MHC genomic organisation, expression and disease association Flashcards
Where is the HLA located
Located on the short arm of chromosome 6
At murine 17
Where is the B2 microglobulin chain encoded?
Its encoded on chromosome 15
At murine 2
Where are the class II genes?
They are closest to the centromere
Where are the class III genes
They are telomeric to the class II region
What do class III genes do?
(2)
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)
What do class III genes do?
(2)
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)
Class III genes encode what components of complement
C4
Factor B
C2
Class III genes encode what components involved in inflammation
(4)
HSP-70
TNFa
LTa (TNFB)
Two steroid 21-hydroxylases (congenital adrenal hyperplasia)
List the alleles of class I in order
B
C
A
List the alleles of class II in order
DP
DQ
DR
What does each exon of the class I and II proteins, encode for?
Separate exons encode each region of class I and class II
Write about the structure of human class I gene
(2)
- a 5’ leader exon
- 5/6 exons encoding the alpha chain (a1, a2, a3), transmembrane and one or two cytoplasmic exons
-
What does the 5’ leader exon of class I encode
A short signal peptide which facilitates insertion into the ER - cleaved on the completion of translation
What do the 5/6 exons of class I do?
Encode the alpha chain
Encode transmembrane
Encode one or two cytoplasmic exons
What are the components of class II genes
(5)
a 5’ leader exon
an alpha 1 or B1 exon
An alpha 2 or B2 exon
A transmembrane exon
One or more cytoplasmic exons
Where are class I molecules found?
(2)
Present on virtually all nucleated cells
Levels of expression differ by cell
Where are the highest levels of MHC I expression found?
On lymphocytes
1% of the total membrane proteins
Why are high levels of MHC I found on lymphocytes
The ability of cytotoxic T lymphocytes to lyse a virally infected cell depends on the quantity of class I molecules expressed
On what type of cells are MHC class I found in very low levels
Fibroblasts
Muscle cells
Hepatocytes
Neural cells
What cells lack MHC Class I
Neurons
Sperm cells
What do class I molecules display in healthy individuals
Self peptides
What do class I molecules display in virally infected cells
Viral and self peptides are displayed
What cells are MHC II found on
(3)
B lymphocytes
Macrophages
DCs
i.e. APC
Why is the amount of cells than can express MHC class II limited?
So that fewer cell types can present antibodies to T helper cells
What cells can be induced to express class II
Thymic epithelial cells and some other cell types
What does class II expression depend on?
(2)
Differentiation stage -> pre B cells vs mature B cells
Activation stage -> monocytes and macrophages
What MHC molecules do rbcs express
They done express I or II
Write a note on the biosynthesis/expression of MHC
(4)
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)
Describe the translation of MHC
MHC translated from mRNA on membrane-bound ribosomes and co-translationally inserted into the ER membrane
What happens to MHC in the Golgi
Mature glycoproteins are then transported to the plasma membrane by vesicular transport
What happens with the the recently synthesised class II?
(2)
They are associated with a third non-polymorphic chain
y chain or invariant chain (li)
How is MHC expression regulated?
(5)
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
How is the rate of transcription of MHC regulated
Regulated by transcription factors
What do defects in transcription factors of MHC do?
Defects cause one form of bare lymphocyte syndrome -> these lack class II on cells -> a severe immunodeficiency
How do cytokines regulate MHC
Cytokines modulate the rate of constitutive transcription of MHC molecules
(NEED TO LOOK AT POWERPOINT)
What do corticosteroids and prostaglandins do to MHC?
They down regulate class II expression
What can some viruses do to the regulation of MHC
(3)
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
How is MHC expressed
(3)
CIITA binds RFX
RFX binds MHC promoter
Binding activates transcription of the gene
What cytokines modulate transcription
(2)
Interferons a, B and y
TNF
How do cytokines regulate transcription of MHC?
(3)
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
Transcription and expression of the various MHC genes are co-ordinately regulated, comment on this
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
Different haplotypes exist for class II exist and these have variation in immune responsiveness, why is this?
(2)
The determinant selection model
The holes-in-the-repertoire model
What is the determinant selection model
Different class II molecules differ in their ability to bind processed Ag
What is the holes-in-the-repertoire model?
T cells bearing receptors that recognise Ags that resemble self Ags may be eliminated during thymic selection
Certain MHC alleles are heightened in certain disease cases, name these cases?
(5)
Autoimmune disorders
Certain viral diseases
Disorders of the complement system
Some neurologic disorders
Several different allergies
What does a relative risk with a disease and an associated HLA higher than 1 mean
(2)
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
What does a weak association between HLA allele and disease?
(3)
Reflected by low relative risk value
It is likely that multiple genes influence susceptibility
Environmental factors also play a role
Describe the relationship between allelic forms of MHC genes and viruses
(2)
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
