Page 95 - Clinical Immunology_ Principles and Practice ( PDFDrive )

80 PARt oNE Principles of Immune Response

G
A
B
H B B
F T R
E N 1
Tel
26195K 29750K
Extended Class I (~4Mb)

H H H H H H M M
L L L L L L I I
A A A A A A C C
F G A E C B A B
29800K 32300K
Class I (1.8Mb)
C
N C Y C
F L L 6 L L L L H H H P Y A N
K Y Y O Y Y Y Y S S S 2 P G O
B T L N A 6 6 R 6 6 6 6 P P P R 1 T 2 H P R P T
I L N L S C I G G F G G G G A A A N D C A N C 1 L A A B C
L T F T T R F 5 5 2 6 6 6 6 1 1 1 E C B B R 4 1 X 4 A A T G x H
1 A a B 1 3 1 b b 1 e d c b L A B U 2 F P P B P A A 2 F 1 E 2 4
31633K RC CX 32300K
Class III (0.7Mb)
H H H H H H
H L L L L H H H H L L
B L A A A A L P P L L L A A T K
T A D D D D A T S T S A A A D D R A I
N D R R Q Q D A M A M D D D P P X P F
L R B B A B O P B P B M M O A B R B C
2 A 3 1 1 1 B 2 8 1 9 B A A 1 1 B P 1
32470K 33275K 33485K
Class II (0.8Mb) Extended Class II (0.3Mb)
FIG 5.1 Gene Map of the Extended Major Histocompatibility Complex (MHC) Complex. The
core of the MHC complex consists of three major regions: class I, class III, and class II. The
extended regions of the complex fare denoted as extended class I and extended class II. Sequence
numbering begins at the telomere. The map depicts immune-related expressed genes as well
as certain reference genes. The approximate locations of these selected genes near the start or
end of the regions are indicated. [Modified from Beck S, Trowsdale J. The human major histo-
compatibility complex: lessons from the DNA sequence. Annu Rev Genomics Hum Genet 2000;
1:117–37.]

structures of the derived molecules have a striking resemblance the children and typically differs from a child by one haplotype.
that presents a unique example of convergent evolution, perhaps Two siblings may share two, one, or no haplotypes and thus
driven by the shared role of these molecules in presenting peptide range from being HLA identical, through haploidentical, to HLA
to the T-cell receptor (TCR). disparate. Parents are usually only haploidentical with their
Another unique characteristic of the MHC is the extensive children. Exceptions to this rule may occur in inbred populations,
linkage disequilibrium (LD) observed among the very distant where both parents may share an identical HLA allele by descent.
genomic regions of HLA-A, HLA-B, HLA-C, HLA-DR, and The HLA alleles originating from the maternal and paternal
HLA-DQ genes, but not the HLA-DP gene. LD is the phenomenon haplotypes are both expressed.
whereby particular alleles of gene loci on the same strand of Ten years of genome-wide association studies (GWAS) have
DNA are inherited together more often that would be expected revealed a large number (884) of single nucleotide polymorphisms
by chance. Anthropological population studies have suggested (SNPs) within the MHC that are associated with many (479) traits
that the particular combinations of alleles of the different genes, and diseases, establishing the MHC as the only region in the genome
as distant as they may be, provide a survival advantage, perhaps with this high density of SNPs that is associated with so many
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reflecting functional interdependence in antigen-specific immune diseases. The complexity of the region, with its many insertions,
responses. deletions, duplications, and LD, does not allow for an easy dissection
A particular combination of alleles of different loci in LD on of disease-causing variants. However, recent developments in
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the same strand of DNA is called a haplotype. The frequency of next-generation sequencing (NGS) of the entire MHC will most
a given haplotype varies among different populations, reflecting likely advance our understanding of the principles underlying this
distant selection by pathogens, ethnic admixture, and drastic complex genomic organization, how this complexity results in so
population reductions (genetic bottlenecks). LD is strongest many biological interdependencies, and how it contributes to the
between HLA-B and HLA-C and between HLA-DR and HLA-DQ, pathophysiology of the diseases associated with the MHC.
most likely because of their physical proximity. However, there
is no LD between DP and the rest of the haplotype because of STRUCTURE AND FUNCTION OF
a hot spot of recombination between DQ and DP, even though THE HLA MOLECULES
these two loci are relatively proximal to each other.
The haplotype is the unit of inheritance of the MHC from The main function of both class I and class II HLA molecules
either parent. Each parent shares one haplotype with each of is to bind peptides derived from self or nonself antigens and