MHC Class I-related Chain A Research Articles

MICA-129 genotype, soluble MICA, and anti-MICA antibodies as biomarkers of chronic graft-versus-host disease

AbstractThe MHC class I–related chain A (MICA) molecules exist as membrane-bound and soluble isoforms and are encoded by a polymorphic gene. Their genetic and phenotype characteristics have been studied in various pathologic settings but not in the context of hematopoietic stem cell transplantation (HSCT). Here, we evaluated whether MICA-related features namely MICA-129 gene polymorphism, serum levels of soluble MICA (sMICA) and anti-MICA antibodies (MICA Abs) before and after HSCT could influence the incidence of chronic graft-versus-host disease (cGVHD) and relapse of their disease in 211 HLA-identical sibling pairs and in a subset of 116 recipients, respectively. Although the MICA-129 val/val genotype and elevated sMICA serum levels after HSCT are independently associated with the incidence of cGVHD (P = .002 and .001) regardless of history of acute GVHD, the presence of MICA Abs before transplantation confers protection against cGVHD (P = .04). There is an inverse relationship between MICA Abs and sMICA, suggesting an antibody-based neutralization of deleterious effects of sMICA. Similarly, these genetic and phenotype characteristics of MICA influence the incidence of relapse. Altogether, these data suggest that the studied MICA genotype and phenotype specificities could be used as relevant biomarkers for cGVHD monitoring.

Sorafenib inhibits the shedding of major histocompatibility complex class I–related chain A on hepatocellular carcinoma cells by down‐regulating a disintegrin and metalloproteinase 9†

The ectodomain of major histocompatibility complex class I-related chain A (MICA) is shed from tumor cells, and may be an important means of evading antitumor immunity. This study investigated the roles of a disintegrin and metalloproteinase 9 (ADAM9) in the shedding of MICA in human hepatocellular carcinoma (HCC). Small interfering RNA-mediated knockdown (KD) of ADAM9 resulted in up-regulation of membrane-bound MICA expression on the HepG2 and PLC/PRF/5 cellular surfaces and down-regulation of soluble MICA levels in their culture supernatant. ADAM9 was cleaved at a site between Gln347 and Val348 of MICA in vitro. We constructed a plasmid of the MICA gene with mutation or deletion of the ADAM9 cleavage site to examine the detailed mechanism of MICA shedding by ADAM9 protease. The results suggested that MICA might be cleaved at the intracellular ADAM9-recognized cleavage site and was further cleaved at the extracellular ADAM9-independent cleavage site in HCC cells, resulting in the production of soluble MICA. Immunohistochemical analysis revealed that ADAM9 was overexpressed in human HCC compared to normal liver tissues. The cytolytic activity of natural killer (NK) cells against ADAM9KD-HCC cells was higher than that against control cells, and the enhancement of this cytotoxicity depended on the MICA/B and NK group 2, member D pathway. Sorafenib treatment resulted in decreased expression of ADAM9, increased expression of membrane-bound MICA expression, and decreased levels of soluble MICA in HCC cells. Adding sorafenib enhanced the NK sensitivity of HCC cells via increased expression of membrane-bound MICA. ADAM9 is involved in MICA ectodomain shedding in HCC cells, and sorafenib can modulate ADAM9 expression. Sorafenib therapy may have a previously unrecognized effect on antitumor immunity in patients with HCC.

MICA-129 Genotype, Soluble MICA and Anti-MICA Antibodies as Biomarkers of Chronic Graft Versus Host Disease.

Abstract 1138Poster Board I-160 BackgroundThe MHC class I-related chain A (MICA) molecules is of particular in non T-cell receptor (TCR)-mediated immune function. MICA engages NKG2D, a C-type lectin expressed on effector cells including NK, and T cells. Such engagement triggers NK cells and co-simulates T lymphocytes to mount adequate immune response. Further, a soluble isoform of MICA (sMICA) has been implicated in the pathogenesis of a variety of cancers, auto-immune and other organ transplant-related disorders through NKG2D receptor down regulation. Functionally relevant polymorphism of the MICA gene may also contribute to inter-patients variability in allo-immune responses as observed in various clinical settings including organ-transplantation. A methionine (met) to valine (val) change at position 129 of the alpha 2-heavy chain domain categorized the MICA alleles into strong (MICA-129 met) and weak (MICA-129 val) binders of NKG2D receptor. Given the demonstrated importance of MICA in immune pathways, in this study, we explored the MICA-related parameters namely MICA-129 gene polymorphism, pre- and post-transplant serum levels of soluble MICA (sMICA) and anti-MICA antibodies (MICA Abs) in a HLA-matched sibling HSCT setting. ResultsWe evaluated whether MICA-129 gene polymorphism, pre- and post-HSCT sMICA and MICA Abs could influence the incidence of chronic graft-versus-host disease (c.GvHD) and relapse of their disease in 211 HLA-identical sibling pairs.In multivariate analysis on chronic GvHD risk, 3 factors reached significance: recipient MICA-129 val/val genotype (HR = 1.52; 95% confidence interval [95%CI] = 1.02-2.24; P =.04), older recipient age (3 15 years) (HR = 3.36; 95%CI = 1.65-6.84; P =.001) and source of stem cells (PBSC vs BM) (HR = 1.67; 95%CI = 1.10-2.53; P =.017). Since acute GvHD (aGvHD) is a major risk factor of subsequent c.GvHD, we then introduced aGvHD as a time-dependant co-variate in the multivariate analysis model. This analysis confirmed that the risk conferred by the MICA-129 val/val genotype is independent from aGvHD. Elevated post-HSCT sMICA serum levels were also independently associated with c.GvHD (p =.0001) regardless of history of acute GvHD. On the contrary, the presence of pre-transplant MICA Abs confers protection against c.GvHD (p =.04). There was an inverse relationship between MICA Abs and sMICA suggesting an antibody-based neutralization of deleterious effects of sMICA. Similarly, these genetic and phenotype characteristics of MICA influence the incidence of relapse. ConclusionAltogether, these data suggest that the studied MICA genotype and phenotype specificities could be used as relevant biomarkers for c.GvHD monitoring. DisclosuresNo relevant conflicts of interest to declare.

NKG2D ligand MICA is retained in the cis-Golgi apparatus by human cytomegalovirus protein UL142.

Human cytomegalovirus (HCMV) evades T-cell recognition by down-regulating expression of major histocompatibility complex (MHC) class I and II molecules on the surfaces of infected cells. Contrary to the "missing-self" hypothesis, HCMV-infected cells are refractory to lysis by natural killer (NK) cells. Inhibition of NK cell function is mediated by a number of HCMV immune evasion molecules, which operate by delivering inhibitory signals to NK cells and preventing engagement of activating ligands. One such molecule is UL142, which is an MHC class I-related glycoprotein encoded by clinical isolates and low-passage-number strains of HCMV. UL142 is known to down-modulate surface expression of MHC class I-related chain A (MICA), which is a ligand of the activating NK receptor NKG2D. However, the mechanism by which UL142 interferes with MICA is unknown. Here, we show that UL142 localizes predominantly to the endoplasmic reticulum (ER) and cis-Golgi apparatus. The transmembrane domain of UL142 mediates its ER localization, while we propose that the UL142 luminal domain is involved in its cis-Golgi localization. We also confirm that UL142 down-modulates surface expression of full-length MICA alleles while having no effect on the truncated allele MICA*008. However, we demonstrate for the first time that UL142 retains full-length MICA alleles in the cis-Golgi apparatus. In addition, we propose that UL142 interacts with nascent MICA en route to the cell surface but not mature MICA at the cell surface. Our data also demonstrate that the UL142 luminal and transmembrane domains are involved in recognition and intracellular sequestration of full-length MICA alleles.

Association of MICA gene polymorphisms with Chlamydia trachomatis infection and related tubal pathology in infertile women

The course and morbidity of Chlamydia trachomatis infections are determined by host genetic factors, virulence of the micro-organism and environmental factors. Major histocompatibility complex class I chain-related A (MICA) gene is highly polymorphic as a potential host genetic candidate. The aim of this study was to investigate the association of polymorphic extracellular domains of MICA with C. trachomatis infection and related tubal factor infertility. Effect of MICA on the susceptibility to C. trachomatis infection and its association with tubal pathology were investigated in 214 infertile women recruited during the period from 2004 to 2007. Subjects were tested for C. trachomatis antibodies, and were further divided into two groups: those with (n = 42) and without (n = 59) tubal pathology based on laparoscopy results. The relationship between prevalence of C. trachomatis, tubal pathology and MICA allele polymorphisms was analysed. Women with tubal infertility more often had antibodies to C. trachomatis [66.7 versus 39.1%; odds ratio (OR): 3.12, 95% CI: 1.68-5.78, P = 0.004] than infertile women without tubal pathology. Moreover, allele 008 had a highly negative correlation with C. trachomatis infection (P(c) = 0.0036, OR: 2.14), while other allele polymorphisms showed no significant association with the disease. No statistically significant differences were found in the MICA allele frequencies of C. trachomatis-positive women with or without tubal pathology. The association of a specific MICA allele with C. trachomatis IgG antibodies among women with infertility suggests that the MICA locus might modify host susceptibility to C. trachomatis infection.

Identification ofMICAas a Susceptibility Gene for PulmonaryMycobacterium aviumComplex Infection

Host genetic susceptibility to adult pulmonary Mycobacterium avium complex disease remains unknown. To identify genetic loci for the disease, we prepared 3 sets of pooled DNA samples from 300 patients and 300 sex-matched control subjects and genotyped 19,651 microsatellite markers in a case-control manner. D6S0009i-located in the MICA (major histocompatibility complex class I chain-related A) gene, which encodes a ligand of the NKG2D receptor-had the lowest P value in pooled and individual DNA typing. The A6 allele of the microsatellite was significantly associated with female patients (P <. 001), whereas the classical HLA-B and HLA-DRB1 alleles did not show significant association. Functional analysis of allelic expression imbalance revealed that A6-derived messenger RNA was more highly expressed than non-A6-derived messenger RNA in human bronchial epithelial cells. MICA was expressed in bronchiolar epithelium, alveolar macrophages, and granulomatous lesions. These findings suggest that MICA might be one of the immune molecules affecting the pathogenesis of the disease.

Detection of the NK cell stimulatory receptor NKG2D and its soluble ligand MICA in patients with esophageal carcinoma.

Objective To investigate the expression of NKG2D peripheral blood of patients with esophageal carcinoma and expression of the soluble form of major histocompatibility complex class Ⅰ-related chain A (MICA). To analyze and discuss the function of NKG2D in anti-esophageal carcinoma mechanism and its relation with escape of immunosurveillance of cancer. Methods Flow cytometry analysis was used to detect NKG2D in the peripheral blood of 50 patients with esophageal carcinoma and 25 normal control individuals. Enzyme-linked immunoabsorbent assay was used to measure serum levels of soluble MICA. Results The expression of NKG2D were(87.25±3.06), (88.38±4.24), (92.46±1.46) respectively. Compared with the normal control individual, the expression of NKG2D in esophageal carcinoma group was significantly low; Among patients categorized according to most disease parameters tested (tumor size, grade of differentiation, regional lymph node status, disease stage), soluble MICA levels in sera did not statistically differ from those in normal control individuals. Patients with stage Ⅳ disease and/or regional lymph node metastasis, exhibited significantly higher serum levels of soluble MICA than control individuals. Conclusion The activity of NK cell and the anti-cancer cellular immunity level reduce in patients with esophageal carcinoma. The decrease of the receptor NKG2D is a reason for the descend of the the activity of NK cells. The escape of immunosurveiilance with esophagal carcinoma may correlate with down-regulate of NKG2D expression and up-regulate of sMICA. Key words: Esophageal neoplasms; Killer cells, natural; Receptors, neurokinin-2; Genes, MHCclass Ⅰ

MICA-HLA-B haplotype diversity and linkage disequilibrium in a population of Jewish descent from Majorca (the Balearic Islands)

The major histocompatibility complex class I chain-related A (MICA) gene is located 46 kb centromeric of human leukocyte antigen (HLA)-B and is highly polymorphic, similar to HLA genes. This allelic variation may influence the affinity of MICA molecules to their receptor on natural killer, γδ T and CD8 + T cells, NKG2D, and the immune response to organ transplantation and disease susceptibility. In the present study, we typed MICA and HLA-B polymorphisms in 95 individuals from a population of Jewish descent (Chuetas) and 195 individuals of Caucasian origin from Majorca (the Balearic Islands). MICA*008, -*004, and -*002 were the most common alleles and accounted for 53 and 60% in Chuetas and Majorcans, respectively. Other common alleles (frequency >5%) were MICA*016, -*009, -*012, -*007, and -*017 in Chuetas and -*009, -*001, and -*018 in Majorcans. We also studied two-locus haplotype diversity and linkage disequilibrium (LD). Both populations presented haplotypes with significant LD that were shared by other Caucasians populations, but we reported particular haplotypes in the Chueta group: MICA*002–HLA-B*38, MICA*016–HLA-B*35, MICA*012–HLA-B*55, and MICA*017–HLA-B*57. These haplotypes were not reported in other studies at high frequencies. In conclusion, the Chueta population presents a particular genetic pool but has affinities with the host population.

MicroRNAs regulate NKG2D ligands on tumor cells (88.21)

Abstract NKG2D is a receptor used by NK cells to detect virally infected and transformed cells. It recognizes ligands that are expressed constitutively on primary tumors and tumor cell lines. We have identified four microRNAs (miRNAs) that each was sufficient to reduce the expression of the NKG2D ligand MHC class I-related chain A (MICA). These include miR-106b, -302b, -372, and -520b. Interestingly, mir-372 was also found to reduce the expression of another NKG2D ligand, UL-16 binding protein 2 (ULBP2). One of these miRNAs (miR-520b) was induced by IFN-gamma, leading to a reduction in MICA surface protein levels. miR-520b acted on both the MICA 3'-untranslated region and the promoter region and caused a decrease in the levels of MICA transcript. In contrast, an antisense oligonucleotide inhibitor of miR-520b increased the expression of a reporter construct containing the MICA 3'-untranslated region but not the MICA promoter region. These findings demonstrate the novel regulation of NKG2D ligands by endogenous microRNAs.

Normally occurring NKG2D+CD4+ T cells are immunosuppressive and inversely correlated with disease activity in juvenile-onset lupus

The NKG2D receptor stimulates natural killer cell and T cell responses upon engagement of ligands associated with malignancies and certain autoimmune diseases. However, conditions of persistent NKG2D ligand expression can lead to immunosuppression. In cancer patients, tumor expression and shedding of the MHC class I–related chain A (MICA) ligand of NKG2D drives proliferative expansions of NKG2D+CD4+ T cells that produce interleukin-10 (IL-10) and transforming growth factor-β, as well as Fas ligand, which inhibits bystander T cell proliferation in vitro. Here, we show that increased frequencies of functionally equivalent NKG2D+CD4+ T cells are inversely correlated with disease activity in juvenile-onset systemic lupus erythematosus (SLE), suggesting that these T cells may have regulatory effects. The NKG2D+CD4+ T cells correspond to a normally occurring small CD4 T cell subset that is autoreactive, primed to produce IL-10, and clearly distinct from proinflammatory and cytolytic CD4 T cells with cytokine-induced NKG2D expression that occur in rheumatoid arthritis and Crohn's disease. As classical regulatory T cell functions are typically impaired in SLE, it may be clinically significant that the immunosuppressive NKG2D+CD4+ T cells appear functionally uncompromised in this disease.

Two novel MICA alleles, MICA*054 and MICA*056

We report the identification of two novel major histocompatibility complex (MHC) class I-related chain A (MICA) alleles. MICA*054 has a nucleotide substitution of A to G at position 871 (codon 268), encoding an amino acid change of serine to glycine in the alpha-3 domain. MICA*056 has a nucleotide substitution at position 758 of G to C resulting in the substitution of tryptophan for serine at codon 230, also in the alpha-3 domain.

Cutting Edge: Down-Regulation of MHC Class I-Related Chain A on Tumor Cells by IFN-γ-Induced MicroRNA

NKG2D is a receptor used by NK cells to detect virally infected and transformed cells. It recognizes ligands that are expressed constitutively on primary tumors and tumor cell lines. In this report, we have identified four microRNAs (miRNAs) that each was sufficient to reduce the expression of the NKG2D ligand MHC class I-related chain A (MICA). One of these miRNAs (miR-520b) was induced by IFN-gamma, leading to a reduction in MICA surface protein levels. Interestingly, miR-520b acted on both the MICA 3'-untranslated region and the promoter region and caused a decrease in the levels of MICA transcript. In contrast, an antisense oligonucleotide inhibitor of miR-520b increased the expression of a reporter construct containing the MICA 3'-untranslated region but not the MICA promoter region. These findings demonstrate the novel regulation of an NKG2D ligand by an endogenous microRNA that is itself induced by IFN-gamma.

Relationship between soluble MICA and the MICA A5.1 homozygous genotype in patients with oral squamous cell carcinoma

NK and cytotoxic T cells play an important role in the elimination of virus-infected and tumor cells through NKG2D activating receptors, which can promote the lysis of target cells by binding to the major histocompatibility complex class I-related chain A (MICA) proteins. Polymorphisms in MICA may influence its binding to the NKG2D. The soluble form of MICA is released from the surface of tumor cells of epithelial origin. Whereas MICA expressed on the cell surface stimulates the immunoreceptor natural killer group 2, member D (NKG2D), the secreted form down-regulates NKG2D activity, thus allowing the tumor to escape immunosurveillance by NKG2D-expressing cells. In this study, we examined the association between MICA gene microsatellite polymorphisms and serum levels of soluble MICA in patients with oral squamous cell carcinoma (OSCC). We found that patients with OSCC were more likely to have the A5.1 allele when compared to healthy subjects and also more likely to be homozygous for this allele ( p = 0.041). Patients with the homozygous A5.1 genotype had higher levels of soluble MICA ( p = 0.031) and a lower survival rate ( p = 0.026).

Die Rolle von Endothelzellen in der Transplantatabstoßung

Endothelial cells (EC) are crucially involved in allograft rejection. They are prime targets of alloreactivity but also key players in the recruitment and extravasation of immune cells. These mechanisms also become clear in allograft biopsies with antibody-mediated complement deposition on EC and associated intracapillary accumulation of immune cells. HLA molecules are the most prominent targets of alloantibodies in AB0 compatible transplantation. Clinically relevant antibodies against other antigens such as MICA (MHC class I-related chain A) or the angiotensin II Type-1 receptor could also be convincingly demonstrated. The lack of generally available diagnostic tests for such non-HLA antibodies hampers their introduction into clinical practice. Alloantibodies undoubtedly cause allograft rejection. However, our knowledge of the molecular mechanisms underlying graft dysfunction in antibody-mediated rejection (AMR) is still fragmentary. Activation of EC by anti-endothelial cell antibodies was demonstrated in several experimental systems. Recent animal studies employing immune cell deficient transplant recipients or in-vitro assays, however, failed to demonstrate an immediate response of EC upon antibody binding and complement activation. It might therefore be considered that direct antibody- or complement-mediated EC damage is not necessarily the leading event in acute AMR. Antibody- and/or complement-induced recruitment of immune cells might rather be of crucial importance at least in the early phases of AMR.

Allelic diversity of MICA gene and MICA/HLA-B haplotypic variation in a population of the Murcia region in southeastern Spain

Major histocompatibility complex class I-related chain A (MICA) is located at 46 kb centromeric of HLA-B. It is highly polymorphic and interacts with NKG2D, its receptor on the surface of NK, Tgammadelta and T CD8 lymphocytes. Data on MICA polymorphism in different populations are still limited. Our aim was to establish allelic diversity of MICA gene and linkage disequilibrium with HLA-B in our population. DNA was obtained from 154 unrelated healthy individuals from the Murcia region in southeastern Spain. HLA-B genotyping was performed using polymerase chain reaction (PCR)-sequence-specific oligonucleotide probes and allele-specific PCR-sequence-specific primers, and MICA genotyping by using PCR-sequence-specific oligonucleotide probes. A total of 19 MICA alleles were detected on this study. MICA*008 was the most frequent allele (25.3%), followed by MICA*002 (16.1%), MICA*004 (14.9%), MICA*001 (7.8%), MICA*009 and MICA*016 (7.1%), and MICA*010 (4.6%). Eleven alleles had frequencies of <1%. In the haplotype analysis, MICA*008-B*0702 was found to be the most common, followed by MICA*004-B*4403 and MICA*001-B*1801, MICA*002-B*3501, MICA*008-B*4402, MICA*004-B*4901, MICA*008-B*0801, and MICA*002-B*3801. The frequency of MICA*010-B*1501, MICA*008-B*1302, MICA*015-B*4501, and MICA*008-B*4001 was remarkable inasmuch as these two last haplotypes have not been reported in Spanish population. Indeed, MICA*016 linked to B*1402 has also not been reported in the literature. In conclusion, the allelic diversity in our population is similar to other Caucasian populations; however we found a series of less frequent alleles, in addition to as-yet-undescribed haplotypic associations in other populations of Caucasian origin.

Renal Transplantation

It has been known for many years that patients with well-matched kidney transplants, even those who are matched at HLA-A, -B, and -DR, do not have indefinite allograft survival, and some kidneys fail as a result of rejection. In an attempt to understand the mechanism for rejection with graft loss in the face of excellent HLA matching, Zou et al. took pretransplantation sera from 1910 kidney transplant recipients and tested these sera for antibodies to MHC class I–related chain A (MICA) antigens. These antigens are expressed on the surface of epithelial cells, endothelial cells, fibroblasts, and monocytes. The MICA antigens are ligands of an activating receptor on natural killer cells and CD8+ T lymphocytes. Genes for these antigens are located close to the HLA-A and -B loci. ### Findings. Antibodies against these MICA antigens were detected in 11.4% of the 1910 patients. More important, the presence of these antibodies was associated with inferior graft survival compared with transplant centers without such antibodies (88 versus 93%; P = 0.01). In patients with good HLA matching (zero or one antigen mismatch of HLA-A plus HLA-B plus HLA-DR), sensitization to MICA was associated with even worse graft survival (83 versus 95% in individuals without such antibodies; P = 0.002). ### Commentary. This study provides a mechanism by which some allografts can be rejected, despite excellent matching and without anti-HLA antibodies. An editorial accompanying this article suggested that anti-MICA antibodies might be surrogate markers for a fundamental mechanism that mediates graft rejection, specifically, natural killer cell alloreactivity, which is due to these antigens’ binding to an activating ligand (1). It is possible that exploring this further may lead to better screening and cross-matching and further understanding of the role that these antigens may play in development of chronic allograft nephropathy.

Opposing effects of interferon‐α and interferon‐γ on the expression of major histocompatibility complex class I chain‐related A in tumors

Natural killer cells are an important component of innate resistance to viruses, bacteria, certain parasites, and tumors. The activating receptor natural killer group 2D (NKG2D) plays a critical role in the elimination of tumor cells by cytotoxic effector cells. It has been shown that the strength of an antitumor immune response might be critically dependent on NKG2D ligard surface levels. Thus, it is essential to regulate the expression of NKG2D ligands in order to ensure effective tumor immunosurveillance and the elimination of pathogen-infected cells. In the present study, we found that interferon (IFN)-alpha and IFNgamma exert opposing effects on major histocompatibility complex class I-related chain A (MICA) expression in human tumor cells. IFNalpha promotes expression of the NKG2D ligand MICA in tumor cells and therefore enhances their sensitivity to natural killer lysis. In contrast, IFNgamma exerts the opposite effect. IFNalpha promotes MICA expression at the level of transcription by augmenting MICA promoter activity. IFNgamma modulates MICA expression not only at the transcriptional level, but also at the post-translational level by promoting proteolytic cleavage by matrix metalloproteinases. Further study is needed to clarify the precise regulatory mechanisms. The pathways involved in NKG2D ligand induction might represent a promising target for improving immune responses to cancer or infections.

Down-regulation of NKG2D and NKp80 ligands by Kaposi's sarcoma-associated herpesvirus K5 protects against NK cell cytotoxicity

Natural killer (NK) cells are important early mediators of host immunity to viral infections. The NK activatory receptors NKG2D and NKp80, both C-type lectin-like homodimeric receptors, stimulate NK cell cytotoxicity toward target cells. Like other herpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV) down-regulates MHC class I molecules to avoid detection by cytotoxic T lymphocytes but renders cells susceptible to NK cell cytotoxicity. We now show that the KSHV immune evasion gene, K5, reduces cell surface expression of the NKG2D ligands MHC class I-related chain A (MICA), MICB, and the newly defined ligand for NKp80, activation-induced C-type lectin (AICL). Down-regulation of both MICA and AICL requires the ubiquitin E3 ligase activity of K5 to target substrate cytoplasmic tail lysine residues. The common MICA *008 allele has a frameshift mutation leading to a premature stop codon and is resistant to down-regulation because of the loss of lysine residues. K5-mediated ubiquitylation signals internalization but not degradation of MICA and causes a potent reduction in NK cell-mediated cytotoxicity. The down-regulation of ligands for both the NKG2D and NKp80 activation pathways provides KSHV with a powerful mechanism for evasion of NK cell antiviral functions.

Association between soluble MICA levels and disease stage IV oral squamous cell carcinoma in Japanese patients

The soluble form of major histocompatibility complex class I-related chain A (MICA) is released from the surface of tumor cells of epithelial origin. Although MICA expressed on the cell surface stimulates the immunoreceptor natural killer (NK) group 2, member D (NKG2D), the secreted form downregulates NKG2D activity, thus allowing the tumor to escape immunosurveillance by NKG2D-expressing cells. In this study, we examined the association between serum levels of soluble MICA and the severity of disease in patients with oral squamous cell carcinoma (OSCC). We used enzyme-linked immunoabsorbent assay to measure serum levels of soluble MICA in OSCC patients and normal control individuals. Among patients categorized according to most disease parameters tested (tumor size, location, grade of differentiation, regional lymph node status, disease stage), soluble MICA levels in sera did not statistically differ from those in normal control individuals. Patients with stage IV disease and/or regional lymph node metastasis did, however, exhibit significantly higher serum levels of soluble MICA than control individuals (95% confidence interval (CI), 0.65-2.45, p = 0.021, and 95% CI, 0.62-4.42, p = 0.031, respectively). Overall survival rates were significantly higher for OSCC patients with low soluble MICA levels (<50 pg/ml) than for those with high soluble MICA levels (>50 pg/ml) (95% CI, 0.43-2.75, p = 0.03). Serum levels of soluble MICA may be useful in the diagnosis of advanced stage OSCC and as an indicator of regional lymph node metastasis.

Evaluation of human major histocompatibility complex class I chain-related A as a potential target for tumor imaging

To investigate the feasibility of using human major histocompatibility complex class I chain-related A (MICA) as a target for tumor imaging diagnosis, 10C6, a monoclonal antibody (mAb) that specifically recognizes MICA in vitro, was labeled with 99mTc (technetium) and administered into mice bearing MICA-positive human ovarian epithelial carcinoma line SKOV3. Measurement of organ-specific radioactivity showed that tumor accumulated radioactivity continuously, while the uptake in the other organs decreased over time. Scintigram showed that the tumor became clearly visible at 24 h post-injection of radio-labeled 10C6 mAb. These results suggest that MICA is a promising target for tumor imaging and mAb 10C6 may be used clinically for early tumor diagnosis.