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.
M.Tevfik Dorak, M.D., Ph.D.
23 January 2007