The major histocompatibility complex class I related chain (MIC) was first described in the 1990’s. The genes are located centromeric to the HLA class I B gene. The only two MIC genes which are expressed are MICA and MICB. MICA and MICB share a significant amount of sequence homology with HLA class I and have some similarity in their conformation. MICA and MICB antigens have α1, 2 and 3 domains like classical HLA antigens but do not associate with β2 microglobulin and do not bind peptide for presentation to T cells. Instead MIC antigens serve as ligands for the NKG2D receptor on NK cells and on some T cells.


MICA and MICB genes are polymorphic but not as much as the classical HLA class I genes. Over 70 MICA alleles and over 30 MICB alleles have been described. Unlike HLA class I where the polymorphic residues are located mainly in the region that forms the peptide binding groove, polymorphism in MIC is more dispersed throughout the α2 and α3 domains. There is also polymorphism in the trans-membrane region. Many MIC antigens have the same extracellular domains with the only differences lying in the trans-membrane regions.


MICA and MICB antigens are constitutively expressed on epithelial cells, especially those of the gastrointestinal tract and on fibroblasts, monocytes, dendritic cells and on endothelial cells. They are not constitutively expressed on lymphocytes. They are however up regulated in stressed cells.


The structure of MICA is similar to that of HLA class I but has some sticking differences. Like HLA class I, MICA has three extracellular domains (α1, 2 and 3), a transmembrane region and a cytoplasmic domain. Unlike HLA class I, the MICA protein does not associate with β2 microglobulin. The MICA α1 and 2 domains from a platform that is analogous to the platform formed by HLA class I α1 and 2 domains. In HLA class I, this platform forms the peptide binding groove. The MICA molecule however has extensive disordering of sections of the alpha helix in the α2 domain resulting in a very shallow groove, incapable of binding peptide. The MICA α1 and 2 platform domains do not interact with the α3 domain except for being linked together through a short linker chain. This allows for some flexibility in the structure.


The NKG2D receptor forms a complex with MICA by binding orthogonal to the alpha helices of the platform α1 and 2 domains.


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