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THE STRUCTURE OF MHC MOLECULES

THE STRUCTURE OF MHC MOLECULES. 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

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THE STRUCTURE OF MHC MOLECULES

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  1. THE STRUCTURE OF MHC MOLECULES

  2. 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

  3. 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

  4. 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

  5. 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 http://webace.sanger.ac.uk/cgi-bin/ace/pic/6ace?name=MHC&class=Map&click=400-1

  6. 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

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

  8. 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 1200 different alleles can be expressed with any other allele ~6 x 1015individual combinations Only monozygous twins are identical at the HLA locus The human population is extensively outbred MHC genetics in humans is extremely complex

  9. DISTRIBUTION OF MHC ALLELES IN THE HUMAN POPULATION Class I 657 alleles 381 Polymorphism (number of alleles) Frequency (%) 185 Class II 492 alleles 317 Allelic groups CAU ASI AFR HLA-A1 HLA- A2 HLA- A3 HLA- A28 HLA- A36 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 91 89 45 b a b a b a 19 20 A B C 2 DR DP DQ Alleles are not distributed evenly in the population Alleles are segregated among races SELECTION

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

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