MHCbasicimmuno

MHC
Major Histocompatibility Complex

Format
How was it discovered?

What is its function?
Classification of genes
Structure of the MHC protein
Peptide binding to MHC
Clinical Relevance
How was the MHC discovered?
George Snell experiments 1940s
Inbred mouse strains
Transplant skin from

one to other
To Inbred To Outbred
Graft acceptance or rejection is
genetically determined
THERE IS A GENETIC LOCUS WHOSE PROTEIN

PRODUCTS ARE RESPONSIBLE FOR REJECTION OF
TRANSPLANTS
WHICH CHROMOSOME, WHICH LOCATION

Discovery of genetic location
Congenic mouse strains

Located MHC on chromosome 17 in mice
Same location as previously described blood group
antigen II
Name H-2
Initially though single gene but later realised
multiple genes
Is this the real reason MHC are
there?
TRANSPLANTATION IS NOT A NATURAL

PHENOMENON…..
Rediscovery of the MHC
1960s and 1970s

Inbred stains of mice and guinea pigs differed in
ability to make antibodies against simple peptides
and this was genetically determined
Mapped to same H-2 locus
Called immune response genes
What does the MHC do?
Important in the
immune response.
Nomenclature of MHC in mice
Class I
 H2k, H2l, H2d
Class II
 IA,IE
Inbred strains have been denoted by lower case letters

– a, b, c, d
 These inbred strains are homozygous
 There haplotype is designated a, b, c, d
Non inbred strains
 H2ka/b H2db/c
Discovery of human MHC
Blood transfusion reactions to WBCs

Organ transplants (Kidney)
These patients have circulating antibodies against

antigens on WBC
 MHC antigens
So , also named Human leucocyte antigens

Classification of human MHC
Collected alloantisera from the above 2 and

Multiparous women, Volunteers – typing
 HLA A, B and C
Mixed leucocyte reaction

 Proliferation of T cells
 Does the T cell recognize foreign antigens?
 In vitro model of direct allograft rejection
 Identified HLA D
LOCATION OF THE MHC GENES
Chro
moso
me 6
Chro
moso
me 17
Properties of MHC genes
Polymorphic
Co-dominant
MHC class I and II
STRUCTURE OF THE MHC
The MHC is a receptor! – a receptor for
antigens
Comparing to TCR and BCR/Ig
What are
the
differences
?
1. Number of chains: 4,2,2

2. Covalent vs. non covlaent links between chains
3. Peptide/Antigen binds where? (ANTIGEN
BINDING SITE): CDRs in Vh, Vl and Valpha,
V beta
4. Nature of antigen bound
5. Nature of antigenic determinants:
Conformational versus linear
What are
the
similarities
?
All Ig
superfamily
All
polymorphic
Structure of MHC
What are the

differences in the
structure?
Structure of MHC
1. Type of Chains
2. Chains forming the
Peptide binding cleft
Top view of MHC
Peptide binding to MHC
MHC are peptide

displayers of the
immune system
To T cells
How to study peptide binding to MHC
Functional studies: T cells with APCs and put in

various peptides: Look at ones that elicit T response
Purified MHC with fluorescent labelled peptides
X-Ray crystallographic analyses
What are the characteristics of this
association?
MHC molecules have broad specificity

 Although one at a time bind peptides
 Can bind multiple peptides
There are AA in peptides which have interactions
with some specific MHC peptides
Saturable interaction with slow on off rates
 Persist long enough for T cell recognition
Do Not discriminate between self and non self
MHC-Peptide interaction anatomy
 Non covalent interaction

 Each peptide usually contains only
1-2 anchor AA residues which fill
pockets in MHC through
hydrophobic interactions –
located in the middle or the ends
 But in class 2 molecules: Salt
bridges and H2 bonds between the
peptides and alpha helixes`
Specific expression of MHCs
MHC I
 All nucleated cells
 Low on Muscle cells, thyroid
 Display of intracellular antigens – viruses
Class II
 Antigen presenting cells
 DCs, Macrophages, Monocytes, B cells
Expression of MHC increased by specific cytokines

 IFN, TNF, LT
 Increase transcription factor expression
 In MHCII – CIITA main
Recapitualtion
How was it discovered?

What is its function?
Classification of genes
Structure of the MHC protein
Peptide binding to MHC
Clinical Relevance

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MHCbasicimmuno

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MHC

Major Histocompatibility Complex

How was it discovered?

George Snell experiments 1940s

Inbred mouse strains

Transplant skin from

THERE IS A GENETIC LOCUS WHOSE PROTEIN

WHICH CHROMOSOME, WHICH LOCATION

Congenic mouse strains

TRANSPLANTATION IS NOT A NATURAL

1960s and 1970s

Inbred strains have been denoted by lower case letters

Blood transfusion reactions to WBCs

These patients have circulating antibodies against

So , also named Human leucocyte antigens

Collected alloantisera from the above 2 and

Mixed leucocyte reaction

1. Number of chains: 4,2,2

What are the

MHC are peptide

Functional studies: T cells with APCs and put in

MHC molecules have broad specificity

 Non covalent interaction

Expression of MHC increased by specific cytokines

How was it discovered?

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