General organization and inheritance of MHC

General organization and inheritance of MHC

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

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

3. Genes Of MHC Organized In 3 Classes Class I MHC genes Glycoproteins expressed on all nucleated cells Major function to present peptide Antigens to T C Class II MHC genes Glycoproteins expressed on Macrophages, B-cells, DCs Major function to present processed Antigens peptides to T H 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, TNF α, TNF β, heat shock proteins (HSP)( include secreted proteins) CLASSES OF MHC

4. 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 com p lex. MHC classical HLA- A, HLA-B & HLA C. 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

5. 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 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

6. 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 i n cluster is conseved in all species with MHC

7. 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 8 2 15 Class I 1318 alleles (998 in October 2003) (657 in July 2000) No of polymorphisms A B C E F G 699 Data from www.anthonynolan.org.uk/HIG/index.html September 2005

8. 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 28 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 No of po l ymorphisms A 1 B1 A 1 B1 A B A B DQ DP DM DO

9. 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 No of serologically- defined antigens 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

10. DP DQ DR B C A Polygeny B C A DP DQ DR Variant alleles poly m orph i sm B C A DP 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

11. Inheritance of MHC haplotypes A DP DQ DR B C A DP DQ DR B C A DP DQ DR B C A DP DQ DR B C X P a r ents DP-1,2 DQ-3,4 DR-5,6 B-7,8 C-9,10 A- 1 1 , 1 2 DP-9,8 D Q- 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- 1 1 , 1 DP-2,8 DQ-4,6 DR-6,4 B-8,2 C-10,8 A- 1 2 , 1 DP-2,9 DQ-4,7 DR-6,5 B-8,3 C-10,10 A-12,9 A DP DQ DR B C A DP DQ DR B C A DP DQ DR B C A DP DQ DR B C A DP DQ DR B C A DP DQ DR B C A DP DQ DR B C A DP DQ DR B C Chi l d r en

12. THANK YOU