Lecture 7, MHC

Question 1

What is the physiological function of MHC?

How is this accomplished?

Answer 1

To present peptides to T lymphocytes

- Sampling intracellular pools of peptides and presenting them at the cell’s surface

Question 2

Is MHC generally polymorphic or monomorphic?

Answer 2

• Polymorphic

Question 3

What # c’some encodes MHC?

Answer 3

C’some 6

Question 4

Why are MHC so polymorphic?

Answer 4

Because they have to present a variety of different polypeptides (which are also polymorphic)

Question 5

What are the 2 broad categories of MHC loci?

What subtypes fall into each category?

Answer 5

• Class I MHC (1, 2, 3)

- Class II MHC (DP, DQ, DR)

Question 6

*On what cells are class I MHC found?

Answer 6

On all nucleated cells

Question 7

*On what cells are class II MHC found?

Answer 7

B cells, monocytes, macrophages, DCs

Question 8

*What types of T cells do class I MHC-presenting cells interact w/?

Answer 8

CD8+ Killer T lymphocytes

Question 9

*What types of T cells to class II MHC-presenting cells interact w/?

Answer 9

CD4+ Helper T lymphocytes

Question 10

Describe the general quaternary structure of a class I MHC.

Answer 10

• Peptide-binding region made up of alpha-1 and alpha-2 subunits.
• Attached to cell surface via alpha-3 subunit (attached to alpha-2)
• Beneath alpha-1 is beta-2 microglobulin (not attached directly to cell surface)

Question 11

Describe the peptide-binding region of class I MHC in detail (i.e. how the subunits contribute)

Answer 11

• Alpha-1 and alpha-2 each contribute an alpha helix

- Each also contain 4 of the 8 beta-pleated sheets each (that the Ag sits on)

Question 12

Why are organ transplants always rejected if immunosuppressants are not given?

Answer 12

Because MHC are highly polymorphic, there are no perfect matches b/w individuals.

Question 13

Describe the general quaternary structure of a class II MHC.

Answer 13

• Peptide-binding region made up of alpha-1 and beta-1 subunits.
• Below each, both attaching to cell surface, are alpha-2 and beta-2 subunits

Question 14

Describe the peptide-binding region of class II MHC in detail (i.e. how the subunits contribute)

Answer 14

• Alpha-1 and beta-1 each contribute an alpha helix

- Each also contain 4 of the 8 beta-pleated sheets each (that the Ag sits on)

Question 15

How long of polypeptides do class I MHC bind?
Class II MHC?

Answer 15

• Class I: 8-10

- Class II: 13-17

Question 16

What is the “anchor sequence,” w/r/t an antigen?

Answer 16

The conserved sequence to which the HLA actually binds the Ag (for presentation)

Question 17

How many anchor sequence sites are there for peptides binding HLA class I?

Answer 17

2

Question 18

How many anchor sequence sites are there for peptides binding HLA class II?

Answer 18

4

Question 19

Genetically, by what pattern are HLA genes inherited?
How many maternal and how many paternal loci of each HLA class are there?

Answer 19

Co-dominantly
- 3 maternal and 3 paternal class I molecular types, as well as 3 maternal and 3 paternal class II molecular types

Question 20

What is the name of a half-set of genes that are inherited from each parent (co-dominantly, in this case)?

Answer 20

Haplotype

Question 21

Regarding organ transplantation to a boy, which of the following family members would be best to donate the organ to? Explain.

a) Mom
b) Dad
c) Brother
d) Sister

Answer 21

c) Brother
- Because each parent can only have up to 1/2 of the same HLA DNA as the child, they are excluded
- Sister is excluded because her X c’some differs from the male’s Y c’some
- Larger family would be ideal because there are more sibs to choose from

Question 22

Explain how HLA polymorphism is important by using the e.g. of Malaria and the HLA-B53 allele.

Answer 22

This allele is very common in West Africa where malaria is endemic and rare where malaria is absent.

• HLA-B53, in particular, has the almost unique capacity to present particular epitope of Malaria -> survival
• Those w/o this allele have much lower survival cuz lower capacity to present peptide appropriately

(Black Death is another e.g. of this)

Question 23

About how many molecular combinations are there for each class of HLA?

Answer 23

5,000

Question 24

Cytolytic T lymphocytes (CD8+) are specific for foreign Ag plus products of class __ loci, whereas T helper (CD4+) lymphocytes are specific for foreign Ag plus products of the class __ loci.

Answer 24

I (all nucleated cells)

II (DCs, monocytes, macrophages, B cells)

Question 25

Explain the concept of MHC restriction.

Answer 25

T cell reactivity doesn’t depend on foreign Ag alone- the correct MHC is also required

Question 26

If a host cell carries foreign Ag (e.g. it’s infected by a virus or has become tumorigenic), from what type of T cell would it elicit a response?
(and what is the CD marker?)

Answer 26

Cytotoxic T lymphocyte (CD8+)

Question 27

What types of cells does Malaria typically affect?

Why is it so difficult to treat, in terms of MHC?

Answer 27

RBCs
- Since they have no nuclei, can't present MHC class I or II, so difficult to recognize

Question 28

If you took salivary lysozyme from each person in the room, how would they be different/same?
What about if you took HLA from each person in the room?

Answer 28

• Exactly the same

- Exactly different

Question 29

What are HLA class III genes?

Answer 29

These are genes that happen to reside in the MHC region but do not present ag to T cells.

Question 30

In MHC I, which domains have variability and which are conserved?
What about MHC II?

Answer 30

I: Alpha 1, 2, and 3 have variability and beta-microglobulin are conserved throughout all cells.
II: Alpha 1, 2 and beta 1, 2 all have variability (much more in Ag-presenting site)

Question 31

Identify the order of Class I, II, and III MHC loci you’d find on c’some 6, from N to C terminal.

Answer 31

Class II, III, I