MICA Gene Research Articles

Association study among HLA, KIR, MICA, PARK2, and cytokine genes in patients with leprosy from Southern Brazil

Event Abstract Back to Event Association study among HLA, KIR, MICA, PARK2, and cytokine genes in patients with leprosy from Southern Brazil Priscila S. Mazini1*, Danilo A. Francechi1, Pãmela G. Reis1, Ana M. Sell1 and Jeane E. Visentainer1 1 State University Maringá, Biosciences Applied to Pharmacy, Brazil Polymorphisms of HLA, KIR, MICA, PARK and cytokine genes were analysed in patients with leprosy and healthy volunteers from Brazil. HLA, KIR and MICA genes were genotyped by PCR-SSO. PARK2-2599 polymorphism was investigated by real time PCR. PCR-SSP was performed for: TNF-308/-238; IL2-330/+166; IL6-174; IFNG+874; TGFB1+869/+915; and IL10-592/-819/-1082. HLA-DRB1*16 was associated to per se leprosy (P=0.0059), tuberculoid and dimorph forms (P=0.016 and P=0.001, respectivelly), while the HLA-DRB1*16:02 was associated to lepromatous form (P=0.023). KIR2DS2 and KIR2DS3 frequencies were higher in tuberculoid leprosy when compared to lepromatous leprosy. Analysis of KIR-ligands reveled KIR2DL1-C2/C2 elevated in tuberculoid in comparison to all other leprosy subgroups and controls. A negative association between KIR2DL3-C1 and KIR2DL3-C1/C1 and the tuberculoid group was identified. Borderline patients exhibited a higher frequency of KIR3DL2-A3/11 than the controls and lepromatous patients, and a lower frequency of KIR2DL1-C2 than the controls and tuberculoid subgroup. MICA*027 allele was decreased (P= 0.01) in leprosy patients and MICA*010 (P = 0.05) and MICA*027 alleles (P = 0.01) in multibacillary leprosy patients compared to the control group. No significant difference of genotype frequencies among the groups for PARK2 gene was observed. For TNF-308, a higher frequency of GG genotype (P = 0.009), along with a decreased frequency of GA/AA genotypes was observed among leprosy patients as compared to the control group (P = 0.009). Analysis of IL10 genotypes revealed lower frequency of GCC/GCC haplotype in lepromatous leprosy patients (6.2%) in comparison to controls (15.4%). The study suggests the involvement of immune response genes in leprosy.

Role of HLA, KIR, MICA, and cytokines genes in leprosy.

Many genes including HLA, KIR, and MICA genes, as well as polymorphisms in cytokines have been investigated for their role in infectious disease. HLA alleles may influence not only susceptibility or resistance to leprosy, but also the course of the disease. Some combinations of HLA and KIR may result in negative as well as positive interactions between NK cells and infected host cells with M. leprae, resulting in activation or inhibition of NK cells and, consequently, in death of bacillus. In addition, studies have demonstrated the influence of MICA genes in the pathogenesis of leprosy. Specifically, they may play a role in the interaction between NK cells and infected cells. Finally, pro- and anti-inflammatory cytokines have been influencing the clinical course of leprosy. Data from a wide variety of sources support the existence of genetic factors influencing the leprosy pathogenesis. These sources include twin studies, segregation analyses, family-based linkage and association studies, candidate gene association studies, and, most recently, genome-wide association studies (GWAS). The purpose of this brief review was to highlight the importance of some immune response genes and their correlation with the clinical forms of leprosy, as well as their implications for disease resistance and susceptibility.

Expression of ligands for NK cell receptors NKG2D and DNAM-1 on drug-induced senescent Multiple Myeloma cells depends on redox signaling.

Event Abstract Back to Event Expression of ligands for NK cell receptors NKG2D and DNAM-1 on drug-induced senescent Multiple Myeloma cells depends on redox signaling. Biancamaria Ricci1*, Alessandra Soriani1, Maria Luisa Iannitto1, Cinzia Fionda1, Marco Cippitelli1, Stefania Morrone2, Maria Teresa Petrucci3, Maria Rosaria Ricciardi3 and Angela Santoni1 1 "Sapienza" University of Rome, Department of Molecular Medicine, Italy 2 "Sapienza" University of Rome, Department of Experimental Medicine, Italy 3 "Sapienza" University of Rome, Department of Cellular Biotechnologies and Hematology, Italy Natural Killer (NK) cells represent a key component of anti-tumor immune response exhibiting cytotoxic functions and secreting several cytokines and chemokines. Particularly relevant for tumor cell recognition are the activating receptors NKG2D that binds MICA/B and ULBPs, and DNAM1 that recognizes nectin/nectin-like molecules (Nec2 and NecL5/PVR). We have previously demonstrated that NK cells exhibit an enhanced cytotoxic activity against drug-induced senescent Multiple Myeloma (MM) cells due to an increased expression of NKG2DLs and DNAM1Ls. Little is known about the mechanisms underlying the up-regulation of these ligands induced by genotoxic agents. The present study is focused on the identification of the molecular mechanisms underlying NKG2DL and DNAM-1L drug-induced expression on MM cells with particular attention to the role played by changes in the cellular redox state. Our data indicate that low doses of doxorubicin and melphalan can trigger the activation of DNA Damage Response (DDR) and up-regulate NKG2DLs and DNAM1Ls, both at protein and mRNA levels, in an ATM/ATR and Chk1/2-dependent and p53-independent manner. Exposure of MM cells to free radical scavenger N-Acetyl-L-Cysteine (NAC) abrogates DDR activation and senescent associated-cell cycle G2M arrest, induced by doxorubicin and melphalan. Moreover, drug-dependent NKG2DLs and DNAM1Ls induction is inhibited by NAC on both MM cell lines and patient CD138+ malignant plasma cells. Finally, we have demonstrated the involvement of E2F1 transcription factor in the redox signaling-dependent induction of MICA and PVR genes following drug treatment. The finding of new players regulating NK cell activating ligands on tumor cells might provide novel immunotherapeutic tools. References ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Soriani A, Zingoni A, Cerboni C, Iannitto ML, Ricciardi MR, Di Gialleonardo V, Cippitelli M, Fionda C, Petrucci MT, Guarini A, Foà R, Santoni A. Blood. 2009 Apr 9;113(15):3503-11. doi: 10.1182/blood-2008-08-173914. DNAM-1 ligand expression on Ag-stimulated T lymphocytes is mediated by ROS-dependent activation of DNA-damage response: relevance for NK-T cell interaction. Ardolino M, Zingoni A, Cerboni C, Cecere F, Soriani A, Iannitto ML, Santoni A. Blood. 2011 May 5;117(18):4778-86. doi: 10.1182/blood-2010-08-300954. Keywords: NKG2DLs, DNAM1Ls, ROS, DDR, Multiple Myeloma. Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Innate immunity Citation: Ricci B, Soriani A, Iannitto M, Fionda C, Cippitelli M, Morrone S, Petrucci M, Ricciardi M and Santoni A (2013). Expression of ligands for NK cell receptors NKG2D and DNAM-1 on drug-induced senescent Multiple Myeloma cells depends on redox signaling.. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00271 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 12 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Biancamaria Ricci, "Sapienza" University of Rome, Department of Molecular Medicine, Rome, 00161, Italy, biancamaria.ricci@uniroma1.it Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Biancamaria Ricci Alessandra Soriani Maria Luisa Iannitto Cinzia Fionda Marco Cippitelli Stefania Morrone Maria Teresa Petrucci Maria Rosaria Ricciardi Angela Santoni Google Biancamaria Ricci Alessandra Soriani Maria Luisa Iannitto Cinzia Fionda Marco Cippitelli Stefania Morrone Maria Teresa Petrucci Maria Rosaria Ricciardi Angela Santoni Google Scholar Biancamaria Ricci Alessandra Soriani Maria Luisa Iannitto Cinzia Fionda Marco Cippitelli Stefania Morrone Maria Teresa Petrucci Maria Rosaria Ricciardi Angela Santoni PubMed Biancamaria Ricci Alessandra Soriani Maria Luisa Iannitto Cinzia Fionda Marco Cippitelli Stefania Morrone Maria Teresa Petrucci Maria Rosaria Ricciardi Angela Santoni Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

MIC and NKG2D genes polymorphism in Mexican population

Event Abstract Back to Event MIC and NKG2D genes polymorphism in Mexican population Miriam Nieves-Ramirez1, Eyerahi Bravo-Flores1, Pedro Alegre-Crespo2, Maria Del Carmen Tapia-Lugo2 and Martha Perez-Rodriguez1* 1 Mexican Institute of Social Security, Pediatric Hospital, National Medical Center S-XXI, Mexico 2 Mexican Institute of Social Security, General Hospital 1A "Venados", Mexico Nowadays, different knowledge polymorphism in genes involved in the immune response helps to identify the susceptibility or risk in the development of different human diseases. Therefore, the objective was to determine the distribution of MIC gene polymorphisms and Single Nucleotide Polymorphisms (SNP) rs1049174, rs2255336 and rs2617160 of KLRK1 (NKG2D) gene in the Mexican population by their interaction, MICA/MICB-NKG2D. The polymorphism of MICA and MICB genes and the SNPs of NKG2D were analyzed by Reference Strand Conformation Analysis (RSCA) and Sequence Specific Oligonucleotide Probes (SSOP)-Single Specific Primer (SSP) and allelic discrimination, respectively. We genotyped 336 samples of persons clinically healthy and MICA, MICB and NKG2D polymorphisms were identified by RSCA, SSOP-SSP and allelic discrimination, techniques, respectively. The most frequent allele were MICA *002:01 (33.28%), MICB *005:02 (63.09%), NKG2D rs1049174 *T (61.31%), NKG2D rs2255336 *C (61.31%) and NKG2D rs2617160 *G (93.30%). We also found that the most frequent combination of genotypes in the genes MICA/MICB was *002:01-*002:01/*005:02-*005:02 with 7.44%, while the combination of genotypes at SNPs NKG2D in positions rs1049174/rs2255336/rs2617160 was *A-*T/*C-*G/*G-*G with 45.53%. The data obtained provide other genetic markers involved in the immune innate response that can be considered for the study of susceptibility or protection in different diseases of public health and participation in transplants in Mexican individuals. Acknowledgements Work performed with support FOFOI 2005/1/I/016, CONACYT 14019. Keywords: Polymorphism, Genetic, Polymorphism, Single Nucleotide, Polymorphism, Single-Stranded Conformational, Sequence Specific Oligonucleotide Probes, Single Specific Primer Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Innate immunity Citation: Nieves-Ramirez M, Bravo-Flores E, Alegre-Crespo P, Tapia-Lugo M and Perez-Rodriguez M (2013). MIC and NKG2D genes polymorphism in Mexican population. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00764 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 17 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Prof. Martha Perez-Rodriguez, Mexican Institute of Social Security, Pediatric Hospital, National Medical Center S-XXI, Mexico City, Mexico, meperezrodriguez@yahoo.com.mx Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Miriam Nieves-Ramirez Eyerahi Bravo-Flores Pedro Alegre-Crespo Maria Del Carmen Tapia-Lugo Martha Perez-Rodriguez Google Miriam Nieves-Ramirez Eyerahi Bravo-Flores Pedro Alegre-Crespo Maria Del Carmen Tapia-Lugo Martha Perez-Rodriguez Google Scholar Miriam Nieves-Ramirez Eyerahi Bravo-Flores Pedro Alegre-Crespo Maria Del Carmen Tapia-Lugo Martha Perez-Rodriguez PubMed Miriam Nieves-Ramirez Eyerahi Bravo-Flores Pedro Alegre-Crespo Maria Del Carmen Tapia-Lugo Martha Perez-Rodriguez Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Role of mica repeat polymorphism in the manifestation of type 1 diabetes mellitus in Bengali Indian patients

Background. The major histocompatibility complex class I chain-related gene A (MICA) (OMIM-600169) is a polymorphic gene in the HLA region expressed mainly by epithelial cells. The MICA protein encoded by the allele influences the activation of NK cells, which modify ?-cells destruction and has been found to be involved in susceptibility of T1DM. Objective. The aim of this study was to find the association of MICA alleles with T1DM among eastern Indian population. Subjects and methods.Study was conducted in 134 eastern Indian patients and with 137 healthy controls for the possible role of MICA gene in T1DM pathogenesis. Results. The MICA*A5 microsatellite allele, showed significantly higher frequencies in patients than controls (p=0.003, OR= 1.746, CI= 1.206-2.528). MICA A*6 was found to be protective in our study (p=<0.01, OR=0.406, CI= 0.268-0.616).

Association of MICA gene with the development of chronic chagasic cardiopathy

Association of MICA gene with the development of chronic chagasic cardiopathy

Establishment of a large-scale bi-directional sequencing and genotyping platform for MICA gene exons 2 to 4

To establish a stable and large-scale bi-directional sequencing platform for genotyping MICA gene exons 2 to 4, and to analyze single nucleotide polymorphisms(SNP) of the region. Primers for particular alleles of MICA gene exons 2 to 5 were designed. Optimal conditions for PCR amplification and sequencing reaction were explored. A commercialized one-way sequencing kit for MICA allele was used as a parallel control. Four samples carrying a MICA *010 allele were subjected to cloning and haplotype sequencing. Results of MICA allele typing of 100 samples for a parallel control group were confirmed by the establish method. Twenty-two SNP in MICA gene exons 2 to 4 were detected in Chinese population. Two novel allelic sequences were accepted by GenBank and IMGT/HLA database and officially named as MICA*065 and MICA*066 by the WHO Nomenclature Committee. A novel SNP in MICA gene intron 3 was discovered, with allelic sequence submitted to GenBank and IMGT/HLA database. The bi-directional sequencing genotyping platform may be applied for large-scale study of MICA allelic polymorphisms, tissue typing, organ transplantation and disease research.

Effects of astragalus polysaccharide on MICA gene expression in leukemia cell lines and NK cells cytotoxicity

Effects of astragalus polysaccharide on MICA gene expression in leukemia cell lines and NK cells cytotoxicity

168-P

Aim The objective of this study was to evaluate the influence of HLA and MICA alleles in the development of leprosy and its clinical forms in a population with leprosy from the region of Santo Antonio do Prata – PA, Brazil. Methods Fifty-one families were genotyped for HLA and MICA genes by PCR-SSOP, LuminexO methodology (One Lambda) and Dynal AutoRELITM 48 Instrument (Invitrogen) Dynal-RELITM SSO HLA Typing. Statistical Analysis was based on the Transmission Disequilibrium Test (TDT) software FBAT 2.0.4. Results The alleles HLA-A∗03/11 (P=0.041), HLA-C∗04 (P=0.025), HLA-DRB1∗16 (P=0.048), DQB1∗05 (P=0.004) and MICA∗002 (P = 0.003) showed significant positive association with the occurrence of leprosy in this population, while the alleles HLA-C∗12 (P = 0.095), DRB1∗15/16 (P = 0.055), and MICA∗008 (P = 0.075) showed a tendency to positive association. Conclusions This study suggests that the alleles HLA-A∗03/∗11, HLA-C∗04, HLA-DRB1∗16, DQB1∗05 and MICA∗002 may be associated with susceptibility to leprosy in this population and HLA-C∗12, DRB1∗15/16 and MICA∗008 should be further investigated.

Full sequence analysis for a null allele of MICA gene (MICA*063N)

To analyze the full nucleotide sequence of a null allele of major histocompatibility complex class I chain-related gene (MICA). A sequence-based typing method was used to determine the nucleotide sequence of the MICA gene. Potential alleles were identified with a computer program. The identified allele has possessed a sequence similar to that of MICA*027 except for a C→T substitution at position 184 in codon 62 (CAG→TAG) of exon 2. As a stop codon, this may result in a truncated protein. A null allele of MICA gene has been identified. The sequence has been submitted to the Genbank nucleotide sequence database (submission No. HWS10011131), which was officially named as MICA*063N by the WHO Nomenclature Committee in October 2010.

Abstract 1648: MICA variation and soluble MICA are possible prognostic biomarkers for HBV-induced hepatocellular carcinoma

Abstract Hepatitis B virus (HBV) infection still remains to be one of the dominant risk factor for hepatocellular carcinoma (HCC). Both genetic as well as environmental factors influence the progression of chronic hepatitis B (CHB) to HCC. MHC class I polypeptide-related chain A and B (MICA and MICB) molecules are induced in response to viral infection as well as various stresses. We have recently revealed that SNP in MICA promoter was significantly associated with HCV-induced HCC risk as well as lower sMICA level in serum. To investigate the possible involvement of MICA in hepatocellular carcinogenesis caused by HBV-infection, we analyzed MICA gene polymorphisms and the levels of soluble MICA (sMICA) in HBV-induced HCC patients. The genetic association analysis revealed a nominal association at rs2596542 in which G allele was associated with susceptibility to HBV-induced HCC (P=0.029 with odds ratio of 1.19). We also found a significant elevation of sMICA in HBV-induced HCC cases. Moreover, genotypes at SNP rs2596542 located in the upstream of MICA promoter, was significantly associated with sMICA levels (P = 0.009). Interestingly. HCC patients with high sMICA (> 5 pg/ml) exhibited poor prognosis compared with patients with low sMICA (P = 0.008). Thus, our results highlight the importance of MICA genetic variations and sMICA as predictive biomarkers for HBV-induced HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1648. doi:1538-7445.AM2012-1648

NF-κB Regulates MICA Gene Transcription in Endothelial Cell through a Genetically Inhibitable Control Site

Endothelial cells form a barrier between blood and the underlying vessel wall, which characteristically demonstrates inflammatory damage in atherosclerotic disease. MICA is a highly polymorphic ligand for the activating immune receptor NKG2D and can be expressed on endothelial cells. We hypothesized that damaged vessel walls, such as those involved in atherosclerosis, might express MICA, which could contribute to the vascular immunopathology. Immune activation resulting from MICA expression could play a significant role in the development of vascular damage. We have demonstrated that TNFα up-regulates MICA on human endothelial cells. The up-regulation is mediated by NF-κB, and we have defined the regulatory control site responsible for this at -130 bp upstream of the MICA transcription start site. This site overlaps with a heat shock response element and integrates input from the two pathways. We have shown that in atherosclerotic lesions there is expression of MICA on endothelial cells. Using lentivirus-mediated gene delivery in primary human endothelial cells, we were able to inhibit the MICA response to TNFα with a truncated HSF1 that lacked a transactivation domain. This highlights the potential for transcription-based therapeutic approaches in atherosclerotic vascular disease to reduce immune-mediated endothelial and vessel wall damage.

Frequencies of MICA alleles in patients from southern Brazil with multibacillary and paucibacillary leprosy

Leprosy is a chronic infectious disease caused by Mycobacterium leprae, which mainly affects the skin and nervous system. The disease has several clinical forms. This study investigated the MICA and HLA-B genes in 223 samples from leprosy patients and 201 samples from healthy individuals matched for age, gender and ethnical background. Of the patients, 153 had multibacillary, 45 paucibacillary and 25 indeterminate leprosy. The aim of this case-control study was to assess whether the MICA alleles influence susceptibility for leprosy or affect the subtype of the disease in a population of southern Brazil. There were significant differences in frequencies of the MICA*027 allele (4.7% vs 1.8%, P-value = 0.01, OR = 0.37; 95% CI = 0.16-0.85) between leprosy patients and controls, and of the MICA*010 (4.5% vs 1.6%, P-value = 0.05, OR = 0.35, 95% CI = 0.13-0.97) and MICA*027 alleles (4.7% vs 1.3%, P-value = 0.01; OR = 0.27; 95% CI = 0.09-0.79) between multibacillary leprosy patients and the control group. There were no significant differences in the frequency of MICA alleles between paucibacillary leprosy patients and controls. Thus, the MICA*027 allele is associated with a protective effect for leprosy per se, while the MICA*010 and MICA*027 alleles are associated with protection against multibacillary leprosy, the most severe clinical subtype.

Distribution of MICA haplotypes in a Chinese Han population

The MICA gene encodes nonclassical major histocompatibility complex class I molecules, centromeric to HLA-B and telomeric to HLA-DRB1. The MICA genes are polymorphic. The immune response against MICA may correlate with a decrease in graft survival after transplantation. However, data on the frequency of MICA polymorphisms in different populations are limited. In this study, we determined MICA allelic frequencies in a Han population living in Guangdong Province in south China. A total of 15 MICA alleles were identified using sequence-based typing. The most frequent allele was MICA*010 (22.22%), followed by MICA*002:01(18.56%), MICA*008:01(16.32%), and MICA*019(14.93%). The MICA null gene (MICA*Del) exhibited a frequency of 1.743% in this population. MICA and HLA, MICA-HLA-B, and MICA-HLA-A/HLA-B/HLA-DRB1 haplotype frequencies were estimated. The most common 2-, 3- and 4-locus haplotypes were HLA-B*40:01-MICA*008:01 (13.70%), HLA-A*11:01-B*40:01-MICA*008:01(8.25%), and HLA-A*33:03-B*58:01-DRB1*03:01-MICA*002:01(5.22%). A new MICA allele, MICA*061, was identified and appears to be evolutionarily related to MICA*012:01. This study provides high-resolution information on the distribution of haplotypes with MICA, HLA-A, HLA-B, and HLA-DRB1 in China. This information should help determine the mechanisms underlying diseases and allotransplant rejection associated with MICA polymorphisms in the southern Chinese Han population.

Role of theMICApolymorphism in systemic lupus erythematosus

To study the genetic contribution of major histocompatibility complex class I polypeptide-related sequence A (MICA), important in natural killer (NK) cell function, in patients with systemic lupus erythematosus (SLE). Japanese patients with SLE (n=716), those with rheumatoid arthritis (RA) (n=327), and healthy control subjects (n=351) were genotyped for the Val129 Met polymorphism (rs1051792) and transmembrane (TM) alanine-encoding GCT repeats, termed A4, A5, A5.1, A6, and A9, in the MICA gene. Recombinant human MICA-GST fusion proteins were tested on the NK cell line NK92MI for the expression of NK group 2, member D (NKG2-D), NK cell-mediated cytotoxicity, and interferon-γ (IFNγ) production. The MICA 129Met allele, TMA9 allele, and 129Met/Met genotype were positively associated with SLE (corrected P [Pcorr]=0.01 and odds ratio [OR] 1.3, Pcorr=0.003 and OR 1.6, and Pcorr=0.02 and OR 1.8, respectively), while the MICA 129Val allele was negatively associated with SLE (Pcorr=0.01, OR 0.8). The MICA 129Met;A9 haplotype was also associated with SLE (Pcorr=0.0006, OR 1.8), and there was an additive genetic effect between the MICA 129Met;A9 haplotype and HLA-DRB1*15:01. When NK92MI cells were incubated in vitro with recombinant human disease-associated 129Met;A9 (the combination of polymorphisms at 129Met and TMA9), expression of NKG2-D on NK92MI cells and cytotoxicity of the NK cells were inhibited, but production of IFNγ from NK92MI cells was enhanced. The MICA polymorphism is genetically associated with SLE, and MICA appears to contribute to the pathogenesis of SLE by modulating NK cell function.

Positive association of major histocompatibility complex class I chain‐related gene A polymorphism with leukemia susceptibility in the people of Han nationality of Southern China

To assess the potential contribution of major histocompatibility complex class I chain-related gene A (MICA) polymorphisms toward the pathogenesis of leukemia, 107 leukemia patients and 162 ethnically matched controls from Hunan province, Southern China, were genotyped for the MICA polymorphism using polymerase chain reaction-sequence-specific priming (PCR-SSP) and sequence-based typing (PCR-SBT). The relevance between these genotypes and risk of leukemia was assessed by means of odds ratio (OR) with 95% confidence intervals (95% CIs). Allele frequencies of MICA-sequence and MICA-STR were different in leukemia patients in comparison with normal controls (both P < 0.05). MICA A5 was directly associated with leukemia (OR = 2.3257, Pc < 0.0005), whereas MICA A5.1 and MICA*008 were inversely associated with leukemia (OR = 0.5874, Pc = 0.0235 and OR = 0.5874, Pc = 0.0329, respectively). In addition, we found that homozygotes for MICA A5 (OR = 14.0659, 95% CI: 3.1627-62.5574, Pc < 0.0001) and MICA*010 (OR = 10.1053, 95% CI: 2.2139-46.1260, Pc < 0.0004) were at an increased risk for leukemia, whereas heterozygotes for MICA*008 and MICA A5.1 were linked to a decreased risk for leukemia (OR = 0.4609, 95% CI: 0.2799-0.7590, Pc = 0.0027). MICA allelic variation is associated with leukemia in Hunan Han population; the data also suggest that MICA gene polymorphism affects susceptibility to different clinical subtypes of leukemia.

Upregulation of NKG2D ligands and enhanced natural killer cell cytotoxicity by hydralazine and valproate

Natural killer cells play a role in the immune antitumor response by recognizing and eliminating tumor cells through the engagement of NKG2D receptors with their ligands on target cells. This work aimed to investigate whether epigenetic drugs are able to increase MICA and MICB expression as well as NK cell cytotoxicity. Prostate, colon, breast and cervical cancer cell lines were analyzed for the expression of MICA and MICB at the mRNA and protein levels by RT-PCR, Western blot, flow cytometry and ELISA. The activating mark H3K4m2 at the MICA and MICB promoters was investigated by ChIP assays. Cytotoxicity of NK cells against the target epithelial cancer cells was investigated with the CD107 cytotoxicity assay. The results show that hydralazine and valproic acid not only increase the expression of MICA and MICB ligands of target cells, but also reduce their shedding to the supernatant. This upregulation occurs at the transcriptional level as revealed by increase of the H3K4 activating mark at the promoter of MICA and MICB genes. These effects are paralleled by increased cytotoxicity of NK cells, which was attenuated at different degrees by using blocking antibodies against the NKG2D receptor and ligands. In conclusion, our results demonstrate the ability of hydralazine and valproate to increase the NK activity against epithelial cancer cell lines and suggest that these drugs could reduce the levels of soluble MICA and MICB helping in avoiding tumor-induced suppression of NK cytotoxicity against the tumor.

A gender-specific association of CNV at 6p21.3 with NPC susceptibility

Copy number variations (CNVs), a major source of human genetic polymorphism, have been suggested to have an important role in genetic susceptibility to common diseases such as cancer, immune diseases and neurological disorders. Nasopharyngeal carcinoma (NPC) is a multifactorial tumor closely associated with genetic background and with a male preponderance over female (3:1). Previous genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) that are associated with NPC susceptibility. Here, we sought to explore the possible association of CNVs with NPC predisposition. Utilizing genome-wide SNP-based arrays and five CNV-prediction algorithms, we identified eight regions with CNV that were significantly overrepresented in NPC patients compared with healthy controls. These CNVs included six deletions (on chromosomes 3, 6, 7, 8 and 19), and two duplications (on chromosomes 7 and 12). Among them, the CNV located at chromosome 6p21.3, with single-copy deletion of the MICA and HCP5 genes, showed the highest association with NPC. Interestingly, it was more specifically associated with an increased NPC risk among males. This gender-specific association was replicated in an independent case-control sample using a self-established deletion-specific polymerase chain reaction strategy. To the best of our knowledge, this is the first study to explore the role of constitutional CNVs in NPC, using a genome-wide platform. Moreover, we identified eight novel candidate regions with CNV that merit future investigation, and our results suggest that similar to neuroblastoma and prostate cancer, genetic structural variations might contribute to NPC predisposition.

Characterization of the micA gene encoding a small regulatory σE-dependent RNA in Salmonella enterica serovar Typhimurium

The role of MicA (repressing small regulatory non-coding RNAs of two Salmonella porins) was determined in virulence of Salmonella enterica serovar Typhimurium. Transcriptional analysis revealed that the expression of the micA gene is driven by a single σ(E)-dependent promoter, micAp. Its activity increased towards stationary phase; in exponential phase, the activity was induced by several stresses by a DegS-dependent mechanism. Although phenotypic analysis revealed no significant differences between wild-type and the micA mutant strains, in vivo studies showed that this mutant is more virulent in the mouse model.

93-P: Exogenous Antigen Can Induce Cell Proliferation and Expression of MICA Gene in Endothelial Cell

93-P: Exogenous Antigen Can Induce Cell Proliferation and Expression of MICA Gene in Endothelial Cell