6 - The Major Histocompatibility Complex: Structure and Function

Question 1

What happens ~7 after you inject a mouse with a virus called LCMV?

Answer 1

The mouse will make LCMV-specific B cells that secrete Abs.

Question 2

What happens if you inject a non-infected mouse with the serum antibodies made by a mouse infected with a LCMV virus? Will it be protected from the virus? What is the half life of the Ig?

Answer 2

YES. This passive immunization and the strategy used to protect us from viral infections that is commonly used.

Half life: 30 days

Question 3

What is given to HIV patients for passive immunization? What about for hepatitis patients?

Answer 3

Gamma-globulin (IgG) injections.

HBsIgs for hepatitis patients can prevent infection after exposure.

This is called IVIg - IV immunoglobulins

Question 4

What happens if you transfer the T cells of an LCMV (virus) infected mouse to a non-infected (but genetically identical [syngeneic]) mouse? Will the mouse be protected from LCMV?

Answer 4

YES.

T cells will divide, so the half-life involved in transferring the B cells isn’t an issue here.

Question 5

What happens if you isolate and transfer LCMV-specific T cells to a non-infected mouse - but a different strain of mouse? Will the mouse be protected?

Answer 5

Allogeneic - genetically different mice.

NO. Although the T cells are specific for theLCMV antigen, the new mouse never sees it because the new strain of mouse has a different non-self MHC molecules presenting the antigen.

Question 6

What is MHC restriction?

Answer 6

T cells are restricted by self-MHC, so even if an allogeneic molecule presents the same peptide, the transferred T cell will not recognize it.

Only able to recognize peptides in the context of self MHC.

Question 7

What happens when tumors are transplanted from one strain of mice (A/A) into mice with the same inbred strain (syngeneic)? What about when tumor is injected into a different inbred strain of mouse (allogeneic; B/B)? What do these experiments indicate?

Answer 7

Syngeneic: Tumors flourished and killed these mice.

Allogeneic: Tumors of mice (A/A) were rejected.

Indicates that tissue rejection is a genetically inheritable trait and that the tumor rejection genes are codominant (A/B mice will not reject both a/a or b/b tumors).

Question 8

What is the genetic locus responsible for tissue rejection?

Answer 8

The major histocompatibility complex.

These genes encode the MHC molecules that are responsible for MHC restriction.

Question 9

What is the structure of the MHC?

Answer 9

Over 200 genes encoded with ~7 mil base pairs on Chromosome 6.

Question 10

What three genes encode class I molecules? What are the six genes that encode class II MHC molecules? What other proteins are encoded by MHC?

Answer 10

Genes that encode class I: HLA-A, -B, and -C (heavy chains)

Class II: HLA-DR, -DQ, -DP (alpha and beta chains)

Others: HLA-DM, TAP

HLA stands for human leukocyte antigen.

Question 11

What are the most polymorphic genes in the genome?

Answer 11

MHC class I and Class II genes.

Question 12

MHC genes are ______, _____, and ______. This allows them to recognize almost any foreign antigen in the context of self MHC.

Answer 12

Polymorphic, codominant, and polygenic.

Question 13

Describe how MHC molecules are polymorphic, codominant, and polygenic.

Answer 13

Polymorphic: many different alleles in the population

Codominant: you express one from each parents

Polygenic: three different types of genes can encode class I and 6 genes that encode class II molecules.

Question 14

There’s a : chance of another sibling matching for all 10 gene products for a bone marrow transplant, assuming no recombination. Why do they only check for 10 gene products if we know there’s 12 possible? Why does the BM registry only use 8?

Answer 14

1:4 chance.

HLA-DP is not bothered with because it doesn’t appear to have an impact on graft rejection.

HLA-DQ not used in BM registry for the same reason.

Question 15

MHC polymorphisms can be used for what?

Answer 15

Tracing location of people over time.

People of easter island with HLA-A29, B-12 were traced back to spain.

Question 16

_____ play a major role in allograft rejection.

Answer 16

Class I MHC molecules.

Question 17

What do the alpha chains of class I molecules associate with?

Answer 17

Non-covalently with non-MHC encoded polypeptide called Beta2-microgrlobulin (B2m).

Question 18

Where does the peptide bind on class I molecules?

Answer 18

Firmly within the groove and is considered a subunit of the class I MHC complex.

Question 19

What domains are common in the structure of immunoglobulins (antibodies) and other immune-related molecules. Each domain consists of a series of B sheets and are often held together by a disulfide bonds.

Answer 19

Immunoglobulin (Ig) domains.

Question 20

Class II MHC molecules are ____ of two polypeptide chains ___ and __.

Answer 20

Heterodimers.

Alpha and beta - each of which is encoded by a different gene.

Question 21

Which chain of MHC class II molecules is the more polymorphic?

Answer 21

The beta chain.

In tissue typing for class II, only the beta chains are tissue typed.

Question 22

Describe the binding groove for class II molecules?

Answer 22

It’s an intermesh of the alpha and beta chains.

Question 23

What does a T cell receptors (TCR) recognize?

Answer 23

A combination of both peptide and class I (or class II) helices.

Question 24

Where are the polymorphic regions found in class 1 and II molecules? What is the effect of these?

Answer 24

Class I: in the alpha helices and beta sheet of the heavy chain.

Class II: occur in the alpha helices and beta sheet of the beta chain.

These effect what peptides can bind within the groove.

Question 25

About how many molecules can bind to each class I molecule?

Answer 25

> 1000

Each type of class I MHC molecules (HLA-A, -B, -C) binds to a unique set of peptides (same applies to class II).

Question 26

Class __ peptides are not anchored at the ends.

Answer 26

Class II.

Question 27

A single nucleated cell expresses ____ copies of each class I molecule, thus estimated that each of the _____ distinct peptides is presented with the frequency of 100-4000 copies per cell.

Answer 27

10^5 (100,000) copies of each class I molecule

10000 distinct peptides

Question 28

Is it possible that a virus could escape efficient presentation on a given individuals 6 MHC molecules with 100,000 copies of each type?

Answer 28

Yes, it would be rare but could occur.

But there’s virtually no chance of that virus escaping presentation on all 1000 allelic variants within the pop; So the individual would be susceptible to the virus but the pop would be ok.

Question 29

What is ankylosing spondylosis (AS)? What tissue type is associated with it? What does this suggest?

Answer 29

An inflammatory, possible autoimmune disease of vertebral joints.

HLA-B27 tissue type is only in 6% of the population, but in ~93% of individuals with AS.

Suggests that having HLA-B27 predisposes individuals to developing AS.

Question 30

How many genes encode the three types of class II molecules?

Answer 30

6

Question 31

How many genes encode for class I molecules? How many distinct class I molecules do we have?

Answer 31

We have 6 distinct lass I molecules on the surface of all of our nucleated cells because we inherit one from each parent.

Question 32

Why was the transferred graft rejected (killed) by the immune system in mouse B that got an A mouse graft?

Answer 32

Because the donor MHC is not what the T cells in the recipient were trained to recognize when selected in the thymus.

Alloreactivity explains this. (reaction of T cells to non-self MHC class I or II molecules)

Question 33

Why did the transferred T cells from an infected mouse to a non-infected mouse not protect the mouse against the virus once it was infected?

Answer 33

After infection, the peptide is being displayed on the recipients class I MHC.

The injected T cell cannot recognize the recipients MHC-peptide complex.