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Cansever M, Göktaş MA, Arslan D, Patiroğlu T. Serum levels of soluble HLA-G correlate with disease activity in pediatric patients with Crohn's disease. Saudi J Gastroenterol 2022; 28:233-238. [PMID: 35042317 PMCID: PMC9212116 DOI: 10.4103/sjg.sjg_327_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND Human leukocyte antigen (HLA)-G, a member of the HLA family, is crucial for fetomaternal tolerance. Transmembrane or circulating/soluble HLA-G (sHLA-G) is elevated in autoimmune conditions and the tumor microenvironment. Circulating sHLA-G levels and their association with disease activity have not yet been assessed in pediatric patients with inflammatory bowel disease (IBD). This study aimed to quantify the serum sHLA-G levels of pediatric patients with IBD and assess the association of serum sHLA-G with disease activity. METHODS : We enrolled 24 pediatric IBD patients Crohn's disease (CD) and ulcerative colitis (UC), n = 12 each] and 24 healthy controls. Based on the disease activity index, five and seven of the CD patients had mild and moderate/severe disease, respectively, whereas six of the UC patients were in remission and six had mild disease. Serum was collected and sHLA-G levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS : Pediatric patients with CD had significantly higher sHLA-G levels compared with patients with UC and healthy controls. Notably, serum sHLA-G levels were significantly higher in patients with moderate/severe CD than in those with mild CD. CONCLUSIONS : Serum sHLA-G levels correlate with disease activity in pediatric patients with CD and are higher in CD patients than in UC patients. Thus, sHLA-G is a potential biomarker for disease activity in CD.
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Affiliation(s)
- Murat Cansever
- Department of Pediatrics, Division of Immunology, School of Medicine, Erciyes University, Kayseri, Turkey,Address for correspondence: Dr. Murat Cansever, Department of Pediatrics, Division of Immunology, Faculty of Medicine, Erciyes University, 38034, Kayseri, Turkey. E-mail:
| | - Mehmet Akif Göktaş
- Department of Pediatrics, Division of Gastroenterology, School of Medicine, Hacettepe University, Kayseri, Turkey
| | - Duran Arslan
- Department of Pediatrics, Division of Gastroenterology, School of Medicine, Erciyes University, Kayseri, Turkey
| | - Türkan Patiroğlu
- Department of Pediatrics, Division of Immunology, School of Medicine, Erciyes University, Kayseri, Turkey
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2
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The HLA-G Immune Checkpoint Plays a Pivotal Role in the Regulation of Immune Response in Autoimmune Diseases. Int J Mol Sci 2021; 22:ijms222413348. [PMID: 34948145 PMCID: PMC8706866 DOI: 10.3390/ijms222413348] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/10/2021] [Accepted: 12/10/2021] [Indexed: 12/11/2022] Open
Abstract
The human G-leukocyte antigen (HLA-G) molecule is a non-classical major histocompatibility complex (MHC) class I molecule. The pertinence of HLA-G has been investigated in numerous studies which have sought to elucidate the relevance of HLA-G in pathologic conditions, such as autoimmune diseases, cancers, and hematologic malignancies. One of the main goals of the current research on HLA-G is to use this molecule in clinical practice, either in diagnostics or as a therapeutic target. Since HLA-G antigens are currently considered as immunomodulatory molecules that are involved in reducing inflammatory and immune responses, in this review, we decided to focus on this group of antigens as potential determinants of progression in autoimmune diseases. This article highlights what we consider as recent pivotal findings on the immunomodulatory function of HLA-G, not only to establish the role of HLA-G in the human body, but also to explain how these proteins mediate the immune response.
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da Costa Ferreira S, Sadissou IA, Parra RS, Feitosa MR, Neto FSL, Pretti da Cunha Tirapelli D, Ramalho LNZ, Féres O, da Rocha JJR, Donadi EA, de Almeida Troncon LE. Increased HLA-G Expression in Tissue-Infiltrating Cells in Inflammatory Bowel Diseases. Dig Dis Sci 2021; 66:2610-2618. [PMID: 32839905 DOI: 10.1007/s10620-020-06561-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 08/11/2020] [Indexed: 01/08/2023]
Abstract
BACKGROUND Since HLA-G is an immune checkpoint molecule and since Crohn's disease (CD) and ulcerative colitis (UC) exhibit deregulated immune-mediated mechanisms, we aimed to evaluate intestinal HLA-G expression and soluble HLA-G (sHLA-G) levels in CD/UC patients stratified according to the CD phenotype/localization and UC extension. METHODS HLA-G tissue expression was assessed by immunohistochemistry in biopsies collected from 151 patients (90 CD, 61 UC) and in surgical resection specimens (28 CD, 12 UC). Surgical material from 24 healthy controls was also assessed. Plasma sHLA-G levels (97 CD, 81 UC, and 120 controls) were evaluated using ELISA. RESULTS HLA-G expression was similarly observed in the intestinal epithelial cells of control and CD/UC specimens. However, in biopsies, the plasma cells/lymphocytes infiltrating the lamina propria in CD/UC presented (1) increased HLA-G expression compared to controls (P < 0.0001), (2) greater cell staining in UC cells than in CD cells irrespective of disease extent (P = 0.0011), and (3) an increased number of infiltrating cells in the inflammatory CD phenotype compared to that in the stenosing and fistulizing phenotypes (P = 0.0407). In surgical specimens, CD/UC patients exhibited higher infiltrating cell HLA-G expression in lesion areas than in margins. sHLA-G levels were higher in UC/CD patients (P < 0.0001) than in controls, but no difference was observed between diseases. CONCLUSIONS Increased infiltrating cell HLA-G expression associated with increased sHLA-G levels in CD/UC patients may reflect ongoing host strategies to suppress chronic inflammation.
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Affiliation(s)
- Sandro da Costa Ferreira
- Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, SP, 14049-900, Brazil.
| | - Ibrahim Abiodoun Sadissou
- Division of Clinical Immunology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Rogério Serafim Parra
- Division of Coloproctology, Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Marley Ribeiro Feitosa
- Division of Coloproctology, Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Fermino Sanches Lizarte Neto
- Molecular Biology Laboratory, Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Daniela Pretti da Cunha Tirapelli
- Molecular Biology Laboratory, Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | | | - Omar Féres
- Division of Coloproctology, Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - José Joaquim Ribeiro da Rocha
- Division of Coloproctology, Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Eduardo Antônio Donadi
- Division of Clinical Immunology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Luiz Ernesto de Almeida Troncon
- Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, SP, 14049-900, Brazil
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Abdul-Hussein SS, Ali EN, Zaki NH, Ad’hiah AH. Genetic polymorphism of HLA-G gene (G*01:03, G*01:04, and G*01:05N) in Iraqi patients with inflammatory bowel disease (ulcerative colitis and Crohn’s disease). EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2021. [DOI: 10.1186/s43042-021-00158-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Abstract
Background
Human leukocyte antigen-G (HLA-G) has been proposed to influence susceptibility to inflammatory bowel disease (IBD). Therefore, the genetic association between HLA-G alleles and two clinical phenotypes of IBD (ulcerative colitis [UC] and Crohn’s disease [CD]) was evaluated in Iraqi patients. A case-control study was performed on 50 UC and 50 CD patients and 100 healthy controls (HC). Three HLA-G alleles (G*01:03, G*01:04, and G*01:05N) were determined using sequence-specific polymerase chain reaction assay followed by product digestion with restriction endonucleases (Hinf-I, BseR-I, and PpuM-I, respectively).
Results
The G*01:03 allele was not detected in IBD patients (UC and CD) or HC, while G*01:04 and G*01:05N alleles showed polymorphic frequencies. The allele G*01:04 was significantly associated with susceptibility to UC (odds ratio [OR] = 2.55; 95% confidence interval [CI] = 1.27–5.13; corrected probability [pc] = 0.018) and CD (OR = 4.45; 95% CI = 2.11–9.41; pc < 0.001). The allele G*01:05N was also associated with increased risk of UC (OR = 4.17; 95% CI = 1.32–13.21; pc = 0.032) and CD (OR = 4.75; 95% CI = 1.53–14.78; pc = 0.014). These associations were more pronounced in IBD (UC + CD), and a significantly increased risk for IBD was found with the alleles G*01:04 (OR = 3.32; 95% CI = 1.86–5.95; pc < 0.001) and G*01:05N (OR = 4.46; 95% CI = 1.59–12.47; pc = 0.008). A stratification of IBD patients according to some demographic and clinical characteristics revealed that frequencies of both alleles showed no significant differences between the subgroups of patients in each stratum. Soluble HLA-G was not influenced by HLA-G alleles in patients or HC. UC was an exception, and the presence of G*01:04 allele was associated with a significantly higher mean of soluble HLA-G compared to patients without the allele (189.6 ± 24.0 vs. 168.6 ± 27.2 ng/mL; p = 0.033).
Conclusion
This study indicated that HLA-G*01:04 and HLA-G*01:05N alleles may influence susceptibility to UC and CD in Iraqi patients.
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Abdul-Hussein SS, Ali EN, Alkhalidi NMF, Zaki NH, Ad’hiah AH. Susceptibility role of soluble HLA-G and HLA-G 14-bp insertion/deletion polymorphism in inflammatory bowel disease. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2020. [DOI: 10.1186/s43042-020-00104-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Abstract
Background
Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders of the gastrointestinal tract. It is fundamentally related to a dysregulated immune response in the intestinal mucosa against microbiota in genetically predisposed individuals. Among the genetic and immunological factors that are suggested to have role in etiology and pathogenesis of IBD are human leukocyte antigen (HLA)-G molecules. Therefore, soluble HLA-G (sHLA-G) serum level and genetic association with HLA-G 14-bp insertion (Ins)/deletion (Del) polymorphism was analyzed in 100 IBD patients; 50 ulcerative colitis (UC) and 50 Crohn’s disease (CD), and 100 controls.
Results
sHLA-G level was significantly elevated in IBD patients compared to controls (174.7 ± 27.1 vs. 126.8 ± 15.1; corrected probability [pc] < 0.001). The level was also elevated in UC patients compared to CD patients but the difference was not significant (180.5 ± 27.1 vs. 168.9 ± 26.3; p = 0.059). Receiver operating characteristic analysis confirmed the significance of sHLA-G in total IBD, UC, and CD patients (area under curve = 0.944, 0.961, and 0.927, respectively). The genetic association was analyzed under five genetic models (allele, recessive, dominant, overdominant, and codominant). At the allele level, Del allele frequency was significantly increased in total IBD patients (Odds ratio [OR] = 1.93; 95% confidence interval [CI] = 1.27–2.94; pc = 0.018) and CD patients (OR = 2.08; 95% CI = 1.23–3.54; pc = 0.042) compared to controls. Among UC patients, a similar increased frequency was observed, but the pc value was not significance (OR = 1.79; 95% CI = 1.07–3.00; p = 0.031). At the genotypic level, Del/Del genotype was associated with a significantly increased IBD-risk in total patients under codominant model (OR = 4.06; 95% CI = 1.56–10.56; pc = 0.024). sHLA-G level was not influenced by the Ins/Del polymorphism.
Conclusions
This study demonstrated a significant increase in serum level of sHLA-G in UC and CD patients. Further, HLA-G 14-bp Ins/Del polymorphism may be associated with susceptibility to IBD, particularly CD.
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Cruz‐Romero C, Guo A, Bradley WF, Vicentini JR, Yajnik V, Gee MS. Novel Associations Between Genome‐Wide Single Nucleotide Polymorphisms and MR Enterography Features in Crohn's Disease Patients. J Magn Reson Imaging 2020; 53:132-138. [DOI: 10.1002/jmri.27250] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 05/22/2020] [Accepted: 05/22/2020] [Indexed: 12/13/2022] Open
Affiliation(s)
- Cinthia Cruz‐Romero
- Department of Radiology, Beth Israel Deaconess Medical Center Harvard Medical School Boston Massachusetts USA
| | - Abra Guo
- University of Virginia School of Medicine Charlottesville Virginia USA
| | | | - Joao R.T. Vicentini
- Department of Radiology, Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA
| | - Vijay Yajnik
- Takeda Pharmaceuticals Cambridge Massachusetts USA
| | - Michael S. Gee
- Department of Radiology, Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA
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Ashton JJ, Latham K, Beattie RM, Ennis S. Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease. Aliment Pharmacol Ther 2019; 50:885-900. [PMID: 31518029 DOI: 10.1111/apt.15485] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/05/2019] [Accepted: 08/10/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND The human leucocyte antigen (HLA) complex, located at chromosome 6p21.3 is a highly polymorphic region containing the classical class I and II HLA genes. The region is highly associated with inflammatory bowel disease (IBD), largely through genome-wide association studies (GWAS). AIMS To review the role of HLA in immune function, summarise data on risk/protective HLA genotypes for IBD, discuss the role of HLA in IBD pathogenesis, treatment and examine limitations that might be addressed by future research. METHODS An organised search strategy was used to collate articles describing HLA genes in IBD, including Crohn's disease and ulcerative colitis. RESULTS All classical HLA genes with variation (including HLA-A, B, C, DRB1, DQA1, DQB1, DPA1 and DPB1) harbour IBD-associated genotypes. The most implicated gene is HLA-DRB1, with HLA-DRB1*03:01 the most associated risk allele in both Crohn's disease and ulcerative colitis. Elucidating precise disease associations is challenging due to high linkage disequilibrium between HLA genotypes. The mechanisms by which risk alleles cause disease are multifactorial, with the best evidence indicating structural and electrostatic alteration impacting antigen binding and downstream signalling. Adverse medication events have been associated with HLA genotypes including with thiopurines (pancreatitis) and anti-TNF agents (antibody formation). CONCLUSIONS The HLA complex is associated with multiple risk/protective alleles for IBD. Future research utilising long-read technology, ascertainment of zygosity and integration in disease modelling will improve the functional understanding and clinical translation of genetic findings.
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Affiliation(s)
- James J Ashton
- Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.,Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - Katy Latham
- Anthony Nolan Research Institute, University College London, London, UK
| | - Robert Mark Beattie
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - Sarah Ennis
- Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK
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Gomes RG, Brito CAAD, Martinelli VF, Santos RND, Gomes FODS, Peixoto CA, Crispim JO, Diniz GTN, Donadi EA, Lucena-Silva N. HLA-G is expressed in intestinal samples of ulcerative colitis and Crohn’s disease patients and HLA-G5 expression is differentially correlated with TNF and IL-10 cytokine expression. Hum Immunol 2018; 79:477-484. [DOI: 10.1016/j.humimm.2018.03.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 03/23/2018] [Accepted: 03/23/2018] [Indexed: 12/19/2022]
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Cavalcanti A, Almeida R, Mesquita Z, Duarte ALBP, Donadi EA, Lucena-Silva N. Gene polymorphism and HLA-G expression in patients with childhood-onset systemic lupus erythematosus: A pilot study. HLA 2017; 90:219-227. [DOI: 10.1111/tan.13084] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 06/11/2017] [Accepted: 06/15/2017] [Indexed: 11/28/2022]
Affiliation(s)
- A. Cavalcanti
- Pediatric Rheumatology Unit; Federal University of Pernambuco; Recife Brazil
- Department of Immunology, Aggeu Magalhães Research Center; Oswaldo Cruz Foundation; Recife Brazil
| | - R. Almeida
- Department of Immunology, Aggeu Magalhães Research Center; Oswaldo Cruz Foundation; Recife Brazil
| | - Z. Mesquita
- Pediatric Rheumatology Unit; Institute of Integrative Medicine Professor Fernando Figueira; Recife Brazil
| | - A. L. B. P. Duarte
- Pediatric Rheumatology Unit; Federal University of Pernambuco; Recife Brazil
| | - E. A. Donadi
- Department of Clinical Medicine; São Paulo University; Ribeirão Preto Brazil
| | - N. Lucena-Silva
- Department of Immunology, Aggeu Magalhães Research Center; Oswaldo Cruz Foundation; Recife Brazil
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Ferreira SDC, Chachá SGF, Souza FF, Teixeira AC, Santana RDC, Deghaide NHS, Rodrigues S, Marano LA, Mendes-Junior CT, Ramalho LNZ, Zucoloto S, Donadi EA, Martinelli ADLC. The HLA-G 14-base pair deletion allele and the deletion/deletion genotype are associated with persistent HBe antigenemia in chronic hepatis B infection. Hum Immunol 2016; 78:166-171. [PMID: 28041834 DOI: 10.1016/j.humimm.2016.12.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Revised: 12/15/2016] [Accepted: 12/28/2016] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIMS HLA-G has well-recognized immunomodulatory properties, and this molecule is frequently expressed in the livers of hepatitis B virus (HBV)-infected patients. Because the HLA-G 14 bp-insertion/deletion polymorphism (rs371194629) has been associated with the magnitude of HLA-G expression, we evaluated this polymorphism in the recognized evolutionary forms of chronic HBV infection. METHODS We studied 196 chronic HBV-infected patients (118 HBeAg-negative chronic hepatitis, 53 HBeAg-positive chronic hepatitis and 25 inactive carriers exhibiting low levels of serum HBVDNA and persistently normal ALT levels), and 202 healthy individuals. Chronic hepatitis HLA-G typing was performed using PCR-amplified DNA hybridized with specific primers. RESULTS The frequencies of the insertion/deletion alleles and genotypes were very similar in patients and controls. After patient stratification according to the evolutionary form of the chronic HBV infection, the frequencies of the deletion allele (P=0.0460; OR=1.26; 95%CI=1.01-1.45) and of the deletion/deletion genotype (P=0.0356; OR=2.08; 95%CI=1.05-4.09) were overrepresented in HBeAg-positive patients when compared to HBeAg-negative patients. No differences were observed when HBV inactive carriers were compared to HBeAg-negative chronic hepatitis patients. CONCLUSIONS Because the 14-bp deletion allele has been associated with increased HLA-G production and because HLA-G may down regulate the cytotoxic activity of TCD8 and NK cells, patients exhibiting the 14-bp deletion allele at single or double doses are at increased risk for developing chronic forms of HBV associated with persistent viremia and worse prognoses.
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Affiliation(s)
- Sandro da Costa Ferreira
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Brazil.
| | - Silvana Gama Florêncio Chachá
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Brazil; Department of Medicine, University Federal of São Carlos (UFSCAR), Brazil
| | - Fernanda Fernandes Souza
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Brazil
| | - Andreza Corrêa Teixeira
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Brazil
| | - Rodrigo de Carvalho Santana
- Division of Infectious Diseases, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Brazil
| | - Neifi Hassan Saloun Deghaide
- Division of Clinical Immunology, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Brazil
| | - Sandra Rodrigues
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Brazil
| | - Leonardo A Marano
- Department of Genetics, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Brazil
| | | | | | - Sérgio Zucoloto
- Department of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Brazil
| | - Eduardo Antônio Donadi
- Division of Clinical Immunology, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Brazil
| | - Ana de Lourdes Candolo Martinelli
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Brazil
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Ishibashi K, Kumai T, Ohkuri T, Kosaka A, Nagato T, Hirata Y, Ohara K, Oikawa K, Aoki N, Akiyama N, Sado M, Kitada M, Harabuchi Y, Celis E, Kobayashi H. Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy. Oncoimmunology 2016; 5:e1169356. [PMID: 27471649 DOI: 10.1080/2162402x.2016.1169356] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Revised: 03/07/2016] [Accepted: 03/17/2016] [Indexed: 12/28/2022] Open
Abstract
Tumor immune escape has been a major problem for developing effective immunotherapy. The human leukocyte antigen G (HLA-G) is a non-classical MHC class I molecule whose primary function is to protect the fetus from the mother's immune system. While HLA-G is hardly found in normal adult tissues, various tumor cells are known to express it, aiding their escape from the immune system. Thus, HLA-G is an attractive immunotherapy target. CD4(+) helper T lymphocytes (HTLs) play an important role in the immune reaction against tumors by assisting in the generation and persistence of CD8(+) cytotoxic T lymphocytes (CTLs) or by displaying direct antitumor effects. We report here that HLA-G expression in breast cancer significantly correlates with a poor prognosis. Also, we describe that the MHC class II-binding peptide HLA-G26-40 was effective in eliciting tumor-reactive CD4(+) T cell responses. Furthermore, treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine increased HLA-G expression in tumors and subsequently enhanced recognition by HLA-G26-40-specific HTLs. These findings predict that a combination immunotherapy targeting HLA-G together with a DNA methyltransferase inhibitor could be useful against some cancers.
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Affiliation(s)
- Kei Ishibashi
- Department of Pathology, Asahikawa Medical University, Asahikawa, Japan; Respiratory and Breast Center, Asahikawa Medical University Hospital, Asahikawa, Japan
| | - Takumi Kumai
- Department of Pathology, Asahikawa Medical University, Asahikawa, Japan; Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan; Cancer Immunology, Inflammation and Tolerance Program, Augusta University Cancer Center, Augusta, GA, USA
| | - Takayuki Ohkuri
- Department of Pathology, Asahikawa Medical University , Asahikawa, Japan
| | - Akemi Kosaka
- Department of Pathology, Asahikawa Medical University , Asahikawa, Japan
| | - Toshihiro Nagato
- Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University , Asahikawa, Japan
| | - Yui Hirata
- Department of Pathology, Asahikawa Medical University, Asahikawa, Japan; Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Kenzo Ohara
- Department of Pathology, Asahikawa Medical University, Asahikawa, Japan; Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Kensuke Oikawa
- Department of Pathology, Asahikawa Medical University , Asahikawa, Japan
| | - Naoko Aoki
- Department of Pathology, Asahikawa Medical University , Asahikawa, Japan
| | - Naoko Akiyama
- Department of Surgical Pathology, Asahikawa Medical University Hospital , Asahikawa, Japan
| | - Masatoshi Sado
- Department of Surgical Pathology, Asahikawa Medical University Hospital , Asahikawa, Japan
| | - Masahiro Kitada
- Respiratory and Breast Center, Asahikawa Medical University Hospital , Asahikawa, Japan
| | - Yasuaki Harabuchi
- Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University , Asahikawa, Japan
| | - Esteban Celis
- Cancer Immunology, Inflammation and Tolerance Program, Augusta University Cancer Center , Augusta, GA, USA
| | - Hiroya Kobayashi
- Department of Pathology, Asahikawa Medical University , Asahikawa, Japan
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12
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Mahdi BM. Role of HLA typing on Crohn's disease pathogenesis. Ann Med Surg (Lond) 2015; 4:248-53. [PMID: 26288728 PMCID: PMC4537883 DOI: 10.1016/j.amsu.2015.07.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 07/10/2015] [Accepted: 07/15/2015] [Indexed: 02/07/2023] Open
Abstract
Crohn's disease (CD) is the main type of chronic inflammatory bowel disease of unknown etiology. Evidence from family and twin studies suggests that genetics plays a significant role in predisposing an individual to develop Crohn's disease. A susceptibility locus for Crohn's disease has been mapped 3 to chromosome 16: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators which is expressed in hematopoietic compartment cells and intestinal epithelial cells as well as in paneth cells, where NOD2 may play an important role in the pathogenesis of Crohn disease in the gastrointestinal system. This leads to alteration the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has two functions, first an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. Thus, NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in intestinal epithelial cells as well as in paneth cells. Further confirmation of a genetic predisposition comes from studies of the association between the human leukocyte antigen (HLA) system and CD. The immunogenetic predisposition may be considered an important requirement for the development of CD, as several alleles of human major histocompatibility complex had an association with CD. Although it is difficult to estimate the importance of this region in determining overall genetic susceptibility in a population, studies of HLA allele sharing within families suggest that this region contributes between 10% and 33% of the total genetic risk of Crohn's disease.
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Degani Veit T, Bogo Chies JA, Switala M, Wagner B, Horn PA, Busatto M, Viegas Brenol C, Tavares Brenol JC, Machado Xavier R, Rebmann V. The paradox of high availability and low recognition of soluble HLA-G by LILRB1 receptor in rheumatoid arthritis patients. PLoS One 2015; 10:e0123838. [PMID: 25853899 PMCID: PMC4390237 DOI: 10.1371/journal.pone.0123838] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 02/24/2015] [Indexed: 11/23/2022] Open
Abstract
HLA-G is a regulatory molecule involved in immunologic tolerance. Growing evidence indicates that HLA-G plays a role in the regulation of inflammatory processes and autoimmune diseases. This study aimed at a systematic evaluation of soluble HLA-G (sHLA-G) in plasma of rheumatoid arthritis (RA) patients with long-lasting chronic inflammation. RA patients (n=68) and healthy controls (n=26) had their plasmatic sHLA-G measured by ELISA whereas the binding capability of sHLA-G to its cognate LILRB1 receptor was measured by a Luminex-based assay. All subjects were PCR-genotyped for HLA-G 14bp polymorphism (rs66554220). Significantly higher sHLA-G levels were observed in patients (p<0.001), however no significant differences were observed in LILRB1 binding capacity between RA patients and controls. Remarkably, the proportion of patients presenting specific binding of sHLA-G to LILRB1 was significantly decreased as compared to controls (56% vs. 81%, p=0.027). Patients without rheumatoid factor (RF-) were significantly overrepresented in the group of patients positive for LILRB1 binding as compared to patients without LILRB1 binding (31% vs 10%, p=0.033). Furthermore, methotrexate treated patients (n=58) revealed significantly lower LILRB1 binding to sHLA-G molecules than non-treated patients (medians: 12.2 vs. 67.7 units/ml, p=0.031). Unlike in controls, no significant differences in sHLA-G levels were observed among patients grouped by 14pb genotype. Thus, in a substantial number of late RA patients, the circulating sHLA-G molecules are impaired regarding LILRB1 recognition, meaning that although increased levels are observed; these molecules are not qualified to exert their protective functions against inflammation. Our findings offer new insights into the immunopathology of RA patients with long-lasting anti-RA-treatment and highlight the importance to also measure the binding capability of sHLA-G to LILRB1.
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Affiliation(s)
- Tiago Degani Veit
- Laboratório de Imunogenética, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - José Artur Bogo Chies
- Laboratório de Imunogenética, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Magdalena Switala
- Institute for Transfusion Medicine, University Hospital of Essen, Essen, Germany
| | - Bettina Wagner
- Institute for Transfusion Medicine, University Hospital of Essen, Essen, Germany
| | - Peter A. Horn
- Institute for Transfusion Medicine, University Hospital of Essen, Essen, Germany
| | - Mauricio Busatto
- Laboratório de Imunogenética, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | | | | | | | - Vera Rebmann
- Institute for Transfusion Medicine, University Hospital of Essen, Essen, Germany
- * E-mail:
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Chua KH, Lian LH, Khor WC, Lee WS, Hilmi I, Goh KL, Kee BP. Association between genetic polymorphisms in interferon regulatory factor 5 (IRF5) gene and Malaysian patients with Crohn's disease. J Dig Dis 2015; 16:205-216. [PMID: 25564941 DOI: 10.1111/1751-2980.12229] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The study aimed to investigate the association between the interferon regulatory factor 5 (IRF5) gene polymorphisms and the onset of Crohn's disease (CD) in a Malaysian cohort. METHODS Genomic DNA was extracted from blood samples collected from 91 CD patients and 100 healthy individuals via a conventional phenol-chloroform extraction method. Screening of the four target single nucleotide polymorphisms (SNPs), including rs3807306, rs4728142, rs10954213 and rs11770589 was carried out in a real-time polymerase chain reaction (PCR) thermal cycler using TaqMan genotyping assay. The genetic data obtained was subsequently subjected to statistical analysis to relate the SNPs to the onset of CD in the Malaysian population. The genotyping assay and data were further validated selectively by conventional PCR amplification of the SNP sites and DNA sequencing. RESULTS The rs3807306 G allele was a risk factor for CD (OR 2.3630, P = 0.00004), whereas the homozygous T genotype was protective against the disease (OR 0.2038, P = 0.00004). The heterozygous A/G genotype of rs10954213 was significantly associated with CD (OR 4.319, P = 0.0377). On the other hand, the homozygous A and heterozygous A/G genotypes of the rs11770589 were significant in the controls (OR 0.4242, P = 0.0166) and patients (OR 2.000, P = 0.0179), respectively. In the ethnic-stratification analysis, the rs11770589 homozygous A genotype was protective in Indians (OR 0.1551, P = 0.0112). CONCLUSION IRF5 gene polymorphisms may play a role in the development of CD in the Malaysian population.
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Affiliation(s)
- Kek Heng Chua
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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Brugière O, Thabut G, Krawice-Radanne I, Rizzo R, Dauriat G, Danel C, Suberbielle C, Mal H, Stern M, Schilte C, Pretolani M, Carosella ED, Rouas-Freiss N. Role of HLA-G as a predictive marker of low risk of chronic rejection in lung transplant recipients: a clinical prospective study. Am J Transplant 2015; 15:461-71. [PMID: 25488753 DOI: 10.1111/ajt.12977] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Revised: 08/04/2014] [Accepted: 08/07/2014] [Indexed: 01/25/2023]
Abstract
Human leukocyte antigen G (HLA-G) expression is thought to be associated with a tolerance state following solid organ transplantation. In a lung transplant (LTx) recipient cohort, we assessed (1) the role of HLA-G expression as a predictor of graft acceptance, and (2) the relationship between (i) graft and peripheral HLA-G expression, (ii) HLA-G expression and humoral immunity and (iii) HLA-G expression and lung microenvironment. We prospectively enrolled 63 LTx recipients (median follow-up 3.26 years [min: 0.44-max: 5.03]). At 3 and 12 months post-LTx, we analyzed graft HLA-G expression by immunohistochemistry, plasma soluble HLA-G (sHLA-G) level by enzyme-linked immunosorbent assay, bronchoalveolar lavage fluid (BALF) levels of cytokines involved in chronic lung allograft dysfunction (CLAD) and anti-HLA antibodies (Abs) in serum. In a time-dependent Cox model, lung HLA-G expression had a protective effect on CLAD occurrence (hazard ratio: 0.13 [0.03-0.58]; p = 0.008). The same results were found when computing 3-month and 1-year conditional freedom from CLAD (p = 0.03 and 0.04, respectively [log-rank test]). Presence of anti-HLA Abs was inversely associated with graft HLA-G expression (p = 0.02). Increased BALF level of transforming growth factor-β was associated with high plasma sHLA-G level (p = 0.02). In conclusion, early graft HLA-G expression in LTx recipients with a stable condition was associated with graft acceptance in the long term.
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Affiliation(s)
- O Brugière
- Service de Pneumologie B et de Transplantation Pulmonaire, Centre Hospitalier Universitaire (CHU) Bichat-Claude Bernard, Paris, France; Faculté de Médecine Denis Diderot, Université Paris 7, Paris, France; Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France; DHU Fire, Paris, France; CEA, Institut des Maladies Emergentes et des Therapies Innovantes (IMETI), Service de Recherche en Hemato-Immunologie (SRHI), Hopital Saint-Louis, Paris, France; Sorbonne Paris Cité, University Paris Diderot, IUH, Hopital Saint-Louis, Paris, France
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Zidi I, Ben Yahia H, Bortolotti D, Mouelhi L, Laaribi AB, Ayadi S, Zidi N, Houissa F, Debbech R, Boudabous A, Najjar T, Di Luca D, Rizzo R. Association between sHLA-G and HLA-G 14-bp deletion/insertion polymorphism in Crohn’s disease. Int Immunol 2015; 27:289-96. [DOI: 10.1093/intimm/dxv002] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 01/07/2015] [Indexed: 12/13/2022] Open
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HLA-G and susceptibility to develop celiac disease. Hum Immunol 2015; 76:36-41. [DOI: 10.1016/j.humimm.2014.12.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Revised: 05/19/2014] [Accepted: 12/03/2014] [Indexed: 11/20/2022]
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Ramos CS, Gonçalves AS, Marinho LC, Gomes Avelino MA, Saddi VA, Lopes AC, Simões RT, Wastowski IJ. Analysis of HLA-G gene polymorphism and protein expression in invasive breast ductal carcinoma. Hum Immunol 2014; 75:667-72. [PMID: 24759678 DOI: 10.1016/j.humimm.2014.04.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Revised: 02/19/2014] [Accepted: 04/06/2014] [Indexed: 12/22/2022]
Abstract
The human leukocyte antigen G (HLA-G) is a non-classical HLA class I molecule predominantly expressed in trophoblastic placental cells to protect the fetus during pregnancy. However, evidence has shown that this molecule may be implicated in the immune escape mechanism of tumor cells. Thus, the aim of this study was to evaluate the frequency of 14-bp insertion/deletion HLA-G polymorphism, as well as the expression of this molecule in patients with invasive breast ductal carcinoma (IDC). A significant association between the expression of HLA-G and the presence of metastasis in lymph nodes (p=0.01) was observed and the expression of HLA-G was significantly higher in patients with shorter survival time (p=0.03). The analysis suggests that the polymorphism observed in patients with IDC may be inducing a higher expression of the HLA-G molecule, which may possibly contribute to shorter survival time and a worse clinical prognosis for such patients.
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Affiliation(s)
- Caroline Steglich Ramos
- Master's Program in Genetics, Pontifical Catholic University of Goiás, Goiânia, Goiás 74000, Brazil
| | - Andréia Souza Gonçalves
- Department of Stomatology [Oral Pathology], Dental School, Federal University of Goiás, Goiânia, Goiás 74000, Brazil
| | - Larissa Cardoso Marinho
- Departament of Medicine, Pontifical Catholic University of Goiás, Goiânia, Goiás 74000, Brazil
| | | | - Vera Aparecida Saddi
- Master's Program in Genetics, Pontifical Catholic University of Goiás, Goiânia, Goiás 74000, Brazil; Departament of Medicine, Pontifical Catholic University of Goiás, Goiânia, Goiás 74000, Brazil; Laboratory of Oncogenetics and Radiobiology, Association of Cancer Combat in Goiás, Brazil
| | - Aryanne Cristina Lopes
- Departament of Medicine, Pontifical Catholic University of Goiás, Goiânia, Goiás 74000, Brazil
| | - Renata Toscano Simões
- Institute of Education and Research, Santa Casa de Belo Horizonte, Belo Horizonte, Minas Gerais 31000, Brazil
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Bortolotti D, Gentili V, Rotola A, Cassai E, Rizzo R, Luca DD. Impact of HLA-G analysis in prevention, diagnosis and treatment of pathological conditions. World J Methodol 2014; 4:11-25. [PMID: 25237627 PMCID: PMC4145573 DOI: 10.5662/wjm.v4.i1.11] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 12/28/2013] [Accepted: 01/16/2014] [Indexed: 02/06/2023] Open
Abstract
Human leukocyte antigen-G (HLA-G) is a non-classical HLA class I molecule that differs from classical HLA class I molecules by low polymorphism and tissue distribution. HLA-G is a tolerogenic molecule with an immune-modulatory and anti-inflammatory function on both innate and adaptative immunity. This peculiar characteristic of HLA-G has led to investigations of its role in pathological conditions in order to define possible uses in diagnosis, prevention and treatment. In recent years, HLA-G has been shown to have an important implication in different inflammatory and autoimmune diseases, pregnancy complications, tumor development and aggressiveness, and susceptibility to viral infections. In fact, HLA-G molecules have been reported to alternate at both genetic and protein level in different disease situations, supporting its crucial role in pathological conditions. Specific pathologies show altered levels of soluble (s)HLA-G and different HLA-G gene polymorphisms seem to correlate with disease. This review aims to update scientific knowledge on the contribution of HLA-G in managing pathological conditions.
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Heparin increases HLA-G levels in primary antiphospholipid syndrome. Clin Dev Immunol 2012; 2012:232390. [PMID: 22654952 PMCID: PMC3359668 DOI: 10.1155/2012/232390] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2011] [Revised: 03/03/2012] [Accepted: 03/05/2012] [Indexed: 01/20/2023]
Abstract
Objectives. The aim of this study was to investigate the HLA-G serum levels in Primary Antiphospholipid Syndrome (PAPS) patients, its impact on clinical and laboratory findings, and heparin treatment. Methods. Forty-four PAPS patients were age and gender matched with 43 controls. HLA-G serum levels were measured using an enzyme-linked immunosorbent assay (ELISA). Results. An increase in soluble HLA-G levels was found in patients compared to controls (3.35 (0–22.9) versus 1.1 (0–14), P = 0.017). There were no significant differences in HLA-G levels between patients with and without obstetric events, arterial thrombosis, venous thrombosis, or stroke. Sixty-six percent of patients were being treated with heparin. Interestingly, patients treated with heparin had higher HLA-G levels than ones who were not treated with this medication (5 (0–22.9) versus 1.8 (0–16) ng/mL, P = 0.038). Furthermore, patients on heparin who experienced obstetric events had a trend to increased HLA-G levels compared to patients who were not on heparin and did not have obstetric events (5.8 (0–22.9) versus 2 (0–15.2) ng/mL, P = 0.05). Conclusion. This is the first study to demonstrate that serum HLA-G levels are increased in APS patients. We also demonstrated that heparin increases HLA-G levels and may increase tolerance towards autoantigens.
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White SR. Human leucocyte antigen-G: expression and function in airway allergic disease. Clin Exp Allergy 2011; 42:208-17. [PMID: 22092595 DOI: 10.1111/j.1365-2222.2011.03881.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Human leucocyte antigen-G (HLA-G) is a non-classical HLA class I molecule demonstrated originally in placental trophoblast cells. Recognition of the importance of HLA-G to the maternal immune accommodation of the semi-allogeneic fetus has led to investigations of its role in the suppression of immune responses and induction of tolerance. More recently, HLA-G has been shown to have increased expression in several immunological diseases including asthma and allergic rhinitis. The focus of this review is the potential role of HLA-G in immunological airway diseases.
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Affiliation(s)
- S R White
- Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
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Monsiváis-Urenda AE, Baranda L, Alvarez-Quiroga C, Abud-Mendoza C, González-Amaro R. Expression and functional role of HLA-G in immune cells from patients with systemic lupus erythematosus. J Clin Immunol 2011; 31:369-78. [PMID: 21188486 DOI: 10.1007/s10875-010-9496-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2010] [Accepted: 12/07/2010] [Indexed: 10/18/2022]
Abstract
Human leukocyte antigen (HLA)-G is a class I non-classical HLA molecule with an important regulatory role on the immune response. The possible role of this molecule in the pathogenesis of SLE has not been explored. In this work, we evaluated the expression and function of HLA-G in SLE patients. We studied 37 SLE patients as well as 25 healthy donors. Peripheral blood monocytes and in vitro-generated dendritic cells (DCs) were analyzed for HLA-G expression by flow cytometry. We found that monocytes from SLE patients as well as mature CD83+ DCs showed a diminished expression of HLA-G compared with healthy controls. In addition, monocytes from SLE patients showed a diminished induction of HLA-G expression in response to stimulation with IL-10. Furthermore, functional assays showed that these monocytes pre-treated with IFN-γ exhibited a diminished capability to inhibit the proliferation of autologous lymphocytes. Finally, lymphocytes from SLE patients tended to display a lower acquisition of HLA-G (by trogocytosis) from autologous monocytes compared to controls. Our results might have implications for the immune abnormalities observed in patients with SLE.
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Lin A, Zhu CC, Chen HX, Chen BF, Zhang X, Zhang JG, Wang Q, Zhou WJ, Hu W, Yang HH, Xu HH, Yan WH. Clinical relevance and functional implications for human leucocyte antigen-g expression in non-small-cell lung cancer. J Cell Mol Med 2011; 14:2318-29. [PMID: 19602033 PMCID: PMC3822572 DOI: 10.1111/j.1582-4934.2009.00858.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
HLA-G has been documented both in establishment of anti-tumour immune responses and in tumour evasion. To investigate the clinical relevance of HLA-G in non-small-cell lung cancer (NSCLC), expression status and potential significance of HLA-G in NSCLC were analysed. In this study, HLA-G expression in 101 NSCLC primary lesions and plasma soluble HLA-G (sHLA-G) from 91 patients were analysed with immunohistochemistry and ELISA, respectively. Correlations between HLA-G status and various clinical parameters including survival time were evaluated. Meanwhile, functional analysis of transfected cell surface HLA-G expression and plasma sHLA-G form NSCLC patients on natural killer (NK) cell cytolysis were performed. Data revealed that HLA-G was expressed in 41.6% (42/101) NSCLC primary lesions, while undetectable in adjacent normal lung tissues. HLA-G expression in NSCLC lesions was strongly correlated to disease stages (P= 0.002). Plasma sHLA-G from NSCLC patients was markedly higher than that in normal controls (P= 0.004), which was significantly associated with the disease stages (I versus IV, P= 0.025; II versus IV, P= 0.029). Patient plasma sHLA-G level (≥median, 32.0 U/ml) had a significantly shorter survival time (P= 0.044); however, no similar significance was observed for the lesion HLA-G expression. In vitro data showed that both cell surface HLA-G and patient plasma sHLA-G could dramatically decrease the NK cell cytolysis. Our findings indicated that both lesion HLA-G expression and plasma sHLA-G in NSCLC is related to the disease stage and can exert immunosuppression to the NK cell cytolysis, indicating that HLA-G could be a potential therapeutic target. Moreover, plasma sHLA-G in NSCLC patients could be used as a prognosis factor for NSCLC.
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Affiliation(s)
- A Lin
- Human Tissue Bank, Taizhou Hospital of Zhejiang Province, Wenzhou Medical College, Linhai, Zhejiang, China
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Carosella ED, LeMaoult J. HLA-G: a look back, a look forward. Cell Mol Life Sci 2011; 68:337-40. [PMID: 21088981 PMCID: PMC11114643 DOI: 10.1007/s00018-010-0577-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2010] [Accepted: 10/22/2010] [Indexed: 01/03/2023]
Affiliation(s)
- Edgardo D Carosella
- CEA, I2BM, Service de Recherches en Hemato-Immunologie, 75475 Paris, France.
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Fainardi E, Castellazzi M, Stignani M, Morandi F, Sana G, Gonzalez R, Pistoia V, Baricordi OR, Sokal E, Peña J. Emerging topics and new perspectives on HLA-G. Cell Mol Life Sci 2011; 68:433-51. [PMID: 21080027 PMCID: PMC11114687 DOI: 10.1007/s00018-010-0584-3] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2010] [Accepted: 10/22/2010] [Indexed: 02/07/2023]
Abstract
Following the Fifth International Conference on non-classical HLA-G antigens (HLA-G), held in Paris in July 2009, we selected some topics which focus on emerging aspects in the setting of HLA-G functions. In particular, HLA-G molecules could play a role in: (1) various inflammatory disorders, such as multiple sclerosis, intracerebral hemorrhage, gastrointestinal, skin and rheumatic diseases, and asthma, where they may act as immunoregulatory factors; (2) the mechanisms to escape immune surveillance utilized by several viruses, such as human cytomegalovirus, herpes simplex virus type 1, rabies virus, hepatitis C virus, influenza virus type A and human immunodeficiency virus 1 (HIV-1); and (3) cytokine/chemokine network and stem cell transplantation, since they seem to modulate cell migration by the downregulation of chemokine receptor expression and mesenchymal stem cell activity blocking of effector cell functions and the generation of regulatory T cells. However, the immunomodulatory circuits mediated by HLA-G proteins still remain to be clarified.
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Affiliation(s)
- Enrico Fainardi
- Neuroradiology Unit, Department of Neurosciences and Rehabilitation, Azienda Ospedaliera-Universitaria, Arcispedale S. Anna, Corso della Giovecca 203, 44100 Ferrara, Italy.
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Cardili RN, Alves TG, Freitas JCOC, Soares CP, Mendes-Junior CT, Soares EG, Donadi EA, Silva-Souza C. Expression of human leucocyte antigen-G primarily targets affected skin of patients with psoriasis. Br J Dermatol 2010; 163:769-75. [PMID: 20560954 DOI: 10.1111/j.1365-2133.2010.09917.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND The nonclassical human leucocyte antigen (HLA)-G molecule has been well recognized as a tolerogenic molecule and few studies have evaluated the role of the molecule in inflammatory cutaneous autoimmune diseases. OBJECTIVES To evaluate the expression of HLA-G in skin specimens of patients with psoriasis and to analyse its correlation with epidemiological and clinical variables. METHODS Thirty untreated patients with psoriasis and 32 healthy individuals were enrolled. Immunohistochemistry was applied to identify HLA-G expression in formalin-fixed paraffin-embedded cutaneous skin biopsies. RESULTS Soluble and membrane-bound HLA-G expression was detected in 30 (90%) of the skin specimens from patients presenting clinical and histopathological features of psoriasis. Although infiltrating lymphomononuclear cells of the dermis exhibited HLA-G expression, the epidermis was primarily targeted. HLA-G expression was also observed in 27% (three of 11) of the specimens that exhibited no clinical and histopathological features of psoriasis (nonaffected areas). In contrast, skin specimens obtained from healthy individuals exhibited no HLA-G expression (P < 0·0001). The intensity of HLA-G expression was not associated with type I/II psoriasis, Psoriasis Area and Severity Index score or clinical forms. CONCLUSIONS As the HLA-G molecule was consistently expressed in affected and, to a lesser extent, in nonaffected areas of untreated patients with psoriasis, irrespective of the severity of the clinical variants, one may hypothesize that the presence of HLA-G may be responsible, at least in part, for the regulation of autoimmune effector cells.
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Affiliation(s)
- R N Cardili
- Department of Internal Medicine, Division of Dermatology, School of Medicine of Ribeirão Preto, University of São Paulo, USP, Ribeirão Preto, São Paulo, Brazil
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Kusanovic JP, Romero R, Jodicke C, Mazaki-Tovi S, Vaisbuch E, Erez O, Mittal P, Gotsch F, Chaiworapongsa T, Edwin SS, Pacora P, Hassan SS. Amniotic fluid soluble human leukocyte antigen-G in term and preterm parturition, and intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med 2009; 22:1151-66. [PMID: 19916713 PMCID: PMC3424396 DOI: 10.3109/14767050903019684] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE Circulating soluble human leukocyte antigen-G (sHLA-G) has been associated with pregnancy complications, and determination of sHLA-G concentrations in amniotic fluid (AF) has been reported in normal pregnancies. Our aim was to determine if the AF concentrations of sHLA-G change with advancing gestation, spontaneous labor at term, and in patients with spontaneous preterm labor (PTL) with intact membranes, as well as in those with preterm prelabor rupture of membranes (PROM), in the presence or absence of intra-amniotic infection/inflammation (IAI). STUDY DESIGN This cross-sectional study included the following groups: (1) mid-trimester (n = 55); (2) normal pregnancy at term with (n = 50) and without (n = 50) labor; (3) spontaneous PTL with intact membranes divided into: (a) PTL who delivered at term (n = 153); (b) PTL who delivered preterm without IAI (n = 108); and (c) PTL with IAI (n = 84); and (4) preterm PROM with (n = 46) and without (n = 44) IAI. sHLA-G concentrations were determined by ELISA. Non-parametric statistics were used for analysis. RESULTS (1) Among patients with PTL, the median AF sHLA-G concentration was higher in patients with IAI than in those without IAI or women that delivered at term (p < 0.001 for both comparisons); (2) Similarly, patients with preterm PROM and IAI had higher median AF sHLA-G concentrations than those without IAI (p = 0.004); (3) Among patients with PTL and delivery, those with histologic chorioamnionitis and/or funisitis had a higher median AF sHLA-G concentration than those without histologic inflammation (p < 0.001); and (4) The median AF sHLA-G concentration did not change with advancing gestational age. CONCLUSIONS AF sHLA-G concentrations are elevated in preterm parturition associated to IAI as well as in histologic chorioamnionitis. We propose that sHLA-G may participate in the regulation of the host immune response against intra-amniotic infection.
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Affiliation(s)
- Juan Pedro Kusanovic
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
| | - Roberto Romero
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, USA
| | - Cristiano Jodicke
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
| | - Shali Mazaki-Tovi
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
| | - Edi Vaisbuch
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
| | - Offer Erez
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
| | - Pooja Mittal
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
| | - Francesca Gotsch
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
| | - Tinnakorn Chaiworapongsa
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
| | - Sam S. Edwin
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
| | - Percy Pacora
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
| | - Sonia S. Hassan
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
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Veit TD, Cordero EAA, Mucenic T, Monticielo OA, Brenol JCT, Xavier RM, Delgado-Cañedo A, Chies JAB. Association of the HLA-G 14 bp polymorphism with systemic lupus erythematosus. Lupus 2009; 18:424-30. [PMID: 19318395 DOI: 10.1177/0961203308098187] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Human leukocyte antigen-G (HLA-G) is a nonclassical class I major histocompatibility complex molecule which is induced at the course of inflammatory pathologies, and its expression has been suggested as a possible mechanism of tissue protection against autoimmune inflammatory responses, therefore acting as a mechanism of immune surveillance. We investigated the influence of the 14 bp polymorphism of the HLA-G gene on systemic lupus erythematosus (SLE) by analyzing 293 patients with SLE and 460 healthy controls. The patient's group was not in Hardy-Weinberg equilibrium, presenting an excess of heterozygotes (P = 0.014). The heterozygote group exhibited lower systemic lupus erythematosus disease activity indexes than the homozygous deletion group and the homozygous insertion group (mean value = 2.29 against 2.97 and 3.4, respectively, P = 0.035). Photosensitive patients showed a higher frequency of heterozygotes and an equivalent lower frequency of homozygotes for deletion; on the other hand, patients without arthritis presented a higher frequency of heterozygotes than the arthritis group and also a lower frequency of the del/del genotype. Overall, our results support the idea of a role of the HLA-G insertion/deletion polymorphism and therefore a role for the HLA-G molecule, on the pathology of SLE.
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Affiliation(s)
- T D Veit
- Genetics Department, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
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31
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Meresse B, Cerf-Bensussan N. Innate T cell responses in human gut. Semin Immunol 2009; 21:121-9. [PMID: 19231234 DOI: 10.1016/j.smim.2009.01.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2008] [Accepted: 01/20/2009] [Indexed: 01/27/2023]
Abstract
One arm of the gut-associated immune system is represented by a vast collection of T lymphocytes which participate in the subtle interplay between innate and adaptive immune mechanisms and maintain homeostasis at the main body external surface. Mounting data are providing exciting new insight into the innate-like mechanisms which enable intestinal T cells to rapidly sense local conditions and which broaden the spectrum of their functions and regulation at this strategic location. Herein we discuss how innate-like T cell recognition by unconventional T cell subsets and expression of innate NK receptors might modulate immune T cell responses in the human normal or diseased intestine.
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Affiliation(s)
- Bertrand Meresse
- INSERM U793, Université Paris Descartes, Medical School, 156 rue de Vaugirard, 75737 Paris Cedex 15, France.
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32
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Genetic variants in the HLA-G region are associated with Kawasaki disease. Hum Immunol 2008; 69:867-71. [PMID: 18976687 DOI: 10.1016/j.humimm.2008.10.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2008] [Revised: 09/12/2008] [Accepted: 10/01/2008] [Indexed: 11/23/2022]
Abstract
Kawasaki disease is an acute, self-limited vasculitis of infants and children, manifest as fever and signs of mucocutaneous inflammation. Treatment with high-dose immunoglobulin reduces systemic inflammation and prevents coronary artery lesions in Kawasaki disease. In this study, we investigated the possible association of the major histocompatibililty complex (MHC) region for the susceptibility to Kawasaki disease using an MHC panel of 2360 single nucleotide polymorphism (SNP) markers. Analysis of data obtained from screening MHC-specific SNP chips with 48 case and 90 control subjects revealed five candidate loci with significance levels of uncorrected p < 0.01. However, only one candidate locus (HLA-G) was confirmed to have a significant association with Kawasaki disease (rs2523790, odds ratio [OR] = 3.00, 95% confidence interval [95% CI] = 1.14-7.91, uncorrected p = 0.0263) in the replication study using 44 new case subjects and the previous 90 controls. In the fine mapping of the HLA-G locus, in particular, a nonsynonymous SNP (C/A) of the HLA-G gene (rs12722477, Leu134Ile) was significantly associated with Kawasaki disease (OR = 3.23, 95% CI = 1.12-9.32). A subgroup analysis showed that this association was more apparent in patients with coronary artery aneurysms (OR = 4.02, 95% CI = 1.23-13.19). Therefore, our results indicate that HLA-G may play a crucial role for the susceptibility to Kawasaki disease.
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33
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A critical look at HLA-G. Trends Immunol 2008; 29:313-21. [DOI: 10.1016/j.it.2008.02.012] [Citation(s) in RCA: 170] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2008] [Revised: 02/04/2008] [Accepted: 02/19/2008] [Indexed: 01/10/2023]
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34
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Veit TD, Vianna P, Scheibel I, Brenol C, Brenol JCT, Xavier RM, Delgado-Cañedo A, Gutierrez JE, Brandalize APC, Schuler-Faccini L, Chies JAB. Association of the HLA-G 14-bp insertion/deletion polymorphism with juvenile idiopathic arthritis and rheumatoid arthritis. ACTA ACUST UNITED AC 2008; 71:440-6. [DOI: 10.1111/j.1399-0039.2008.01019.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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35
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Torres MI, Ríos A. Current view of the immunopathogenesis in inflammatory bowel disease and its implications for therapy. World J Gastroenterol 2008; 14:1972-80. [PMID: 18395894 PMCID: PMC2701515 DOI: 10.3748/wjg.14.1972] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Although the aetiology of inflammatory bowel disease (IBD) remains unknown, the pathogenesis is gradually being unravelled, seeming to be the result of a combination of environmental, genetic, and immunological factors in which an uncontrolled immune response within the intestinal lumen leads to inflammation in genetically predisposed individuals. Multifactorial evidence suggests that a defect of innate immune response to microbial agents is involved in IBD. This editorial outlines the immunopathogenesis of IBD and their current and future therapy. We present IBD as a result of dysregulated mucosal response in the intestinal wall facilitated by defects in epithelial barrier function and the mucosal immune system with excessive production of cytokines growth factors, adhesion molecules, and reactive oxygen metabolites, resulting in tissue injury. Established and evolving therapies are discussed in the second part of this editorial and at the end of this section we review new therapies to modulate the immune system in patients with IBD.
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36
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Carosella ED, Moreau P, Lemaoult J, Rouas-Freiss N. HLA-G: from biology to clinical benefits. Trends Immunol 2008; 29:125-32. [PMID: 18249584 DOI: 10.1016/j.it.2007.11.005] [Citation(s) in RCA: 284] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2007] [Revised: 11/20/2007] [Accepted: 11/27/2007] [Indexed: 02/07/2023]
Abstract
The relevance of the nonclassical human leukocyte antigen (HLA) class I molecule HLA-G in human physiological and pathological contexts has been the center of intense investigation. In light of the recent advances, we report here the clinical implications of HLA-G as a tolerogenic molecule promoting uterine implantation of the embryo or acceptance of solid allografts while allowing the evasion of tumors or viruses from the immune response. These recent findings are important in terms of clinical benefits at both diagnostic and therapeutic levels.
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Affiliation(s)
- Edgardo D Carosella
- Institut Universitaire d'Hématologie, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, IUH, 1 75010 Paris, France
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37
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Rosado S, Perez-Chacon G, Mellor-Pita S, Sanchez-Vegazo I, Bellas-Menendez C, Citores MJ, Losada-Fernandez I, Martin-Donaire T, Rebolleda N, Perez-Aciego P. Expression of human leukocyte antigen-G in systemic lupus erythematosus. Hum Immunol 2008; 69:9-15. [PMID: 18295670 DOI: 10.1016/j.humimm.2007.11.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2007] [Revised: 10/27/2007] [Accepted: 11/01/2007] [Indexed: 02/05/2023]
Abstract
The purpose of this study was to examine the expression of human leukocyte antigen-G (HLA-G) in patients with systemic lupus erythematosus (SLE) and its relation with interleukin-10 (IL-10) production. The study included 50 female SLE patients and 59 healthy female donors. HLA-G expression in peripheral blood and cutaneous biopsies was determined by flow cytometry and immunohistochemistry, respectively. Soluble HLA-G (sHLA-G) and IL-10 were quantified in serum samples by enzyme-linked immunosorbent assay. SLE patients presented with serum sHLA-G and IL-10 levels significantly higher than that observed in controls (median [interquartile range (IQR)] = 43.6 U/ml [23.2-150.2] vs 26.84 U/ml [6.0-45.2], p = 0.004; and 1.4 pg/ml [0-2.3] vs 0 pg/ml [0-1.5], p = 0.01, respectively). But no correlation was observed between sHLA-G and both IL-10 levels and the disease activity index for SLE patients. The expression of membrane HLA-G in peripheral lymphocytes from SLE patients was low, but higher than in controls (median [IQR] = 1.5% [0.6-1.8] and 0.3% [0.2-0.8], respectively; p = 0.02). Finally, these findings were in accordance with the weak expression of HLA-G in skin biopsies. Despite the fact that patients present higher levels of HLA-G than healthy controls, which suggests a possible relevance of this molecule in SLE, it seems not to be related to IL-10 production or disease activity.
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38
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Rizzo R, Melchiorri L, Simone L, Stignani M, Marzola A, Gullini S, Baricordi OR. Different production of soluble HLA-G antigens by peripheral blood mononuclear cells in ulcerative colitis and Crohn's disease: a noninvasive diagnostic tool? Inflamm Bowel Dis 2008; 14:100-5. [PMID: 17886287 DOI: 10.1002/ibd.20281] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND HLA-G antigens are nonclassical major histocompatibility complex (MHC) class I molecules characterized by tolerogenic and antiinflammatory properties. Recently, a different expression of HLA-G antigens has been observed between intestinal biopsies of ulcerative colitis (UC) and Crohn's disease (CD) patients. These data suggested a functional role for HLA-G molecules in the diseases and proposed the HLA-G modulation as a marker for the diagnosis of UC and CD. The soluble HLA-G antigens (sHLA-G) are circulating molecules mainly produced by activated peripheral blood CD14+ monocytes. METHODS We tested, by specific enzyme-linked immunosorbent assay (ELISA), the sHLA-G molecule levels in the supernatants of unstimulated and bacterial lipopolysaccharide (LPS)-stimulated cultures of peripheral blood mononuclear cells (PBMC) from 30 healthy subjects, 10 CD, and 18 UC patients. The data were not influenced by treatment or disease activity. RESULTS The results confirmed a different sHLA-G expression between the diseases, with a spontaneous secretion of sHLA-G in CD patients but not in UC and healthy subjects. Moreover, a lack of sHLA-G antigens has been reported in UC patient cultures after LPS activation but not in healthy subjects and CD patients. The defective sHLA-G production was related to an impaired IL-10 secretion in UC but not in CD. CONCLUSIONS Overall, these results confirm the presence of a different biological characteristic between CD and UC patients and suggest sHLA-G production by PBMC as a noninvasive diagnostic tool in the early phases of the diseases.
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Affiliation(s)
- Roberta Rizzo
- Department of Experimental and Diagnostic Medicine, Section of Medical Genetics, University of Ferrara, Italy.
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39
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Downs-Kelly E, Schade AE, Hansel DE. The role of HLA-G in gastrointestinal inflammatory disease and malignancy. Semin Cancer Biol 2007; 17:451-8. [PMID: 17716911 DOI: 10.1016/j.semcancer.2007.07.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2007] [Revised: 06/22/2007] [Accepted: 07/04/2007] [Indexed: 10/23/2022]
Abstract
Human leukocyte antigen (HLA)-G has been shown to act as an immune-inhibitory molecule and to interfere with the normal functions of natural killer (NK) cells and T-cells, conferring a potential route for HLA-G expressing cells to escape host immune surveillance. These findings have led to the rather intense study of HLA-G expression in several different arenas, including organ transplantation, inflammatory conditions, and in a wide variety of neoplasms including hematolymphoid neoplasms, visceral carcinomas, gliomas, and dermal-based neoplasms. This review will focus on the role of HLA-G in inflammatory conditions of the bowel, which can serve as an initiator of neoplastic alterations, as well as examine HLA-G expression and function in a variety of gastrointestinal malignancies. Although there are only a limited number of studies that have examined HLA-G in the gastrointestinal tract, the role of HLA-G has been controversial in this organ system with conflicting results reported even within the same tumor type.
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Affiliation(s)
- Erinn Downs-Kelly
- Department of Pathology and Laboratory Medicine, The Cleveland Clinic, L25, 9500 Euclid Ave., Cleveland, OH 44195, United States
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40
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Abstract
Celiac disease (CD) is a common autoimmune disorder characterized by an immune response to ingested gluten and has a strong HLA association with HLA-DQ2 and HLA-DQ8 molecules, but human HLA-DQ risk factors do not explain the entire genetic susceptibility to gluten intolerance. CD is caused by the lack of immune tolerance (oral tolerance) to wheat gluten. In this sense, the expression of soluble HLA-G in CD is of special interest because the molecule plays an important role in the induction of immune tolerance. The enhanced expression of soluble HLA-G found in CD may be part of a mechanism to restore the gluten intolerance. In this editorial, we review recent progress in understanding CD in relation to its prevalence, diagnosis and possible mechanisms of pathogenesis.
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41
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Jabri B, Ebert E. Human CD8+intraepithelial lymphocytes: a unique model to study the regulation of effector cytotoxic T lymphocytes in tissue. Immunol Rev 2007; 215:202-14. [PMID: 17291290 DOI: 10.1111/j.1600-065x.2006.00481.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The epithelium of the human small intestine contains a large population of intraepithelial cytolytic alphabeta T-cell receptor (TCR) CD8 alpha beta T lymphocytes (IE-CTLs), whose main role is to sustain epithelial integrity by rapidly eliminating infected and damaged cells. In mouse, the recognition of inducible/modified self-molecules, i.e. non-classical major histocompatibility complex (MHC) class I molecules, is mediated by the TCR and natural killer receptors (NKRs) co-expressed on the cell surface of a non-conventional autoreactive CD8 alpha alpha alpha beta TCR cell subset. In contrast, in humans, the recognition of non-classical MHC class I molecules induced by stress and inflammation on intestinal epithelial cells (IECs) is principally mediated by NKRs expressed on conventional CD8 alpha beta alpha beta TCR cells. By sensing microenvironmental signals of inflammation and stress through NKRs, IE-CTLs fine tune their TCR activation threshold. Furthermore, IE-CTLs under particular conditions, involving interleukin-15 upregulation, acquire the capacity to kill distressed intestinal epithelial cells in an antigen non-specific manner. Adaptive IE-CTLs appear hence to have autoreactive properties and modulate their immune response based on innate signals, reflecting the fitness of the tissue.
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Affiliation(s)
- Bana Jabri
- Department of Pathology, Medicine and Pediatrics, University of Chicago, Chicago, IL 60637, USA.
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42
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Singh AM, Moore PE, Gern JE, Lemanske RF, Hartert TV. Bronchiolitis to asthma: a review and call for studies of gene-virus interactions in asthma causation. Am J Respir Crit Care Med 2006; 175:108-19. [PMID: 17053206 DOI: 10.1164/rccm.200603-435pp] [Citation(s) in RCA: 163] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Viral infections are important causes of asthma exacerbations in children, and lower respiratory tract infections (LRTIs), caused by viruses such as respiratory syncytial virus (RSV) and rhinovirus (RV), are a leading cause of bronchiolitis in infants. Infants hospitalized with bronchiolitis are at significantly increased risk for both recurrent wheezing and childhood asthma. To date, studies addressing the incidence of asthma after bronchiolitis severe enough to warrant hospitalization have focused almost exclusively on RSV, but a number of recent studies suggest that other respiratory pathogens, including RV, may contribute as well. It is not known whether viral bronchiolitis directly contributes to asthma causation or simply identifies infants at risk for subsequent wheezing, as from an atopic predisposition or preexisting abnormal lung function. Alternatively, the properties of the infecting virus may be important. Thus, many possible determinants exist that may contribute to the severity of bronchiolitis and the subsequent development of asthma. One such determinant is the potential involvement of genetic susceptibility loci to asthma after viral bronchiolitis, a critical area that is just beginning to be evaluated. By clarifying the roles of both host- (genetic) and virus- (environment) specific factors that contribute to the frequency and severity of viral LRTI, it may be possible to determine if severe LRTIs cause asthma, or if asthma susceptibility predisposes patients to severe LRTI in response to viral infection. Characterizing these relationships offers the potential of identifying at-risk hosts in whom preventing or delaying infection could alter the phenotypic expression of asthma.
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Affiliation(s)
- Anne Marie Singh
- Department of Medicine, University of Wisconsin-Madison, Madison, WI 53792, USA.
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43
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Luque J, Torres MI, Aumente MD, Marín J, García-Jurado G, González R, Pascual D, Guerra N, López-Rubio F, Alvarez-López MR, Arizón JM, Peña J. Soluble HLA-G in heart transplantation: their relationship to rejection episodes and immunosuppressive therapy. Hum Immunol 2006; 67:257-63. [PMID: 16720205 DOI: 10.1016/j.humimm.2006.02.034] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2005] [Indexed: 11/20/2022]
Abstract
The aims of this study were to quantify the level of soluble HLA-G in heart transplant patients, to determine the relationship between the sHLA-G levels and the appearance of acute rejection episodes, and to identify the influence of immunosuppressive therapy on sHLA-G levels. Analysis of sHLA-G, measured by enzyme-linked immunosorbent assay in the transplant patients, revealed the existence of two similarly sized groups of patients. One group displayed a significant increase (p < 0.001) in sHLA-G during the first month after transplantation while the other group maintained low levels of the molecule (0-30 ng/ml) throughout the study. The latter group displayed a high incidence of recurrent severe rejection. A significant increase (p < 0.01) in sHLA-G 2 hours after administration of immunosuppressive treatment (mycophenolate mofetil, cyclosporine A/FK506, corticoids) was found. These results suggest that sHLA-G participates in the induction of certain levels of immunological tolerance in these recipients.
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Affiliation(s)
- J Luque
- Service of Immunology, Reina Sofía University Hospital, Cordoba, Spain
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44
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Torres MI, López-Casado MA, Luque J, Peña J, Ríos A. New advances in coeliac disease: serum and intestinal expression of HLA-G. Int Immunol 2006; 18:713-8. [PMID: 16569678 DOI: 10.1093/intimm/dxl008] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Coeliac disease (CD) is a common autoimmune disorder characterized by an immune response to ingested gluten and has a strong HLA association with HLA-DQ2 and HLA-DQ8, but as human HLA-DQ risk factors do not explain the entire genetic susceptibility to gluten intolerance. Our aim was to investigate whether HLA-G, a gene located in the MHC class I region, and with important role in the induction of immunotolerance, may contribute to CD susceptibility. We demonstrated the expression of soluble HLA-G (sHLA-G) forms in intestinal biopsy and in serum of patients with CD. Indeed, all patients tested showed a positive expression of HLA-G in intestinal mucosa with different grade of immunoreaction. The serum levels of sHLA-G found in coeliac patients depend on the association with other diseases of autoimmune nature or genetics, and also depend on the transgressions in the diet with gluten ingested. The enhancer expression of sHLA-G in CD could be due as part of a mechanism to try restore the tolerance process towards oral antigens in a disease caused by loss of tolerance to dietary antigens and counteract the inflammation. In summary, in this paper, we demonstrate the association of CD with sHLA-G expression.
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Affiliation(s)
- M I Torres
- Department of Experimental Biology, Faculty of Sciences, University of Jaén, Paraje de las Lagunillas s/n, 23071 Jaén, Spain.
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45
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Abstract
We identified HLA-G as an asthma susceptibility gene in multiple populations and demonstrated that variation in this gene influences subsequent risk for asthma. Prenatal exposure to factors that are correlated with maternal BHR (or perhaps BHR itself) interacts with fetal genotype to determine risk, however. Among fetuses of unaffected mothers, the +1489TT genotype is a marker for increased risk, whereas among fetuses of affected mothers the +1489CC genotype is a marker for increased risk. Studies are underway to understand the mechanism for this interaction and the role of this gene in the pathogenesis of asthma.
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Affiliation(s)
- Carole Ober
- Department of Human Genetics and Obstetrics and Gynecology, University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA.
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46
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Abstract
In a homogeneous group of samples, there are genes whose expression variations can be attributed to factors other than experimental errors. These factors can include natural biological oscillations or metabolic processes. These genes are rarely classified as 'interesting' based on their variability profile. However, their dynamic behaviour can tease out important clues about naturally occurring biological processes in the organism under study and can be used for group classification. Dynamical discriminate function analysis was developed on the concept that stable classification parameters (roots) can be derived from highly variable gene-expression data. Stability of these combinations implies a strongly compensatory relationship that may divulge functional interconnections.
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Affiliation(s)
- I M Dozmorov
- Department of Arthritis and Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
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47
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Tan Z, Shon AM, Ober C. Evidence of balancing selection at the HLA-G promoter region. Hum Mol Genet 2005; 14:3619-28. [PMID: 16236759 DOI: 10.1093/hmg/ddi389] [Citation(s) in RCA: 147] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
HLA-G is a class Ib HLA gene with unique tissue expression pattern and immunomodulatory properties. Polymorphisms in the HLA-G promoter region have been associated with miscarriage and asthma, whereas expression levels have been associated with a wide range of pathologic conditions as well as survival of embryos after in vitro fertilization and of organs after transplantation. Here, we characterize the sequence variation and haplotype structure of the HLA-G promoter and flanking sequences in 44 African Americans, 47 European Americans and 43 Han Chinese by haplotype-specific PCR and sequencing. In all three populations, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, and a genealogy with two common haplotypes separated by deep branches, features that are suggestive of balancing selection acting in this region. Comparisons to HLA-A and a pseudogene, HLA-J, suggested that the observed pattern of sequence variation in the HLA-G promoter region is not likely due to other selected HLA genes. We suggest that the mechanism for this selection is related to the highly regulated expression pattern of HLA-G and that high- and low-expressing promoters may be favored under temporally and/or spatially varying selective pressures.
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Affiliation(s)
- Zheng Tan
- Department of Human Genetics, The University of Chicago, IL 60637, USA.
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Modifications de la réponse immune durant la grossesse : implications dans la polyarthrite rhumatoïde et le lupus systémique. ACTA ACUST UNITED AC 2005. [DOI: 10.1016/j.rhum.2005.02.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Thompson-Chagoyán OC, Maldonado J, Gil A. Aetiology of inflammatory bowel disease (IBD): role of intestinal microbiota and gut-associated lymphoid tissue immune response. Clin Nutr 2005; 24:339-52. [PMID: 15896420 DOI: 10.1016/j.clnu.2005.02.009] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2005] [Accepted: 02/21/2005] [Indexed: 01/01/2023]
Abstract
The aetiology of inflammatory bowel disease (IBD) probably involves a combination of genetic predisposition and environmental factors that may be channelled through an abnormality in gut-barrier function, with a loss of antigen tolerance. Some genetic markers that predispose to inflammatory disease have been identified (alleles DR2, DRB1*0103, DRB1*12 and mutations in the NOD2/CARD15 gene on chromosome 16). Alterations in the pattern of cytokine production by T cell subclasses leading to loss of tolerance to oral antigens have been documented. Moreover, a number of environmental factors (cigarette smoking, use of non-steroid anti-inflammatory drugs, psychological stress and the presence of the caecal appendix) have been postulated as a trigger of IBD. It has also been suggested that the gut microbiota plays a major role in the development and persistence of IBD, and numerous modifications of intestinal microbiota composition have been identified. As a result, manipulation of the microbiota with antibiotics is a current therapeutic strategy; more recently, however, a number of studies have reported promising results when using probiotic organisms to manipulate gut microbiota composition in order to restore tolerance to microbial antigens of the host's own microbiota.
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Affiliation(s)
- Oscar C Thompson-Chagoyán
- Department of Paediatrics, Los Venados General Hospital, Mexican Institute of Social Security, México City, México
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Nicolae D, Cox NJ, Lester LA, Schneider D, Tan Z, Billstrand C, Kuldanek S, Donfack J, Kogut P, Patel NM, Goodenbour J, Howard T, Wolf R, Koppelman GH, White SR, Parry R, Postma DS, Meyers D, Bleecker ER, Hunt JS, Solway J, Ober C. Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21. Am J Hum Genet 2005; 76:349-57. [PMID: 15611928 PMCID: PMC1196380 DOI: 10.1086/427763] [Citation(s) in RCA: 209] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2004] [Accepted: 11/23/2004] [Indexed: 11/03/2022] Open
Abstract
Asthma affects nearly 14 million people worldwide and has been steadily increasing in frequency for the past 50 years. Although environmental factors clearly influence the onset, progression, and severity of this disease, family and twin studies indicate that genetic variation also influences susceptibility. Linkage of asthma and related phenotypes to chromosome 6p21 has been reported in seven genome screens, making it the most replicated region of the genome. However, because many genes with individually small effects are likely to contribute to risk, identification of asthma susceptibility loci has been challenging. In this study, we present evidence from four independent samples in support of HLA-G as a novel asthma and bronchial hyperresponsiveness susceptibility gene in the human leukocyte antigen region on chromosome 6p21, and we speculate that this gene might contribute to risk for other inflammatory diseases that show linkage to this region.
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Affiliation(s)
- Dan Nicolae
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Nancy J. Cox
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Lucille A. Lester
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Daniel Schneider
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Zheng Tan
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Christine Billstrand
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Susan Kuldanek
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Joseph Donfack
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Paul Kogut
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Nina M. Patel
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Jeffrey Goodenbour
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Timothy Howard
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Raoul Wolf
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Gerard H. Koppelman
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Steven R. White
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Rodney Parry
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Dirkje S. Postma
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Deborah Meyers
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Eugene R. Bleecker
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Joan S. Hunt
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Julian Solway
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
| | - Carole Ober
- Departments of Statistics, Human Genetics, Medicine, Pediatrics, and Obstetrics and Gynecology, The University of Chicago, Chicago; Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City; Center for Human Genetics and Departments of Pediatrics and Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, University of South Dakota, Sioux Falls; and Beatrix Children’s Hospital and Department of Pulmonology, University Hospital Groningen, Groningen, The Netherlands
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