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MICA
Polymorphisms in Conserved Extended Haplotypes - EFI 2006 Poster
Dorak MT et al: Conserved Extended Haplotypes Update. Genes & Immunity, Sept 2006
MIC genes were first discovered as a second lineage of mammalian MHC
class I genes by Bahram
et al (1994). The MICA (PERB11.1) gene spans a 11kb stretch of DNA and is
approximately 46kb centromeric to HLA-B. MICB (PERB11.2) is 89 kb farther
centromeric to MICA (MICC, MICD and MICE are pseudogenes). The MICA and MICB
genes show high sequence homology (about 85%) to each other (Shiina
T et al, 1998). Both genes are highly polymorphic at all three alpha
domains and show 15-36% sequence similarity to classical class I genes. MIC
genes are classified as MHC class Ic genes (Hughes
AL et al, 1999) in the beta block of MHC. MICA alleles were included in the
HLA Nomenclature Committee report in 1998 (Bodmer JG et al,
1998) and 16 alleles were officially recognized initially. As of October
2003, the number of MICA alleles approved by the Committee is 56 (ANRI website; Marsh SG et al,
2002). The nomenclature is similar to that of HLA alleles: MICA*001 to
MICA*049 (no *003) including some five-digit designations such as MICA*01201.
Although initially PCR-SSP and SSOP techniques were used for typing, currently
SBT is the method of choice as typing involves three exons (Katsuyama
Y et al, 1999; Fodil
N et al, 1999; Yao
Z et al, 1999; Visser
CJ et al, 1999). More recently, high-resolution PCR-SSP typing methods have
been presented (Collins
RW et al, 2002; Ahmad
T et al, 2002). The application of the RSCA method to MICA typing resulted
in identification of new alleles (Perez-Rodriguez
M et al, 2002) and this study showed the necessity to include exon 5
typings for complete MICA designation. The most common alleles at MICA are
MICA*008 (5A5.1) and MICA*010 (5A5), whereas in MICB, the most common alleles
are MICB*01021 and MICB*0103101 (out of 16 known alleles) (Fodil
N et al, 1999; Fischer
G et al, 2000). The alleles MICA*005, *013, and *014 do not have any
reference samples and they are not seen in population studies (Perez-Rodriguez
M et al, 2002). Their presence, therefore, are in question. All IHW
homozygous cell lines were typed at the MICA and MICB loci (see UWA CMII website
for the cell line data), and linkage disequilibrium with HLA-B has been
described (Fodil
N et al, 1999; Visser
CJ et al, 1999; Petersdorf
EW et al, 1999; Fischer
G et al, 2000). In a Japanese
haplotype both MICA and MICB genes lost their ability to be expressed.
Komatsu-Wakui and colleagues (1999)
reported that HLA-B*4801 is the MICA-MICB null haplotype, HLA-B*4801-MICA
deletion (MICA-del) -MICB*0107 N, in East Asians, which includes the Japanese.
In this haplotype, a 100-kb deletion containing the entire MICA gene and a stop
codon in exon 3 of MICB*0107 N result in the lack of expression of MICA and
MICB, respectively (Ando
et al. 1997; Komatsu-Wakui
et al. 1999).
In addition to the nucleotide substitution polymorphism in coding
regions, there are also microsatellite polymorphisms in exon 5 - transmembrane
region of MICA (MICA-GCT) and intron 1 of MICB (MICB-CA). The MICA-GCT has five
common alleles, 5A5.1 and 5A5 being the most common ones (Mizuki
N et al, 1997; Perez-Rodriguez
M et al, 2000). The haplotypes of MICA exon 2-4 alleles and MICA-CGT have
been studied in detail and correlations have been worked out (Fodil
N et al, 1999; Perez-Rodriguez
M et al, 2002). It appears that as opposed to the MICA/MICB exon 2-5
polymorphisms, which co-evolved with HLA-B (cross-reactive) lineages, the
alleles of the transmembrane polymorphism MICA-GCT are not associated with
either MICA/MICB alleles or HLA-B (Dunn
DS et al, 2000). Three rare alleles of MICA STR polymorphism have been
reported: A7 (Rueda
B et al, 2002); A10 (Perez-Rodriguez
M et al, 2000); and A6new (Vitiani
LR et al, 1998; Obuchi
N et al, 2001; Perez-Rodriguez
M et al, 2002). The latter allele, A6new, appears to be associated with
HLA-B*1402 ancestral haplotypes 65.1 and 65.2 as part of MICA*011 allele (Perez-Rodriguez
M et al, 2002).
The MIC genes are expressed mainly on epithelial surfaces and
fibroblasts (Bahram
et al, 1994) but also on thymic cortical epithelium (Braud
VM et al, 1999), endothelial cells and monocytes (but not in CD4+, CD8+, or
CD19+ lymphocytes) (Zwirner
NW et al, 1999). In the intestine, they act as a restriction element for gd T-cells (Zwirner
NW et al, 1999). This expression pattern, together with the recognition of
MICA/MICB by gamma-delta T cells (Groh
V et al, 1998), their interaction with NK cell receptor NKG2D on NK and
CD8+ T-cells (Bauer
S et al, 1999; Groh
V et al, 2001), and finally demonstration of specific anti-MICA antisera in
transplant recipients (Zwirner
NW et al, 2000) along with identification of MICA as the target of humoral
immune response in transplant rejection (Sumitran-Holgersson
S, 2002) suggest an immunological role for these MHC class I-like
molecules. Their role seems to be stimulating innate antitumor and antiviral
immune surveillance against transformed/infected cells expressing MICA/MICB (Groh
V et al, 2001, Wu
J et al, 1999, Steinle
A et al, 2001). CMV protein UL142 down-regulates MICA expression as another
immunoevasive strategy of CMV (Chalupny, 2006).
Whereas MHC class I expression serves as an indicator of cellular integrity,
MICA and MICB signal cellular distress and evoke immune responses even when MHC
class I expression is intact (Stephens
HA, 2001; Das
H et al, 2001). In its interaction with the activating lectin-like NK cell
receptor NKG2D, the MICA polymorphism at amino acid 129 (methionine/valine;
M129V) in the a2
domain (exon 3, A454G) seems to be functional whereas MICB alleles are not
polymorphic at the same position (they all have valine) (Steinle
A et al, 2001). The activating receptor NKG2D is also expressed by gd T-cells and MICA expression
during microbial infection activates these T cells considerably (Das
H et al, 2001). The proportion of gd T-cells is increased during HIV infection (De
Maria et al, 1992) that may suggest a role for MICA - gd T-cells interaction during
the progression of HIV-1 infection.
See: Shao W et al. MICA
intron 1 sequences of conserved extended HLA haplotypes: implications for
sequencing-based typing. Genes & Immunity 2004 May 27
MICA References
for Each Allele
M.Tevfik Dorak, M.D., Ph.D.
23 January 2007
Inf & Imm HLA MHC Evolution Genetics
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