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molecules, was shown to result in NKG2D receptor downregulation. The
ensuing immune modulation highlights the functional duality of the mem-
brane-bound and soluble MICA isoforms. Preferentially expressed on epi-
thelial and endothelial cells, MICA and MICB appear more ubiquitous at
the mRNA level. Expression has also been reported in activated immune
cells including DCs and T lymphocytes. The specific patterns of expres-
sion of MICA/B are related to the regulatory sequences which are devoid
of interferon response elements, while a stress response element has been
identified in the promoter region [23] .
CLASS II
Historically the class II region has been known as the “HLA-D” region
following the characterization of HLA-A, HLA-B and HLA-C. The class II
region has since been extensively sequenced, and its organization has
been well-defined in many populations [3] . Not only does the class II
region encode genes that define the classical HLA-DR, HLA-DQ and HLA-
DP alloantigens, but it also contains genes that play a critical role in anti-
gen loading and presentation (TAP and LMP); the concentration of genes
with related function make class II a truly unique region of the human
genome.
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The specific genes that define class II phenotypes are DRA1 and DRB1
(HLA-DR), DRB3 (HLA-DR52), DRB4 (HLA-DR53), DRB5 (HLA-DR54),
DQA1 and DQB1 (HLA-DQ), and DPA1 and DPB1 (HLA-DP). The A genes
(DRA1, DQA1 and DPA1) each encode the α chain of the mature class II mol-
ecule, and have limited sequence diversity. The B genes (DRB1, DQB1 and
DPB1) are each defined by a highly polymorphic exon 2 that gives rise to the
β chain of the molecule. The α chain is noncovalently bound to the β chain
[24] . The α-β heterodimer defines the phenotype of the antigen (e.g. DR1 or
DQ2), with the β chain contributing the majority of the polymorphism that
distinguishes unique allelic variants.
The “supratypic” loci, DRB3, DRB4 and DRB5, are highly organized on
DRB1 haplotypes, such that certain DRB1 genes have DRB3, DRB4 or DRB5
genes linked to their haplotype, whereas other DRB1 genes have no addi-
tional supratypic loci. In summary, DR1 and DR10 phenotypes have no
additional supratypic gene; DR2 phenotypes have DRB5 that defines DR52;
DR3, DR5 and DR6 have the DRB3 gene that defines the DR53 specificity,
and DR4, DR7 and DR9 have the DRB4 gene that defines the DR54 specific-
ity. Since a variable number of DRB genes are linked on haplotypes, differ-
ent haplotypes have different lengths within the class II region. Yet another
source of potential variation arising from class II is contributed by DQA1
and DQB1. Trans pairing of DQ α encoded by one parental chromosome
with a DQ β encoded by the other parental chromosome, can give rise to up
to four unique HLA-DQ antigens [25] .
Like class I genes, HLA-DRB1, DQB1 and DPB1 genes are highly polymor-
phic, with more than 1166 HLA-DRB1, 162 HLA-DQB1 and 152 DPB1 alleles
recognized as of March 2012 [7,8] . Also similar to class I, the polymorphic
sites within class II molecules are localized to discrete regions of the α1 and
β1 domains of the α and β chains, respectively, to promote a large array of
peptides that can be presented [9,26] .
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