Histocompatibility Complex Class I-related Chain Research Articles

Impact of MICA 3'UTR allelic variability on miRNA binding prediction, a bioinformatic approach.

MicroRNAs (miRNAs) are small non-coding RNAs that participate as powerful genetic regulators. MiRNAs can interfere with cellular processes by interacting with a broad spectrum of target genes under physiological and pathological states, including cancer development and progression. Major histocompatibility complex major histocompatibility complex class I-related chain A (MICA) belongs to a family of proteins that bind the natural-killer group 2, member D (NKG2D) receptor on Natural Killer cells and other cytotoxic lymphocytes. MICA plays a crucial role in the host's innate immune response to several disease settings, including cancer. MICA harbors various single nucleotide polymorphisms (SNPs) located in its 3'-untranslated region (3'UTR), a characteristic that increases the complexity of MICA regulation, favoring its post-transcriptional modulation by miRNAs under physiological and pathological conditions. Here, we conducted an in-depth analysis of MICA 3'UTR sequences according to each MICA allele described to date using NCBI database. We also systematically evaluated interactions between miRNAs and their putative targets on MICA 3'UTR containing SNPs using in silico analysis. Our in silico results showed that MICA SNPs rs9266829, rs 1880, and rs9266825, located in the target sequence of miRNAs hsa-miR-106a-5p, hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-20b-5p, hsa-miR-93, hsa-miR-1207.5p, and hsa-miR-711 could modify the binding free energy between -8.62 and -18.14kcal/mol, which may affect the regulation of MICA expression. We believe that our results may provide a starting point for further exploration of miRNA regulatory effects depending on MICA allelic variability; they may also be a guide to conduct miRNA in silico analysis for other highly polymorphic genes.

Downregulation of MICA/B tumor surface expressions and augmented soluble MICA serum levels correlate with disease stage in breast cancer.

In this study, the profiling of the expression of major histocompatibility complex (MHC) class I-related chain A and B (MICA/B) in human breast cancer tumor tissue, saliva, and urine samples of breast cancer patients and control is carried out. MICA/B is ligand of NKG2D receptor expressed on malignant cells. The release of MICA/B from tumor tissue comprises an immune escape mechanism that impairs antitumor immunity. Based on this literature we explored the potential of soluble MICA (sMICA) as a marker in breast cancer (BC). The expression was profiled by using immunohistochemistry (MICA/B), western blot (MICA/B) and ELISA (MICA). The optical density of western blot of MICA/B in different stages of BC illustrated significant difference as per one way analysis of variance and significant difference with stage III and IV by Dunnett's multiple comparisons test respectively. Analysis of sMICA in serum, saliva and urine of BC patients revealed significantly higher levels (median 41.0 ± 4.1 pg/ml in pre-treatment sera, 181.9 ± 1.6 pg/ml in saliva and 90.7 ± 1.7 pg/ml in urine) than in control (median <1.2 pg/ml). The elevated levels of sMICA were related to the cancer stage. The elevated levels of sMICA were observed in patients with well differentiated cancer while the poor expression of sMICA was observed in patients with poorly differentiated tumors. Tumor immunity is impaired by the release of MICA in the biofluids and may be useful for detection and diagnosis of the stage of BC.

Major histocompatibility complex class I-related chain A and macrophage migration inhibitory factor gene polymorphisms in a Turkish patient population with vitiligo

Major histocompatibility complex class I-related chain A and macrophage migration inhibitory factor gene polymorphisms in a Turkish patient population with vitiligo

Posttransplant-Alloantibodies Against MICA Antigens Associated With Decreased Long-Term Allograft Survival of Kidney Transplant Recipients

Previous evidence showed that antibodies against major histocompatibility complex class I-related chain A (MICA) could lead to antibody-mediated rejection in kidney transplantation in case where the patients had no alloantibodies against HLA. However, the effects of posttransplant anti-MICA antibodies on long-term renal allograft survival and function remained unsettled. We tested the posttransplant anti-MICA antibodies in 150 kidney transplant patients. The aim of this study was to compare the long-term graft survival and function between patients who were MICA positive and those who were negative. The posttransplant serum samples from 150 patients receiving kidney transplantation in our center from 2012 to 2013 were tested for MICA antibodies and HLA antibodies by Luminex single antigen array technology. Graft survival and function were followed up for a mean time of 74.2 months. The research was conducted in accordance with the Helsinki Congress and the Declaration of Istanbul. Of the 150 patients, 38 (25.3%) were sensitized against MICA after transplantation. The anti-MICA antibodies-positive (anti-MICA+) group had a worse long-term renal allograft survival than that of anti-MICA-negative (anti-MICA-) group (P = .029), even when stratified by posttransplant HLA sensitization status or donor source. Anti-MICA antibodies also had a detrimental impact on renal allograft function, but only at 1 year posttransplantation (estimated glomerular filtration rates at 1 year: anti-MICA+ 66.6 mL/min/1.73 m2 vs anti-MICA- 78.7 mL/min/1.73 m2; P = .023). Posttransplant anti-MICA antibodies were associated with decreased long-term renal allograft survival and short-term renal allograft function.

A comparative study of smica in various body fluids of diagnosed cervical cancer patients and healthy women.

ObjectiveCervical cancer (CC) is a major public health problem in women, and its early detection can help reduce morbidity and mortality. The objective of this study was to compare serum levels of soluble major histocompatibility complex class I-related chain A (sMICA) levels in various body fluids between women diagnosed with CC and healthy women.MethodsA case-control study was conducted at a tertiary care hospital and a cancer center in Kolhapur, India. Overall, 150 individuals (100 CC patients and 50 healthy women) participated after providing informed written consent. Demographic data, histopathology history, parity, and tumor, node, and metastasis (TNM) staging data were collected. Pap smears, saliva, blood, and urine samples were collected. Pap smears were examined microscopically, and sMICA levels in all samples were determined by enzyme-linked immunoassay (ELISA).ResultsThe mean age of women with cervical cancer was 49.86±8.18 years. Squamous cell carcinoma (70%) was the most common histological variant in CC patients. Serum soluble sMICA levels differed significantly with parity and TNM staging (P<0.05). Mean levels of sMICA were significantly different in samples (CC cases vs. healthy patients; saliva: 166.721±108.718 vs. 0.039±0.005 pg/mL; urine: 82.921±45.580 vs. 0.010±0.005 pg/mL; serum: 35.756±10.799 vs. 0.039±0.005 pg/mL, P<0.001).ConclusionLevels of sMICA in body fluids can be considered as a diagnostic or prognostic tool to determine disease progression or tumor regression.

Distribution of MICA alleles and haplotypes associated with HLA-B in Greek population

IntroductionThe Major Histocompatibility Complex Class I-related chain A gene (MICA) is a highly polymorphic functional gene located close to the HLA-B locus. Certain MICA alleles have been related to inflammatory and autoimmune diseases while MICA antibodies have been implicated in organ allograft rejection or graft-versus-host disease (GVHD). AimThe aim of this study was to identify the frequencies of MICA alleles and MICA ~ HLA-B haplotypes in the Greek population since, as far as we know, these data are still limited. MethodsDNA was obtained from 277 unrelated healthy Greek individuals of Caucasian origin, volunteer donors of blood stem cells. HLA-B* and MICA* genotyping was performed by reverse PCR-SSOP. ResultsA total of 18 MICA alleles were defined in the present study. The five most frequent alleles in the Greek population were MICA*008 (24.6%), MICA*009 (22.36%), MICA*018 (16.03%), MICA*002 (8.02%) and MICA*004 (7.17%) which altogether account for 77.8% of all alleles. The most common MICA ~ HLA-B haplotypes were MICA*018 ~ B*18 (12.5%) and MICA*009 ~ B*51(11.5%). ConclusionsThe five most frequent MICA alleles in the Greek population were *008, *009, *018, *002, *004. In other Caucasian populations, two of these alleles (*008, and *004) were observed in similar frequencies. MICA*002 was observed less frequently (8.02%) in the Greek population compared to other Caucasian groups (frequencies > 15%). Also, MICA*009 and MICA*018 had elevated frequencies (above 15%) whereas in other Caucasian populations they were found around 10% or less. These data may be important for the elucidation of the role that MICA polymorphisms play in organ and stem cell transplantation and to identify the relation of certain MICA with susceptibility to specific diseases.

Increased Concentrations of Circulating Soluble MHC Class I-Related Chain A (sMICA) and sMICB and Modulation of Plasma Membrane MICA Expression: Potential Mechanisms and Correlation With Natural Killer Cell Activity in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a severe autoimmune disease of unknown etiology. The major histocompatibility complex (MHC) class I-related chain A (MICA) and B (MICB) are stress-inducible cell surface molecules. MICA and MICB label malfunctioning cells for their recognition by cytotoxic lymphocytes such as natural killer (NK) cells. Alterations in this recognition have been found in SLE. MICA/MICB can be shed from the cell surface, subsequently acting either as a soluble decoy receptor (sMICA/sMICB) or in CD4+ T-cell expansion. Conversely, NK cells are frequently defective in SLE and lower NK cell numbers have been reported in patients with active SLE. However, these cells are also thought to exert regulatory functions and to prevent autoimmunity. We therefore investigated whether, and how, plasma membrane and soluble MICA/B are modulated in SLE and whether they influence NK cell activity, in order to better understand how MICA/B may participate in disease development. We report significantly elevated concentrations of circulating sMICA/B in SLE patients compared with healthy individuals or a control patient group. In SLE patients, sMICA concentrations were significantly higher in patients positive for anti-SSB and anti-RNP autoantibodies. In order to study the mechanism and the potential source of sMICA, we analyzed circulating sMICA concentration in Behcet patients before and after interferon (IFN)-α therapy: no modulation was observed, suggesting that IFN-α is not intrinsically crucial for sMICA release in vivo. We also show that monocytes and neutrophils stimulated in vitro with cytokines or extracellular chromatin up-regulate plasma membrane MICA expression, without releasing sMICA. Importantly, in peripheral blood mononuclear cells from healthy individuals stimulated in vitro by cell-free chromatin, NK cells up-regulate CD69 and CD107 in a monocyte-dependent manner and at least partly via MICA-NKG2D interaction, whereas NK cells were exhausted in SLE patients. In conclusion, sMICA concentrations are elevated in SLE patients, whereas plasma membrane MICA is up-regulated in response to some lupus stimuli and triggers NK cell activation. Those results suggest the requirement for a tight control in vivo and highlight the complex role of the MICA/sMICA system in SLE.

The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing.

Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells without prior sensitization. One pivotal activating NK receptor is NKG2D, which binds a family of eight ligands, including the major histocompatibility complex (MHC) class I-related chain A (MICA). Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus causing morbidity and mortality in immunosuppressed patients and congenitally infected infants. HCMV encodes multiple antagonists of NK cell activation, including many mechanisms targeting MICA. However, only one of these mechanisms, the HCMV protein US9, counters the most prevalent MICA allele, MICA*008. Here, we discover that a hitherto uncharacterized HCMV protein, UL147A, specifically downregulates MICA*008. UL147A primarily induces MICA*008 maturation arrest, and additionally targets it to proteasomal degradation, acting additively with US9 during HCMV infection. Thus, UL147A hinders NKG2D-mediated elimination of HCMV-infected cells by NK cells. Mechanistic analyses disclose that the non-canonical GPI anchoring pathway of immature MICA*008 constitutes the determinant of UL147A specificity for this MICA allele. These findings advance our understanding of the complex and rapidly evolving HCMV immune evasion mechanisms, which may facilitate the development of antiviral drugs and vaccines.

MICA A5.1 homozygous genotype is associated with a risk for early-onset oral cancer

ObjectivesGenetic predisposition is reportedly involved in early-onset oral cancer, although the genetic basis of this cancer remains unclear. The major histocompatibility complex class I-related chain A (MICA) plays a crucial role in eliminating malignant tumors by activating NKG2D, the natural killer (NK) receptor. MICA polymorphism might affect its binding to NKG2D. We aimed to find whether MICA gene microsatellite polymorphism is involved in the risk of oral squamous cell carcinoma (OSCC) development in a Japanese population. Materials and methodsWe recruited 386 patients with OSCC and 103 healthy controls. Genomic DNA was analyzed by PCR for microsatellite repeat polymorphism in the transmembrane region of the MICA gene. The groups were compared for the prevalence of various alleles and their association with disease prognosis and survival. ResultsWe found that adolescents and young adults (AYA) with OSCC were more likely to have the MICA A5.1 homozygous genotype than healthy controls (P = 0.0001), but their survival rate was higher than with other MICA genotypes (P = 0.0185). ConclusionThese results suggest that cancer’s immune escape is facilitated by MICA’s failure to activate the NK cells. MICA A5.1 homozygosity plays a role in individual susceptibility to OSCC, increasing the risk of early‐onset oral cancer. However, such patients have a better prognosis than those with other MICA genotypes.

Analysis of Serum Vitamin D and Major Histocompatibility Complex Class I-Related Chain a (Mica) Levels in Patients With Breast Carcinoma

Introduction: Breast carcinoma is the most deadly cancer in women worldwide, with an incidence rateof 26 cases per 100,000 women in Indonesia. Treatment and prognosis is very dependent on the stage ofbreast carcinoma. Vitamin D can inhibit proliferation and invasive cancer cells, induction of differentiation,apoptosis and promotion of angiogenesis. Major Histocompatibility Complex class I - related chain A(MICA) plays a role in reducing the expression of NKG2D receptors in breast carcinomas so that they canbe targeted for treatment of breast carcinoma treatment. The aim of this study was to determine vitamin Dand MICA levels in serum patients with non-metastatic and metastatic breast carcinoma.Method: We examined 86 samples of breast carcinoma patients (44 non-metastatic samples and 42metastatic samples) with a range of 29 - 68 years old. Vitamin D levels were examined by the EnzymeLinked Flourescent Assay (ELFA) method while the MICA levels were examined by Enzyme LinkedImmunoabsorbant Assay (ELISA).Result: There were significant differences in mean vitamin D levels in non-metastatic and metastatic breastcarcinomas (29.88 ng/mlvs19.06 ng/ml; p &lt;0.01).Serum MICA levels in patients with non-metastatic breastcarcinoma were lower (333.52 pg/ml) than in metastatic breast carcinoma(333.52 pg/mlvs528.71 pg/ml; p&lt;0.01).A negative correlation was found between vitamin D levels andMICA in both groups (Pearson correlation, p: -0.58).Conclusion: Metastatic breast carcinoma had lower vitamin D levels and higher serum MICA levels thannon-metastatic breast carcinoma.

Major Histocompatibility Complex Class I-Related Chain A Alleles and Histology of Nonalcoholic Fatty Liver Disease.

Major histocompatibility complex class I‐related chain A (MICA) is a highly polymorphic gene that modulates immune surveillance by binding to its receptor on natural killer cells, and its genetic polymorphisms have been associated with chronic immune‐mediated diseases. The progressive form of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), is characterized by accumulation of fat and inflammatory cells in the hepatic parenchyma, potentially leading to liver cell injury and fibrosis. To date, there are no data describing the potential role of MICA in the pathogenesis of NAFLD. Therefore, our aim was to assess the association between MICA polymorphism and NASH and its histologic features. A total of 134 subjects were included. DNA from patients with biopsy‐proven NAFLD were genotyped using polymerase chain reaction–sequence‐specific oligonucleotide for MICA alleles. Liver biopsies were assessed for histologic diagnosis of NASH and specific pathologic features, including stage of fibrosis and grade of inflammation. Multivariate analysis was performed to draw associations between MICA alleles and the different variables; P ≤ 0.05 was considered significant. Univariate analysis showed that MICA*011 (odds ratio [OR], 7.14; 95% confidence interval [CI], 1.24‐41.0; P = 0.04) was associated with a higher risk for histologic NASH. Multivariate analysis showed that MICA*002 was independently associated with a lower risk for focal hepatocyte necrosis (OR, 0.24; 95% CI, 0.08‐0.74; P = 0.013) and advanced fibrosis (OR, 0.11; 95% CI, 0.02‐0.70; P = 0.019). MICA*017 was independently associated with a higher risk for lymphocyte‐mediated inflammation (OR, 5.12; 95% CI, 1.12‐23.5; P = 0.035). Conclusion: MICA alleles may be associated with NASH and its histologic features of inflammation and fibrosis. Additional research is required to investigate the potential role of MICA in increased risk or protection against NAFLD.

Metformin inhibits cervical cancer cell proliferation by modulating PI3K/Akt-induced major histocompatibility complex class I-related chain A gene expression

BackgroundRecent studies have shown that the classic hypoglycemic drug metformin inhibits tumor growth; however, the underlying mechanism remains unclear. We previously showed that metformin disrupts the sponge effect of long non-coding RNA MALAT1/miR-142-3p to inhibit cervical cancer cell proliferation. In this study, we interrogated the ability of metformin to modulate the anti-tumor immune response in cervical cancer.MethodsThe cell counting kit-8 assay was used to detect the viability of cervical cancer cells. Flow cytometry assays were performed to measure cell apoptosis and cell cycle. Lactate dehydrogenase (LDH) cytotoxicity assay was used to detect NK Cell Cytotoxicity. Relative protein levels were determined by immunoblotting and relative gene levels were determined by quantitative real-time PCR. Tumor Xenograft Modeling was used to evaluate the effect of metformin in vivo.ResultsMetformin inhibited cervical cancer cell proliferation, cervical cancer xenograft growth, expression of PCNA, p-PI3K and p-Akt. Moreover metformin induced cervical cancer cell apoptosis and caused cancer cell cycle arrest. In addition, metformin upregulated the expression of DDR-1 and p53 in human cervical cancer cells. Furthermore, metformin also regulated the mRNA and protein expression of MICA and HSP70 on the surface of human cervical cancer cells via the PI3K/Akt pathway, enhancing NK cell cytotoxicity.ConclusionsIn conclusion, our results suggest that metformin may be used as immunopotentiator to inhibit cervical cancer progression and may be considered a viable candidate for combination therapy with immunotherapy.

BCMA-targeting Bispecific Antibody That Simultaneously Stimulates NKG2D-enhanced Efficacy Against Multiple Myeloma.

B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein expressed on malignant plasma cells of patients with multiple myeloma (MM), and it is a defined therapeutic target. Major histocompatibility complex class I-related chain A (MICA) is frequently expressed in lymphoproliferative malignancies including MM. MICA activates natural killer (NK) cells and costimulates T cells by interaction with its immunoreceptor NK cell receptor G2D (NKG2D). Nonetheless, during full-blown MM, tumor cells promote efficient MICA shedding, which evokes NKG2D internalization and immune suppression. To enhance the directional killing efficacy of immune cells against myeloma cells, we constructed a novel bispecific antibody 2A9-MICA and explored its potential antimyeloma activity against MM. 2A9-MICA consists of human MICA extracellular region and a single-chain antibody fragment (scFv) that targets BCMA generated by phage display technology. In vitro, 2A9-MICA activated NK cell-mediated cytotoxicity and induced NK cells to kill BCMA-positive human myeloma cells. Moreover, in BCMA-positive, MM-bearing nude mice, 2A9-MICA specifically targeted tumor tissue, where it effectively recruited immune cells and inhibited tumor tissue growth showed superior antitumor activity. Taken together, bispecific antibody 2A9-MICA provides a new approach for MM-targeting immunotherapy and has attractive potential for clinical applications.

MICA-129 Met/Val polymorphism could be a genetic biomarker for Familial Breast Cancer in the Tunisian population.

Identification of candidate genes associated with susceptibility of breast cancer can have a significant impact at a cancer management national healthcare systems level, making genetic testing more affordable and cost-effective. We have previously shown that the major histocompatibility complex class I-related chain A (MICA) was related to breast cancer and plays an important role in modulating immune response mechanisms through NKG2D receptor activation. Compared to our previous study, in this work, we recruited a new cohort composed of 354 unrelated Tunisian women affected by breast cancer and 380 age-matched women as controls, all genotyped for MICA-129 Met/Val (rs 1051792). Subsequently, we exanimated the distribution of this polymorphism in ten families. As a result, an association was found between the Val allele and Val/Val genotype and the risk of breast cancer (p=2.5×10-15 ; OR=2.40; p=6.5×10-13 ; OR=3.03, respectively). Stratified analysis with age and family history of cancer revealed an association between the Val/Val genotype and younger patients <40years (p=.003; OR=2.03). Among those patients having a family history of cancer, 68% had a Val/Val genotype (p=.02; OR=1.82). In the family study, an analyse of pedigrees revealed that the majority of families showed the development of breast cancer at a young age. Moreover, all patients diagnosed with early-onset breast cancer had a Val/Val genotype. Our results lead us to propose that this polymorphism may be an inherited genetic biomarker contributing to an increased breast cancer risk in Tunisian women.

Anterior gradient 2–derived peptide upregulates major histocompatibility complex class I–related chains A/B in hepatocellular carcinoma cells

AimsHepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. Decrease in NKG2D ligand levels and exhaustion of NK cells in HCC patients are major causes of immune escape, high recurrence, poor prognosis, and low overall survival. Enhancing the susceptibility of HCC to NK cells by upregulating NKG2DLs on tumor cells is an effective treatment strategy. This study aimed to identify the effect of the Anterior gradient 2 (AGR2)-derived peptide P1, which was reported to bind to HLA-A*0201 as an epitope, on both the expression of major histocompatibility complex class I-related chains A/B (MICA/B) on HCC cells and the cytotoxicity of NK cells. Main methodsThe effect of P1 on MICA/B expression on HCC cells was determined by qRT-PCR, western blotting, and flow cytometry analysis. HCC cells were pre-treated with various pathway inhibitors to identify the molecular pathways associated with P1 treatment. The cytotoxicity of NK cells toward HCC was investigated by LDH cytotoxicity assay. The tumor-suppression effect of P1 was determined in vivo using a NOD/SCID mice HCC model. Key findingsP1 significantly increased MICA/B expression on HCC cells, thereby enhancing their susceptibility to the cytotoxicity of NK cells in vitro and in vivo. Further, p38 MAPK cell signaling pathway inhibitor SB203580 significantly attenuated the effects of P1 in vivo and in vitro. SignificanceP1 upregulates MICA and MICB expression on HCC cells, thereby promoting their recognition and elimination by NK cells, which makes P1 an attractive novel immunotherapy agent.

MiR-20a regulates sensitivity of colorectal cancer cells to NK cells by targeting MICA.

Colorectal cancer (CRC) is one of the leading cancer-related causes of deaths in the world. Recently, microRNAs have been reported to regulate the tumor growth, invasion and the immunosuppression. In the present study, we found that miR-20a was increased in human CRC specimens compared with the healthy normal tissues. However, miR-20a overexpression and knockdown did not impair the CRC cell growth in vitro. Our results indicated that CD107a+ NK cells are increased in CRC group. Furthermore, cytotoxicity assays demonstrated that miR-20a knockdown promoted the CRC cells sensitive to NK cells, whereas miR-20a overexpression showed the opposite results. Our results suggest that the regulation of NK cells by miR-20a depends on NKG2D. Luciferase reporter assays revealed that the NKG2D ligand Major Histocompatibility Complex (MHC) class I-related chain genes A (MICA) is the direct target of miR-20a. Flow cytometry showed the MICA protein level is significantly reduced in miR-20a-overexpressing CRC cells and increased in miR-20a knockdown CRC cells. Taken together, our results suggest that miR-20a regulates sensitivity of CRC cells to NK cells by targeting MICA.

Single nucleotide polymorphism of rs2596542 and the risk of hepatocellular carcinoma development: A meta-analysis.

Major histocompatibility complex class I-related chain A (MICA) is considered as a tumor antigen, and its expression is affected by its genetic polymorphisms. However, the relationship between rs2596542 polymorphisms in MICA promoter region and hepatocellular carcinoma (HCC) is not fully elucidated so far. This study aims to explore the relationship between single nucleotide polymorphism of rs2596542 and the risk of HCC development through meta-analysis. MEDLINE, Web of Science, and EMBASE databases were systematically searched to identify relevant studies. A meta-analysis was performed to examine the association between MICA rs2596542 polymorphism and susceptibility to HCC. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Fourteen case-control studies involving 4,900 HCC cases and 19,519 controls were included. The MICA rs2596542C allele was significantly associated with decreased risk of HCC based on allelic contrast (OR = 0.76, 95% CI = 0.69-0.83, P < .001), homozygote comparison (OR = 0.57, 95% CI = 0.48-0.69, P < .001), and a recessive genetic model (OR = 0.77, 95% CI = 0.65-0.91, P < .001), whereas patients carrying the MICA rs2596542TT genotype had significantly higher risk of HCC than those with the CT or CC genotype (TT vs CT + CC, OR = 1.57, 95% CI = 1.36-1.81, P < .001). Subgroups analyses based on the ethnic or the source of control groups found very similar findings. The C allele in MICA rs2596542 is a protective factor for hepatocarcinogenesis, whereas the T allele is a risk factor. Further large and well-designed studies are needed to confirm this conclusion.

A subgroup of lupus patients with nephritis, innate T cell activation and low vitamin D is identified by the enhancement of circulating MHC class I-related chain A.

The major histocompatibility complex (MHC) class I-related chain A (MICA) is induced upon stress, and labels malfunctioning cells for their recognition by cytotoxic lymphocytes. Alterations in this recognition and also abnormal natural killer (NK) functions have been found in systemic lupus erythematosus (SLE). MICA can be shed from cells, subsequently acting as a soluble decoy receptor (sMICA). Our purpose was to study circulating sMICA levels in relationship with the activation of innate pathways in PBMC in a cohort of lupus patients. NK cells were characterized by flow cytometry. Gene expression of Toll-like receptors (TLR), interferon (IFN)-I sensitive genes and MICA were separately analyzed in monocytes, T cells and B cells. Serum sMICA was measured with enzyme-linked immunosorbent assay (ELISA). In our cohort, NK cell counts dropped in relationship with disease activity. sMICA showed an inverse trend with NK cell counts, as well as a significant association with activity indices, but not with complement decrease. Levels of sMICA associated to proteinuria and active nephritis. A multivariate regression model revealed anti-nuclear antibody (ANA) titres, the up-regulation of TLR-4 in T cells and lower vitamin D as predictors of sMICA enhancement. Interestingly, vitamin D showed an inverse association with proteinuria and a strong correlation with T cell MICA mRNA levels. According to our data, circulating sMICA identifies a subgroup of lupus patients with low vitamin D, innate activation of T cells and nephritis. We propose that lymphocyte shedding could account for the enhancement of sMICA and reflect an immune evasion mechanism driving disease activation in lupus.

Soluble MICA in Biofluids as Biomarker in Detection of Oral Cancer Which Correlates with Disease Stage

Expression of major histocompatibility complex class I-related chain A/B (MICA/B) has been intended to play significant role in tumor immunosurveillance. Downregulation of MICA/B expression in tissue and augmented sera levels assumed to impair antitumor immune response. In this study, the potential of sMICA as a marker for oral cancer (OC) was investigated. The sMICA levels in sera, saliva and urine of OC patients differ significantly from control. The sMICA was correlated with tumor stage to evaluate the diagnostic power of MICA as marker. However, the findings indicate that the expression of MICA/B in positive control and Stage I and IV showed significant difference as per one way analysis of variance (P value < 0.0001). Serum levels of sMICA showed significant difference in positive control and Stage I and IV (P value <0.0001). Stage II and III also show significant difference with P value 0.0028and 0.0003 respectively with positive control MICA/B expression. Analysis of sMICA in serum, saliva and urine of OC patients revealed significantly (P value < 0.0001) higher levels (median 34.25± 3.57 pg/ml in pre-treatment sera, 193.93 ±1.95 pg/ml in saliva and 109.89± 1.59 pg/ml in urine) than in control (median <1.2pg/ml).Patients with poorly differentiated tumor exhibited a smaller amount of sMICA levels and well differentiated tumor revealed higher sMICA levels in biofluids. The release of sMICA and its expressions in biofluids reflect impairment of tumorimmunity. The sMICA levels may provide useful additional information in the diagnosis, staging and prognosis of cancer. Funding Statement: This study was supported by a grant to Dr. Meghnad G Joshi from Department of Science and Technology (DST), Govt. of India (SB/SO/HS/0198/2013). Declaration of Interests: All authors have no conflict of interest. Ethics Approval Statement: These activities were approved by Institutional Ethical Committee and all subjects gave provided written informed consent.

Prognostic significance of soluble major histocompatibility complex class I-related chain A (sMICA) in gastric cancer

The major histocompatibility complex class I-related chain genes A and B (MICA and MICB, present at 6p21.33) encode cell surface transmembrane glycoproteins related to those of the HLA system, and ...