L7 - A Kelly - MHC

Question 1

The Major Histocompatibility Complex (MHC) is a large genetic locus on chromosome __ that codes for MHC class I and class II molecules and many other proteins involved in the processing and presentation of antigens to T cells.

Answer 1

The Major Histocompatibility Complex (MHC) is a large genetic locus on chromosome 6 that codes for MHC class I and class II molecules and many other proteins involved in the processing and presentation of antigens to T cells.

Question 2

function of MHC class I and class II molecules?

Answer 2

MHC class I and class II molecules are cell surface glycoproteins whose function is to present peptides to T cells

Question 3

Describe MHC class 1 structure

Answer 3

• α chain (45kD) (3 extracelllar domains - α1,2,3)
• non-covalently linked to b2-microglobulin (12kD).
• α1 and α2 form the peptide binding groove
• can accomodate peptides that are often 8-9 amino acids in length

Question 4

describe the structure of MHC class 2 molecules

Answer 4

• Similar to MHC class 1
• made from two similar sized transmembrane chains (a 33kD and b 30kD).
• The peptide binding groove is formed by the a1 and b 1 domains and is supported by the membrane proximal a2 and b2 domains.

Question 5

do MHC class molecules have great specificity?

Answer 5

no.

able to bind a broad range of peptides composed of different amino acid combinations

Question 6

which MHC molecule can accomodate longer peptides

Answer 6

MHC class 2 - 13-25 amino acids

class 1: 8-9 amino acids

Question 7

what are MHC class 1 and 2 molecules also known as?

Answer 7

Human Leukocyte Antigens (HLA)

Question 8

MHC class 1 interacting with a cytotoxic t cell

Answer 8

Question 9

MHC class 2 interacting with a T helper cell

Answer 9

Question 10

4 ways MHc molecules can ensure that they can present peptides from virtually any pathogen?

Answer 10

• Polygeny
• Polymorphism
• Inheritance of MHC haplotypes
• Peptide binding properties of MHC molecule

Question 11

describe polygeny - relation to MHC molecules

Answer 11

expression of multiple independent loci encoding class I and class II genes:

class 1:

• HLA-A,
• HLA-B
• HLA-C

Class 2:

• HLA-DP,
• HLA-DQ
• HLA-DR

isotypes

Question 12

describe polymorphism in relation to MHc molecules

Answer 12

Polymorphism refers to the existence of many alternative forms of the same gene within the human population.

(MHC genes are the most polymorphic genes known.)

Question 13

how amny MHC class 1 alleles are there?

Answer 13

over 13,000!

Question 14

do individuals express amny unique combinations of alleles?

Answer 14

yep

Question 15

will some MHC alleles be associated with disease susceptibility?

Answer 15

yep

some are weaker than others.

Question 16

expression of MHC alleles can be describes as

Answer 16

co-dominant

Question 17

MHC gene polymorphism picutre

Answer 17

Question 18

MHC genes are inherited as ______

Answer 18

MHC genes are inherited as haplotypes

Question 19

what is meant by haplotypes?

Answer 19

since MHC loci are so closely linked - theyre often inherited as haplotypes

Question 20

why amy it be beneficial for MHC genes to be inehrited as haplotypes?

Answer 20

Advantageous combinations conserved?

Question 21

do MHC genes under go recombination?

how frequently?

Answer 21

Recombination generates new combinations of alleles (haplotypes) to be tested for beneficial/adverse effects (3% births)

Question 22

T or f:

MHC alleles, in most cases (97%), are inherited together as sets of alleles or haplotypes.

Answer 22

T

Question 23

are MHC alleles co-dominantly expressed?

Answer 23

Alleles are co-dominantly expressed meaning that both maternal and paternal haplotypes are expressed together on the same cell.

Question 24

in outbred populations polymorphism at each loci makes it _________ for two individuals to express the same combination of MHC alleles.

Answer 24

n outbred populations polymorphism at each loci makes it virtually impossible for two individuals to express the same combination of MHC alleles.

Question 25

whats the advantage of being heterozygous for MHC alleles

Answer 25

Heterozygotes can present more peptides and activate more T cells than homozygotes.

Question 26

where on the MHC molecule is the polymorphism concentrated?

Answer 26

Polymorphism is concentrated in the peptide binding domain

Question 27

T or F

The polymorphism in MHC molecules is concentrated in the domains of the molecule that bind peptide and interact with the T-cell receptor

Answer 27

T

Question 28

which parts of the MHc molecule does the TCR interact with?

Answer 28

The T cell receptor sees a combination of a particular MHC molecule associated with a particular peptide (MHC restriction). It is very unusual for a TCR to be able to respond the same peptide presented by a different MHC allele.

Question 29

what are anchor residues?

Answer 29

specific amino acids in the peptide which bind specifically to pockets in the binding groove.

They determine the peptide-binding motif for that particular MHC molecule.

Question 30

do you understand how MHC class molecules can bind a wide variety of peptides.

Answer 30

Amino acids at non-anchor positions are not under such strict constraints and may vary considerably. This accounts for the diversity of peptides presented by a single MHC molecule.

Question 31

In the absence of infection MHC molecules are occupied by….

Answer 31

In the absence of infection MHC molecules are occupied by self peptides

Question 32

Peptide presentation requires a balance in binding characteristics because……..

Answer 32

If a large number of different peptides can bind only a few copies of any particular peptide-MHC combination will be presented at the cell surface.

If a small number of different peptides can bind, many copies of the same peptide-MHC will be present at the surface. However pathogens with a small genome may not have a suitable peptide for presentation by the host’s MHC

molecules

Question 33

Roughly 1/1,000-1/10,000 random peptides are able to bind a particular MHC allele.

T ormF

Answer 33

T

Question 34

Tmor F

T cells may be able to be activated by a single MHC-peptide complex (up to a few

thousand).

Answer 34

T

T cells may be able to be activated by a single MHC-peptide complex (up to a few

thousand).

Question 35

describe the Evidence that MHC polymorphism is pathogen driven

Answer 35

chickens = a single dominantly expressed MHC class I molecule.

Promiscuous MHCI molecules bind a wide range of peptides and give more or less protection against a wide range of pathogens.

Fastidious chicken MHCI alleles bind fewer peptides and confer either resistance or susceptibility to a given pathogen

After infection with Marek’s Disease Virus (MDV) the percentage of promiscuous chicken MHCI haplotypes (B21 and B2) in the flock increases substantially. Fastidious chicken MHCI haplotypes (B12-B19) are greatly reduced or eliminated, presumably because they were unable to find viral peptides to present.

Question 36

MHC class I molecules present peptides from …..proteins. MHC class II molecules present peptides from ,……..

Answer 36

MHC class I molecules present peptides from endogenous proteins e.g. viral proteins. MHC class II molecules present peptides from exogenous proteins e.g. bacterial proteins.

Question 37

describe the MHC class 1 processing pathway

Answer 37

• internal peptides
• proteins in cytosol degraded by proteosome
• proteins move to ER via Transporter associated with Antigen Processing (TAP)
• Peptides of suitable length and sequence are loaded onto partially folded class I molecules in a complex process that is assisted by a range of chaperone proteins assembled into a Peptide Loading Complex.
• Fully loaded MHC peptide complexes are released from the chaperones, pass through the golgi, and follow the secretory pathway to the cell surface.

Question 38

describe the MHC class II antigen processing pathway

Answer 38

• during synthesis, class 2 molecules pass through the ER.
• class 2 molecules associate with a third component invariant chain (Ii)
• Class II/Ii complexes pass through golgi
• sorted into endocytic pathway (where li is partailly removed - leaving CLIP in peptide-binding groove)
• antigen taken up by endocytosis - degraded my proteases
• in peptide loading compartments, known as MIIC compartments, the CLIP peptide is removed and antigen derived peptides, with appropriate binding motifs are loaded onto the empty class II molecules with the help of the class II related molecule HLA- DM
• MHC class II/peptide complexes are transported to the cell surface for presentation to CD4 T cells, but the pathway used is unknown.

Question 39

is the MHC just one gene

Answer 39

The MHC contains many genes involved in antigen presentation

Question 40

In addition to classical Class I and Class II genes the MHC encodes ,….

Answer 40

In addition to classical Class I and Class II genes the MHC encodes other components of the antigen processing machinery

Question 41

some exmaples of other stuff encoded for my MHC

Answer 41

HLA- DM and HLA-DO are involved in regulating peptide presentation by MHC class II molecules. Two LMP components of the proteasome, TAP1 and TAP2, and TAP Binding Protein (TAPBP, aka Tapasin) are involved in peptide generation, peptide transport and peptide loading onto MHC class I molecules. The reason why all these genes are located together in the MHC class II region is hotly debated.

Question 42

fat

Answer 42

mamba