MICA Gene Research Articles

New biomarkers for antenatal infection: MICA and MICB gene expression in preterm babies

The human major histocompatibility complex class I chain-related gene A and B (MICA and MICB) is one of the genes in chromosome 6. As MIC expression is inducible by heat, viral infection, inflammation and DNA damage, the molecules have been thought to be stress markers for the cells. We aimed to find the level of mRNA concentrations of MICA and MICB in neonates without any evidence of early onset infection.

OR31 New NGS assays for MHC class I-associated genes MICA and MICB

Aim Next-generation sequencing (NGS) is a powerful method for determining the sequence, and thereby the genotype, of highly polymorphic genes. NGS-based assays have been developed by GenDx for different HLA loci, which can be applied in HLA matching for transplantation purposes. There is evidence that matching for additional genes can further improve the outcome of transplantation. To this end, we are developing new NGS-based typing strategies for the polymorphic MICA and MICB genes. Methods MICA and MICB genes were amplified by long range PCR. Amplicons were processed in the NGSgo® library preparation procedure and paired-end sequenced on the Illumina MiSeq (GenDx) or using the Ion Torrent S5 machine. All data is analyzed with the software package NGSengine® (GenDx). Results Amplicons generated for MICA and MICB genes can be sequenced to allelic level by means of NGS. Data analysis reveals unexpected phenomena in the sequence of these genes, making the initial typing challenging using the current sequence information from the IMGT database. To this end, tailored MICA and MICB genomic databases have been built that can be utilized for NGS data analysis with the NGSengine software, allowing for accurate genotyping of these genes to the allelic level. Conclusions Preliminary data shows that MICA and MICB can be amplified, sequenced and analyzed with the new NGS-based typing strategies using NGSgo® and NGSengine®. These NGS-based typing results may assist clinically as it allows for even better matching in transplantation, on top of the matching for the HLA loci that are currently routinely typed.

Association of MICA-129 polymorphism and circulating soluble MICA level with rheumatoid arthritis in a south Indian Tamil population.

Rheumatoid arthritis (RA) is a clinically heterogeneous chronic inflammatory disorder characterized by synovitis leading to joint destruction. Both genetic and environmental factors are involved in the pathogenesis of RA. Significant dysregulation of NKG2D, an activating receptor of natural killer and certain autoreactive T cells as well as its ligand major histocompatibility complex class I chain-related gene A (MICA) has been implicated in perpetuating the pathology of RA. Since the genetic polymorphism in MICA gene (MICA-129 met/val polymorphism at codon 129) is known to affect its binding affinity to NKG2D, we explored its influence on RA susceptibility and disease severity. The MICA-129 met/val polymorphism was examined in 270 patients with RA and 232 healthy controls by TaqMan 5'-nuclease assay. Serum soluble MICA (sMICA) was measured in a subset of 89 patients and 80 controls by enzyme-linked immunosorbent assay. We observed that the frequency of MICA-129 val allele (73% vs. 65%, Pc = 0.006, odds ratio = 1.48, 95% CI = 1.12-1.95) was higher in patients than in controls. sMICA levels were significantly higher in patients with RA than in controls (P < 0.0001). sMICA levels were higher in patients with val/val genotype than in those with met/val or met/met genotype (P = 0.03). The MICA-129 val/val genotype was associated with high titers of sMICA in patients with deforming RA phenotype (P = 0.02), suggesting a role in determination of severity of RA. MICA-129 val/val genotype, associated with higher levels of circulating sMICA, may influence disease susceptibility and associate with increased severity of RA in south Indian Tamils.

Transcriptional activation of the MICA gene with an engineered CRISPR-Cas9 system

Major histocompatibility complex class I polypeptide-related sequence A (MICA) is a prototypical NKG2D ligand. Because immune cells, such as natural killer (NK) cells, recognize virally infected or transformed cells and eliminate them through the interaction between NKG2D receptors on NK cells and NKG2D ligands on pathogenic cells, MICA expression levels are associated with NK cell-mediated immunity. Here, we report that an engineered clustered regularly interspaced short palindromic repeats-Cas9-related complex targeting MICA gene promoter sequences activates transcription of the MICA gene from its endogenous locus. Inhibiting microRNA function, which targets the 3′ untranslated region of the MICA gene, enhances this activation. These results demonstrate that the combination of Cas9-based transcriptional activators and simultaneous modulation of microRNA function may be a powerful tool for enhancing MICA protein expression and efficient anti-pathogenic cell immunity.

Study of Association Between the Polymorphism of MICA Gene (met 129 val) and Ankylosing Spondylitis in a Sample of the Population of Western Algeria

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatism characterized by a predominantly axial (spinal) localization, followed by joint damage and enthesis. The AS may be associated with other conditions such as reactive arthritis, psoriatic arthritis, chronic inflammation of the intestine and pulmonary manifestation. In this case, we speak of Spondylarthroparies (SPA). The etiology of AS is not well known, however, genetic factors as well as environmental factors can play a very important role in the onset of the disease. Although several genes appear to be associated with SA, the concept of genetic ground relies heavily on the association with HLA-B27 specificity. Recently, the MICA gene has aroused the interest of several studies of associations MICA and autoimmune diseases (MAI), in particular, the association MICA and SA. In our work, we are interested in the polymorphism existing at exon 3 and which encodes the α2 domain of the MICA protein. This polymorphism has the position 129 either the methionine (met) allele or the valine (val) allele. MICA proteins with methionine residue at position 129 react strongly with its NKG2D receptors found on the surface of NK and LT, thereby increasing the cytotoxicity threshold. In contrast, MICA proteins that have a valine residue at the same position have a low affinity with NKG2D. This weakens the threshold of cytotoxicity. The aim of our work is to look for the associations between the polymorphism MICA met129val and the SA in a sample of 90 cases suffering from the SA and 78 controls, within the population of western Algeria. We then tested the effect of this polymorphism on HLA-B27 status. Finally, we looked for a possible association between the MICA-129 genotyping and the early onset of SA. The results show that the MICA-129met allele is strongly associated with SA in patients compared to controls since it is found at an allelic frequency of 0.54 vs 0.30 (p=11.10-6). On the other hand, the MICA-129val allele is strongly found in the controls than in the cases, with a frequency of 0.70 vs 0.46 (p=11.10-4). However, the polymorphism MICA met129val showed no synergistic or independent effect on the distribution of HLA-B27 specificity in either cases or patients. It is interesting in this case to study other interactions between this polymorphism and other genes or alleles already associated with SA. In our work, we could not determine the effect of MICA-129 genotypes on the early onset of the disease, as reported by another similar study carried out in an Algerian population.

MICA Gene Deletion in 3411 DNA Samples from Five Distinct Populations in Mainland China and Lack of Association with Nasopharyngeal Carcinoma (NPC) in a Southern Chinese Han population.

Deletion of major histocompatibility complex class I chain-related genes A (MICA*Del) was investigated in 3,411 DNA samples from two southern Chinese Han populations (Hunan Han, HNH; Guangdong Han, GDH), two northern Chinese populations (Inner Mongolia Han, IMH; Inner Mongolia Mongol, IMM) and one southeastern Chinese Han population (Fujian Han, FJH) using an in-house polymerase chain reaction-sequence specific priming (PCR-SSP) assay, which enables direct discrimination between heterozygote and homozygote for MICA*Del. MICA*Del showed a frequency ranging from 0.8% in FJH to 5.7% in IMM (Pcorrected < 0.05), indicating northward increase in frequency of MICA*Del in Chinese populations. In contrast to the association reported recently in a Taiwan Chinese population and aMalaysian Chinese cohort, MICA*Del distribution did not differ between 1,120 patients with nasopharyngeal carcinoma (NPC) and 1,483 normal controls in the HNH population (1.03% in NPC cases vs 1.18% in the controls, OR (95% CI) = 0.87 (0.51-1.47), p = 0.69). Further gender-stratified analysis also failed to disclose any male-specific association reported in a Taiwan Chinese population. Multi-locus typing of the 94 samples carrying MICA*Del revealed two new haplotypes, HLA-A*11:01-B*13:01-MICA*Del-MICB*009N-DRB1*04:06 and HLA-B*35:01-MICA*Del-MICB*009N-DRB1*15:01, in addition to HLA-B*48-MICA*Del. Unexpectedly, two samples with MICA*Del in the HNH population were each consistently found to have two distinct MICA alleles, indicating the existence of two MICA gene copies on certain HLA haplotypes. Based on the results from a sizeable case-control study, our data suggest that there is no association between MICA*Del and NPC in the southern Chinese Han population.

Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

AbstractGraft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain–related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B. Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA. MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.

Analysis on polymorphism of major histocompatibility complex class I chain related gene A genes in Han nationality population from southern China

Objective To explore genetic polymorphism and distribution characteristics of major histocompatibility complex class I chain related gene (MIC) A gene in Han nationality population from southern China. Methods From July 1st, 2014 to December 31st, a total of 250 voluntary blood donors in Shenzhen Blood Center were included in this study. The donors' MICA gene exons 2-4 were sequenced by polymerase chain reaction-direct sequencing (PCR-SBT), and allele frequencies and genetic polymorphism results of population in different areas were compared with statistical methods. The study protocol was approved by the Ethical Review Board of Investigation in Human Being of Shenzhen Blood Center. Informed consent was obtained from all donors before blood collection. Results 21 MICA alleles and 45 MICA genotypes were detected in these donors. MICA*00801 was dominant in MICA allele, accounted for 27.8%, and the others were MICA*010 (19.8%), MICA*00201(16.2%), and MICA*019 (11%), respectively. MICA*00801-MICA*010 (10%) was dominant in MICA genotype. Compare with results of MICA gene distribution in South Korea, Thailand, Austria and Morocco, MICA*045 allele was only detected in Han nationality population from southern China. Conclusions There are genetic polymorphism and distribution characteristics of MICA alleles in Han nationality population from southern China compared with people in different areas of the world. The MICA distribution data in this study would be helpful for research of anthropology and MICA related disease. Key words: Polymorphism, genetic; Major histocompatibility complex; Genes, MHC class Ⅰ; China, southern, Han nationality

The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma.

Immunomodulatory drugs (IMiDs) have potent anti-tumor activities in multiple myeloma (MM) and are able to enhance the cytotoxic function of natural killer (NK) cells, important effectors of the immune response against MM. Here, we show that these drugs can enhance the expression of the NKG2D and DNAM-1 activating receptor ligands MICA and PVR/CD155 in human MM cell lines and primary malignant plasma cells. Depletion of cereblon (CRBN) by shRNA interference strongly impaired upregulation of these ligands and, more interestingly, IMiDs/CRBN-mediated downregulation of the transcription factors Ikaros (IKZF1), Aiolos (IKZF3) and IRF4 was critical for these regulatory mechanisms. Indeed, shRNA knockdown of IKZF1 or IKZF3 expression was both necessary and sufficient for the upregulation of MICA and PVR/CD155 expression, suggesting that these transcription factors can repress these genes; accordingly, the direct interaction and the negative role of IKZF1 and IKZF3 proteins on MICA and PVR/CD155 promoters were demonstrated. Finally, MICA expression was enhanced in IRF4-silenced cells, indicating a specific suppressive role of this transcription factor on MICA gene expression in MM cells.Taken together, these findings describe novel molecular pathways involved in the regulation of MICA and PVR/CD155 gene expression and identify the transcription factors IKZF-1/IKZF-3 and IRF4 as repressors of these genes in MM cells.

Two novel 5' promoter sequences of the MHC class I-related chain A gene.

In this study, we have characterized two novel polymorphism of the 5' promoter sequence of MICA gene, MICA-P13 and MICA-P14, by sequence-based typing and cloning.

MICA∗078: A novel allele identified in a Moroccan individual affected by celiac disease

A novel MICA allele, MICA∗078, has been identified during HLA/MICA high resolution typing of Moroccan patients with celiac disease. MICA∗078 shows an uncommon variation at a highly conserved nucleotide position (nt 493, G→A), resulting in one amino acid change at codon 142 (V→I) of MICA gene (compared to MICA∗002:01), located in the α2-domain, in which V142 is the common residue.

MHC class I chain-related gene a diversity in patients with cutaneous malignant melanoma from southeastern Spain.

A limited number of studies have been performed so far on the polymorphism in the transmembrane region (exon 5) of the major histocompatibility complex class I chain-related gene A (MICA) in patients with melanoma. However, the influence of MICA polymorphism in extracellular domains (exons 2, 3, and 4) has not been investigated on melanoma disease. This study aims to characterize the influence of extracellular MICA polymorphism, and its previously described linkage disequilibrium with HLA-B locus, on patients with cutaneous melanoma from southeastern Spain. For this purpose, MICA and HLA-B genotyping was performed in 233 patients and 200 ethnically matched controls by luminex technology. Patients were classified according to the presence of methionine or valine at codon 129 of MICA gene. We found a high frequency of MICA*009 in melanoma patients compared with controls (P = 0.002, Pc = 0.03). Our results also showed an association between MICA*009 and HLA-B*51 alleles in both patients and controls. This association was stronger in patients than controls (P = 0.015). However, a multivariate logistic regression model showed that neither MICA*009 nor the combination MICA*009/HLA-B*51 was associated with melanoma susceptibility. No relationship was observed between MICA-129 dimorphism and melanoma nor when MICA polymorphism was evaluated according to clinical findings at diagnosis.

MICA polymorphism: biology and importance in cancer.

The major histocompatibility complex class I polypeptide-related sequence A gene (MICA) encodes a membrane-bound protein acting as a ligand to stimulate an activating receptor, NKG2D, expressed on the surface of essentially all human natural killer (NK), γδ T and CD8(+) αβ T cells. MICA protein is absent from most cells but can be induced by infections and oncogenic transformation and is frequently expressed in epithelial tumors. Upon binding to MICA, NKG2D activates cytolytic responses of NK and γδ T cells against infected and tumor cells expressing MICA. Therefore, membrane-bound MICA acts as a signal during the early immune response against infection or spontaneously arising tumors. On the other hand, human tumor cells spontaneously release a soluble form of MICA, causing the downregulation of NKG2D and in turn severe impairment of the antitumor immune response of NK and CD8(+) T cells. This is considered to promote tumor immune evasion and also to compromise host resistance to infections. MICA is the most polymorphic non-classical class I gene. A possible association of MICA polymorphism with genetic predisposition to different cancer types has been investigated in candidate gene-based studies. Two genome-wide association studies have identified loci in MICA that influence susceptibility to cervical neoplasia and hepatitis C virus-induced hepatocellular carcinoma, respectively. Given the current level of interest in the field of MICA gene, we discuss the genetics and biology of the MICA gene and the role of its polymorphism in cancer. Gaps in our understanding and future research needs are also discussed.

Reactive oxygen species- and DNA damage response-dependent NK cell activating ligand upregulation occurs at transcriptional levels and requires the transcriptional factor E2F1.

Increasing evidence indicates that cancer cell stress induced by chemotherapeutic agents promote antitumor immune responses and contribute to their full clinical efficacy. In this article, we identify the signaling events underlying chemotherapy-induced NKG2D and DNAM-1 ligand expression on multiple myeloma (MM) cells. Our findings indicate that sublethal doses of doxorubicin and melphalan initiate a DNA damage response (DDR) controlling ligand upregulation on MM cell lines and patient-derived malignant plasma cells in Chk1/2-dependent and p53-independent manner. Drug-induced MICA and PVR gene expression are transcriptionally regulated and involve DDR-dependent E2F1 transcription factor activity. We also describe the involvement of changes in the redox state in the control of DDR-dependent upregulation of ligand surface expression and gene transcriptional activity by using the antioxidant agent N-acetyl-L-cysteine. Finally, in accordance with much evidence indicating that DDR and oxidative stress are major determinants of cellular senescence, we found that redox-dependent DDR activation upon chemotherapeutic treatment is critical for MM cell entry in premature senescence and is required for the preferential ligand upregulation on senescent cells, which are preferentially killed by NK cells and trigger potent IFN-γ production. We propose immunogenic senescence as a mechanism that promotes the clearance of drug-treated tumor cells by innate effector lymphocytes, including NK cells.

Association of ABCB1,CYP3A4,EPHX1,FAS,SCN1A,MICA, andBAG6 polymorphisms with the risk of carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in Chinese Han patients with epilepsy.

This study explored the association between the risk of carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and CBZ dose, dose-adjusted concentration, and ABCB1, CYP3A4, EPHX1, FAS, SCN1A, MICA, and BAG6 polymorphisms in patients of Han ethnicity with epilepsy who were living in northeastern China. We determined the genotypes of patients with CBZ-SJS/TEN and CBZ-tolerant patients, who were used as controls, for ABCB1, CYP3A4, EPHX1, FAS, SCN1A, MICA, and BAG6 polymorphisms by polymerase chain reaction (PCR) amplification and direct sequencing. We measured the steady-state serum CBZ concentrations using fluorescence polarization immunoassay for the control patients. We observed statistically significant differences in EPHX1 c.337T>C polymorphisms between patients with CBZ-SJS/TEN and CBZ-tolerant controls in terms of allelic and genotypic frequencies (p = 0.011 and p = 0.007, respectively). The C allele and the C-G diplotype of EPHX1 may play important roles in increasing the risk of CBZ-SJS/TEN development (odds ratio [OR] 0.478, 95% confidence interval [CI] = 0.267-0.855, p = 0.011; OR = 0.213, 95% CI = 0.049-0.930, p = 0.025, respectively). We did not observe any significant associations between ABCB1, CYP3A4, EPHX1, FAS, SCN1A, MICA or BAG6 genes and CBZ dose or dose-adjusted concentration in CBZ-tolerant patients. We found a significant association between EPHX1 c.337T>C polymorphisms and the development of CBZ-SJS/TEN in patients of Han ethnicity living in northeastern China. EPHX1 c.337T>C polymorphisms may contribute to the risk of severe CBZ-SJS/TEN by increasing the concentration of a CBZ metabolite, CBZ-10,11-epoxide, in patients with epilepsy.

Study of association between the polymorphism of MICA gene (met 129 val) and Ankylosing Spondylitis in a sample of the population of western Algeria

Event Abstract Back to Event Study of association between the polymorphism of MICA gene (met 129 val) and Ankylosing Spondylitis in a sample of the population of western Algeria Bouras Noria1*, Benzaoui Ahmed2*, Messal Ibtissem1* and Boudjema Abdallah1* 1 University of Science and Technology of Oran USTO, Algeria 2 Oran University Hospital, Rheumatology Service, Algeria Ankylosing Spondylitis (AS) is a chronic inflammatory arthritis characterized by a predominant axial location (spine), followed by joint damage and entheses. Although several genes appear to be associated with AS, the concept of genetic predisposition is largely based on the association with HLA-B27 specificity. Recently, the MICA gene has attracted the interest of several studies of autoimmune diseases and MICA associations, in particular MICA association and AS. In our work, we are interested in existing polymorphism in exon 3 and which encodes the α2 domain of MICA protein. This polymorphism has at the position 129 either methionine allele (met) or allele valine (val). The MICA protein with methionine residue at position 129, reacts strongly with NKG2D receptors found on the surface of NK and LT, thus increasing the threshold of cytotoxicity. However, MICA protein has a valine residue at the same position, and has a low affinity with NKG2D. This fact weakens the threshold of cytotoxicity. The aim of our work is to look for associations between the polymorphism and MICA met129val AS in a sample of 90 cases suffering from AS, and 78 witnesses in the Western Algerian population. Then, we have tested the effect of this polymorphism with respect to HLA-B27 status. We have finally looked for a possible association between the MICA-129 genotype and early onset of SA. The results showed that the MICA allele-129met is strongly associated with the AS of patients compared with controls, since it is found at an allelic frequency of 0, 54 vs 0, 30 (p=11. 10 -6). On the other hand, the allele-MICA 129val is strongly found in controls as compared to the cases with a frequency 0, 70 vs 0, 46 (p=11. 10-4). However, MICA polymorphism 129val met has showed no effect, synergistic or independent on the distribution of the HLA-B27 specificity on whether on cases or on patients. It is interesting in this case to consider other associations between this polymorphism and other genes or alleles previously associated with AS. In our work, we have not been able to determine the effect of MICA-129 genotype on the early onset of the disease, contrary to what was reported by another similar study on a population of Algiers. Keywords: ankylosing spondylitis, HLA-B27, MICA, NKG2D, Cytotoxicity Conference: The First International Congress of Immunology and Molecular Immunopathology (CIMIP2014), Tlemcen, Algeria, 17 Oct - 20 Oct, 2014. Presentation Type: Poster Presentation Topic: Autoimmunity Citation: Noria B, Ahmed B, Ibtissem M and Abdallah B (2014). Study of association between the polymorphism of MICA gene (met 129 val) and Ankylosing Spondylitis in a sample of the population of western Algeria. Front. Immunol. Conference Abstract: The First International Congress of Immunology and Molecular Immunopathology (CIMIP2014). doi: 10.3389/conf.fimmu.2014.04.00001 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: 07 Sep 2014; Published Online: 01 Dec 2014. * Correspondence: Mrs. Bouras Noria, University of Science and Technology of Oran USTO, Oran, Algeria, noriabouras@yahoo.fr Prof. Benzaoui Ahmed, Oran University Hospital, Rheumatology Service, Oran, Algeria, benzaouiahmed@yahoo.fr Mrs. Messal Ibtissem, University of Science and Technology of Oran USTO, Oran, Algeria, messalibtissem@yahoo.fr Prof. Boudjema Abdallah, University of Science and Technology of Oran USTO, Oran, Algeria, abdallah.boudjema@gmail.com 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 Bouras Noria Benzaoui Ahmed Messal Ibtissem Boudjema Abdallah Google Bouras Noria Benzaoui Ahmed Messal Ibtissem Boudjema Abdallah Google Scholar Bouras Noria Benzaoui Ahmed Messal Ibtissem Boudjema Abdallah PubMed Bouras Noria Benzaoui Ahmed Messal Ibtissem Boudjema Abdallah 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.

93-P: MIC AND NKG2D GENES POLYMORPHISM IN MEXICAN POPULATION

Aim 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. Methods 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. Results 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%. Conclusions 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. FOFOI 2005/1/I/016, CONACYT 14019.

MICA Polymorphism, Association with Diseases and the Role of Anti-MICA Antibodies in Organ and Stem Cell Transplantation

Major histocompatibility complex class 1 chain-related genes (MIC) are part of the non-classical MHC genes located on the short arm of chromosome 6. MICA comprises of approximately 11 kb DNA and encodes polypeptide of 383 amino acids. The expression of MICA is limited to the surface of the epithelial cells, fibroblasts, keratinocytes and monocytes, but not on the surface of CD4+, CD8+ and CD19+ lymphocytes. It manifests its role by binding with the NK cell receptor NKG2D. There are 84 different alleles for MICA due to discovered polymorphisms in the exons 2 to 5. The aim of this review is to present the data known so far about the association of MICA with different diseases and the role of anti-MICA antibodies in organ and stem cell transplantation. The frequency of different MICA alleles and their association with different HLA- B alleles, as well as the association of MICA with different inflammatory diseases, infection diseases and tumors was determined. Post- and pre-transplant anti-MICA antibodies are associated with antibody-mediated rejection in kidney and heart transplantation. Patients with hematopoietic stem cell transplantation, which have MICA mismatch, have higher frequency of graft versus host disease episodes. In spite of lack of conclusive data about the role of anti- MICA antibodies in organ and stem cell transplantation, there is still clinical relevance for investigation of the polymorphisms of the MICA gene and anti-MICA antibodies.

Identification of multiple independent susceptibility loci in the HLA region in Behçet's disease

Behçet's disease is an inflammatory disease characterized by recurrent oral and genital ulcers and significant organ involvement. Localizing the genetic association between HLA-B*51 and Behçet's disease and exploring additional susceptibility loci in the human leukocyte antigen (HLA) region are complicated by the strong linkage disequilibrium in this region. We genotyped 8,572 variants in the extended HLA locus and carried out imputation and meta-analysis of 24,834 variants in 2 independent Behçet's disease cohorts from 2 ancestry groups. Genotyped SNPs were used to infer classical HLA alleles in the HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1 and HLA-DRB1 loci. Our data suggest that the robust HLA-B*51 association in Behçet's disease is explained by a variant located between the HLA-B and MICA genes (rs116799036: odds ratio (OR) = 3.88, P = 9.42 × 10(-50)). Three additional independent genetic associations within PSORS1C1 (rs12525170: OR = 3.01, P = 3.01 × 10(-26)), upstream of HLA-F-AS1 (rs114854070: OR = 1.95, P = 7.84 × 10(-14)) and with HLA-Cw*1602 (OR = 5.38, P = 6.07 × 10(-18)) were also identified and replicated.

MICA Molecules in Disease and Transplantation, a Double-Edged Sword?

Major histocompatibility complex class I chain-related member A (MICA) encodes a stress-induced cellsurface glycoprotein that is expressed in keratinocytes, fibroblasts and gastrointestinal epithelium, among others. MICA is not associated with β2-microglobulin and does not appear to present peptides. MICA displays a high degree of allele polymorphism within the non-classical HLA gene loci. The functional significance of these polymorphisms is unknown, although certain changes in protein amino acid sequence cause an abnormal expression or affinity with NKG2D, its ligand on the surface of NK, γδ-T and CD8+ lymphocytes, affecting NK-cell activation and T-cell response modulation. Indeed, many tumoral cells express MICA on their surface, and circulating soluble MICA also triggers NKG2D downregulation and impairs lymphocyte cytotoxicity in tumoral escape. This demonstrates the therapeutic potential of anti-MICA antibodies to overcome immune suppression and trigger tumor destruction. MICA also affects organ transplants outcome, as MICA antigens elicit a very powerful antibody response in recipients of organ allografts. NKG2D ligand induction might also participate in the amplification loop that leads to tissue damage during acute graft vs. host disease. MICA is also an important candidate gene for a number of clinically significant diseases, including diabetes, rheumatoid arthritis, and other autoimmune diseases. This updated version of our previous review highlights the advantages and limitations of MICA gene studies in several pathologies and transplantation, and critically discusses the most recent and updated findings in this rapidly evolving field. Keywords: MICA, transplant, tumours, polymorphism, natural killer (NK), NKG2D, NKG2DL, HLA, MHC, allele frequencies, homeostasis