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311 - Molecular Immunology > 10 - MHC - Partridge > Flashcards

10 - MHC - Partridge Flashcards

1
Q

What does MHC stand for?

A

major histocompatibility complex

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2
Q

Where are the MHC genes located and how was the complex first discovered?

A

located on chromosome 6. first discovered in graft rejection research

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3
Q

What is MHC also known as in humans?

A

HLA - human leucocyte antigen (eg HLA-A/B/C)

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4
Q

Give one feature of MHC molecules that enables it to do its ob in recognising antigen

A

very polymorphic. eg > 1400 alleles of HLA-B locus. with each allele containing around 20 different aa substitutions

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5
Q

What is the overall role of the MHC complex?

A

major role in antigen presentation and stimulating T cell responses

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6
Q

T lymphocytes can only recognise ____ in the context of ___-___ molecules

A

antigen

self-MHC

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7
Q

Describe an experiment that identified the use of an MHC molecule. What 2 proposals were then suggested from this? (draw a diagram)

A
  • 2 mice infected with virus
  • virally infected cells from mouse A isolated
  • T cells from both mice A/B obtained and shown that T cells from mouse A could respond and kill the virally infected cell
  • 2 proposals; 1) 2 receptors on T cells. one for MHC and one for antigen. 2) one TCR which recognised both antigen and MHC

311 - 10 word

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8
Q

Why is it that there is a lower chance of graft rejection if receive transplant off a family member?

A

inherit MHC alleles from family therefore lower chance of rejection because have the same MHC

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9
Q

How was the MHC-TCR complex finally observed?

A

X ray crystallography

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10
Q

Describe the 2 causes of MHC proteins (including their gene loci, what cells express them, what peptides they process)

A

MHC class I (HLA-A/B/C);

  • expressed by all nucleated cells (not RBCs, hence why blood transfusions aren’t as complex)
  • present peptides derived from endogenous proteins as a result of cell viral/intracellular bacteria infection
  • present to CTT (CD8+ve)

MHC Class II (HLA-DP/DQ/DR)

  • expressed by B cells, dendritic cells, macrophages
  • present peptides derived from exogenous proteins (eg macrophages taking up bacteria) to helper T cells (CD4+ve)
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11
Q

Draw the MHC-1 protein structure

A

311 - 10 word

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12
Q

Draw the MHC-II protein structure

A

311 - 10 word

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13
Q

Talking about MHCI/II protein structure…

what are the membrane proximal / distal domains like?

A

proximal; Ig like

distal; contain polymorphisms that bind peptide

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14
Q

DESCRIBE (overall) the structure of the MHCI/II molecules

A

MHCI - polymorphic TM a chain, invariant B2-microglobulin domain

MHCII - polymorphic TM a and B chains

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15
Q

What are the similarities between MHC-I/II structures and how they bind the peptides

A
  • both peptide binding grooves contain a B sheet
  • polymorphic residues form specificity pockets on the MHC which bind certain anchor residues along the peptide which hold it in place
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16
Q

Describe the peptides MHC I binds and how they bind int

A
  • MHCI binds peptides around 8-10aa long. crystal structure = > closed than MHC II
  • the N/C terminus of the peptide binds invariant residues at the ends of the grooves
  • 2/3 anchor residues bind to the specificity pockets formed by polymorphic residues
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17
Q

Describe the peptides MHC II binds and how they bind int

A
  • peptides are slightly longer - 13-25aa
  • crystal structure = > open groove therefore binding to bigger structures
  • anchor residues bind specificity pockets…
18
Q

What were the 2 results that crystallographic studies showed?

A

1) MHC binds antigen

2) TCR binds antigen associated with self-MHC

19
Q

Draw a diagram showing the TCR binding to the MHC-I molecule

A

311 -10 word

20
Q

What are the functions of the CDR1/2/3 regions of V region in the TCR?

A

CDR1/2 binds self MHC (germline encoded)

CDR3 binds peptide (variation introduced by junctional diversity)

21
Q

Describe the specificity of MHC molecules

A

degenerate specificity. recognise a wide variety of peptides, unlike TCRs

22
Q

When are MHC molecules expressed on the surface of antigen presenting cells and when do the bound peptides dissociate from MHC?

A
  • expressed on surface when they become associated with the peptide. peptide is an integral part of MHC strucutre
  • bound peptides dissociate v slowly from MHC. allows interaction with TCR that has the correct receptor
23
Q

What are the circumstances for RECOGNITION/NO RECOGNITION when a TCR binds to antigen + MHC?

A

RECOGNITION;
- T cell w/ correct receptor binds to both peptide and self-MHC
NO RECOGNITION;
- T cell does not have correct receptor for antigen but can recognise self MHC
- T cell cannot recognise self MHC (wrong class)

24
Q

Describe the whole process of antigen presentation by MHCI

A
  • eg virally infected host cell presenting to CD8+ve cytotoxic T cell
  • intracellular antigen taken up by proteasome (IFN exposure can modify the proteasome -> immunoproteasome which better cleaves the proteins to peptides 8-10aa long)
  • peptides of correct length released -> cytosol
  • moved to ER by ATP-hydrolysis dependent TAP protein (transporter associated w/ antigen presentation)
  • peptide loaded onto MHCI molecules(requires chaperones) and expressed on cell surface
25
Q

Describe the whole process of antigen presentation by MHCII

A
  • eg B cells, macrophages, dendritic cells taking up exogenous antigen and require T cell help
  • extracellular antigen taken up by phagocytosis, endocytosis -> phagolysosome
  • acidification and enzymes unfold the proteins and and break them down (proteolysis)
  • associate w/ MHCII in endocytic compartment and expressed on surface
  • T cell now produces cytokines that aid in dealing with infection
26
Q

What is cross presentation and what does it allow to happen?

A

eg DCs can take up extracellular antigen and associate it with MHCI molecules to present to cytotoxic T cells.

27
Q

Draw and describe the components of the TCR complex

A
  • T cell receptor
  • ζ chain
  • CD3 regions x2

311 -10 word

28
Q

What are the functions of the co-receptors?

A

1) stabilise interactions between TCR and MHC ligand

2) facilitate signalling

29
Q

Name the co receptors associated with MHCI/II

A

antigen + MHCI - CD8

antigen + MHCII - CD4

30
Q

Draw a diagram and explain briefly what happens when TCRs bind correct MHC ligand

A
  • in resting T cell, ITAMs are not P
  • binding of MHC ligand to TCR -> P of ITAMs of both zeta chains and CD3 intracellular regions by receptor associated kinases
  • CD4/8 coreceptor bind invariant regions of MHC I/II (these are the Ig regions close to the membrane)
  • when co-receptor binds, ZAP70 binds to P ζ chain ITAMs and is P and activated by lack tyrosine kinase that is associated w/ CD8/4
31
Q

Draw the simplified gene structure of human MHC

A

311 -10

32
Q

Describe the MHC gene loci, state how the alleles are organised and how the genes are expressed

A

MHC gene loci are v polymorphic
each loci has multiple alleles and each allele is numbered eg HLA-B1 - HLA-B2668.

MHC genes are expressed codominantly. increases the no. different MHC molecules expressed on the cell

33
Q

Describe the regions where there are high numbers of polymorphisms within MHC - I/II

A

in MHCI;
high regions of variability in a1/2

in MHCII;
variability in in a1 and B1

overall; high no. of polymorphisms in distal peptide binding regions

34
Q

State all the consequences of polymorphism (there are 7)

A

1) graft rejection
2) antigen presentation to T cells
3) T cell activation
4) self/non self recognition (NK cell killing inhibitory receptors)
5) asssociation with autoimmune diseases
6) development of T cell repertoire/tolerance in the thymus
7) chic of mate??

35
Q

What do polymorphisms allow MHC classes to do?

A

recognise a wide variety of foreign peptides HOWEVER, varibililty of MHC small in comparison to TCR (all inherited in genome)

36
Q

Describe responders and non responders in terms of MHC class

A

T cell responses determined by MHC type of individuals (MHC restriction)

  • 2 classes; responders / non
  • each MHC allele can only bind a restricted no. related peptides
  • MHC polymorphism thought to evolved in response to pathogens eg HIV. eg in Africa (HIV endemic), particular mHC alleles are being selected for because show good response against HIV
37
Q

Give an example of an autoimmune disease associated w/ a particular HLA subtype and name this sybstype. also state what the relative risk is of suffering from this disease if you have the subtype

A

ankylosing spondylitis

  • HLA-B27
  • 87% risk
38
Q

Draw a diagram showing how thymus selection occurs and state which 2 structures a T cell will be sent for apoptosis if it recognises/doesnt

A 
if a T cell recognises... 
- self-peptide and self-MHC 
or doesn't recognise/bind strongly enough...
- self MHC
it will be sent for apoptosis
39
Q

What does AIRE stand for and what does it do during thymus selection?

A

Autoimmune regulator.

because thymus is a small organ, TCR may not come across certain proteins therefore cannot be sure it won’t recognise them –> autoimmunity. eg insulin protein

this protein allows transcription of proteins that would not usually be found in thymus so T cells can be checked if they respond to certain self peptides

if they do they will be sent for apoptosis

40
Q

what do deficiencies in AIRE lead to?

A

autoimmune diseases

41
Q

Describe how MHC type may lead to choice of mate

A

certain MHC classes produced may be smelt. attracted to those with different classes of MHC allowing for an increase in diversity of MHC classes in children

311 - Molecular Immunology (18 decks)

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