General organization and inheritance of MHC

1. INDIAN INSTITUTE OF TECHNOLOGY ROORKEE
GENERAL ORGANIZATION AND
INHERITANCE OF MHC
Assignment
Submitted by Sourik Dey (18610023), M.Sc Biotechnology, 1st Year, 2018-2019
Immunology and Immunotechnology (BTN-522)
Submitted to
Dr. R. P. Singh

2. 2
MAJOR HISTOCOMPATIBILITY COMPLEX
• Cluster of genes found in all mammals.
• Its products play a role in discriminating self/non-self.
• Participant in both humoral and cell mediated immunity.
• MHC act as Antigen Presenting Structures.
• In Humans MHC is found on Chromosome 6 – Referred to as
HLA Complex.
• In mice MHC is found on Chromosome 17 – Referred to as H2
Complex.
MHC

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 Genes Of MHC Organized In 3 Classes
 Class I MHC genes
 Glycoproteins expressed on all nucleated cells
 Major function to present peptide Antigens to TC
 Class II MHC genes
 Glycoproteins expressed on Macrophages, B-cells, DCs
 Major function to present processed Antigens peptides to TH
 Class III MHC genes
 Class III molecules are not membrane proteins, are not related
structurally to class I and class II molecules, and have no role in Ag
presentation, although most play some role in immune responses.
e.g., C2, C4a, C4b, factor B, 21-hydroxylase enzymes, TNFα,
TNFβ, heat shock proteins (HSP)( include secreted proteins)
CLASSES OF MHC

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Detailed Genomic Map of MHC genes
The MHC spans 4000 Kb of human DNA at chromosome no 6
The human class 1 region span about 2000 kb at the telomeric end of HLA complex.
1. MHC classical HLA- A, HLA-B & HLA C.
2. MHC Class 1b genes.
Encoding MHC class I-like proteins that associate with β-2 microglobulin:-
• HLA – E, F, G, J & X (some are pseudogenes)
• HLA-G binds to CD94, an NK-cell receptor. Inhibits NK attack of foetus/ tumors.
• HLA-E binds conserved leader peptides from HLA-A, B, C. Interacts with CD94.
• HLA-F function unknown

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1. HLA DR, DP&DQ multiple α & β chain DR:-
• 3-4 functional β chain,1 α chain . DP & DQ region each
contains two of each α & β chain
MHC Class II genes NON CLASSICAL GENES
2. Encoding several antigen processing genes:-
• HLA-DM α & β loading of antigenic peptide , proteasome
components LMP-2 & 7, peptide transporters.
• TAP-1 & 2, HLA-DO α and DO β (thymus & mature B cells
regulators of loading antigen peptide)
• Many pseudogenes
CLASS 2 MHC GENES are located at the centromeric end of HLA

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MHC Class III genes
CLASS 3 genes are between CLASS 1 & 2
• Encoding complement proteins C4A and C4B, C2 and Factor B
Tumour Necrosis Factors α and β.
• Immunologically irrelevant genes.
• Genes encoding 21-hydroxylase, RNA Helicase, Caesin kinase,
Heat shock protein 70, Sialidase.
• Congenital adrenal hyperplasia , mutation in gene encoding 21
hydroxylase.
• The presence of linked class 3 genes in cluster is conseved in all
species with MHC

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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.
396
198
82
15
Class I
1318 alleles
(998 in October
2003)
(657 in July 2000)
Noof
polymorphisms
A B C E F G
699
Data from www.anthonynolan.org.uk/HIG/index.html September 2005

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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
2328
66
Data from www.anthonynolan.org.uk/HIG/index.html September 2005
733 alleles
(668 in October 2003)
(492 in July 2000)
119
4 7 9 9
Class II
A B1
DR
Noof
polymorphisms
A1 B1 A1 B1 A B A B
DQ DP DM DO

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28
9 6
25
10
Class I - ~100 antigens
Class II - ~40 antigens
(Figure hasn’t changed since October 2003)
62
A B C DR DQ DP
Noof
serologically-
definedantigens
Diversity of MHC Class I and II antigens
Because so many MHC class I & II alleles are null, or contain synonymous
mutations, the diversity of MHC molecules that can be identified by antibodies
i.e. SEROLOGICALLY, is considerably fewer than that by DNA sequencing
Data from www.anthonynolan.org.uk/HIG/index.html September 2005

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DP DQ DR B C A
Polygeny
B C ADP DQ DR
Variant alleles
polymorphism
B C ADP DQ DR
Additional set of
variant alleles on
second
chromosome
MHC molecules are CODOMINANTLY expressed
Two of each of the six types of MHC molecule are expressed
Genes in the MHC are tightly LINKED and usually inherited in a unit called an MHC
HAPLOTYPE
Inherited as 2 sets (one from father, one from mother)
Diversity of MHC molecules in the individual
HAPLOTYPE 1
HAPLOTYPE 2

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

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THANK YOU