MICA and to a lesser extent MICB are polymorphic, comprising more than 50 and about 15 amino acid substitutions in their extracellular a1a2a3 domains, respectively (Stephens 2001). Unlike MHC class I alleles, all these substitutions are only biallelic and appear randomly distributed. Little is known regarding the functional significance of this allelic variation; however, many substitutions are not conservative, suggesting evolutionary selection instead of random fixation. Mapping onto the MICA crystal structure suggests that some variant amino acid positions may affect interactions with NKG2D whereas most are distant from the NKG2D binding platform or buried inside the folded polypeptide. Analysis of the binding strength of soluble recombinant NKG2D to transfectants expressing five of the most frequent MICA alleles has revealed substantial variations in binding affinities in the range of 10- to 50fold. These differences are associated with a single amino acid substitution at position 129, methionine or valine, which determines strong (MICA*01 and *07) and weak binding (MICA*04, *08 and *016) alleles, respectively (Steinle et al. 2001). This polymorphism may affect thresholds of NK and T cell activation. In the crystal structure of MICA*01, position 129 is located in the p4 strand of the p-pleated sheet in the a2 domain. Because the side chain of methionine is partially buried and forms hydrophobic interactions with glutamine 136, alanine 139, and methionine 140 in the first a2 helical stretch, its substitution by valine likely affects NKG2D binding indirectly by a conformational change.
Extensive sequence diversity occurs within the MICA transmembrane region, mainly in the number of polyalanine repeats associated with different alleles (Stephens 2001). The MICA*08 allele, which has the highest frequency in Caucasians and Oriental populations, has a premature stop codon resulting in loss of part of the transmembrane region and the cytoplasmic tail. This protein is membrane anchored but fails to be properly sorted in polarized epithelial cells (Suemizu et al. 2002). Another defective allele is MICA*010, which has a single proline for arginine substitution at position 6 in the first p-strand of the a1 domain. This change blocks a p-sheet hydrogen bond with the histidine carbonyl at position 27 on the p2-strand and is incompatible with p-sheet secondary structure, thus interfering with a stable protein fold (Li et al. 2000). Of particular interest is a MIC-null haplotype associated with HLA-B*4801 that is relatively common among the Japanese and very frequent (56.5%) within an Amerindian community in Paraguay (Ota et al. 2000; Rus-somando et al. 2002). In this haplotype, the entire MICA gene is within a 100-(kb deletion and MICB has a stop codon in exon 3 encoding the a2 do main. Because individuals homozygous for this haplotype have no discernible immunological deficiency, and significant common disease histories are not apparent, these observations have led to the conclusion that MIC function may not be essential or part of a redundant system. However, a more compelling explanation may eventually emerge, perhaps that loss of MIC expression may confer a selective advantage under certain environmental conditions.
Numerous studies have investigated relationships between MICA alleles and susceptibility to diseases that are associated with the closely linked HLA-B and -C genes, including ankylosing spondylitis, psoriasis vulgaris, psoriatic arthritis, and Behcet disease (Stephens 2001). However, positive associations are likely secondary because of strong linkage disequilibrium between MICA and the two MHC class I genes nearby and have not been confirmed by analyses of different HLA haplotypes in diverse ethnic groups. MICA has also been associated with MHC class II-linked diseases such as insulin-dependent diabetes mellitus (IDDM), Addision disease, sclerosing cholangitis, and celiac disease. However, as yet there is no evidence of a primary genetic association of MICA or MICB with any disease, and the functional significance of most of the allelic variation of these genes has remained unclear.
As with MHC class I molecules, a direct consequence of MICA polymorphism is the occurrence of autoantibodies in patients with irreversible rejection of allogeneic kidney and pancreas transplants. These show epithelial expression of MIC, which is not seen with normal organs or nonrejected transplants (Hankey et al. 2002; Sumitran-Holgersson et al. 2002). Thus MIC may contribute to allograft rejection, suggesting that matching of donor and recipients may improve clinical outcomes.
Acknowledgements S.G. was supported by the Spanish Fondo de Investigaciones Sanitarias (PI030067). Work from the authors' laboratory was supported by National Institutes of Health Grants AI-30581 and AI-52319.
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