MHC genomic organisation, expression and disease association

Question 1

Where is the HLA located

Answer 1

Located on the short arm of chromosome 6

At murine 17

Question 2

Where is the B2 microglobulin chain encoded?

Answer 2

Its encoded on chromosome 15

At murine 2

Question 3

Where are the class II genes?

Answer 3

They are closest to the centromere

Question 4

Where are the class III genes

Answer 4

They are telomeric to the class II region

Question 5

What do class III genes do?
(2)

Answer 5

Encode components of the complement system
- C4
- Factor B
- C2

Encodes molecules involved in inflammation
- HSP-70
- TNFa
- LTa (TNFB)
- 2 steroid 21-hydroxylases (congenital adrenal hyperplasia)

Question 5

What do class III genes do?
(2)

Answer 5

Encode components of the complement system
- C4
- Factor B
- C2

Encodes molecules involved in inflammation
- HSP-70
- TNFa
- LTa (TNFB)
- 2 steroid 21-hydroxylases (congenital adrenal hyperplasia)

Question 6

Class III genes encode what components of complement

Answer 6

C4
Factor B
C2

Question 7

Class III genes encode what components involved in inflammation
(4)

Answer 7

HSP-70

TNFa

LTa (TNFB)

Two steroid 21-hydroxylases (congenital adrenal hyperplasia)

Question 8

List the alleles of class I in order

Answer 8

B
C
A

Question 9

List the alleles of class II in order

Answer 9

DP

DQ

DR

Question 10

What does each exon of the class I and II proteins, encode for?

Answer 10

Separate exons encode each region of class I and class II

Question 11

Write about the structure of human class I gene
(2)

Answer 11

• a 5’ leader exon
• 5/6 exons encoding the alpha chain (a1, a2, a3), transmembrane and one or two cytoplasmic exons

-

Question 12

What does the 5’ leader exon of class I encode

Answer 12

A short signal peptide which facilitates insertion into the ER - cleaved on the completion of translation

Question 13

What do the 5/6 exons of class I do?

Answer 13

Encode the alpha chain

Encode transmembrane

Encode one or two cytoplasmic exons

Question 14

What are the components of class II genes
(5)

Answer 14

a 5’ leader exon

an alpha 1 or B1 exon

An alpha 2 or B2 exon

A transmembrane exon

One or more cytoplasmic exons

Question 15

Where are class I molecules found?
(2)

Answer 15

Present on virtually all nucleated cells

Levels of expression differ by cell

Question 16

Where are the highest levels of MHC I expression found?

Answer 16

On lymphocytes

1% of the total membrane proteins

Question 17

Why are high levels of MHC I found on lymphocytes

Answer 17

The ability of cytotoxic T lymphocytes to lyse a virally infected cell depends on the quantity of class I molecules expressed

Question 18

On what type of cells are MHC class I found in very low levels

Answer 18

Fibroblasts

Muscle cells

Hepatocytes

Neural cells

Question 19

What cells lack MHC Class I

Answer 19

Neurons

Sperm cells

Question 20

What do class I molecules display in healthy individuals

Answer 20

Self peptides

Question 21

What do class I molecules display in virally infected cells

Answer 21

Viral and self peptides are displayed

Question 22

What cells are MHC II found on
(3)

Answer 22

B lymphocytes

Macrophages

DCs

i.e. APC

Question 23

Why is the amount of cells than can express MHC class II limited?

Answer 23

So that fewer cell types can present antibodies to T helper cells

Question 24

What cells can be induced to express class II

Answer 24

Thymic epithelial cells and some other cell types

Question 25

What does class II expression depend on? (2)

Answer 25

Differentiation stage -> pre B cells vs mature B cells Activation stage -> monocytes and macrophages

Question 26

What MHC molecules do rbcs express

Answer 26

They done express I or II

Question 27

Write a note on the biosynthesis/expression of MHC (4)

Answer 27

MHC translated from mRNA on membrane-bound ribosomes and co-translationally inserted into the ER membrane MHC molecules than pass to the Golgi apparatus Mature glycoproteins are then transported to the plasma membrane by vesicular transport Recently synthesised class II are associated with a third non-polymorphic chain - y or invariant chain (li)

Question 28

Describe the translation of MHC

Answer 28

MHC translated from mRNA on membrane-bound ribosomes and co-translationally inserted into the ER membrane

Question 29

What happens to MHC in the Golgi

Answer 29

Mature glycoproteins are then transported to the plasma membrane by vesicular transport

Question 30

What happens with the the recently synthesised class II? (2)

Answer 30

They are associated with a third non-polymorphic chain y chain or invariant chain (li)

Question 31

How is MHC expression regulated? (5)

Answer 31

The rate of transcription is regulated Cytokines can modulate the rate of constitutive transcription of MHC molecules Corticosteroids and prostaglandins also down regulate class II expression Infection with certain viruses decrease MHC expression Transcription and expression of the various MHC genes are co-ordinately regulated

Question 32

How is the rate of transcription of MHC regulated

Answer 32

Regulated by transcription factors

Question 33

What do defects in transcription factors of MHC do?

Answer 33

Defects cause one form of bare lymphocyte syndrome -> these lack class II on cells -> a severe immunodeficiency

Question 34

How do cytokines regulate MHC

Answer 34

Cytokines modulate the rate of constitutive transcription of MHC molecules (NEED TO LOOK AT POWERPOINT)

Question 35

What do corticosteroids and prostaglandins do to MHC?

Answer 35

They down regulate class II expression

Question 36

What can some viruses do to the regulation of MHC (3)

Answer 36

Infection with certain viruses decreases MHC expression e.g. cytomegalovirus (CMV) - CMV viral proteins bind B2 microglobulin e.g. hepatitis B virus result in pronounced downregulation of TAP1 and TAP2

Question 37

How is MHC expressed (3)

Answer 37

CIITA binds RFX RFX binds MHC promoter Binding activates transcription of the gene

Question 38

What cytokines modulate transcription (2)

Answer 38

Interferons a, B and y TNF

Question 39

How do cytokines regulate transcription of MHC? (3)

Answer 39

IFNy induces the formation of a transcription factor that binds the promoter sequence for MHC class I genes IFNy induces expression of CIITA which binds RFX which binds MHC promoter and activates transcription of the MHC class II genes IFNy downregulates class II expression

Question 40

Transcription and expression of the various MHC genes are co-ordinately regulated, comment on this

Answer 40

The B2 microglobulin is co-ordinately regulated with class I alpha chain The y chain is co-ordinately regulated with the class II a and B chains

Question 41

Different haplotypes exist for class II exist and these have variation in immune responsiveness, why is this? (2)

Answer 41

The determinant selection model The holes-in-the-repertoire model

Question 42

What is the determinant selection model

Answer 42

Different class II molecules differ in their ability to bind processed Ag

Question 43

What is the holes-in-the-repertoire model?

Answer 43

T cells bearing receptors that recognise Ags that resemble self Ags may be eliminated during thymic selection

Question 44

Certain MHC alleles are heightened in certain disease cases, name these cases? (5)

Answer 44

Autoimmune disorders Certain viral diseases Disorders of the complement system Some neurologic disorders Several different allergies

Question 45

What does a relative risk with a disease and an associated HLA higher than 1 mean (2)

Answer 45

A value of 1 indicates the alelle confers no increased risk for the disease A value significantly above 1 indicates an association between the allele and the disease

Question 46

What does a weak association between HLA allele and disease? (3)

Answer 46

Reflected by low relative risk value It is likely that multiple genes influence susceptibility Environmental factors also play a role

Question 47

Describe the relationship between allelic forms of MHC genes and viruses (2)

Answer 47

Some allelic forms of MHC genes may encode molecules that act as receptors for viruses or bacterial toxins Reduction in MHC polymorphism may predispose a species to infectious disease