the same HLA molecules)
Parents are not likely to share both HLA haplotypes with a child due to the high polymorphism.
Variability plots show that the genetic polymorphism localizes mainly to where?
DNA sequences for the a1 and b1 domains of the HLA-II molecule and a1, a2 domains of the HLA-I molecule because these make the peptide binding groove.
What is the heterozygote advantage?
The more HLA variants one has, the higher the person's fitness if there is balancing selection (no 1 HLA confers advantage or detriment). This is because since HLA are codominantly expressed, the more antigens the HLA can bind
The more __________________ the haplotypes of the parent, the more antigens the offsprings HLA will be able to bind.
What is the difference between balancing and directional selection?
Balancing is where no particular gene confers advantage against a pathogen. (heterozygores are better to phase these situations because they can recognize a larger range of pathogens).
Directional selection is when one particular gene confers advantage over the others and allele frequency shifts toward that particular gene
What accounts for the rapid emergence of new HLA variants in order to bind mutating microbes?
gene duplication, point mutations, gene conversion events
What is the difference between interallelic conversion and gene conversion?
Interallelic conversion involves the exchange of alleles of the same gene
Gene conversion involves looping of DNA and the exchange of alleles of different genes
What gene predisposes people to Ankylosing Spondilosis? Where is this gene most common?
What is this the reverse of? (making us think selectivity for an allele fighting this pathogen may have purged the allele for AS)
HLA-B27 is most common further from the equator.
This is the opposite of malaria so most likely an HLA-B that confers malarial resistance is more common than HLA-B27 near the equator
What factors shape the geographical distribution of HLA alleles?
1. influx of HLA and non-HLA gene pools via migration of people
2. local pathogenic pressures (kill out "bad" alleles)
3. other selection processes (effect of HLA allele on reproductive success
What does it mean that HLA-B27 has a high relative risk for Ankylosing spondylosis?
People that have HLA-B27 are still not likely to get AS (5%), but people that have AS are VERY likely to have HLA-B27 (95%).
This shows that HLA-B27 allele probably is a contributing factor, but is not sufficient to cause the disease.
Almost all people for narcolepy have what HLA allele?
What has it been difficult to demonstrate that disorders linked to HLA are actually brought about by peptides binding to unique HLA alleles?
1. linkage disequilibrium which misidentifies the causative HLA gene
2. HLA loci are involved in cis and trans
3. HLA is not causative but amplifies phenotype
Why do we care about the HLA linkage to certain diseases?
1. aid in diagnosis
2. delineating the pathogenesis of these conditions
What HLA genes are associated with diabetes (type 1) and celiacs?
DQ2 and DQ8
What is Celiac Disease (CD)?
pathological immune response to gluten in wheat rye and barley that causes inflammation in the small intestine
What is the HLA gene that contributes to CD? What percent of the caucasian population has this gene? What percent of people actually get CD?
HLA-DQ2 is in 25% of the Caucasian population but only 4% develop CD so there are other genes/factors that contribute to susceptiblity
What HLA genes are HLA-DQ2 frequently encoded with?
HLA-DQ2 is on the highly conserved haplotype 8.1 with B8 and DR3.
CD is also associated with HLA-DQ8 but to a lesser extent.
What peptide combination and gene dosage gives the worst CD?
DQ2/DQ8 together in trans or homozygous individuals for these alleles
What peptides can the HLA-DQ2 groove bind?
Gliadin peptides (proline rich gluten epitopes)
When gliadin peptides from gluten bind HLA-DQ2 what happens?
CD4 T cells make IFN gamma which can be cytotoxic to epithelial cells in the small intestine
Is CD an autoimmune disorder?
No because gluten is not a component of the host cell. It is more of an inflammatory disease
What enzyme modifies the peptides in gluten so that they can bind HLA-DQ2?
When gliadin in the HLA-DQ2 molecule activates a CD4 T cell, what happens?
1. The activated T cell kills epithelial cells by binding Fas receptor.
2. The T cell secretes IFN gamma which activates the epithelial cell
How does gluten also affect class I like molecules?
IFNgamma released from the T cell stimulates MICA and MICB which activate intraepithelial T lymphocytes (IEL) via NKG2D receptors which kill the epithelium
What is type 1 diabetes?
the autoimmune destruction of insulin-secreting B- pancreatic islets of Langerhans
What HLA peptide is associated with T1D?
DQ8 (and a little bit DQ2)
What is the most likely autoantigen that binds DQ8/DQ2 in T1D?
Who has the highest risk for developing type 1 diabetes?1
DQ8/DQ2 heterozygotes have a higher risk of disease (so trans heterodimer individuals)
What haplotype linkage disequilibrium has the strongest T1D risk?
DR3-DR2 and DQ8-DR4 haplotypes