1. TISSUE TRANSPLANTATION IS RESTRICTED BY MHC MOLECULES
VIRUS-INFECTED CELLS ARE RECOGNIZED BY T-LYMPHOCYTES IN MHC-DEPENDENT MANNER
TISSUE TRANSPLANTATION IS RESTRICTED BY MHC MOLECULES
THE IMMUNE RESPONSE TO PROTEIN ANTIGENS IS REGULATED BY INDIVIDUALLY POLYMORPHIC MHC GENES
T-LYMPHOCYTES RECOGNIZE ANTIGEN-DERIVED PROTEIN FRAGMENTS (PEPTIDES) EXPRESSED ON THE SURFACE OF SELF ANTIGEN PRESENTING CELLS

2. ANTIGEN PRESENTING CELLS
Synthesize antigens – endogenous antigens (virus, tumor)
Internalize antigens – exogenous antigens (any protein)
Degrade protein antigens to peptides – processing
Protein – derived peptides are presented by MHC (HLA) membrane proteins – antigen presentation
MHC molecules present both self and non-self protein – derived peptides
MHC class I molecules are expressed in all nucleated cells
MHC class II molecules are expressed by professional antigen presenting cells

3. Y ANTIGEN RECOGNITION BY T-CELLS REQUIRES
PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS
THAT EXPRESS MHC MOLECULES T Y
Cell surface MHC-peptide complex
T-cell response
soluble Ag
Peptide
antigen
Native
membrane Ag
Cell surface
peptides
APC
No T-cell response

4. THE STRUCTURE OF MHC GENES AND PROTEINS

5. MOLECULES CONTAINING ONE OR MORE Ig DOMAIN(S)
MEMBERS OF THE IMMUNOGLOBULIN SUPERGENE FAMILY
MOLECULES CONTAINING ONE OR MORE Ig DOMAIN(S)
V or C domain related
FUNCTION
RECOGNITION
Ig, TCR, MHC-I, MHC-II
ADHESION
ICAM-1, ICAM-2, VCAM-1, NCAM
BINDING
CD4, CD8, CD28, B7, IL-1RI, PDGFR, FcRII, poly-IgR

6. 3 and 2m Ig supergene family 2 and 2
THE STRUCTURE OF MHC GENE PRODUCTS 2 1 1 1 3 2 2
2m
  3
 2
 2
3 and 2m Ig supergene family 2 and 2

7. FROM THE HUMAN GENOME PROJECT
MAP OF THE HUMAN MHC
FROM THE HUMAN GENOME PROJECT
3,838,986 bp
224 genes
on chromosome 6
The MHC sequencing consortium
Nature 401, 1999

8. LOCALIZATION OF MHC GENES
Chromosome 6 short arm MHC
Chromosome 15 2m
Non- classical MHC genes
E, G, F
Classical MHC genes POLYMORPHIC
HLA – Human Leukocyte Antigen
HLA –A, B, C class I
EXPRESSED IN ALL NUCLEATED CELLS
HLA – DR, DP, DQ class II
EXPRESSED IN PROFESSIONAL APC
Class III genes

10. Differential distribution of MHC molecules
Tissue MHC class I MHC class II
T cells /-
B cells
Macrophages
Other APC
Epithelial
cells of thymus
Neutrophils
Hepatocytes
Kidney
Brain
Erythrocytes
Cell activation affects the level of MHC expression
The pattern of expression reflects the function of MHC molecules
Class I is involved in anti-viral immune responses
Class II involved in activation of other cells of the immune system

11. INHERITANCE OF MHC CLASS I AND CLASS II GENES HUMAN LEUKOCYTE ANTIGEN
HLA
EVERY CELL
CLASS I
CLASS II
α1β1
α2β2
PROFESSIONAL APC

12. POLYMORPHISM OF MHC MOLECULES IN THE HUMAN POPULATION
POSTULATION
• every individual has 6 MHC class I molecules
• alleles of all MHC types are distributed randomly in the population
• every one of the different alleles can be expressed with any other allele
~6 x 1015 individual combinations
Only monozygous twins are identical at the HLA locus
The human population is extensively outbred
MHC genetics in humans is extremely complex
POLYGENIC & POLYMORPHIC

13. DISTRIBUTION OF MHC ALLELES IN THE HUMAN POPULATION
Polymorphism (number of alleles)
Class I
657 alleles
185 91
381
15.18
28.65
13.38
4.46
0.02
5.72
18.88
8.44
9.92
1.88
4.48
24.63
2.64
1.76
0.01
CAU
AFR
ASI
Frequency (%)
HLA-A1
HLA- A2
HLA- A3
HLA- A28
HLA- A36
Allelic groups
Class II
492 alleles a b 2
317 19 89 20 45 DR DP DQ
Alleles are not distributed evenly in the population
Alleles are segregated among races
SELECTION

15. Inheritance of MHC haplotypesB C A DP DQ DR
Children
DP-1,8
DQ-3,6
DR-5,4
B-7,2
C-9,8
A-11,10
DP-1,9
DQ-3,7
DR-5,5
B-7,3
C-9,1
A-11,9
DP-2,8
DQ-4,6
DR-6,4
B-8,2
C-10,8
A-12,10
DP-2,9
DQ-4,7
DR-6,5
B-8,3
C-10,10
A-12,9
Inheritance of MHC haplotypes B C A DP DQ DR X
Parents B C A DP DQ DR
DP-1,2
DQ-3,4
DR-5,6
B-7,8
C-9,10
A-11,12
DP-9,8
DQ-7,6
DR-5,4
B-3,2
C-1,8
A-9,10 B C A DP DQ DR B C A DP DQ DR

16. FUNCTIONS OF MHC MEMBRANE PROTEINS

17. STRUCTURE OF CLASS I MHC MOLECULES EXPRESSED BY ALL NUCLEATED CELLS
PEPTIDE 1 3 2
2m
EXPRESSED BY ALL NUCLEATED CELLS

18. STRUCTURE OF CLASS II MHC MOLECULES
PEPTIDE 2 1 2 1
EXPRESSED BY PROFESSIONAL ANTIGEN PRESENTING CELLS
CAN BE INDUCED IN OTHER CELLS (endothel, microglia, astocyte)

19. Intracellular peptide binding capacity
MEMBRANE RECEPTORS
Intracellular peptide binding capacity
One binding site can accomodate multiple peptides

20. MHC – PEPTIDE COMPLEXES

21. Allelic polymorphism is concentrated in
the peptide antigen binding site
Class I
Class II
(HLA-DR) 1 3 2
2m 2 1 2 1
Polymorphism in the MHC affects peptide antigen binding
Allelic variants may differ by 20 amino acids

22. Cleft geometry b2-M a-chain Peptide a-chain b-chain Peptide
MHC class I accommodate
peptides of 8-10 amino acids
MHC class II accommodate
peptides of >13 amino acids

23. Most polymorphisms are point mutations
DPB1*01011 TAC GCG CGC TTC GAC AGC GAC GTG GGG GAG TTC CGG GCG GTG ACG GAG CTG GGG CGG CCT GCT GCG GAG TAC TGG AAC AGC CAG AAG GAC ATC CTG GAG GAG DPB1* A DPB1* T- -T A- -A DPB1* T- -T AC -A DPB1*0202 CT- -T AG DPB1* T- -T A- -A- --C C DPB1* T DPB1* T- -T A- -A DPB1*0501 CT- -T AG DPB1* T- -T A- -A- --C C DPB1* T- -T A- -A DPB1* T- -T A- -A- --C DPB1* T- -T A- -A DPB1* A C DPB1* A C DPB1* DPB1* T- -T A- -A- --C C DPB1* A C DPB1* T- -T A- -A DPB1* T- -T A- -A- --C DPB1* T- -T A- -A DPB1* T- -T AG DPB1* T- -T A- -A- --C C DPB1* T- -T A- -A- --C C DPB1*2101 CT- -T AG DPB1*2201 CT- -T AG DPB1* T- -T DPB1* T AG DPB1* T- -T A- -A C DPB1* A DPB1*
30 HLA-DPb allele sequences between
Nucleotides 204 and 290
(amino acids 35-68)
Polymorphic nucleotides encode amino acids associated with the peptide binding site
Y-F
A-V
Silent
A-D
A-E
E-A
I-L

24. STRUCTURE OF THE PEPTIDE BINDING SITE
Amino acid side chains of the ‘core’ region occupy evenly distributed pockets
P2 & P9 interact with hydrophobic pockets

25. Peptides can be eluted from MHC molecules
Acid elute peptides

26. Eluted peptides from MHC molecules have different sequences but contain motifs
Peptides bound to a particular type of MHC class I molecule have conserved patterns of amino acids
A common sequence in a peptide antigen that binds to an MHC molecule is called a MOTIF R T Y Q L V N C P E I Y S F H
Amino acids common to many peptides tether the peptide to structural features of the MHC molecule
ANCHOR RESIDUES A V T Y K Q L P S A Y I K
Tethering amino acids need not be identical but must be related
Y & F are aromatic
V, L & I are hydrophobic R G Y V Q L S I F N E K L A P G Y N L
Side chains of anchor residues bind into POCKETS in the MHC molecule
Different types of MHC molecule bind peptides with different patterns of conserved amino acids

27. PEPTIDE MOTIFS IN SELF AND FOREIGN PROTEINS

28. Kidney epithelial cell B-cell, macrophage, dendritic cell
MHC MOLECULES ARE EXPRESSED IN THE CELL SURFACE MEMBRANE WITH BOUND PEPTIDES DERIVED FROM SELF OR NON-SELF PROTEINS
Kidney epithelial cell
B-cell, macrophage, dendritic cell
Present intra- and extracellular environment
Liver cell
Class II MHC
Overlapping peptides of various sizes, which derive from membrane/exogeneous proteins
70% derives from MHC molecules
Present intracellular environment
Class I MHC – code of 6
Immunological ID
Peptides of restricted size, which derive from cytosolic or nuclear proteins

29. BENEFITS OF MHC POLYMORPHISM IN THE POPULATION

30. COMBINATION OF MHC ALLOTYPES IN INDIVIDUALS AND IN THE POPULATION
* *
* * * *

31. Populations need to express variants of each type of MHC molecule
• The rate of replication by pathogenic microorganisms is faster than human reproduction
• In a given time a pathogen can mutate genes more frequently than humans and can easily evade changes in MHC molecules
• The number of types of MHC molecules are limited
To counteract the flexibility of pathogens
• The MHC has developed many variants of each type of MHC molecule
• These variants may not necessarily protect all individuals from every pathogen, but will protect the population from extinction

32. THE OUTCOME OF INFECTION IN A POPULATION WITH POLYMORPHIC MHC GENES
Example: If MHC X was the only type of MHC molecule
MHC-Gen v
Pathogen that evades MHC X
MHC XX
Population threatened
with extinction
Population is protected

33. Molecular basis of MHC types and variants
POLYGENISM
Several MHC class I and class II genes encoding different types of MHC molecule with a range of peptide-binding specificities.
POLYMORPHISM
Variation >1% at a single genetic locus in a population of individuals
MHC genes are the most polymorphic known
The type and variant MHC molecules do not vary in the lifetime of the individual
The diversity in MHC molecules exists at the population level
This sharply contrast diversity in T and B cell antigen receptors which exists within the individual

34. Peptides recognized by an individual
Foreign peptides
Peptides recognized by an individual

35. CHANGES OF GENETIC POLYMORPHISM IN THE POPULATION

36. Multiple heterozygous allele
Homozygous

37. FUNCTIONS OF MHC CLASSICAL MHC GENE PRODUCTS NON CLASSICAL MHC GENES
Presentation of peptides derived from self proteins – continuos presentation of self for the immune system
Determination of immunological self
Self MHC + self peptides
Presentation of peptides derived from foreign (antigenic) proteins
Determination of non-self
Self MHC + non-self peptides
Allogeneic immune response against non-self MHC (transplantation)
Recognition of non-self MHC + peptide combinations – consequence of MHC-restricted T-cell recognition
NK cell recognition
T-lymphocyte differentiation and selection in the thymus
T-lymphocyte survival in the periphery
NON CLASSICAL MHC GENES
Specialized functions
PROTEINS STRUCTURALLY RELATED TO CLASSICAL MHC MOLECULES

38. OTHER GENES IN THE MHC – not polymorphic
MHC Class 1b genes
Encoding MHC class I-like proteins that associate with -2 microglobulin
Restricted tissue expression
HLA-G trophoblast, interacts CD94 (NK-cell receptor). Inhibits NK cell attack of foetus/ tumours
HLA-E in the membrane of certain cells, binds conserved leader peptides from HLA-A, B, C. Interacts with CD94
HLA-F fetal liver, eosinophil surface, function unknown
MHC Class II genes
Encoding several antigen processing genes
HLA-DM and  in professional APC, proteasome components (LMP-2 & 7), peptide transporters (TAP-1 & 2), HLA-DO and DO
Many pseudogenes
MHC Class III genes
Encoding complement proteins C4A and C4B, C2 and FACTOR B
TUMOUR NECROSIS FACTORS-/
Immunologically irrelevant genes
Genes encoding 21-hydroxylase, RNA Helicase, Caesin kinase
Heat shock protein 70, Sialidase