major histocompatability complex

1. MHC -Major
Histocompatability
complex
PRESENTED BY
R.PRATHISHA
MFT16087(AAH)

2. Cell Membrane
Peptide
MHC class I MHC class II
MHC molecules
Peptide
binding groove

3. Differential distribution of MHC molecules
Cell activation affects the
level of MHC
expression.
• Class I is involved in the
regulation of anti-viral
immune responses
• Class II involved in
regulation of the cells of
the immune system
Anucleate erythrocytes
can not support virus
replication - hence no
MHC class I.
Tissue MHC class I MHC class II
T cells +++ +/-
B cells +++ +++
Macrophages +++ ++
Other APC +++ +++
Thymus epithelium + +++
Neutrophils +++ -
Hepatocytes + -
Kidney + -
Brain + -
Erythrocytes - -

4. 1
3
2
Overall structure of MHC class I molecules
2m
Class I molecules are composed of two
polypeptide chains; one encoded by the
BCA region and another (ß2-
microglobulin) that is encoded
elsewhere.
The MHC-encoded polypeptide is
about 350 amino acids long and
glycosylated, giving a total molecular
weight of about 45 kDa.
This polypeptide folds into three
separate domains called alpha-1, alpha-
2 and alpha-3.
ß2-microglobulin is a 12 kDa
polypeptide that is non-covalently
associated with the alpha-3 domain.

5. MHC class I molecule structure
Chains Structures
2-micro-
globulin
Peptide
-chain

6. • MHC (major Histocompatability complex)
Class II molecules are found only on a few
specialized cell types, including macrophages,
dendritic cells and B cells, all of which are
professional antigen-presenting cells (APCs).

7. 2
1
2
1
Overall structure of MHC class II molecules
MHC-encoded, -chain of 34kDa and a -
chain of 29kDa
and  chains anchored to the cell
membrane
No -2 microglobulin
Peptide antigen in a groove formed from a
pair of -helicies on a floor of anti-parallel 
strands
2 & 2 domains have structural & amino
acid sequence homology with Ig C domains
Ig GENE SUPERFAMILY

8. MHC location on Chromosome 6
• The major
Histocompatibility
complex is encoded by
several genes located on
human chromosome 6.
Class I molecules are
encoded by the BCA region
while class II molecules are
encoded by the D region. A
region between these two
on chromosome 6 encodes
class III molecules, including
some complement
components.
Dr.T.V.Rao MD 9

9. • Expression Is Regulated By Many Cytokines
– IFN, IFN, IFN and TNF Increase MHC expression
• Transcription Factors That Increase MHC gene
Expression
– CIITA (Trans activator), RFX (Trans activator)
• Some Viruses Decrease MHC Expression
– CMV, HBV, Ad12
• Reduction Of MHC May Allow For Immune System
Evasion
MHC Expression

10. MHC class II molecule structure
-chain
Peptide
-chain
Cleft is made of both
 and  chains

11. MHC class I
MHC class II
Cleft geometry
Peptide is held in the cleft by non-covalent forces

12. MHC class I accommodate
peptides of 8-10 amino acids
Cleft geometry
MHC class II accommodate
peptides of >13 amino acids
2-M
-chain
Peptide
-chain
-chainPeptide

13. MHC-binding peptides
Each human usually expresses:
3 types of MHC class I (A, B, C) and
3 types of MHC class II (DR, DP,DQ)
The number of different T cell antigen receptors is estimated to be
1,000,000,000,000,000
Each of which may potentially recognise a different peptide antigen
Thus 6 invariant molecules have the capacity to
bind to 1,000,000,000,000,000 different peptides

14. Molecular basis of MHC types and variants
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
Diversity in MHC molecules exists at the population level
This sharply contrasts diversity in T and B cell antigen receptors which are in a constant
state of flux within the individual.
POLYGENISM
Several MHC class I and class II genes encoding
different types of MHC molecule with a range of
peptide-binding specificities.

15. Simplified map of the HLA region
Maximum of 9 types of antigen presenting molecule allow interaction with a wide
range of peptides.
Class III
MHC Class II
 
DP
 
LMP/TAPDM
 
DQ

DR
1
B C A
MHC Class I
Polygeny
CLASS I: 3 types HLA-A, HLA-B, HLA-C (sometimes called class Ia genes)
CLASS II: 3 types HLA-DP HLA-DQ HLA-DR.
4 53
3 extra DR genes in some individuals can allow 3 extra HLA-DR molecules

16. Other genes in the MHC
MHC Class 1b genes
Encoding MHC class I-like proteins that associate with -2 microglobulin:
HLA-G binds to CD94, an NK-cell receptor. Inhibits NK attack of foetus/ tumours
HLA-E binds conserved leader peptides from HLA-A, B, C. Interacts with CD94
HLA-F function unknown
MHC Class II genes
Encoding several antigen processing genes:
HLA-DM and , 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  AND 
Immunologically irrelevant genes
Genes encoding 21-hydroxylase, RNA Helicase, Caesin kinase
Heat shock protein 70, Sialidase

17. Polymorphism in MHC Class I genes
Variation >1% at a single genetic locus in a population of individuals
In the human population, over 1300 MHC class I alleles have been identified - some are null
alleles, synonyms or differ in regions outside the coding region
699
396
198
Data from www.anthonynolan.org.uk/HIG/index.html September 2005
1318 alleles
(998 in October 2003)
(657 in July 2000)
8 2 15
Class I
A B C
Noof
polymorphisms
E F G

18. Polymorphism in MHC Class II genes
Over 700 human MHC class II alleles have been identified - some are null alleles, synonyms
or differ in regions outside the coding region
3
494
23
119
28
66
Data from www.anthonynolan.org.uk/HIG/index.html September 2005
733 alleles
(668 in October 2003)
(492 in July 2000)
4 7 9 9
DR DPDQ DM DO
Class II
A B1 A1 B1A1 B1
Noof
polymorphisms
A B A B

19. Peptide Binding to MHC Molecules: Class I vs. II
Class I Class II
• Generated by proteasome (cytosol) • Generated in endosomes/lysosomes
• Transported to ER by TAP1/2 • Bind in specialized vessicles (MIIC)
• Restricted length, 8-9 residues • Any length, extend from MHC
Dr.T.V.Rao MD 20

20. MHC-Linked Diseases
• Defects in MHC gene expression lead
to immunodeficiencies (MHC
molecules are required for both T
cell development and activation)
• Some MHC alleles are associated
with susceptibility or resistance to
autoimmune diseases
Dr.T.V.Rao MD 21

21. MHC-Linked Immunodeficiencies
Bare Lymphocyte Syndromes lead to loss of
MHC molecule expression:
• Defects in TAP genes prevent MHC Class I
protein surface expression (even though MHC
proteins are normal), so no CD8+ T cells -
surprisingly mild immunodeficiency (respiratory
and skin infections)
• Defects in block CD4+ T cell development - result
in SCID (severe combined immunodeficiency)
Dr.T.V.Rao MD 22