1. dia

1
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
ANTIGEN RECOGNITION BY T-CELLS REQUIRES PEPTIDE
ANTIGENS AND ANTIGEN PRESENTING CELLS THAT
EXPRESS MHC MOLECULES
T
Y
soluble Ag
Peptide antigen
Native membrane Ag
Cell surface peptides
APC
No T-cell response
4
THE STRUCTURE OF MHC GENES AND PROTEINS
5
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
THE STRUCTURE OF MHC GENE PRODUCTS
?2
?1
?1
?1
?3
?2
?2
?2m
?1 ?2 ?3
?1 ?2
?1 ?2
?3 and ?2m Ig supergene family ?2 and ?2
7
MAP OF THE HUMAN MHC FROM THE HUMAN GENOME
PROJECT
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
9
(No Transcript)
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
(No Transcript)
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 1 200 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
Alleles are not distributed evenly in the
population Alleles are segregated among races
SELECTION
14
(No Transcript)
15
Inheritance of MHC haplotypes
16
FUNCTIONS OF MHC MEMBRANE PROTEINS
17
STRUCTURE OF CLASS I MHC MOLECULES
PEPTIDE
EXPRESSED BY ALL NUCLEATED CELLS
18
STRUCTURE OF CLASS II MHC MOLECULES
PEPTIDE
EXPRESSED BY PROFESSIONAL ANTIGEN PRESENTING
CELLS CAN BE INDUCED IN OTHER CELLS (endothel,
microglia, astocyte)
19
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
Polymorphism in the MHC affects peptide antigen
binding Allelic variants may differ by 20 amino
acids
22
Cleft geometry
MHC class I accommodate peptides of 8-10 amino
acids
MHC class II accommodate peptides of gt13 amino
acids
23
Most polymorphisms are point mutations
Polymorphic nucleotides encode amino acids
associated with the peptide binding site
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
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
Amino acids common to many peptides tether the
peptide to structural features of the MHC
molecule ANCHOR RESIDUES
Tethering amino acids need not be identical but
must be related Y F are aromatic V, L I are
hydrophobic
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
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
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 gt1 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
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
• 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