MHC Structure/Genetics (1/8) Flashcards
How are HLA alleles named? i.e what does each part of this nomenclature tell us:
HLA-B*08:01
HLA-B = specificity
08= allele group
01 = subtype
How are HLA alleles inherited?
Codominant inheritance: one from each parent & both are expressed
This means that there is always a one haplotype mismatch between parent & child (unless both parents have same haplotype)
How are HLA involved in autoimmunity?
Certain HLA present self-peptides. If you inherit one of these, you’re at a higher risk for autoimmune disorders
What is the binding site of MHC like?
Forms pockets with charged AAs that bind the peptide of the antigen
Each MHC is specific for different peptides i.e. B27 looks for peptides that bind R at P2 and K at P9
Different individuals recognize different sets of peptides– note that this is important for the species
What’s the clinical application of this variety of MHC binding allelles?
Individuals with different alleles have different ability to survive different disease
If an individual doesn’t have an HLA that can bind a peptide on a virus, they will have a harder time surviving when infected
What is responsible for recognizing which peptides that MHC presents are viral?
T cells
How do peptides get loaded onto the proper kind of MHC molecule?
Class I peptide loading from peptides made in cytosol, loaded in ER
Class II peptide loading from fragments from lysosome
How does the proteasome change during infection?
The peptides in the proteasome changes to favor presentation of peptides to the MHC during immune response
THis causes the proteasome to make hydrophobic peptides which in general have greater affinity for MHC pockets
How does cutting the proteasome relate to MHC?
Cuts precisely at 9 AA for MHC I
But it’s not coordinate with the specificity of the MHC I molecule
What stabilizes the MHC I molecule?
MHC I is unstable unless bound to the peptide & beta 2 microglobulin
How are MHC II loaded?
Vesicles containing peptides from proteases fuse with vesicles containing MHC II molecules
What is invariant chain Ii?
It’s a chaperone that complexes with MHC II molecules during their synthesis in the ER
It blocks loading of MHC I molecules
It reiderects the MHC II to go to the acidic compartment to get loaded with degraded peptide
How does Ii work?
It gets degreaded to CLIP, which binds MHC II
CLIP blocks binding of peptides to MHC II: tells it “you can do better”
HLA-DM (a class II molecule) binds to the MHC II, releasing CLIP & allowng other peptides to bind
then MHC II goes to cell surface
How are MHC I genes expressed? What does this look like on the cell surface?
Codominant expression –> 6 types of class I molecules on the surface of each cell
Each of these molecules selects its own T cell repertoir –> each of the 6 alleles is specific for a T cell
How are MHC II genes expressed? What does it look like on the cell surface?
MHC II alpha has one variant; beta chain has variants which give 2 different HLA-DR molecules on the cell surface
Transallelic combination of DQ molecules into complexes –> 4 combinations possible
