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Ayo CM, Bestetti RB, de Campos Junior E, Ronchi LS, Borim AA, Brandão CC, de Matttos LC. MICA and KIR: Immunogenetic Factors Influencing Left Ventricular Systolic Dysfunction and Digestive Clinical Form of Chronic Chagas Disease. Front Immunol 2021; 12:714766. [PMID: 34489964 PMCID: PMC8418128 DOI: 10.3389/fimmu.2021.714766] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 07/26/2021] [Indexed: 11/13/2022] Open
Abstract
Tissue damage observed in the clinical forms of chronic symptomatic Chagas disease seems to have a close relationship with the intensity of the inflammatory process. The objective of this study was to investigate whether the MICA (MHC class I-related chain A) and KIR (killer cell immunoglobulin-like receptors) polymorphisms are associated with the cardiac and digestive clinical forms of chronic Chagas disease. Possible influence of these genes polymorphisms on the left ventricular systolic dysfunction (LVSD) in patients with chronic Chagas heart disease was also evaluated. This study enrolled 185 patients with positive serology for Trypanosoma cruzi classified according to the clinical form of the disease: cardiac (n=107) and digestive (n=78). Subsequently, patients with the cardiac form of the disease were sub-classified as with LVSD (n=52) and without LVSD (n=55). A control group was formed of 110 healthy individuals. Genotyping was performed by polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP). Statistical analyzes were carried out using the Chi-square test and odds ratio with 95% confidence interval was also calculated to evaluate the risk association. MICA-129 allele with high affinity for the NKG2D receptor was associated to the LVSD in patients with CCHD. The haplotype MICA*008~HLA-C*06 and the KIR2DS2-/KIR2DL2-/KIR2DL3+/C1+ combination were associated to the digestive clinical form of the disease. Our data showed that the MICA and KIR polymorphisms may exert a role in the LVSD of cardiac patients, and in digestive form of Chagas disease.
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Affiliation(s)
- Christiane Maria Ayo
- Immunogenetics Laboratory, Molecular Biology Department, Medicine School in São José do Rio Preto, São José do Rio Preto, Brazil
| | - Reinaldo Bulgarelli Bestetti
- Department of Cardiology and Cardiovascular Surgery, Medicine School in São José do Rio Preto, São José do Rio Preto, Brazil
| | | | - Luiz Sérgio Ronchi
- Surgery Department, Medicine School in São José do Rio Preto, São José do Rio Preto, Brazil
| | - Aldenis Albaneze Borim
- Surgery Department, Medicine School in São José do Rio Preto, São José do Rio Preto, Brazil
| | - Cinara Cássia Brandão
- Immunogenetics Laboratory, Molecular Biology Department, Medicine School in São José do Rio Preto, São José do Rio Preto, Brazil
| | - Luiz Carlos de Matttos
- Immunogenetics Laboratory, Molecular Biology Department, Medicine School in São José do Rio Preto, São José do Rio Preto, Brazil
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Yang X, Kuang S, Wang L, Wei Y. MHC class I chain-related A: Polymorphism, regulation and therapeutic value in cancer. Biomed Pharmacother 2018; 103:111-117. [PMID: 29635123 DOI: 10.1016/j.biopha.2018.03.177] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 03/27/2018] [Accepted: 03/28/2018] [Indexed: 12/20/2022] Open
Abstract
MICA and MICB are stress-induced molecules recognized by NKG2D, one of major activation receptors of natural killer (NK) cells. Upon binding to NKG2D, NKG2D-mediated cytolytic immune response of immune effector cells will be activated against virally infected and tumor cells expressing MICA. In the early oncogenic development, membrane-bound MICA serves as a key signal to recruit anti-tumor immune effectors. Nevertheless, both MICA polymorphic features and its dysregulated expression in evolving tumors have resulted in tumor evasion in various cancer types. Therefore, in order to reconstitute tumor immunosurveilance, it is of great significance that we understand MICA genetics, polymorphisms, mechanisms of MICA-associated tumor escape and molecular/cellular modulation of MICA. In this review, the MICA-associated co-expression networks involving microRNAs (miRNAs) and novel candidate long non-coding RNAs (lncRNAs) were also discussed. Given the current importance in the study of MICA gene, this review paper focuses on the role of MICA in different cancer types, and strategies that we manipulate MICA regulation against tumor proliferation.
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Affiliation(s)
- Xi Yang
- Department of Biological Sciences, Clemson University, USA
| | - Shuzhen Kuang
- Department of Biological Sciences, Clemson University, USA
| | - Liangjiang Wang
- Department of Genetics and Biochemistry, Clemson University, USA.
| | - Yanzhang Wei
- Department of Biological Sciences, Clemson University, USA.
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Luo Q, Guo X, Peng S, Luo W, Tian F, Yu P, Zou Y. The association between MICA/MICB polymorphism and respiratory syncytial virus infection in children. Int J Immunogenet 2017; 44:328-336. [PMID: 28925058 DOI: 10.1111/iji.12338] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 08/10/2017] [Accepted: 08/27/2017] [Indexed: 12/22/2022]
Abstract
MICA/MICB gene polymorphisms are related to several cancers and infectious diseases, but there are no reports on the association between MICA/MICB gene polymorphisms and respiratory syncytial virus (RSV) infection. To clarify the association between MICA/MICB gene polymorphisms and infection of RSV in children, we collected fresh blood samples from paediatric patients with and without pneumonia after RSV infection. The MICA/MICB alleles were characterized by PCR sequence-specific primers (PCR-SSP) and PCR sequence-based genotyping (PCR-SBT), and then, the frequency of the MICA/MICB alleles and haplotypes was calculated. The results showed that the frequencies of MICA*002:01 and MICA-A9 in RSV-infected patients were significantly lower than in controls (9% vs. 20%, pc = 0.04). The allele frequency of MICA*002:01 in pneumonia patients (8%) and nonpneumonia patients (9%) was significantly lower than in controls (20%, pc = 0.02). MICA*002:01-MICB*008(Δrel = 0.616), MICA*009-MICB*016 (Δrel = 0.506), and MICA*045-MICB*014 (Δrel = 0.700) showed linkage disequilibrium in patients infected with RSV. The haplotype frequency of MICA*002:01-MICB*005:02 in RSV-infected patients was significantly lower than in controls (10% vs. 16%, pc = 0.033). In conclusion, allele MICA*002:01/A9 and haplotype MICA*002:01-MICB*005:02 were negatively associated with RSV respiratory tract infections.
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Affiliation(s)
- Q Luo
- Department of Immunology, Xiangya School of Medicine, Central South University, Hunan, China
| | - X Guo
- Department of Immunology, Xiangya School of Medicine, Central South University, Hunan, China.,Medical college of Hebei University of Engineering, Hebei, China
| | - S Peng
- The Second Xiang Ya Hospital of Central South University, Hunan, China
| | - W Luo
- Department of Immunology, Xiangya School of Medicine, Central South University, Hunan, China
| | - F Tian
- Department of Immunology, Xiangya School of Medicine, Central South University, Hunan, China
| | - P Yu
- Department of Immunology, Xiangya School of Medicine, Central South University, Hunan, China
| | - Y Zou
- Department of Immunology, Xiangya School of Medicine, Central South University, Hunan, China
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Sasaki R, Kanda T, Wu S, Nakamoto S, Haga Y, Jiang X, Nakamura M, Shirasawa H, Yokosuka O. Association between hepatitis B virus and MHC class I polypeptide-related chain A in human hepatocytes derived from human-mouse chimeric mouse liver. Biochem Biophys Res Commun 2015; 464:1192-1195. [PMID: 26212443 DOI: 10.1016/j.bbrc.2015.07.102] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 07/21/2015] [Indexed: 01/10/2023]
Abstract
Due to the lack of efficient hepatitis B virus (HBV) infection systems, progress in understanding the role of innate immunity in HBV infection has remained challenging. Here we used human hepatocytes from a humanized severe combined immunodeficiency albumin promoter/enhancer driven-urokinase-type plasminogen activator mouse model for HBV infection. HBV DNA levels in culture medium from these human hepatocytes were 4.8-5.7 log IU/mL between day 16 and day 66 post-infection by HBV genotype C inoculum. HBV surface antigen (HBsAg) was also detected by chemiluminescent immunoassay from day 7 to day 66 post-infection. Western blot analysis revealed that major histocompatibility complex class I-related chain A (MICA), which plays a role in the innate immune system, was induced in HBV-infected human hepatocytes 27 days after infection compared with the uninfected control. MICA was reduced at day 62 and undetectable at day 90. Of interest, MICA expression by human hepatocytes increased after HBV infection and decreased before HBsAg loss. Human hepatocytes derived from chimeric mice with hepatocyte-humanized liver could support HBV genome replication. Further studies of the association between HBV replication and MICA induction should be conducted.
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Affiliation(s)
- Reina Sasaki
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Shuang Wu
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; Department of Molecular Virology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Yuki Haga
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Xia Jiang
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Masato Nakamura
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Hiroshi Shirasawa
- Department of Molecular Virology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
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Pollicino T, Koumbi L. Role natural killer group 2D-ligand interactions in hepatitis B infection. World J Hepatol 2015; 7:819-824. [PMID: 25937859 PMCID: PMC4411524 DOI: 10.4254/wjh.v7.i6.819] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 02/17/2015] [Accepted: 03/16/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is the leading cause of liver disease and hepatocellular carcinoma (HCC) worldwide, in spite of prophylactic vaccination and antiviral treatment modalities. The immunopathogenesis of HBV infection has been intensively studied and is propelled by complex interactions between the virus and the host immune system. Natural killer group 2D (NKG2D) is a well-characterized activating receptor, expressed on natural killer (NK) cells, NK T cells and CD8(+) cytotoxic T cells. This receptor is present in both humans and mice and binds to a diverge family of ligands that resemble the MHC-class I molecules. Increasing evidence shows that NKG2D-ligand interactions are critical in the establishment of HBV persistence and the development of liver injury and HCC. The expression of NKG2D ligands depends on the presence of several polymorphisms and is also modulated post-transcriptionally by HBV. While it is known that HBV circumvents host's innate immunity via the NKG2D pathway but the exact mechanisms involved are still elusive. This letter discusses previous accomplishments on the role of NKG2D ligand regulation in the development of chronic HBV, liver injury and HCC.
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Affiliation(s)
- Teresa Pollicino
- Teresa Pollicino, Department of Pediatric, Gynecologic, Microbiologic, and Biomedical Sciences, University Hospital of Messina, 98124 Messina, Italy
| | - Lemonica Koumbi
- Teresa Pollicino, Department of Pediatric, Gynecologic, Microbiologic, and Biomedical Sciences, University Hospital of Messina, 98124 Messina, Italy
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Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related death globally. Above well-known risk factors for HCC development ranging from various toxins to diseases such as diabetes mellitus, chronic infection with hepatitis B virus and hepatitis C virus (HCV) poses the most serious threat, constituting the cause in more than 80 % of cases. In addition to the viral genes intensively investigated, the pathophysiological importance of host genetic factors has also been greatly and increasingly appreciated. Genome-wide association studies (GWAS) comprehensively search the host genome at the single-nucleotide level, and have successfully identified the genomic region associated with a whole variety of diseases. With respect to HCC, there have been reports from several groups on single nucleotide polymorphisms (SNPs) associated with hepatocarcinogenesis, among which was our GWAS discovering MHC class I polypeptide-related sequence A (MICA) as a susceptibility gene for HCV-induced HCC. MICA is a natural killer (NK) group 2D (NKG2D) ligand, whose interaction with NKG2D triggers NK cell-mediated cytotoxicity toward the target cells, and is a key molecule in tumor immune surveillance as its expression is induced on stressed cells such as transformed tumor cells for the detection by NK cells. In this review, the latest understanding of the MICA-NKG2D system in viral HCC, particularly focused on its antitumor properties and the involvement of MICA SNPs, is summarized, followed by a discussion of targets for state-of-the-art cancer immunotherapy with personalized medicine in view.
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Tong HV, Toan NL, Song LH, Bock CT, Kremsner PG, Velavan TP. Hepatitis B virus-induced hepatocellular carcinoma: functional roles of MICA variants. J Viral Hepat 2013; 20:687-698. [PMID: 24010643 DOI: 10.1111/jvh.12089] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2012] [Accepted: 01/01/2013] [Indexed: 01/05/2023]
Abstract
Hepatitis B virus infection is a high-risk factor for hepatocellular carcinoma. The human major histocompatibility complex class I chain-related gene A (MICA) is a ligand of the NKG2D receptor that modulates the NK and T-cell-mediated immune responses and is associated with several diseases. This study determined the effects of MICA polymorphisms during HBV infection and HBV-induced HCC. We conducted a case-controlled study in a Vietnamese cohort and genotyped ten functional MICA polymorphisms including the microsatellite motif in 552 clinically classified hepatitis B virus patients and 418 healthy controls. The serum soluble MICA levels (sMICA) were correlated with MICA variants and liver enzyme levels. We demonstrated a significant contribution of MICA rs2596542G/A promoter variant and nonsynonymous substitutions MICA-129Met/Val, MICA-251Gln/Arg, MICA-175Gly/Ser, triplet repeat polymorphism and respective haplotypes with HBV-induced HCC and HBV persistence. The circulating sMICA levels in HBV patient groups were elevated significantly compared with healthy controls. A significant contribution of studied MICA variants to sMICA levels was also observed. The liver enzymes alanine amino transferase (ALT), aspartate transaminase (AST), total bilirubin and direct bilirubin were positively correlated with sMICA levels suggesting sMICA as a biomarker for liver injury. We conclude that MICA polymorphisms play a crucial role in modulating innate immune responses, tumour surveillance and regulate disease susceptibility during HBV infection.
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Affiliation(s)
- H V Tong
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
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Al-Qahtani AA, Al-Anazi M, Abdo AA, Sanai FM, Al-Hamoudi W, Alswat KA, Al-Ashgar HI, Khalaf N, Viswan N, Al-Ahdal MN. Genetic variation at -1878 (rs2596542) in MICA gene region is associated with chronic hepatitis B virus infection in Saudi Arabian patients. Exp Mol Pathol 2013; 95:255-8. [PMID: 23994040 DOI: 10.1016/j.yexmp.2013.08.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Revised: 08/13/2013] [Accepted: 08/14/2013] [Indexed: 12/12/2022]
Abstract
MHC class I polypeptide-related chain A (MICA), mapping to 6p21.33, belongs to the non-classical class I family and its expression is induced by several stress factors including viral infection. A recent genome-wide association study has identified a single nucleotide polymorphism (SNP) of MICA, rs2596542 to be significantly associated with hepatitis C-induced hepatocellular carcinoma (HCC) in a Japanese population. Therefore, this study aims to investigate whether the SNP rs2596542 plays any role in hepatitis B virus (HBV) sero-clearance or in the development of complications associated with chronic HBV such as cirrhosis and/or HCC. TaqMan genotyping assay was used to identify the association of the SNP among 584 normal healthy controls and 777 HBV-infected patients. The patient group was further categorized into inactive carriers (Group I), active carriers (Group II), cirrhosis (Group III) and cirrhosis-HCC (Group IV). Variation at this SNP was found to be significantly more frequent in control subjects than in patients (OR = 0.852; 95% C.I. = 0.730-0.994; p = 0.0415). Also, the SNP was found to have a highly significant association when the inactive carriers were compared to the rest of the patients (OR = 1.308; 95% C.I. = 1.058-1.617; p = 0.0130). The TT genotype was found to occur more frequently among active HBV carriers (groups II, III and IV) when compared to inactive HBV carriers, thus suggesting that the rs2596542-T may be recessively associated with an active HBV infection. However, no significant association was observed in the case of HBV-related cirrhosis or HCC. These findings indicate that the MICA rs2596542 has a significant role in HBV infection.
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Affiliation(s)
- Ahmed A Al-Qahtani
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia.
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Jiang X, Huang JF, Huo Z, Zhang Q, Jiang Y, Wu X, Li Y, Jiang G, Zeng L, Yan XX, Yu P, Cao R. Elevation of soluble major histocompatibility complex class I related chain A protein in malignant and infectious diseases in Chinese patients. BMC Immunol 2012. [PMID: 23181907 PMCID: PMC3552998 DOI: 10.1186/1471-2172-13-62] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Background Elevation of soluble major histocompatibility complex class I chain-related gene A (sMICA) products in serum has been linked to tissue/organ transplantation, autoimmune diseases and some malignant disorders. Cells infected by microbiological pathogens may release sMICA, whereas less is known whether and to what extent serum sMICA levels may change in infectious diseases. Methods The present study determined serum sMICA levels by enzyme-linked immunosorbent assay (ELISA) in a southern China population, including patients (n = 1041) suffering from several types of malignant and infectious diseases and healthy controls (n = 141). Results Relative to controls, serum sMICA elevation was significant in patients of hepatic cancer, and was approaching statistical significance in patients with lung, gastric and nasopharyngeal cancers. sMICA elevation was also associated with some bacterial (Enterobacteriaceae, Mycobacterium tuberculosis, non-fermenting Gram-negative bacteria and Gram-positive cocci), viral (hepatitis B and C) and the Microspironema pallidum infections. Conclusion Serum sMICA levels may be informative for the diagnosis of some malignant and infectious diseases. The results also indicate that microbiological infections should be considered as a potential confounding clinical condition causing serum sMICA elevation while using this test to evaluate the status of other disorders, such as cancers, host-graft response and autoimmune diseases.
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Affiliation(s)
- Xiaoxin Jiang
- The First Affiliated Hospital, Nanhua University, Hengyang, China.
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Ibana JA, Aiyar A, Quayle AJ, Schust DJ. Modulation of MICA on the surface of Chlamydia trachomatis-infected endocervical epithelial cells promotes NK cell-mediated killing. FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY 2012; 65:32-42. [PMID: 22251247 PMCID: PMC5029121 DOI: 10.1111/j.1574-695x.2012.00930.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2011] [Revised: 01/09/2012] [Accepted: 01/09/2012] [Indexed: 12/24/2022]
Abstract
Chlamydia trachomatis serovars D-K are obligate intracellular bacteria that have tropism for the columnar epithelial cells of the genital tract. Chlamydia trachomatis infection has been reported to induce modifications in immune cell ligand expression on epithelial host cells. In this study, we used an in vitro infection model that resulted in a partial infection of C. trachomatis-exposed primary-like immortalized endocervical epithelial cells (A2EN). Using this model, we demonstrated that expression of the natural killer (NK) cell activating ligand, MHC class I-related protein A (MICA), was upregulated on C. trachomatis-infected, but not on noninfected bystander cells. MICA upregulation was concomitant with MHC class I downregulation and impacted the susceptibility of C. trachomatis-infected cells to NK cell activity. The specificity of MICA upregulation was reflected by a higher cytolytic activity of an NK cell line (NK92MI) against C. trachomatis-infected cells compared with uninfected control cells. Significantly, data also indicated that NK cells exerted a partial, but incomplete sterilizing effect on C. trachomatis as shown by the reduction in recoverable inclusion forming units (IFU) when cocultured with C. trachomatis-infected cells. Taken together, our data suggest that NK cells may play a significant role in the ability of the host to counter C. trachomatis infection.
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Affiliation(s)
- Joyce Altamarino Ibana
- Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Science Center, New Orleans, LA, USA
| | - Ashok Aiyar
- Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Science Center, New Orleans, LA, USA
| | - Alison Jane Quayle
- Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Science Center, New Orleans, LA, USA
| | - Danny Joseph Schust
- Department of Obstetrics, Gynecology and Women’s Health, University of Missouri School of Medicine, Columbia, MO, USA
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MICA polymorphism: biology and importance in immunity and disease. Trends Mol Med 2010; 16:97-106. [DOI: 10.1016/j.molmed.2010.01.002] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2009] [Revised: 12/17/2009] [Accepted: 01/08/2010] [Indexed: 11/22/2022]
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Kahraman A, Schlattjan M, Kocabayoglu P, Yildiz-Meziletoglu S, Schlensak M, Fingas CD, Wedemeyer I, Marquitan G, Gieseler RK, Baba HA, Gerken G, Canbay A. Major histocompatibility complex class I-related chains A and B (MIC A/B): a novel role in nonalcoholic steatohepatitis. Hepatology 2010; 51:92-102. [PMID: 19998387 DOI: 10.1002/hep.23253] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
UNLABELLED Stress-induced soluble major histocompatibility complex class I-related chains A/B (MIC A/B) are increased in chronic liver diseases and hepatocellular malignancy. We investigated the impact of these molecules on liver injury, apoptosis, and fibrosis in nonalcoholic steatohepatitis (NASH). Blood and liver tissue were obtained from 40 patients with NASH undergoing bariatric surgery for obesity. The control group consisted of 10 healthy individuals. We also investigated 10 patients with nonalcoholic fatty liver (NAFL). Polymerase chain reaction was used to measure messenger RNA (mRNA) transcripts of MIC A/B, natural killer cell receptor G2D (NKG2D), CD95/Fas, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-death receptor 5 (DR5). Apoptosis was quantified by way of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) (intrahepatic) and M30/M65 (systemic). Liver injury was assessed histopathologically and serologically (alanine aminotransferase/aspartate aminotransferase). Fibrosis was identified by Sirius red staining, quantitative morphometry, and alpha-smooth muscle actin and collagen 1alpha transcripts. Compared with controls, patients with NASH revealed significant increases in (1) NKG2D mRNA (13.1-fold) and MIC A/B mRNA (3.6-fold and 15.8-fold, respectively); (2) TRAIL-DR5 and CD95/Fas mRNA (2.7-fold and 3.6-fold, respectively); (3) TUNEL-positive hepatocytes (4.0-fold); and (4) M30 and M65 levels (4.6-fold and 3.4-fold, respectively). We found relevant correlations between MIC protein expression rates and NAS and fibrosis stages. In contrast, NKG2D and MIC A/B transcripts were attenuated in patients with NAFL compared with NASH. Histopathologically, NASH patients revealed increased NAS scores, an accumulation of natural killer cells, and 2.7-fold increased hepatic fibrosis by quantitative morphometry. CONCLUSION Our findings suggest an important role for MIC A/B in liver injury. Therapeutic intervention aimed at reducing MIC A/B levels may beneficially affect the progression of NASH.
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Affiliation(s)
- Alisan Kahraman
- Department of Gastroenterology, University Hospital Essen, Germany
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Truelove AL, Oleksyk TK, Shrestha S, Thio CL, Goedert JJ, Donfield SM, Kirk GD, Thomas DL, O’Brien SJ, Smith MW. Evaluation of IL10, IL19 and IL20 gene polymorphisms and chronic hepatitis B infection outcome. Int J Immunogenet 2008; 35:255-64. [PMID: 18479293 PMCID: PMC2874896 DOI: 10.1111/j.1744-313x.2008.00770.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Hepatitis B virus (HBV) infection remains a serious global health problem despite the availability of a highly effective vaccine. Approximately 5% of HBV-infected adults develop chronic hepatitis B, which may result in liver cirrhosis or hepatocellular carcinoma. Variants of interleukin-10 (IL10) have been previously associated with chronic hepatitis B infection and progression to hepatocellular carcinoma. Single nucleotide polymorphisms (SNP; n = 42) from the IL10, IL19 and IL20 gene regions were examined for an association with HBV infection outcome, either chronic or recovered, in a nested case-control study of African Americans and European Americans. Among African Americans, three nominally statistically significant SNP associations in IL10, two in IL20, and one haplotype association were observed with different HBV infection outcomes (P = 0.005-0.04). A SNP (rs1518108) in IL20 deviated significantly from Hardy-Weinberg equilibrium in African Americans, with a large excess of heterozygotes in chronic HBV-infected cases (P = 0.0006), which suggests a strong genetic effect. Among European Americans, a nominally statistically significant SNP association in IL20 and an IL20 haplotype were associated with HBV recovery (P = 0.01-0.04). These results suggest that IL10 and IL20 gene variants influence HBV infection outcome and encourage the pursuit of further studies of these cytokines in HBV pathogenesis.
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Affiliation(s)
- Ann L. Truelove
- Laboratory of Genomic Diversity, NCI-Frederick, Frederick, MD 21702 USA
- Basic Research Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702 USA
| | - Taras K. Oleksyk
- Laboratory of Genomic Diversity, NCI-Frederick, Frederick, MD 21702 USA
- Basic Research Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702 USA
| | - Sadeep Shrestha
- Laboratory of Genomic Diversity, NCI-Frederick, Frederick, MD 21702 USA
- Basic Research Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702 USA
| | - Chloe L. Thio
- Department of Medicine, Johns Hopkins University, Baltimore, MD USA
| | - James J. Goedert
- Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI-Bethesda, Bethesda, MD, USA
| | | | - Gregory D. Kirk
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - David L. Thomas
- Department of Medicine, Johns Hopkins University, Baltimore, MD USA
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | | | - Michael W. Smith
- Laboratory of Genomic Diversity, NCI-Frederick, Frederick, MD 21702 USA
- Basic Research Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702 USA
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14
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Singh R, Kaul R, Kaul A, Khan K. A comparative review of HLA associations with hepatitis B and C viral infections across global populations. World J Gastroenterol 2007; 13:1770-1787. [PMID: 17465466 PMCID: PMC4149952 DOI: 10.3748/wjg.v13.i12.1770] [Citation(s) in RCA: 168] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2006] [Revised: 01/26/2006] [Accepted: 03/07/2007] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B (HBV) and hepatitis C (HCV) viral infection or co-infection leads to risk of development of chronic infection, cirrhosis and hepatocellular carcinoma (HCC). Immigration and globalization have added to the challenges of public health concerns regarding chronic HBV and HCV infections worldwide. The aim of this study is to review existing global literature across ethnic populations on HBV and HCV related human leukocyte antigen (HLA) associations in relation to susceptibility, viral persistence and treatment. Extensive literature search was conducted to explore the HLA associations in HBV and HCV infections reported across global populations over the past decade to understand the knowledge status, weaknesses and strengths of this information in different ethnic populations. HLA DR13 is consistently associated with HBV clearance globally. HLADRB1*11/*12 alleles and DQB1*0301 are associated with HBV persistence but with HCV clearance worldwide. Consistent association of DRB1*03 and *07 is observed with HCV susceptibility and non-responsiveness to HBV vaccination across the population. HLA DR13 is protective for vertical HBV and HCV transmission in Chinese and Italian neonates, but different alleles are associated with their susceptibility in these populations. HLA class I molecule interactions with Killer cell immunoglobulin like receptors (KIR) of natural killer (NK) cells modulate HCV infection outcome via regulating immune regulatory cells and molecules. HLA associations with HBV vaccination, interferon therapy in HBV and HCV, and with extra hepatic manifestations of viral hepatitis are also discussed. Systematic studies in compliance with global regulatory standards are required to identify the HLA specific viral epitope, stage specific T cell populations interacting with different HLA alleles during disease progression and viral clearance of chronic HBV or HCV infections among different ethnic populations. These studies would facilitate stage specific therapeutic strategies for clearance of HBV and HCV infections or co-infections across global populations and aid in identification of HBV-HCV combined vaccine. HLA associations of chronic HBV or HCV development with confounding host factors including alcohol, drug abuse, insulin resistance, age and gender are lacking and warrant detailed investigation across global populations.
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Affiliation(s)
- Rashmi Singh
- Department of Biochemistry and Microbiology, Oklahoma States University-Center of Health sciences, 1111 W. 17th St. Tulsa, OK 74107, United States.
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15
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Shichi D, Kikkawa EF, Ota M, Katsuyama Y, Kimura A, Matsumori A, Kulski JK, Naruse TK, Inoko H. The haplotype block, NFKBIL1-ATP6V1G2-BAT1-MICB-MICA, within the class III-class I boundary region of the human major histocompatibility complex may control susceptibility to hepatitis C virus-associated dilated cardiomyopathy. ACTA ACUST UNITED AC 2005; 66:200-8. [PMID: 16101831 DOI: 10.1111/j.1399-0039.2005.00457.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Cardiomyopathy is a heart muscle disease with impaired stretch response that can result in severe heart failure and sudden death. A small proportion of hepatitis C virus (HCV)-infected patients may be predisposed to develop dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). The molecular mechanisms involved in the predisposition remain unknown due in part to the lack of information on their genetic background. Because the human leukocyte antigen (HLA) region has a pivotal role in controlling the susceptibility to HCV-induced liver disease, we hypothesized that particular HLA alleles and/or non-HLA gene alleles within the human major histocompatibility complex (MHC) genomic region might control the predisposition to HCV-associated DCM (HCV-DCM) and/or HCV-associated HCM (HCV-HCM). Here, we present mapping results of the MHC-related susceptibility gene locus for HCV-associated cardiomyopathy by analyzing microsatellite and single nucleotide polymorphism markers. To delineate the susceptibility locus, we genotyped 44 polymorphic markers scattered across the entire MHC region in a total of 59 patients (21 HCV-DCM and 38 HCV-HCM) and 120 controls. We mapped HCV-DCM susceptibility to a non-HLA gene locus spanning from NFKBIL1 to MICA gene loci within the MHC class III-class I boundary region. Our results showed that HCV-DCM was more strongly associated with alleles of the non-HLA genes rather than the HLA genes themselves. In addition, no significant association was found between the MHC markers and HCV-HCM. This marked difference in the MHC-related disease susceptibility for HCV- associated cardiomyopathy strongly suggests that the development of HCV- DCM and HCV-HCM is under the control of different pathogenic mechanisms.
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Affiliation(s)
- D Shichi
- Department of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
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16
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Oleksyk TK, Thio CL, Truelove AL, Goedert JJ, Donfield SM, Kirk GD, Thomas DL, O'Brien SJ, Smith MW. Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance. Genes Immun 2005; 6:347-57. [PMID: 15815689 DOI: 10.1038/sj.gene.6364188] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Hepatitis C virus (HCV) is an infectious blood-borne pathogen that usually persists as a chronic infection. However, approximately 15% of the time, patients can clear the virus, indicating that host differences could be critical in determining the course of HCV infection. The inflammatory response is crucial to resolving or failing to resolve an acute HCV infection. Some previous reports have implicated interleukin 10 (IL10) polymorphisms with successful anti-HCV therapy and natural viral clearance. We tested 54 single nucleotide polymorphisms (SNPs) in the IL10 region (+/-300 kb and 24 within the IL10 gene itself), which contains 13 genes including the IL10 immunomodulatory paralogs IL19, IL20, and IL24, for association with HCV clearance vs persistence. SNPs from two haplotype block regions, one at IL10 and the other from IL19/IL20, were associated with HCV clearance in African Americans (91 clearance cases and 183 chronically infected matched controls; P=0.05-0.002) while with expectation-maximization algorithm-reconstructed haplotypes, these associations remained (P=0.05-0.002). However, no significant associations were detected in European Americans (108 clearance and 245 chronic). Our results indicate that variants of the immunomodulatory IL10 and IL19/IL20 genes may be involved in natural clearance of HCV in the African-American population.
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Affiliation(s)
- T K Oleksyk
- Laboratory of Genomic Diversity, National Cancer Institute at Frederick, Frederick, MD 21702, USA
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17
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Bahram S, Inoko H, Shiina T, Radosavljevic M. MIC and other NKG2D ligands: from none to too many. Curr Opin Immunol 2005; 17:505-9. [PMID: 16087327 DOI: 10.1016/j.coi.2005.07.016] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2005] [Accepted: 07/21/2005] [Indexed: 01/05/2023]
Abstract
NKG2D, a prime activatory receptor on human NK, CD8(+) alphabeta and gammadelta cells, has a variety of ligands, which, despite sharing membership of the MHC class I structural club, display an array of unique features. Chronologically, human MIC molecules were the first NKG2D ligands to be identified. Then came RAET1 (ULBP) molecules, which were identified in both man and mouse, as well as H60 and MULT1, which have no counterparts in man to date. The question remains as to why, more than how, the evolutionary conserved, apparently monomorphic, single copy, NKG2D, can/should adapt to this variety of ligands, and when it does, what is the evolutionary advantage of this profusion of ligands for a single receptor?
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Affiliation(s)
- Seiamak Bahram
- Centre de Recherche d'Immunologie et d'Hématologie, Hôpitaux Universitaires de Strasbourg, France
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