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2.1 Molecular Immunology > MHC genomic organisation, expression and disease association > Flashcards

MHC genomic organisation, expression and disease association Flashcards

1
Q

Where is the HLA located

A

Located on the short arm of chromosome 6

At murine 17

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2
Q

Where is the B2 microglobulin chain encoded?

A

Its encoded on chromosome 15

At murine 2

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3
Q

Where are the class II genes?

A

They are closest to the centromere

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4
Q

Where are the class III genes

A

They are telomeric to the class II region

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5
Q

What do class III genes do?
(2)

A

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)

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5
Q

What do class III genes do?
(2)

A

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)

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6
Q

Class III genes encode what components of complement

A

C4
Factor B
C2

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7
Q

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

A

HSP-70

TNFa

LTa (TNFB)

Two steroid 21-hydroxylases (congenital adrenal hyperplasia)

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8
Q

List the alleles of class I in order

A

B
C
A

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9
Q

List the alleles of class II in order

A

DP

DQ

DR

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10
Q

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

A

Separate exons encode each region of class I and class II

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11
Q

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

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

-

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12
Q

What does the 5’ leader exon of class I encode

A

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

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13
Q

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

A

Encode the alpha chain

Encode transmembrane

Encode one or two cytoplasmic exons

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14
Q

What are the components of class II genes
(5)

A

a 5’ leader exon

an alpha 1 or B1 exon

An alpha 2 or B2 exon

A transmembrane exon

One or more cytoplasmic exons

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15
Q

Where are class I molecules found?
(2)

A

Present on virtually all nucleated cells

Levels of expression differ by cell

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16
Q

Where are the highest levels of MHC I expression found?

A

On lymphocytes

1% of the total membrane proteins

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17
Q

Why are high levels of MHC I found on lymphocytes

A

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

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18
Q

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

A

Fibroblasts

Muscle cells

Hepatocytes

Neural cells

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19
Q

What cells lack MHC Class I

A

Neurons

Sperm cells

20
Q

What do class I molecules display in healthy individuals

A

Self peptides

21
Q

What do class I molecules display in virally infected cells

A

Viral and self peptides are displayed

22
Q

What cells are MHC II found on
(3)

A

B lymphocytes

Macrophages

DCs

i.e. APC

23
Q

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

A

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

24
Q

What cells can be induced to express class II

A

Thymic epithelial cells and some other cell types

25
Q

What does class II expression depend on?
(2)

A

Differentiation stage -> pre B cells vs mature B cells

Activation stage -> monocytes and macrophages

26
Q

What MHC molecules do rbcs express

A

They done express I or II

27
Q

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

A

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)

28
Q

Describe the translation of MHC

A

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

29
Q

What happens to MHC in the Golgi

A

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

30
Q

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

A

They are associated with a third non-polymorphic chain

y chain or invariant chain (li)

31
Q

How is MHC expression regulated?
(5)

A

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

32
Q

How is the rate of transcription of MHC regulated

A

Regulated by transcription factors

33
Q

What do defects in transcription factors of MHC do?

A

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

34
Q

How do cytokines regulate MHC

A

Cytokines modulate the rate of constitutive transcription of MHC molecules

(NEED TO LOOK AT POWERPOINT)

35
Q

What do corticosteroids and prostaglandins do to MHC?

A

They down regulate class II expression

36
Q

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

A

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

37
Q

How is MHC expressed
(3)

A

CIITA binds RFX

RFX binds MHC promoter

Binding activates transcription of the gene

38
Q

What cytokines modulate transcription
(2)

A

Interferons a, B and y

TNF

39
Q

How do cytokines regulate transcription of MHC?
(3)

A

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

40
Q

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

A

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

41
Q

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

A

The determinant selection model

The holes-in-the-repertoire model

42
Q

What is the determinant selection model

A

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

43
Q

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

A

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

44
Q

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

A

Autoimmune disorders

Certain viral diseases

Disorders of the complement system

Some neurologic disorders

Several different allergies

45
Q

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

A

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

46
Q

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

A

Reflected by low relative risk value

It is likely that multiple genes influence susceptibility

Environmental factors also play a role

47
Q

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

A

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

2.1 Molecular Immunology (19 decks)

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