HGNC Approved Gene Symbol: MICA
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:31,400,711-31,415,315 (from NCBI)
Major histocompatibility complex (MHC) class I genes typically encode polymorphic peptide-binding chains that are ubiquitously expressed and mediate the recognition of intracellular antigens by cytotoxic T cells. Motivated by the association of HLA-B27 with rheumatoid and inflammatory diseases, Bahram et al. (1994) found a family of sequences in the human MHC that are highly divergent from all of the known MHC class I genes and were presumably derived early in the evolution of mammalian class I genes. These MIC genes (for MHC class I chain-related genes) evolved in parallel with the human class I genes and with those of most, if not all, mammalian orders. Bahram et al. (1994) cloned the MICA gene in this family and stated that it was by far the most divergent mammalian MHC class I gene known. The MICA gene encodes a 383-amino acid polypeptide with a predicted mass of 43 kD. It is further distinguished by its unusual exon-intron organization and preferential expression in fibroblasts and epithelial cells. However, the presence of distinctive residues in the MICA amino acid sequence translated from cDNA suggested that the putative MICA chain folds similarly to typical class I chains and may have the capacity to bind peptide or other short ligands. Thus, a second lineage of evolutionarily conserved MHC class I genes was defined by these results. MICA and other members of this family may have been selected for specialized functions that are either ancient or derived from those of typical MHC class I genes, in analogy to some of the nonclassic mouse H-2 genes.
Bahram et al. (1994) demonstrated that the MICA gene is located near HLA-B (142830) on chromosome 6. Nalabolu et al. (1996) showed that the MICA and MICB (602436) genes occur in a 200-kb region spanning the TNFA (191160) and TNFB (153440) cluster at chromosome 6p21.3.
T cells with variable region V-delta-1 gamma/delta T-cell receptors (see TCRG, 186970, and TCRD, 186810) are distributed throughout the human intestinal epithelium and may function as sentinels that respond to self antigens. The expression of MICA matches this localization. Groh et al. (1998) found that MICA and the closely related MICB were recognized by intestinal epithelial T cells expressing diverse V-delta-1 gamma/delta TCRs. These interactions involved the alpha-1/alpha-2 domains of MICA and MICB but were independent of antigen processing. With intestinal epithelial cell lines, the expression and recognition of MICA and MICB could be stress induced. Thus, these molecules may broadly regulate protective responses by the V-delta-1 gamma/delta T cells in the epithelium of the intestinal tract.
Bauer et al. (1999) found that MICA binds NKG2D (KLRK1; 611817) on gamma/delta T cells, CD8+ alpha/beta T cells, and natural killer (NK) cells. Engagement of NKG2D activated cytolytic responses of gamma/delta T cells and NK cells against transfectants and epithelial tumor cells expressing MICA. These results defined an activating immunoreceptor-MHC ligand interaction that may promote antitumor NK- and T-cell responses.
MIC engagement of NKG2D stimulates NK-cell and T-cell effector functions. Cytomegalovirus (CMV) infection induces the expression of stress proteins such as HSP70 (140550). By flow cytometric analysis, Groh et al. (2001) showed that CMV infection also induces MIC expression and a concurrent downregulation of MHC class I molecules on fibroblasts and endothelial cells. Immunohistochemical analysis of lung sections from patients with CMV interstitial pneumonitis confirmed that induction of MIC expression also occurs in vivo. Functional analysis of T-cell cytotoxicity against CMV-infected fibroblasts showed that early after infection when MIC expression was low, antibodies to MHC class I, but not to MIC or NKG2D, could block T cell-mediated cytolysis. As MIC expression increased, antibody masking of MIC or NKG2D reduced target cell lysis; anti-MHC class I antibodies further reduced cytolysis. The presence of MICA on stimulator cells also substantially enhanced cytokine release by T-cell clones, and anti-MIC antibody abrogated this production, suggesting that the MIC-NKG2D interaction provides an important costimulatory activity.
Groh et al. (2002) showed that NKG2D binding of MIC induces endocytosis and degradation of NKG2D. In cancer patients, NKG2D expression was markedly reduced in both CD8+ tumor-infiltrating T cells and in peripheral blood T cells, associated with circulating tumor-derived soluble MICA. The downregulation of NKG2D causes a severe impairment of tumor antigen-specific effector T cells. Groh et al. (2002) proposed that this mode of T cell silencing through MIC shedding may promote tumor immune evasion and inferred that it could also compromise host resistance to infections.
Using immunohistopathologic and flow cytometric analyses, Hue et al. (2004) found increased expression of MICA at epithelial cell surfaces in celiac disease (CD; 212750) patients exposed to gliadin. Patient biopsy specimens exposed to an IL15 (600554)-inducing gliadin fragment did not express MICA in the presence of anti-IL15. Cytotoxicity assays showed that NKG2D played primarily a costimulatory role on intraepithelial lymphocytes (IELs), with a TCR-mediated signal required for complete activation. However, in refractory celiac sprue patients, NKG2D mediated a direct activating signal. ELISA detected soluble MICA in serum in half of untreated CD patients, but in few patients on gluten-free diets; the presence of soluble MICA was independent of MICA genotype. Hue et al. (2004) proposed that villous atrophy in CD may be ascribed to IEL-mediated damage to enterocytes involving NKG2D-MICA interaction after gliadin-induced expression of MICA on gut epithelium.
Kriegeskorte et al. (2005) showed that the NKG2D ligands H60 and MICA could mediate strong suppressive effects on T-cell proliferation. The suppression did not occur in Il10 (124092)-deficient mice and involved a receptor other than NKG2D. Kriegeskorte et al. (2005) concluded that NKG2D ligands can induce strong inhibitory effects in addition to stimulatory effects
Kaiser et al. (2007) showed that on the surface of tumor cells, MICA associates with endoplasmic reticulum protein-5 (ERP5; 611099), which, similar to protein disulfide isomerase (176790), usually assists in the folding of nascent proteins inside cells. Pharmacologic inhibition of thioreductase activity and ERP5 gene silencing revealed that cell-surface ERP5 function is required for MICA shedding. ERP5 and membrane-anchored MICA formed transitory mixed disulfide complexes from which soluble MICA was released after proteolytic cleavage near the cell membrane. Kaiser et al. (2007) suggested that reduction of the seemingly inaccessible disulfide bond in the membrane-proximal alpha-3 domain of MICA must involve a large conformational change that enables proteolytic cleavage. They concluded that their results uncovered a molecular mechanism whereby domain-specific deconstruction regulates MICA protein shedding, thereby promoting tumor immune evasion, and identified surface ERP5 as a strategic target for therapeutic intervention.
Ferrari de Andrade et al. (2018) rationally designed antibodies targeting the MICA alpha-3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA and MICB (602436) by human cancer cells. These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model. Antitumor immunity was mediated mainly by natural killer cells through activation of NKG2D (611817) and CD16 Fc receptors. Ferrari de Andrade et al. (2018) concluded that their approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity.
Using multiwavelength-anomalous dispersion phases at a resolution of 2.7 angstroms, Li et al. (2001) determined the crystal structure of MICA and NKG2D. They showed that NKG2D forms a homodimer that interacts with a MICA monomer.
The predicted amino acid sequence of the MICA chain suggests that it folds similarly to typical class I chains and may have the capacity to bind peptides or other short ligands (Bahram et al., 1994). Therefore, MICA was predicted to have a specialized function in antigen presentation or T cell recognition. During nucleotide sequence analyses of the MICA genomic clone, Mizuki et al. (1997) found a triplet repeat microsatellite polymorphism (GCT/AGC)n in the transmembrane region of the MICA gene. In 68 HLA homozygous B cell lines, 5 distinct alleles of this microsatellite sequence were detected. One of them contained an additional 1-bp insertion that created a frameshift resulting in a premature termination codon in the transmembrane region. This particular allele was thought to encode a soluble, secreted form of the MICA molecule. Mizuki et al. (1997) also investigated this microsatellite polymorphism in 77 Japanese patients with Behcet disease (109650), which had previously been known to be associated with HLA-B51. The microsatellite allele consisting of 6 repetitions of GCT/AGC was present at significantly higher frequency in the patient population (Pc = 0.00055) than in a control population. Furthermore, the (GCT/AGC)6 allele was present in all B51 positive patients and in an additional 13 B51 negative patients. These results suggested the possibility of a primary association of Behcet disease with MICA rather than HLA-B.
Wallace et al. (1999) investigated the association of the 16 previously described external domain alleles and the transmembrane triplet repeats of the MICA gene with Behcet disease in a Middle Eastern population. The results showed an increase of MICA*009 in the Behcet disease patient group (44 of 95; 46%) compared with controls (24 of 102; 24%), giving an odds ratio (OR) of 2.8. The A6 form of a MICA transmembrane triplet repeat was found to be significantly raised in the patients (80 of 95; 84%) compared with controls (58 of 102; 57%), giving an OR of 4. The most significant association was that between Behcet disease and HLA-B51. Wallace et al. (1999) interpreted the data as indicating that since both MICA*009 and A6 are in strong linkage disequilibrium with HLA-B51, they are unlikely to be the susceptibility genes for Behcet disease but may be markers for additional risk factors.
Mizuki et al. (2000) studied the localization of the pathogenic gene of Behcet disease using microsatellite analysis of 3 different populations: Japanese, Greek, and Italian. In genotypic differentiation between patients and controls, the authors found that only HLA-B51 was significantly associated with BD in all 3 populations. These results suggested that the pathogenic gene of BD is HLA-B51 itself and not other genes located in the vicinity of HLA-B.
The MICA and MICB genes are polymorphic, displaying an unusual distribution of a number of variant amino acids in their extracellular alpha-1, alpha-2, and alpha-3 domains. To further define the polymorphism of MICA, Petersdorf et al. (1999) examined its alleles among 275 individuals with common and rare HLA genotypes. Of 16 previously defined alleles, 12 were confirmed, and 5 new alleles were identified. A 2-by-2 analysis of MICA and HLA-B alleles uncovered a number of significant associations. These results confirmed and extended previous knowledge on the polymorphism of MICA. Petersdorf et al. (1999) suggested that a strong positive linkage of certain MICA and HLA-B alleles may have implications for studies related to MHC-associated diseases and transplantation.
Komatsu-Wakui et al. (1999) studied polymorphisms in the MICA gene in Japanese. They observed 8 MICA alleles in Japanese individuals, among which 1, tentatively named MIC-AMW, had not previously been reported. There was a strong linkage disequilibrium between MICA and HLA-B loci; each MICA allele showed strong association with a particular HLA-B group. Komatsu-Wakui et al. (1999) also identified a MICA-MICB null haplotype, which was associated with HLAB*4801. In this haplotype, they found large-scale deletion (of approximately 100 kb), including the entire MICA gene, and a MICB gene that possessed a stop codon.
To summarize, the MICA gene has a microsatellite repeat, GCT(n), within exon 5, encoding for a variable number of alanines (Ala = A). Perez-Rodriguez et al. (2000) described a novel MICA allele with 10 GCT repeats (A10); 4 different repeats of this microsatellite had been previously reported: A4, A5, A6, and A9. An association of Behcet disease with the A9 repeat had been reported by Mizuki et al. (1997).
Gambelunghe et al. (2001) concluded the existence of distinct genetic markers for childhood/young-onset IDDM (222100) and for adult-onset IDDM, namely the MICA5 and MICA5.1 alleles, respectively.
Mei et al. (2009) analyzed the relationship between Chlamydia trachomatis, tubal pathology, and MICA allele polymorphisms in 214 infertile Chinese women. They found no association between MICA alleles and the presence or absence of tubal pathology in infertile women with antibodies to C. trachomatis. However, an association was found between the MICA*008 allele and infertile women without antibodies to C. trachomatis. Mei et al. (2009) concluded that MICA may modify host susceptibility to C. trachomatis infection.
Aquino-Galvez et al. (2009) analyzed the MICA gene in 80 sporadic patients with idiopathic pulmonary fibrosis (IPF; 178500) and 201 controls and found a significant increase of MICA*001 allele in the IPF cohort (odds ratio, 2.91; corrected p = 0.03). In addition, the MICA *001/*00201 genotype was significantly increased in patients with IPF compared with healthy controls (odds ratio, 4.72; corrected p = 0.01). Strong immunoreactive MICA staining was localized in alveolar epithelial cells and fibroblasts from IPF lungs, whereas control lungs were negative. Soluble MICA was detected in 35% of IPF patients compared to 12% of control subjects (p = 0.0007). The expression of the MICA receptor NKG2D (KLRK1; 611817) was significantly decreased in gamma/delta T cells and natural killer cells obtained from IPF lungs. Aquino-Galvez et al. (2009) concluded that MICA polymorphisms and abnormal expression of NKG2D might contribute to IPF susceptibility.
For a discussion of a possible association between variation in the MICA region and progression from chronic hepatitis C to hepatocellular carcinoma, see 114550.
The MICA/MICB locus is not conserved in mice; however, mice do have counterpart NKG2D ligands, Rae1-beta and H60. Diefenbach et al. (2001) demonstrated that ectopic expression of these ligands in tumor cell lines resulted not only in potent rejection mediated by either NK cells or CD8-positive T cells, but that mice subsequently challenged with tumor cell lines not expressing the ligands were also immune to the tumors. Girardi et al. (2001) determined that immunity to cutaneous malignancies could be mediated by NKG2D-expressing intraepithelial gamma/delta T cells. Girardi et al. (2001) proposed that the diverse expression of NKG2D on cytolytic cell types may allow attacks on tumor cells in different anatomical compartments and that gamma/delta T cells may be particularly important in skin and gut.
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