Lecture 12; MHC structure, function, restriction, transplantation and disease implications.

Question 1

What was learnt about tissue transplantation in the crimean war?

Answer 1

Tissue transplantation between soldiers was rejected after a period of time, inflam etc

However if this soldier received a second transplant from the same donor, the tissue was rejected faster, but a different donor would take equally long as the first time.

i.e the immune system learned and adapted.

This means that whatever was causing the infection was unique to individuals

Question 2

What was the cause of this tissue rejection?

Answer 2

Major Histocompatibility Complex

or

Original name = HLC or H2 in mice

Question 3

What is essential for t cell pathogen recognition?

Answer 3

MHC

Question 4

Describe transplantation and the H2 locus;

Answer 4

A -> B = rejection
B -> A = rejection
A -> AB = Acceptance (neonatal tolerance to A antigen)
AB -> A = rejection

Question 5

What is MHC?

Answer 5

A cell surface antigen.

Expressed mainly on leukocytes, but some somatic cells too.

Question 6

Describe the different types of tissue grafts;

Answer 6

Autograft
Allograft (b/w humans)
Xenograft (animals)
Isograft (twins)

Question 7

Why are isografts and xenografts successful?

Answer 7

Isograft - twins, gentically identicle, therefore very similar MHC complexes

Xenograft = Less likely rejection b/c MHC is so different from humans

Question 8

What causes tissue rejection?

Answer 8

T cells (Thymus derived)

• Express TcR
• Diverse receptor recognition b/c germline gene rearrangement

Question 9

Describe the type of t cells;

Answer 9

CD4

• Th1->cytokines->(innate immunity, macrophage mediated, little AB)
• Th2->cytokines->(humoral- Adaptive immunity i.e AB produced and isotype switching)

CD8
- Cytotoxicity (NO cytokines)

Question 10

What MHC molecules do CD4 and CD8 express?

Answer 10

CD8- recognise MHC class 1

CD4 - recognise MHC class 2

Question 11

What are the types of CD4 and CD8 response?

Answer 11

CD4 = extracellular pathogens

CD8 = Intracellular pathogens

Question 12

Whats a restriction of T cells and what does this mean?

Answer 12

T cells are MHC restricted meaning that their ability to recognise forien antigens is controlled by polymoprhic antigens encoded by a genome region (MHC locus)

i.e T cells = CD4 and CD8 antigens

Question 13

Describe the Rolf Zinkernagel and Peter Doherty experiment;

Answer 13

Infected mice who had two different H2 mice strains that differed in MHC locus.

• Infected with LCMV (lymphocyte choriomeningitis Virus)
• Isolated CD8 cells from each mouse lymph
• Found that the CD8 cells would only kill infected cells from the strain which they originated (named this MHC restriction) (wouldnt recognise MHC of other patients cells)(LCMV is intracellular) Despite CD8 killing the same virus in either instance

i.e CD8 cells would only kill infected cells expressing the correct MHC antigens

Tissue rejection and virus protection were both controlled by MHC

Question 14

What do T cells recognise?

Answer 14

Two components;

• Non self antigen derived from pathogen
• MHC antigens from host

Question 15

What do polymorphisms in MHC regulated?

Answer 15

Regulate Immune protection against pathogen

Question 16

Describe three features of MHC genes;

Answer 16

Polymorphic, polygenic and co-dominant

Question 17

What is meant by polymorphic in terms of MHC genes?

Answer 17

Polymorphic - They vary widely in sequence between individuals but remain constant within each person

Question 18

What is meant by co-dominant in terms of MHC genes?

Answer 18

Each person expresses both maternal and paternal copies

Question 19

What is meant by polygenic in terms of MHC genes?

Answer 19

Each person has more than one version of class one and two antigens

Question 20

Describe some of the CLASSIC MHC HLA polymorphisms in man;

Answer 20

MHC class 1

HLA-A
HLA-B
HLA-C

MHC class 2

HLA-DR (a Chain invariant
HLA-DQ
HLA-DP

MHC class 3
(includes TNF and compliment genes)

Question 21

What are the non-classical MHC genes?

Answer 21

CD1
HLA-E
HLA-F
HLA-G
HLA-H

Much less polymorphic

Question 22

What are the min and max number of different MHC antigens a person can have?

Answer 22

Min 6 and max 12 (codominance)

Thus MHC locus has extreme variability

Question 23

What drives the MHC genes to be polymorphic?

Answer 23

MHC molecules have become polygenic and polymorphic to ensures the species as a whole can cope with a common pathogen

thus different areas of the world possess different MHC’s

Question 24

Describe MHC expression;

Answer 24

MHC molecules are deferentially expressed.

i.e

MHC class One is one all cells except RBC (imp tissue killing and CTL regulation

MHC class 2 are only on select APC’s.

• Macrophages
• B cells
• Dendritic cells
• Activated T cells also

MHC 1 and 2 have very different roles in CD8 + CD4

Question 25

Describe MHC class one structure;

Answer 25

Two chains; H(c) non covalently associated with B-2 microglobulin

Heavy chain has 3 domains , a-1,2,3

• a-1,2 polymorphic
• a-3 binds B2M and CD8

Question 26

Describe the MHC class one antigen binding cleft;

Answer 26

Formed by 8 beta strand antiparallel beta sheet floor over which two long alpah helices lie.

The groove created in MHC class one can bind small peptides (8-10) aa long. (polymorhpism groove)

Thus can bind many peptides as the binding domain is very polymorphic

Question 27

Describe MHC class 2 structure;

Answer 27

2 chains = a and b. non covalently linked

Each has two domains i.e a1 a2

a chain is polymorphic thus forms the binding groove (open at both ends unlike MHC 1) thus can bind peptides of any length

Question 28

Describe adaptive cellular immunity;

Answer 28

• T cells recognise antigens on a cell surface (MHC)

- Antigen recognition of t cells is goverened by MHC locus.

Question 29

Describe MHC class one function;

Answer 29

MHC class one mediate CD8 (CTL) against INTRAcellular pathogens

• Infected cells MHC class one binds viral peptide produced inside the cell.
• This activates CD8 = cytotoxic activity and kills the cell and thus virus.

Question 30

Describe MHC class 2 function;

Answer 30

MHC class 2 mediates CD4 helper t cell of extra cellular pathogens

• APC express pathogen material i.e bacteria, fungi, protozoa on MHC class 2 receptors. this activates CD4 that produce cytokines to help B cells produce antibody or drive CTL to expand and kill infected cells
  i. e TH1 - cytokines - Innate immunity - Macrophage mediated

TH2 - cyotkines - humoral - adpative immunity,ab production

Question 31

When a cell encounters a foreign peptide how does it express it with MHC

Answer 31

Foreign peptide is buried with MHC

subject of another lecture

Question 32

Describe peptide binding motifs for MHC molecules;

Answer 32

Peptides bind by side chains into pockets in the MHC molecule (binding cleft)

For each allele the pocket differs

Each allele has a specific motif for binding

Question 33

Describe CD4

Answer 33

Co-receptor of TcR

• 80% of resting t cells
• monomeric protein
• Binds to the two alpha domains of MHC class 2
• CD4 has tyrosine kinase domain attatched to its intracellular domain which triggers t cell activation through p/ph

Question 34

Describe CD8

Answer 34

Co-receptor of TcR

• Heterodrimer
• 20% of resting peripheral t cells
• Binds a3 domain of MHC class 1
• has tyrosine kinase domain attatched to its intracellular domain which triggers t cell activation through p/ph of TcR

Question 35

Describe MHC and disease susceptibility;

Answer 35

• because MHC locus is polymorphic, it is also strongly associated with disease
  i. e Rheumatoid arthritis, type one diabetes, MS