Lecture 6 - MHC Intro

Question 1

Why is MHC important?

Answer 1

1. Determines fate of engrafted/transplanted tissue

2. Highly polymorphic

Question 2

Answer the following questions for:

1. Class I HLA loci
2. Class II HLA loci
3. CLass III

1.What consists of the HLA (Human Leukocyte
Antigens)

2. Where are they present?
3. And they present antigen to which T-lymphocytes?

Which of these does not present antigen to T lymphocytes?

Answer 2

1. Class I
HLA A
HLA B
HLA C
- present in all nucleated cells
- present CD8+ to T cells (cytotoxic/killer T cells)

2. Class II
   HLA - D which has 3 subset loci: DR, DQ, DP
   - present in Antigen Presenting Cells (APC) like
3. Dendritic
4. B lymphocytes
5. Macrophages

• present CD4+ to T cells

3. Class III
   - genes that happen to reside in MHC region but DO NOT PRESENT ANTIGEN

Question 3

Where is the HLA complex found?

Answer 3

Short arm of chromosome 6

Question 4

Answer the following for Class I Loci molecules (A,B,C)

1. How many polypeptide chains does the loci code for?
2. Are they associated non-covanetly with a lighter chain? What is this chain called if yes?
3. What does the resulting cell surface molecule consist of?
4. Which part of the Class I molecule is transmembrane?

Answer 4

1. ONE polypeptide chain
   - 44,000 daltons
2. Beta 2 Microglobulin , specified by a gene on another chromosome and NOT polymorphic
3. • one alpha chain
     - Class I polypeptide
     - one light chain micro globulin Beta 2
4. Alpha 3 is transmembrane

Question 5

Which aspect of Class I molecule is polymorphic? Which part is the antigen binding site?

Answer 5

1. Alpha 1 and 2 is polymorphic, beta 2 is NOT different in amino acid sequence
2. Alpha 1 and 2 form the peptide binding cleft (supported y beta pleated sheet)

Question 6

Answer the following for Class II HLA -D Loci molecules (subset DQ, DR, DP)

1. How many polypeptide chains does the loci code for?
2. Are they associated non-covanetly with a lighter chain? What is this chain called if yes?
3. What does the resulting cell surface molecule consist of?
4. Which part of the Class I molecule is transmembrane?

Answer 6

1. Codes for 1 polypeptide chain, but 2 polypeptide chains per molecule
   - alpha chain
   - beta chain

• together = 60,000 daltons
  2. NO lighter chain
  3. Consists of alpha 1 and beta 1
  4. Beta 2 and alpha 2 BOTH have a transmembrane C terminal portion)

Question 7

Although the anchor molecules that bind a particular MHC Class I molecule do not need to be identical, they are always related.

In what way? (N terminal & C terminal)

Answer 7

N terminal = AROMATIC RESIDUE

C terminal = HYDROPHOBIC

Question 8

Although the anchor molecules that bind a particular MHC Class II molecule do not need to be identical, they are always related.
HOW? State the 1st, 2nd, 3rd, and 4th anchor molecules

Answer 8

1st anchor - Hydrophobic

2nd - Negatively charged

3rd - Basic AA

4th - Hydrophobic

Question 9

The genes that encode the MHC Class I alpha chains and the MHC Class II alpha and beta chains associate where? Where do they shuttle to?

Answer 9

1. Associate in ER

2. Shuttle to cell surface to become membrane glycoproteins

Question 10

What part of the MHC Class I gene is NOT encoded within the MHC region of chromosome 6?

Answer 10

Beta 2 - Microglobulin

Question 11

Define what it means to express Class I and Class II genes in a codominant fashion of both chromosomes 6.

Discuss how haplotypes come into play and how they are expressed.

Answer 11

Each individual has 3 maternal and 3 paternal class I

AND has 3 maternal and 3 paternal class II molecular types

thus, each person has two “half sets” (haplotypes) of genes

• one haplotype is inherited from each parent and are expressed equally

= CODOMINANT EXPRESSION of MHC ANTIGENS

Question 12

The polymorphism in nucleotide sequence and thus amino acid sequence of the MHC allows for what?

Answer 12

Allow for various peptides to bind and various TCR’s to recognize the MHC

Question 13

Which class of molecules binds short peptides of about 9 amino acids in length?

Long?

Answer 13

1. Class I

2. Class II

Question 14

Where are polymorphisms in the MHC molecule found specifically?

Answer 14

in the Peptide Binding Cleft

Class I – alpha 1 and alpha 2 have high variability
(alpha 3 has little to no variability)

Class II - alpha 1 and Beta 1 have high variability (not beta 2 tho)

Question 15

In order for a cellular interaction to occur between a T cell and the MHC presented on a cell, what must be matched & recognized?

Answer 15

1. Antigen

2. antigenic peptide on MHC molecule

Question 16

What are cytolytic T lymphocytes (CD8) specific for?

T helper cells (CD4)?

Answer 16

1. Foreign Ag products of CLASS I loci

2. Foreign Ag plus products of Class II loci

Question 17

What determines the specificity of the T killer cells?

Answer 17

Viral Peptide in the contact of a host cell’s CLASS I determinant!!

Question 18

What is the following called:

Lymphocytes interact with foreign antigen recognized by the lymphocyte in the context of host (self) MHC molecules

Answer 18

MHC Restriction

Question 19

What is MHC restriction important for? (2)

Answer 19

1. Cytolysis of target cells by cytolytic T lymphocytes

2. T cell APC’s (macrophages, Dendritic cells, B cells) interacting with T cells in the production of CYTOKINES

Question 20

Each person has 2 haplotypes, with codominant genetic expression. Explain the statement

Answer 20

One haplotype is inherited from

each parent. Both of these haplotypes are expressed equally

Question 21

What is MHC restriction?

Answer 21

The dependence of the T cells specific reactivity on foreign Ag plus MHC products rather than on foreign Ag alone

Question 22

Each individual expresses how many maternal and paternal MHC types?

Answer 22

3 maternal and 3 paternal from Class I

3 maternal and 3 paternal from Class II

Question 23

Which part of the HLA complex is not encoded within the MHC region of chromosome 6?

Answer 23

B2 microglobulin

Question 24

Which varies in the different HLA-I molecules, B2 microglobulin or a chain?

Answer 24

a chain

Question 25

What part of the a chain of HLA-I crosses the cell membrane?

Answer 25

C-terminal fragment

Question 26

Summarize the general structure of a Class I HLA molecule.

Answer 26

The B2 microblobiulin and a3 domains support an interactive structure formed by a1 and a2 domains. The interactive structure is a B-pleated sheet platform supporting 2 a helices which form a cleft for binding antigenic peptide fragments.

Question 27

Where are Class I MHCs present? Where are Class II MHCs present?

Answer 27

1. all nucleated cells | 2. dendritic cells, B lymphocytes, macrophages

Question 28

What is the major histocompatibility complex? What is the HLA complex?

Answer 28

A set of closely linked highly polymorphic genetic loci that play a central role in immune reactions. a tightly linked gene cluster of cell surface glycoproteins in humans and other mammals that regulates immune cell interactions and evokes intense allograft rejection.

Question 29

Compare class I and class II gene products Class I:

Answer 29

Each loci codes for polypeptide chain of 44000 daltons. resulting molecule has 1 alpha chain and 1 light chain B2 microglobulin. B2 always the same but a chain varies. C-terminal fragment of a chain crosses membrane. Class II: 2 chains per molecule: a chain and B chain. bind longer peptides than Class I More sets of anchor residues

Question 30

Describe the genes that constitute the major histocompatibility complexes

Answer 30

MHC gene products are generally closely linked and highly polymorphic. Class I: 3 subsets (A-C) present on all nucleated cells. Present antigen to CD8+ T lymphocytes Class II: HLA-D subset. Found on dendritic cells, B lymphocytes, and macrophages. present to CD4+ lymphocytes. Class III: happen to reside in MHC region but do not present antigen.

Question 31

Each person has 2 haplotypes, with codominant genetic expression. Explain the statement

Answer 31

One haplotype is inherited from | each parent. Both of these haplotypes are expressed equally