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Upadhyay S, Murugu L, Svensson L. Tumor cells escape immunosurveillance by hampering LFA-1. Front Immunol 2025; 16:1519841. [PMID: 39911389 PMCID: PMC11794523 DOI: 10.3389/fimmu.2025.1519841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/02/2025] [Indexed: 02/07/2025] Open
Abstract
During tumor immunosurveillance, leukocytes play a crucial role in the cellular defense system, working collaboratively with other immune components to recognize and eliminate aberrant cells. Integral to this process is the integrin Lymphocyte Function-Associated Antigen 1 (LFA-1). LFA-1 facilitates adhesion during leukocyte migration and helps establish stable cell-to-cell contacts between leukocytes and their targets. Additionally, as a receptor, LFA-1 signaling activates leukocytes, promoting their differentiation and effector functions against cancer. However, tumors can develop mechanisms to evade immune clearance by disrupting LFA-1 functions or hijacking its pathways. In this review, we first detail how leukocytes utilize LFA-1 during immunosurveillance and then explore how tumors counteract this process in the tumor microenvironment (TME) by either altering LFA-1 functions or exploiting it to drive tumorigenesis. Moreover, we discuss therapeutic strategies targeting LFA-1, including inhibitors tested in laboratory studies and animal models, highlighting their potential as anticancer interventions and the need for further research to evaluate their clinical utility.
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Affiliation(s)
| | - Lewis Murugu
- Department of Molecular Biology, Umeå University, Umeå, Sweden
| | - Lena Svensson
- Department of Molecular Biology, Umeå University, Umeå, Sweden
- Umeå Centre for Microbial Research, Umeå University, Umeå, Sweden
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2
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Guerra-Espinosa C, Jiménez-Fernández M, Sánchez-Madrid F, Serrador JM. ICAMs in Immunity, Intercellular Adhesion and Communication. Cells 2024; 13:339. [PMID: 38391953 PMCID: PMC10886500 DOI: 10.3390/cells13040339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/07/2024] [Accepted: 02/09/2024] [Indexed: 02/24/2024] Open
Abstract
Interactions among leukocytes and leukocytes with immune-associated auxiliary cells represent an essential feature of the immune response that requires the involvement of cell adhesion molecules (CAMs). In the immune system, CAMs include a wide range of members pertaining to different structural and functional families involved in cell development, activation, differentiation and migration. Among them, β2 integrins (LFA-1, Mac-1, p150,95 and αDβ2) are predominantly involved in homotypic and heterotypic leukocyte adhesion. β2 integrins bind to intercellular (I)CAMs, actin cytoskeleton-linked receptors belonging to immunoglobulin superfamily (IgSF)-CAMs expressed by leukocytes and vascular endothelial cells, enabling leukocyte activation and transendothelial migration. β2 integrins have long been viewed as the most important ICAMs partners, propagating intracellular signalling from β2 integrin-ICAM adhesion receptor interaction. In this review, we present previous evidence from pioneering studies and more recent findings supporting an important role for ICAMs in signal transduction. We also discuss the contribution of immune ICAMs (ICAM-1, -2, and -3) to reciprocal cell signalling and function in processes in which β2 integrins supposedly take the lead, paying particular attention to T cell activation, differentiation and migration.
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Affiliation(s)
- Claudia Guerra-Espinosa
- Immune System Development and Function Unit, Centro de Biología Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain;
| | - María Jiménez-Fernández
- Immunology Department, Instituto de Investigación Sanitaria Hospital Universitario La Princesa, Universidad Autónoma de Madrid, 28006 Madrid, Spain; (M.J.-F.); (F.S.-M.)
- Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 29029 Madrid, Spain
| | - Francisco Sánchez-Madrid
- Immunology Department, Instituto de Investigación Sanitaria Hospital Universitario La Princesa, Universidad Autónoma de Madrid, 28006 Madrid, Spain; (M.J.-F.); (F.S.-M.)
- Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 29029 Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Juan M. Serrador
- Immune System Development and Function Unit, Centro de Biología Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain;
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Sasazaki S, Kondo H, Moriishi Y, Kawaguchi F, Oyama K, Mannen H. Comprehensive genotyping analysis of single nucleotide polymorphisms responsible for beef marbling in Japanese Black cattle. BMC Genom Data 2024; 25:17. [PMID: 38336623 PMCID: PMC10854043 DOI: 10.1186/s12863-024-01199-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
BACKGROUND Beef marbling is considered a desirable trait in the meat industry. Therefore, understanding the genetic factors that cause marbling is important. Previously, we performed a genome-wide association study to examine genetic factors associated with beef marbling in Japanese Black cattle and identified a candidate region between 10-30 Mbp on chromosome 7. We verified the effect of the SNPs in this region on beef marbling using linkage disequilibrium block analysis. We narrowed down the candidate region to a range of 15.8-16.1 Mbp. In this study, we comprehensively detected all of the SNPs in this region and verified their effects on beef marbling. RESULTS Genome resequencing using four animals exhibiting high beef marbling standard (BMS) and four with low BMS revealed a total of 1,846 polymorphisms within the candidate region. Based on the annotation, we selected 13 SNPs exhibiting a moderate impact, as no high-impact SNPs were detected. All of the SNPs represented missense polymorphisms and were located in the following seven genes: RDH8, ANGPTL6, DNMT1, MRPL4, ICAM1, ICAM3, and ICAM5. Finally, we determined the effects of these SNPs on the BMS of a Japanese Black cattle population (n = 529). Analysis of variance revealed that the five SNPs were located in genes encoding the intercellular adhesion molecules (ICAM1, ICAM3, and ICAM5), and showed a highly significant association compared with the remainder (p < 0.01). The lowest p-value was observed for ICAM3_c.739G > A (p = 1.18E-04). Previous studies have suggested that intercellular adhesion molecules (ICAM) may be an upstream factor that regulates adipocyte differentiation. Therefore, considering the polymorphism and putative gene function, we suggest that ICAM1 is potentially responsible for beef marbling. c.470C > G and/or c.994G > A on ICAM1 may be responsible for this quantitative trait locus. CONCLUSIONS Promising SNP candidates responsible for beef marbling were identified using extensive polymorphism verification in a previously reported QTL region. We aim to elucidate the mechanism of beef marbling in future studies by investigating how these polymorphisms alter protein structure and function.
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Affiliation(s)
- Shinji Sasazaki
- Laboratory of Animal Breeding and Genetics, Graduate School of Agricultural Science, Kobe University, Kobe, Japan.
| | - Hina Kondo
- Laboratory of Animal Breeding and Genetics, Graduate School of Agricultural Science, Kobe University, Kobe, Japan
| | - Yurika Moriishi
- Laboratory of Animal Breeding and Genetics, Graduate School of Agricultural Science, Kobe University, Kobe, Japan
| | - Fuki Kawaguchi
- Laboratory of Animal Breeding and Genetics, Graduate School of Agricultural Science, Kobe University, Kobe, Japan
| | - Kenji Oyama
- Food Resources Education & Research Center, Kobe University, Kasai, Japan
| | - Hideyuki Mannen
- Laboratory of Animal Breeding and Genetics, Graduate School of Agricultural Science, Kobe University, Kobe, Japan
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Gammoh O, AlQudah A, Rob OAA, Hmedat A, Kifaieh A, Weshah F, Ennab W, Qnais E. Modulation of salivary ICAM-1 and SIRT1 by disease modifying drugs in undepressed relapsing-remitting multiple sclerosis patients. Mult Scler Relat Disord 2022; 68:104257. [PMID: 36308972 DOI: 10.1016/j.msard.2022.104257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/15/2022] [Accepted: 10/18/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND The pathophysiology of Multiple Sclerosis (MS) is multifactorial where the correlation between inflammation and MS is evident. Adhesion molecules such as Intercellular adhesion molecule-1 (ICAM-1) are implicated in MS. SIRT1 is a member of surtins family that play a protective role in neurodegenerative and inflammatory diseases. Although previously studied in Relapsing-Remitting Multiple Sclerosis (RRMS) patients, however the salivary expression of ICAM-1 and SIRT1 have not been yet studied in patients receiving fingolimod or interferon-β. Therefore, the present research aimed to investigate the expression of salivary ICAM-1 and SIRT1 in RRMS patients treated with fingolimod or interferon-β compared to controls. METHODS RRMS patients attending the neurology department of AL-Bashir Hospital were recruited. Patients' demographics, clinical information, and psychiatric status were evaluated (depression, anxiety and stress). Afterward, matched controls were recruited, then unstimulated whole saliva was obtained from the participants. The salivary expression of ICAM-1 and SIRT1 was investigated using western blot and normalized with β-actin. RESULTS Data were analyzed from 53 participants: 26 on fingolimod, 14 on interferon-β, and 13 control. The interferon-β treated patients showed a significantly (p < 0.001) higher ICAM-1 expression and lower SIRT1 expression (p < 0.05) compared to the control. Levels of ICAM-1 and SIRT1 did not vary between fingolimod and control. CONCLUSION ICAM-1 and SIRT1 expression might be affected with fingolimod or INF- β treatment which should be investigated more in the future.
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Affiliation(s)
- Omar Gammoh
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Yarmouk University, Irbid 21163, Jordan.
| | - Abdelrahim AlQudah
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, the Hashemite University, Zarqa 13133, Jordan
| | - Osama Abo Al Rob
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Yarmouk University, Irbid 21163, Jordan
| | - Ali Hmedat
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University, Irbid 21163, Jordan
| | - Ahlam Kifaieh
- Department of Pharmacy Istishari Hospital, Amman, Jordan
| | - Feras Weshah
- Department of Neurology, Al-Bashir Hospital, Amman 11151, Jordan
| | - Wail Ennab
- Department of Neurology, Al-Bashir Hospital, Amman 11151, Jordan
| | - Esam Qnais
- Department of Biological Sciences, Faculty of Science, the Hashemite University, Zarqa 13133, Jordan
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Understanding the Role of LFA-1 in Leukocyte Adhesion Deficiency Type I (LAD I): Moving towards Inflammation? Int J Mol Sci 2022; 23:ijms23073578. [PMID: 35408940 PMCID: PMC8998723 DOI: 10.3390/ijms23073578] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/18/2022] [Accepted: 03/21/2022] [Indexed: 02/04/2023] Open
Abstract
LFA-1 (Lymphocyte function-associated antigen-1) is a heterodimeric integrin (CD11a/CD18) present on the surface of all leukocytes; it is essential for leukocyte recruitment to the site of tissue inflammation, but also for other immunological processes such as T cell activation and formation of the immunological synapse. Absent or dysfunctional expression of LFA-1, caused by mutations in the ITGB2 (integrin subunit beta 2) gene, results in a rare immunodeficiency syndrome known as Leukocyte adhesion deficiency type I (LAD I). Patients suffering from severe LAD I present with recurrent infections of the skin and mucosa, as well as inflammatory symptoms complicating the clinical course of the disease before and after allogeneic hematopoietic stem cell transplantation (alloHSCT); alloHSCT is currently the only established curative treatment option. With this review, we aim to provide an overview of the intrinsic role of inflammation in LAD I.
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Zhai X, Kong WG, Cheng GF, Cao JF, Dong F, Han GK, Song YL, Qin CJ, Xu Z. Molecular Characterization and Expression Analysis of Intercellular Adhesion Molecule-1 (ICAM-1) Genes in Rainbow Trout ( Oncorhynchus mykiss) in Response to Viral, Bacterial and Parasitic Challenge. Front Immunol 2021; 12:704224. [PMID: 34489953 PMCID: PMC8417878 DOI: 10.3389/fimmu.2021.704224] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 08/02/2021] [Indexed: 01/10/2023] Open
Abstract
The intercellular adhesion molecule-1 (ICAM-1), known as CD54, is a transmembrane cell surface glycoprotein that interacts with two integrins (i.e., LFA-1 and Mac-l) important for trans-endothelial migration of leukocytes. The level of ICAM-1 expression is upregulated in response to some inflammatory stimulations, including pathogen infection and proinflammatory cytokines. Yet, to date, our knowledge regarding the functional role of ICAM-1 in teleost fish remains largely unknown. In this study, we cloned and characterized the sequence of ICAM-1 in rainbow trout (Oncorhynchus mykiss) for the first time, which exhibited that the molecular features of ICAM-1 in fishes were relatively conserved compared with human ICAM-1. The transcriptional level of ICAM-1 was detected in 12 different tissues, and we found high expression of this gene in the head kidney, spleen, gills, skin, nose, and pharynx. Moreover, upon stimulation with infectious hematopoietic necrosis virus (IHNV), Flavobacterium columnare G4 (F. columnare), and Ichthyophthirius multifiliis (Ich) in rainbow trout, the morphological changes were observed in the skin and gills, and enhanced expression of ICAM-1 mRNA was detected both in the systemic and mucosal tissues. These results indicate that ICAM-1 may be implicated in the mucosal immune responses to viral, bacterial, and parasitic infections in teleost fish, meaning that ICAM-1 emerges as a master regulator of mucosal immune responses against pathogen infections in teleost fish.
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Affiliation(s)
- Xue Zhai
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, China
| | - Wei-Guang Kong
- State Key Laboratory of Freshwater Ecology and Biotechnology, Center for Fish Biology and Fishery Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
| | - Gao-Feng Cheng
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, China
| | - Jia-Feng Cao
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, China
| | - Fen Dong
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, China
| | - Guang-Kun Han
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, China
| | - Yan-Ling Song
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, China
| | - Chuan-Jie Qin
- Department of Life Science, Key Laboratory of Sichuan Province for Conservation and Utilization of Fishes Resources in the Upper Reaches of the Yangtze River, Neijiang Normal University, Neijiang, China
| | - Zhen Xu
- State Key Laboratory of Freshwater Ecology and Biotechnology, Center for Fish Biology and Fishery Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
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Dos Santos ACM, Dos Santos BRC, Dos Santos BB, de Moura EL, Ferreira JM, Dos Santos LKC, Oliveira SP, Dias RBF, Pereira E Silva AC, de Farias KF, de Souza Figueiredo EVM. Genetic polymorphisms as multi-biomarkers in severe acute respiratory syndrome (SARS) by coronavirus infection: A systematic review of candidate gene association studies. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2021; 93:104846. [PMID: 33933633 PMCID: PMC8084602 DOI: 10.1016/j.meegid.2021.104846] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 03/27/2021] [Accepted: 04/01/2021] [Indexed: 12/30/2022]
Abstract
The Severe acute respiratory syndrome may be caused by coronavirus disease which has resulted in a global pandemic. Polymorphisms in the population play a role in susceptibility to severity. We aimed to perform a systematic review related to the effect of single nucleotide polymorphisms in the development of severe acute respiratory syndrome (SARS). Twenty-eight eligible articles published were identified in PubMed, ScienceDirect, Web of Science, PMC Central and Portal BVS and additional records, with 20 studies performed in China. Information on study characteristics, genetic polymorphisms, and comorbidities was extracted. Study quality was assessed by the STrengthening the REporting of Genetic Association (STREGA) guideline. Few studies investigated the presence of polymorphisms in HLA, ACE1, OAS-1, MxA, PKR, MBL, E-CR1, FcγRIIA, MBL2, L-SIGN (CLEC4M), IFNG, CD14, ICAM3, RANTES, IL-12 RB1, TNFA, CXCL10/IP-10, CD209 (DC-SIGN), AHSG, CYP4F3 and CCL2 with the susceptibility or protection to SARS-Cov. This review provides comprehensive evidence of the association between genetic polymorphisms and susceptibility or protection to severity SARS-CoV. The literature about coronavirus infection, susceptibility to severe acute respiratory syndrome (SARS) and genetic variations is scarce. Further studies are necessary to provide more concrete evidence, mainly related to Covid-19.
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Affiliation(s)
- Ana Caroline Melo Dos Santos
- Laboratório de Biologia Molecular e Expressão Gênica, Postgraduate Program in Health Sciences, Federal University of Alagoas, Maceió, Alagoas, Brazil; Instituto de Ciências Biológicas e da Saúde (ICBS), Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Bárbara Rayssa Correia Dos Santos
- Laboratório de Biologia Molecular e Expressão Gênica, Postgraduate Program in Health Sciences, Federal University of Alagoas, Maceió, Alagoas, Brazil; Instituto de Ciências Biológicas e da Saúde (ICBS), Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Bruna Brandão Dos Santos
- Laboratório de Biologia Molecular e Expressão Gênica, Postgraduate Program in Health Sciences, Federal University of Alagoas, Maceió, Alagoas, Brazil; Instituto de Ciências Biológicas e da Saúde (ICBS), Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Edilson Leite de Moura
- Laboratório de Biologia Molecular e Expressão Gênica, Postgraduate Program in Health Sciences, Federal University of Alagoas, Maceió, Alagoas, Brazil; Instituto de Ciências Biológicas e da Saúde (ICBS), Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Jean Moisés Ferreira
- Laboratório de Biologia Molecular e Expressão Gênica, Postgraduate Program in Health Sciences, Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Luana Karen Correia Dos Santos
- Laboratório de Biologia Molecular e Expressão Gênica, Postgraduate Program in Health Sciences, Federal University of Alagoas, Maceió, Alagoas, Brazil; Instituto de Ciências Biológicas e da Saúde (ICBS), Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Susana Paiva Oliveira
- Laboratório de Biologia Molecular e Expressão Gênica, Postgraduate Program in Health Sciences, Federal University of Alagoas, Maceió, Alagoas, Brazil; Instituto de Ciências Biológicas e da Saúde (ICBS), Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Renise Bastos Farias Dias
- Laboratório de Biologia Molecular e Expressão Gênica, Postgraduate Program in Health Sciences, Federal University of Alagoas, Maceió, Alagoas, Brazil; Instituto de Ciências Biológicas e da Saúde (ICBS), Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Aline Cristine Pereira E Silva
- Laboratório de Biologia Molecular e Expressão Gênica, Postgraduate Program in Health Sciences, Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Karol Fireman de Farias
- Laboratório de Biologia Molecular e Expressão Gênica, Postgraduate Program in Health Sciences, Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Elaine Virgínia Martins de Souza Figueiredo
- Laboratório de Biologia Molecular e Expressão Gênica, Postgraduate Program in Health Sciences, Federal University of Alagoas, Maceió, Alagoas, Brazil; Instituto de Ciências Biológicas e da Saúde (ICBS), Federal University of Alagoas, Maceió, Alagoas, Brazil..
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Cockram TOJ, Dundee JM, Popescu AS, Brown GC. The Phagocytic Code Regulating Phagocytosis of Mammalian Cells. Front Immunol 2021; 12:629979. [PMID: 34177884 PMCID: PMC8220072 DOI: 10.3389/fimmu.2021.629979] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 05/18/2021] [Indexed: 01/21/2023] Open
Abstract
Mammalian phagocytes can phagocytose (i.e. eat) other mammalian cells in the body if they display certain signals, and this phagocytosis plays fundamental roles in development, cell turnover, tissue homeostasis and disease prevention. To phagocytose the correct cells, phagocytes must discriminate which cells to eat using a 'phagocytic code' - a set of over 50 known phagocytic signals determining whether a cell is eaten or not - comprising find-me signals, eat-me signals, don't-eat-me signals and opsonins. Most opsonins require binding to eat-me signals - for example, the opsonins galectin-3, calreticulin and C1q bind asialoglycan eat-me signals on target cells - to induce phagocytosis. Some proteins act as 'self-opsonins', while others are 'negative opsonins' or 'phagocyte suppressants', inhibiting phagocytosis. We review known phagocytic signals here, both established and novel, and how they integrate to regulate phagocytosis of several mammalian targets - including excess cells in development, senescent and aged cells, infected cells, cancer cells, dead or dying cells, cell debris and neuronal synapses. Understanding the phagocytic code, and how it goes wrong, may enable novel therapies for multiple pathologies with too much or too little phagocytosis, such as: infectious disease, cancer, neurodegeneration, psychiatric disease, cardiovascular disease, ageing and auto-immune disease.
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Affiliation(s)
| | | | | | - Guy C. Brown
- Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
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Resolving the graft ischemia-reperfusion injury during liver transplantation at the single cell resolution. Cell Death Dis 2021; 12:589. [PMID: 34103479 PMCID: PMC8187624 DOI: 10.1038/s41419-021-03878-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 05/25/2021] [Accepted: 05/26/2021] [Indexed: 01/13/2023]
Abstract
Ischemia–reperfusion injury (IRI) remains the major reason for impaired donor graft function and increased mortality post-liver transplantation. The mechanism of IRI involves multiple pathophysiological processes and numerous types of cells. However, a systematic and comprehensive single-cell transcriptional profile of intrahepatic cells during liver transplantation is still unclear. We performed a single-cell transcriptome analysis of 14,313 cells from liver tissues collected from pre-procurement, at the end of preservation and 2 h post-reperfusion. We made detailed annotations of mononuclear phagocyte, endothelial cell, NK/T, B and plasma cell clusters, and we described the dynamic changes of the transcriptome of these clusters during IRI and the interaction between mononuclear phagocyte clusters and other cell clusters. In addition, we found that TNFAIP3 interacting protein 3 (TNIP3), specifically and highly expressed in Kupffer cell clusters post-reperfusion, may have a protective effect on IRI. In summary, our study provides the first dynamic transcriptome map of intrahepatic cell clusters during liver transplantation at single-cell resolution.
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Rahimi N. C-type Lectin CD209L/L-SIGN and CD209/DC-SIGN: Cell Adhesion Molecules Turned to Pathogen Recognition Receptors. BIOLOGY 2020; 10:1. [PMID: 33375175 PMCID: PMC7822156 DOI: 10.3390/biology10010001] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/14/2020] [Accepted: 12/16/2020] [Indexed: 12/19/2022]
Abstract
C-type lectin CD209/DC-SIGN and CD209L/L-SIGN proteins are distinct cell adhesion and pathogen recognition receptors that mediate cellular interactions and recognize a wide range of pathogens, including viruses such as SARS, SARS-CoV-2, bacteria, fungi and parasites. Pathogens exploit CD209 family proteins to promote infection and evade the immune recognition system. CD209L and CD209 are widely expressed in SARS-CoV-2 target organs and can contribute to infection and pathogenesis. CD209 family receptors are highly susceptible to alternative splicing and genomic polymorphism, which may influence virus tropism and transmission in vivo. The carbohydrate recognition domain (CRD) and the neck/repeat region represent the key features of CD209 family proteins that are also central to facilitating cellular ligand interactions and pathogen recognition. While the neck/repeat region is involved in oligomeric dimerization, the CRD recognizes the mannose-containing structures present on specific glycoproteins such as those found on the SARS-CoV-2 spike protein. Considering the role of CD209L and related proteins in diverse pathogen recognition, this review article discusses the recent advances in the cellular and biochemical characterization of CD209 and CD209L and their roles in viral uptake, which has important implications in understanding the host-pathogen interaction, the viral pathobiology and driving vaccine development of SARS-CoV-2.
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Affiliation(s)
- Nader Rahimi
- Department of Pathology, School of Medicine, Boston University Medical Campus, Boston, MA 02118, USA
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11
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Effects of Caloric Intake and Aerobic Activity in Individuals with Prehypertension and Hypertension on Levels of Inflammatory, Adhesion and Prothrombotic Biomarkers-Secondary Analysis of a Randomized Controlled Trial. J Clin Med 2020; 9:jcm9030655. [PMID: 32121255 PMCID: PMC7141349 DOI: 10.3390/jcm9030655] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 02/25/2020] [Accepted: 02/26/2020] [Indexed: 12/17/2022] Open
Abstract
Background: Cardiopulmonary fitness and low calorie diets have been shown to reduce inflammation but few studies have been conducted in individuals with elevated blood pressure (BP) in a randomized intervention setting. Thereby, adhesion biomarkers, e.g., soluble intercellular adhesion molecule (sICAM)-3, have not been examined so far. Methods: Sixty-eight sedentary prehypertensive and mildly hypertensive individuals (mean age ± SEM: 45 ± 1 years; mean BP: 141/84 ± 1/1 mmHg) were randomized to one of three 12-week intervention groups: cardio training and caloric reduction, cardio training alone, or wait-list control group. Plasma levels of inflammatory, adhesion and prothrombotic biomarkers were assessed. In a second step, intervention groups were combined to one sample and multivariate regression analyses were applied in order to account for exercise and diet behavior changes. Results: There were no significant differences among the intervention groups. In the combined sample, greater caloric reduction was associated with a larger increase of sICAM-3 (p = 0.026) and decrease of C-reactive protein (p = 0.018) as a result of the interventions. More cardio training was associated with increases of sICAM-3 (p = 0.046) as well as interleukin-6 (p = 0.004) and a decrease of tumor necrosis factor-α (p = 0.017) levels. Higher BP predicted higher plasminogen activator inhibitor (PAI)-1 (p = 0.001), and greater fitness predicted lower PAI-1 levels (p = 0.006) after the intervention. Conclusions: In prehypertensive and hypertensive patients, plasma levels of the adhesion molecule sICAM-3 and inflammatory biomarkers have different response patterns to cardio training with and without caloric reduction. Such anti-inflammatory and anti-thrombotic effects may have implications for the prevention of atherothrombotic cardiovascular disease among individuals at increased risk.
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Kwun J, Park J, Yi JS, Farris AB, Kirk AD, Knechtle SJ. IL-21 Biased Alemtuzumab Induced Chronic Antibody-Mediated Rejection Is Reversed by LFA-1 Costimulation Blockade. Front Immunol 2018; 9:2323. [PMID: 30374350 PMCID: PMC6196291 DOI: 10.3389/fimmu.2018.02323] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 09/18/2018] [Indexed: 11/25/2022] Open
Abstract
Despite its excellent efficacy in controlling T cell mediated acute rejection, lymphocyte depletion may promote a humoral response. While T cell repopulation after depletion has been evaluated in many aspects, the B cell response has not been fully elucidated. We tested the hypothesis that the mechanisms also involve skewed T helper phenotype after lymphocytic depletion. Post-transplant immune response was measured from alemtuzumab treated hCD52Tg cardiac allograft recipients with or without anti-LFA-1 mAb. Alemtuzumab induction promoted serum DSA, allo-B cells, and CAV in humanized CD52 transgenic (hCD52Tg) mice after heterotopic heart transplantation. Additional anti-LFA-1 mAb treatment resulted in reduced DSA (Fold increase 4.75 ± 6.9 vs. 0.7 ± 0.5; p < 0.01), allo-specific B cells (0.07 ± 0.06 vs. 0.006 ± 0.002 %; p < 0.01), neo-intimal hyperplasia (56 ± 14% vs. 23 ± 13%; p < 0.05), arterial disease (77.8 ± 14.2 vs. 25.8 ± 20.1%; p < 0.05), and fibrosis (15 ± 23.3 vs. 4.3 ± 1.65%; p < 0.05) in this alemtuzumab-induced chronic antibody-mediated rejection (CAMR) model. Surprisingly, elevated serum IL-21 levels in alemtuzumab-treated mice was reduced with LFA-1 blockade. In accordance with the increased serum IL-21 level, alemtuzumab treated mice showed hyperplastic germinal center (GC) development, while the supplemental anti-LFA-1 mAb significantly reduced the GC frequency and size. We report that the incomplete T cell depletion inside of the GC leads to a systemic IL-21 dominant milieu with hyperplastic GC formation and CAMR. Conventional immunosuppression, such as tacrolimus and rapamycin, failed to reverse AMR, while co-stimulation blockade with LFA-1 corrected the GC hyperplastic response. The identification of IL-21 driven chronic AMR elucidates a novel mechanism that suggests a therapeutic approach with cytolytic induction.
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Affiliation(s)
- Jean Kwun
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, United States
| | - Jaeberm Park
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, United States
| | - John S Yi
- Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, Durham, NC, United States
| | - Alton B Farris
- Department of Pathology, Emory University School of Medicine, Atlanta, GA, United States
| | - Allan D Kirk
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, United States
| | - Stuart J Knechtle
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, United States
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13
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Mason JC, Haskard DO. The Clinical Importance of Leucocyte and Endothelial Cell Adhesion Molecules in Inflammation. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/1358863x9400500306] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
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14
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Effect of High Glucose Concentration on Human Preadipocytes and Their Response to Macrophage-Conditioned Medium. Can J Diabetes 2016; 40:411-418. [DOI: 10.1016/j.jcjd.2016.02.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Revised: 01/28/2016] [Accepted: 02/21/2016] [Indexed: 11/18/2022]
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15
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A survey of endogenous retrovirus (ERV) sequences in the vicinity of multiple sclerosis (MS)-associated single nucleotide polymorphisms (SNPs). Mol Biol Rep 2016; 43:827-36. [PMID: 27169423 DOI: 10.1007/s11033-016-4004-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 05/04/2016] [Indexed: 12/18/2022]
Abstract
Although multiple sclerosis (MS) is one of the most common central nervous system diseases in young adults, little is known about its etiology. Several human endogenous retroviruses (ERVs) are considered to play a role in MS. We are interested in which ERVs can be identified in the vicinity of MS associated genetic marker to find potential initiators of MS. We analysed the chromosomal regions surrounding 58 single nucleotide polymorphisms (SNPs) that are associated with MS identified in one of the last major genome wide association studies. We scanned these regions for putative endogenous retrovirus sequences with large open reading frames (ORFs). We observed that more retrovirus-related putative ORFs exist in the relatively close vicinity of SNP marker indices in multiple sclerosis compared to control SNPs. We found very high homologies to HERV-K, HCML-ARV, XMRV, Galidia ERV, HERV-H/env62 and XMRV-like mouse endogenous retrovirus mERV-XL. The associated genes (CYP27B1, CD6, CD58, MPV17L2, IL12RB1, CXCR5, PTGER4, TAGAP, TYK2, ICAM3, CD86, GALC, GPR65 as well as the HLA DRB1*1501) are mainly involved in the immune system, but also in vitamin D regulation. The most frequently detected ERV sequences are related to the multiple sclerosis-associated retrovirus, the human immunodeficiency virus 1, HERV-K, and the Simian foamy virus. Our data shows that there is a relation between MS associated SNPs and the number of retroviral elements compared to control. Our data identifies new ERV sequences that have not been associated with MS, so far.
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16
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Impact of Leukocyte Function-Associated Antigen-1 Blockade on Endogenous Allospecific T Cells to Multiple Minor Histocompatibility Antigen Mismatched Cardiac Allograft. Transplantation 2015; 99:2485-93. [DOI: 10.1097/tp.0000000000000805] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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17
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Arosio D, Chiodo F, Reina JJ, Marelli M, Penadés S, van Kooyk Y, Garcia-Vallejo JJ, Bernardi A. Effective targeting of DC-SIGN by α-fucosylamide functionalized gold nanoparticles. Bioconjug Chem 2014; 25:2244-51. [PMID: 25379972 DOI: 10.1021/bc500467u] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Dendritic Cells (DCs), the most potent antigen-presenting cells, play a critical role in the detection of invading pathogens, which are recognized also by multiple carbohydrate-specific receptors. Among them, DC-SIGN is one of the best characterized, with high-mannose and Lewis-type glycan specificity. In this study, we present a potent DC-SIGN targeting device developed using gold nanoparticles functionalized with α-fucosyl-β-alanyl amide. The nanoparticles bound to cellular DC-SIGN and induced internalization as effectively as similar particles coated with comparable amounts of Lewis(X) oligosaccharide. They were found to be neutral toward dendritic cell maturation and IL-10 production, thus envisaging a possible use as targeted imaging tools and antigen delivery devices.
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Affiliation(s)
- Daniela Arosio
- CNR-Institute of Molecular Science and Technologies (ISTM) , via Golgi 19, I-20133 Milan, Italy
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18
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Chakraborty S, Núñez D, Hu SY, Domingo MP, Pardo J, Karmenyan A, Chiou A. FRET based quantification and screening technology platform for the interactions of leukocyte function-associated antigen-1 (LFA-1) with intercellular adhesion molecule-1 (ICAM-1). PLoS One 2014; 9:e102572. [PMID: 25032811 PMCID: PMC4102529 DOI: 10.1371/journal.pone.0102572] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 06/19/2014] [Indexed: 11/29/2022] Open
Abstract
The interaction between leukocyte function-associated antigen-1(LFA-1) and intercellular adhesion molecule-1 (ICAM-1) plays a pivotal role in cellular adhesion including the extravasation and inflammatory response of leukocytes, and also in the formation of immunological synapse. However, irregular expressions of LFA-1 or ICAM-1 or both may lead to autoimmune diseases, metastasis cancer, etc. Thus, the LFA-1/ICAM-1 interaction may serve as a potential therapeutic target for the treatment of these diseases. Here, we developed one simple 'in solution' steady state fluorescence resonance energy transfer (FRET) technique to obtain the dissociation constant (Kd) of the interaction between LFA-1 and ICAM-1. Moreover, we developed the assay into a screening platform to identify peptides and small molecules that inhibit the LFA-1/ICAM-1 interaction. For the FRET pair, we used Alexa Fluor 488-LFA-1 conjugate as donor and Alexa Fluor 555-human recombinant ICAM-1 (D1-D2-Fc) as acceptor. From our quantitative FRET analysis, the Kd between LFA-1 and D1-D2-Fc was determined to be 17.93±1.34 nM. Both the Kd determination and screening assay were performed in a 96-well plate platform, providing the opportunity to develop it into a high-throughput assay. This is the first reported work which applies FRET based technique to determine Kd as well as classifying inhibitors of the LFA-1/ICAM-1 interaction.
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Affiliation(s)
| | - David Núñez
- Instituto de Carboquímica, CSIC, Zaragoza, Spain
- Immune Effector Cells Group, Aragón Health Research Institute, Biomedical Research Centre of Aragón, Zaragoza, Spain
| | - Shih-Yang Hu
- Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan
| | - María Pilar Domingo
- Instituto de Carboquímica, CSIC, Zaragoza, Spain
- Immune Effector Cells Group, Aragón Health Research Institute, Biomedical Research Centre of Aragón, Zaragoza, Spain
| | - Julian Pardo
- Immune Effector Cells Group, Aragón Health Research Institute, Biomedical Research Centre of Aragón, Zaragoza, Spain
- Department of Biochemistry and Molecular and Cell Biology, Facultad de Ciencias, University of Zaragoza, Zaragoza, Spain
- Aragón I+D Foundation, Government of Aragon, Zaragoza, Spain
- Nanoscience Institute of Aragón, Aragón I+D Foundation, University of Zaragoza, Zaragoza, Spain
| | - Artashes Karmenyan
- Biophotonics & Molecular Imaging Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Eva Ma Gálvez
- Instituto de Carboquímica, CSIC, Zaragoza, Spain
- Immune Effector Cells Group, Aragón Health Research Institute, Biomedical Research Centre of Aragón, Zaragoza, Spain
| | - Arthur Chiou
- Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan
- Biophotonics & Molecular Imaging Research Center, National Yang-Ming University, Taipei, Taiwan
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19
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Wu SH, Núnez D, Hu SY, Domingo MP, Chen YC, Wei PK, Pardo J, Gálvez EM, Chiou A. The effect of acidic pH on the inhibitory efficacy of peptides against the interaction ICAM-1/LFA-1 studied by surface plasmon resonance (SPR). Biosens Bioelectron 2014; 56:159-66. [PMID: 24487103 DOI: 10.1016/j.bios.2014.01.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 01/02/2014] [Accepted: 01/03/2014] [Indexed: 12/19/2022]
Abstract
Synthetic peptides have been developed for therapeutic applications for decades. The therapeutic efficacy often depends not only on the stabilization of the peptides but also on their binding specificity and affinity to the target molecules to interfere with designated molecular interaction. In this study, the binding affinity of human intercellular adhesion molecule 1 (ICAM-1) chimera and leukocyte function-associated antigen-1 (LFA-1) derived peptides was measured by surface plasmon resonance (SPR) detection, and the results were compared with that of the interaction (of ICAM-1) with the LFA-1 whole protein. To mimic diverse pathological situations in vivo where a low pH has been reported, we studied pH regulated binding affinity of ICAM-1/LFA-1 at pH 7.4, 6.5, and 4.0 without and with magnesium ion. We have found that the binding affinity of LFA-1 whole protein and ICAM-1 increases significantly as the environmental pH decreases, regardless of the absence or the presence of magnesium ion. The affinity of different (LFA-1) derived peptides also depends on the pH, although in all cases the peptides retain its ability to inhibit ICAM-1/LFA-1 interaction. The biomedical relevance of these data has been confirmed using a cell aggregation assay, suggesting that LFA-1 derived peptides show great potential for peptide drug development with a wide functional window of pH range for potential applications in LFA-1 related tumor therapy and autoimmune disease treatment.
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Affiliation(s)
- Shu-Han Wu
- Institute of Biophotonics, National Yang-Ming University, No. 155, Section 2, Linong Street, Taipei 11221, Taiwan, ROC; Research Center for Applied Sciences, Academia Sinica, Taipei 11529, Taiwan, ROC
| | - David Núnez
- Immune Effector Cells Group, Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza 50009, Spain; Instituto de Carboquímica ICB-CSIC, Zaragoza 50018, Spain; Department of Biochemistry and Molecular and Cell Biology, Fac. Ciencias, University of Zaragoza, Zaragoza 50009, Spain
| | - Shih-Yang Hu
- Institute of Biophotonics, National Yang-Ming University, No. 155, Section 2, Linong Street, Taipei 11221, Taiwan, ROC
| | - María Pilar Domingo
- Immune Effector Cells Group, Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza 50009, Spain; Instituto de Carboquímica ICB-CSIC, Zaragoza 50018, Spain
| | - Yi-Chun Chen
- Institute of Imaging and Biomedical Photonics, National Chiao Tung University, Tainan 71150, Taiwan, ROC
| | - Pei-Kuen Wei
- Institute of Biophotonics, National Yang-Ming University, No. 155, Section 2, Linong Street, Taipei 11221, Taiwan, ROC; Research Center for Applied Sciences, Academia Sinica, Taipei 11529, Taiwan, ROC
| | - Julián Pardo
- Immune Effector Cells Group, Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza 50009, Spain; Department of Biochemistry and Molecular and Cell Biology, Fac. Ciencias, University of Zaragoza, Zaragoza 50009, Spain; Aragón I+D Foundation (ARAID), Government of Aragon, Zaragoza 50004, Spain; Nanoscience Institute of Aragon (INA), Aragón I+D Foundation (ARAID), University of Zaragoza, Zaragoza 50009, Spain.
| | - Eva M Gálvez
- Immune Effector Cells Group, Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza 50009, Spain; Instituto de Carboquímica ICB-CSIC, Zaragoza 50018, Spain.
| | - Arthur Chiou
- Institute of Biophotonics, National Yang-Ming University, No. 155, Section 2, Linong Street, Taipei 11221, Taiwan, ROC; Biophotonics & Molecular Imaging Research Center (BMIRC), National Yang-Ming University, No. 155, Section 2, Linong Street, Taipei 11221, Taiwan, ROC.
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20
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Bloem K, Vuist IM, van den Berk M, Klaver EJ, van Die I, Knippels LMJ, Garssen J, García-Vallejo JJ, van Vliet SJ, van Kooyk Y. DCIR interacts with ligands from both endogenous and pathogenic origin. Immunol Lett 2013; 158:33-41. [PMID: 24239607 DOI: 10.1016/j.imlet.2013.11.007] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Revised: 10/13/2013] [Accepted: 11/05/2013] [Indexed: 11/24/2022]
Abstract
C-type lectins on dendritic cells function as antigen uptake and signaling receptors, thereby influencing cellular immune responses. Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is one of the best-studied C-type lectin receptors expressed on DCs and its glycan specificity and functional requirements for ligand binding have been intensively investigated. The carbohydrate specificity of dendritic cell immunoreceptor (DCIR), another DC-expressed lectin, was still debated, but we have recently confirmed DCIR as mannose/fucose-binding lectin. Since DC-SIGN and DCIR may potentially share ligands, we set out to elucidate the interaction of DCIR with established DC-SIGN-binding ligands, by comparing the carbohydrate specificity of DCIR and DC-SIGN in more detail. Our results clearly demonstrate that DC-SIGN has a broader glycan specificity compared to DCIR, which interacts only with mannotriose, sulfo-Lewis(a), Lewis(b) and Lewis(a). While most of the tested DC-SIGN ligands bound DCIR as well, Candida albicans and some glycoproteins on some cancer cell lines were identified as DC-SIGN-specific ligands. Interestingly, DCIR strongly bound human immunodeficiency virus type 1 (HIV-1) gp140 glycoproteins, while its interaction with the well-studied DC-SIGN-binding HIV-1 ligand gp120 was much weaker. Furthermore, DCIR-specific ligands were detected on keratinocytes. Furthermore, the interaction of DCIR with its ligands was strongly influenced by the glycosylation of DCIR. In conclusion, we show that sulfo-Lewis(a) is a high affinity ligand for DCIR and that DCIR interacts with ligands from both pathogenic and endogenous origin of which most are shared by DC-SIGN.
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Affiliation(s)
- Karien Bloem
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands; Danone Research, Centre for Specialized Nutrition, Wageningen, The Netherlands
| | - Ilona M Vuist
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Meike van den Berk
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Elsenoor J Klaver
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Irma van Die
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Léon M J Knippels
- Danone Research, Centre for Specialized Nutrition, Wageningen, The Netherlands; Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, The Netherlands
| | - Johan Garssen
- Danone Research, Centre for Specialized Nutrition, Wageningen, The Netherlands; Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, The Netherlands
| | - Juan J García-Vallejo
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Sandra J van Vliet
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Yvette van Kooyk
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
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21
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Chiodo F, Marradi M, Tefsen B, Snippe H, van Die I, Penadés S. High sensitive detection of carbohydrate binding proteins in an ELISA-solid phase assay based on multivalent glyconanoparticles. PLoS One 2013; 8:e73027. [PMID: 24014084 PMCID: PMC3754922 DOI: 10.1371/journal.pone.0073027] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 07/16/2013] [Indexed: 11/19/2022] Open
Abstract
Improved detection of anti-carbohydrate antibodies is a need in clinical identification of biomarkers for cancer cells or pathogens. Here, we report a new ELISA approach for the detection of specific immunoglobulins (IgGs) against carbohydrates. Two nanometer gold glyconanoparticles bearing oligosaccharide epitopes of HIV or Streptococcus pneumoniae were used as antigens to coat ELISA-plates. A ~3,000-fold improved detection of specific IgGs in mice immunized against S. pneumoniae respect to the well known BSA-glycoconjugate ELISA was achieved. Moreover, these multivalent glyconanoparticles have been employed in solid phase assays to detect the carbohydrate-dependent binding of human dendritic cells and the lectin DC-SIGN. Multivalent glyconanoparticles in ELISA provide a versatile, easy and highly sensitive method to detect and quantify the binding of glycan to proteins and to facilitate the identification of biomarkers.
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Affiliation(s)
- Fabrizio Chiodo
- Laboratory of GlycoNanotechnology, Biofunctional Nanomaterials Unit, CIC biomaGUNE, San Sebastián, Spain
| | - Marco Marradi
- Laboratory of GlycoNanotechnology, Biofunctional Nanomaterials Unit, CIC biomaGUNE, San Sebastián, Spain
- Networking Research Centre on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), San Sebastián, Spain
| | - Boris Tefsen
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Harm Snippe
- Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Irma van Die
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Soledad Penadés
- Laboratory of GlycoNanotechnology, Biofunctional Nanomaterials Unit, CIC biomaGUNE, San Sebastián, Spain
- Networking Research Centre on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), San Sebastián, Spain
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22
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Novel role of ICAM3 and LFA-1 in the clearance of apoptotic neutrophils by human macrophages. Apoptosis 2013; 18:1235-51. [DOI: 10.1007/s10495-013-0873-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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23
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Bloem K, Vuist IM, van der Plas AJ, Knippels LMJ, Garssen J, García-Vallejo JJ, van Vliet SJ, van Kooyk Y. Ligand binding and signaling of dendritic cell immunoreceptor (DCIR) is modulated by the glycosylation of the carbohydrate recognition domain. PLoS One 2013; 8:e66266. [PMID: 23776650 PMCID: PMC3679074 DOI: 10.1371/journal.pone.0066266] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Accepted: 05/03/2013] [Indexed: 11/18/2022] Open
Abstract
C-type lectins are innate receptors expressed on antigen-presenting cells that are involved in the recognition of glycosylated pathogens and self-glycoproteins. Upon ligand binding, internalization and/or signaling often occur. Little is known on the glycan specificity and ligands of the Dendritic Cell Immunoreceptor (DCIR), the only classical C-type lectin that contains an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM). Here we show that purified DCIR binds the glycan structures Lewisb and Man3. Interestingly, binding could not be detected when DCIR was expressed on cells. Since DCIR has an N-glycosylation site inside its carbohydrate recognition domain (CRD), we investigated the effect of this glycan in ligand recognition. Removing or truncating the glycans present on purified DCIR increased the affinity for DCIR-binding glycans. Nevertheless, altering the glycosylation status of the DCIR expressing cell or mutating the N-glycosylation site of DCIR itself did not increase glycan binding. In contrast, cis and trans interactions with glycans induced DCIR mediated signaling, resulting in a decreased phosphorylation of the ITIM sequence. These results show that glycan binding to DCIR is influenced by the glycosylation of the CRD region in DCIR and that interaction with its ligands result in signaling via its ITIM motif.
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Affiliation(s)
- Karien Bloem
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
- Danone Research, Centre for Specialized Nutrition, Wageningen, The Netherlands
| | - Ilona M. Vuist
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Arend-Jan van der Plas
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Léon M. J. Knippels
- Danone Research, Centre for Specialized Nutrition, Wageningen, The Netherlands
- Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
| | - Johan Garssen
- Danone Research, Centre for Specialized Nutrition, Wageningen, The Netherlands
- Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
| | - Juan J. García-Vallejo
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Sandra J. van Vliet
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Yvette van Kooyk
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
- * E-mail:
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24
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Garcia-Vallejo JJ, Koning N, Ambrosini M, Kalay H, Vuist I, Sarrami-Forooshani R, Geijtenbeek TBH, van Kooyk Y. Glycodendrimers prevent HIV transmission via DC-SIGN on dendritic cells. Int Immunol 2013; 25:221-33. [PMID: 23291968 DOI: 10.1093/intimm/dxs115] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Dendritic cells (DCs) are antigen-presenting cells efficient in capturing pathogens, and processing their antigenic determinants for presentation to antigen-specific T cells to induce robust immune responses. Their location at peripheral tissues and the expression of pattern-recognition receptors, among them DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), facilitates the capture of pathogens before spreading. However, some pathogens have developed strategies to escape the immune system. One of the most successful is HIV-1, which targets DC-SIGN for transport to the lymph node where the virus infects CD4(+) T cells. Contact of HIV-1 with DC-SIGN is thus the first event in the pathogenic cascade and, therefore, it is the primary target point for therapies aimed at HIV infection prevention. DC-SIGN recognizes specific glycans on HIV-1 and this interaction can be blocked by competitive inhibition through glycans. Although the affinity of glycans is relatively low, multivalency may increase avidity and the strength to compete with HIV-1 virions. We have designed multivalent dendrimeric compounds based on Lewis-type antigens that bind DC-SIGN with high selectivity and avidity and that effectively block gp120 binding to DC-SIGN and, consequently, HIV transmission to CD4(+) T cells. Binding to DC-SIGN and gp120 inhibition was higher on glycodendrimers with larger molecular diameter, indicating that the geometry of the compounds is an important factor determining their functionality. Our compounds elicited DC-SIGN internalization, a property of the receptor upon triggering, but did not affect the maturation status of DCs. Thus, Le(X) glycodendrimers could be incorporated into topic prophylactic approaches for the prevention of HIV-1 transmission.
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Affiliation(s)
- Juan J Garcia-Vallejo
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
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25
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Kim DS, Burt AA, Crosslin DR, Robertson PD, Ranchalis JE, Boyko EJ, Nickerson DA, Furlong CE, Jarvik GP. Novel common and rare genetic determinants of paraoxonase activity: FTO, SERPINA12, and ITGAL. J Lipid Res 2012; 54:552-60. [PMID: 23160181 DOI: 10.1194/jlr.p033266] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
HDL-associated paraoxonase 1 (PON1) activity is associated with cardiovascular and other human diseases. As the role of genetic variants outside of the PON gene cluster on PON1 activity is unknown, we sought to identify common and rare variants in such loci. We typed 33,057 variants on the CVD chip in 1,362 subjects to test for their effects on adjusted-PON1 activity. Three novel genes (FTO, ITGAL, and SERPINA12) and the PON gene cluster had SNPs associated with PON1 arylesterase (AREase) activity. These loci were carried forward for rare-variant analysis using Exome chip genotypes in an overlapping subset of 1,051 subjects using sequence kernel association testing. PON1 (P = 2.24 × 10(-4)), PON3 (P = 0.022), FTO (P = 0.019), and SERPINA12 (P = 0.039) had both common and rare variants associated with PON1 AREase. ITGAL variants were associated with PON1 activity when using weighted sequence kernel association testing (SKAT) analysis (P = 2.63 × 10(-3)). When adjusting for the initial common variants, SERPINA12 became marginally significant (P = 0.09), whereas all other findings remained significant (P < 0.05), suggesting independent rare-variant effects. We present novel findings that common and rare variants in FTO, SERPINA12, and ITGAL predict PON1 activity. These results further link PON1 to diabetes and inflammation and may inform the role of HDL in human disease.
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Affiliation(s)
- Daniel S Kim
- Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
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26
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Appleby SL, Cockshell MP, Pippal JB, Thompson EJ, Barrett JM, Tooley K, Sen S, Sun WY, Grose R, Nicholson I, Levina V, Cooke I, Talbo G, Lopez AF, Bonder CS. Characterization of a distinct population of circulating human non-adherent endothelial forming cells and their recruitment via intercellular adhesion molecule-3. PLoS One 2012; 7:e46996. [PMID: 23144795 PMCID: PMC3492591 DOI: 10.1371/journal.pone.0046996] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Accepted: 09/11/2012] [Indexed: 01/12/2023] Open
Abstract
Circulating vascular progenitor cells contribute to the pathological vasculogenesis of cancer whilst on the other hand offer much promise in therapeutic revascularization in post-occlusion intervention in cardiovascular disease. However, their characterization has been hampered by the many variables to produce them as well as their described phenotypic and functional heterogeneity. Herein we have isolated, enriched for and then characterized a human umbilical cord blood derived CD133+ population of non-adherent endothelial forming cells (naEFCs) which expressed the hematopoietic progenitor cell markers (CD133, CD34, CD117, CD90 and CD38) together with mature endothelial cell markers (VEGFR2, CD144 and CD31). These cells also expressed low levels of CD45 but did not express the lymphoid markers (CD3, CD4, CD8) or myeloid markers (CD11b and CD14) which distinguishes them from ‘early’ endothelial progenitor cells (EPCs). Functional studies demonstrated that these naEFCs (i) bound Ulex europaeus lectin, (ii) demonstrated acetylated-low density lipoprotein uptake, (iii) increased vascular cell adhesion molecule (VCAM-1) surface expression in response to tumor necrosis factor and (iv) in co-culture with mature endothelial cells increased the number of tubes, tubule branching and loops in a 3-dimensional in vitro matrix. More importantly, naEFCs placed in vivo generated new lumen containing vasculature lined by CD144 expressing human endothelial cells (ECs). Extensive genomic and proteomic analyses of the naEFCs showed that intercellular adhesion molecule (ICAM)-3 is expressed on their cell surface but not on mature endothelial cells. Furthermore, functional analysis demonstrated that ICAM-3 mediated the rolling and adhesive events of the naEFCs under shear stress. We suggest that the distinct population of naEFCs identified and characterized here represents a new valuable therapeutic target to control aberrant vasculogenesis.
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Affiliation(s)
- Sarah L. Appleby
- Centre for Cancer Biology, South Australian Pathology, Adelaide, South Australia, Australia
- Co-operative Research Centre for Biomarker Translation, La Trobe University, Melbourne, Victoria, Australia
| | - Michaelia P. Cockshell
- Centre for Cancer Biology, South Australian Pathology, Adelaide, South Australia, Australia
- Co-operative Research Centre for Biomarker Translation, La Trobe University, Melbourne, Victoria, Australia
| | - Jyotsna B. Pippal
- Centre for Cancer Biology, South Australian Pathology, Adelaide, South Australia, Australia
- Co-operative Research Centre for Biomarker Translation, La Trobe University, Melbourne, Victoria, Australia
| | - Emma J. Thompson
- Centre for Cancer Biology, South Australian Pathology, Adelaide, South Australia, Australia
- Co-operative Research Centre for Biomarker Translation, La Trobe University, Melbourne, Victoria, Australia
| | - Jeffrey M. Barrett
- Centre for Cancer Biology, South Australian Pathology, Adelaide, South Australia, Australia
- Co-operative Research Centre for Biomarker Translation, La Trobe University, Melbourne, Victoria, Australia
| | - Katie Tooley
- Centre for Cancer Biology, South Australian Pathology, Adelaide, South Australia, Australia
- Co-operative Research Centre for Biomarker Translation, La Trobe University, Melbourne, Victoria, Australia
| | - Shaundeep Sen
- School of Medicine, University of Adelaide, Adelaide, Australia
| | - Wai Yan Sun
- Centre for Cancer Biology, South Australian Pathology, Adelaide, South Australia, Australia
- Co-operative Research Centre for Biomarker Translation, La Trobe University, Melbourne, Victoria, Australia
- School of Medicine, University of Adelaide, Adelaide, Australia
| | - Randall Grose
- Co-operative Research Centre for Biomarker Translation, La Trobe University, Melbourne, Victoria, Australia
- Leukocyte Biology Laboratory, Women's and Children's Health Research Institute, Adelaide, South Australia, Australia
| | - Ian Nicholson
- Co-operative Research Centre for Biomarker Translation, La Trobe University, Melbourne, Victoria, Australia
- Leukocyte Biology Laboratory, Women's and Children's Health Research Institute, Adelaide, South Australia, Australia
| | - Vitalina Levina
- Co-operative Research Centre for Biomarker Translation, La Trobe University, Melbourne, Victoria, Australia
- La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia
| | - Ira Cooke
- Co-operative Research Centre for Biomarker Translation, La Trobe University, Melbourne, Victoria, Australia
- La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia
| | - Gert Talbo
- Co-operative Research Centre for Biomarker Translation, La Trobe University, Melbourne, Victoria, Australia
- La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia
| | - Angel F. Lopez
- Centre for Cancer Biology, South Australian Pathology, Adelaide, South Australia, Australia
- Co-operative Research Centre for Biomarker Translation, La Trobe University, Melbourne, Victoria, Australia
- School of Medicine, University of Adelaide, Adelaide, Australia
| | - Claudine S. Bonder
- Centre for Cancer Biology, South Australian Pathology, Adelaide, South Australia, Australia
- Co-operative Research Centre for Biomarker Translation, La Trobe University, Melbourne, Victoria, Australia
- School of Medicine, University of Adelaide, Adelaide, Australia
- * E-mail:
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García-Vallejo JJ, Ambrosini M, Overbeek A, van Riel WE, Bloem K, Unger WWJ, Chiodo F, Bolscher JG, Nazmi K, Kalay H, van Kooyk Y. Multivalent glycopeptide dendrimers for the targeted delivery of antigens to dendritic cells. Mol Immunol 2012; 53:387-97. [PMID: 23103377 DOI: 10.1016/j.molimm.2012.09.012] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2012] [Revised: 09/08/2012] [Accepted: 09/23/2012] [Indexed: 01/21/2023]
Abstract
Dendritic cells are the most powerful type of antigen presenting cells. Current immunotherapies targeting dendritic cells have shown a relative degree of success but still require further improvement. One of the most important issues to solve is the efficiency of antigen delivery to dendritic cells in order to achieve an appropriate uptake, processing, and presentation to Ag-specific T cells. C-type lectins have shown to be ideal receptors for the targeting of antigens to dendritic cells and allow the use of their natural ligands - glycans - instead of antibodies. Amongst them, dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN) is an interesting candidate due to its biological properties and the availability of its natural carbohydrate ligands. Using Le(b)-conjugated poly(amido amine) (PAMAM) dendrimers we aimed to characterize the optimal level of multivalency necessary to achieve the desired internalization, lysosomal delivery, Ag-specific T cell proliferation, and cytokine response. Increasing DC-SIGN ligand multivalency directly translated in an enhanced binding, which might also be interesting for blocking purposes. Internalization, routing to lysosomal compartments, antigen presentation and cytokine response could be optimally achieved with glycopeptide dendrimers carrying 16-32 glycan units. This report provides the basis for the design of efficient targeting of peptide antigens for the immunotherapy of cancer, autoimmunity and infectious diseases.
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Affiliation(s)
- Juan J García-Vallejo
- Department of Molecular Cell Biology & Immunology, Faculty of Medicine, VU University Medical Center, Amsterdam, The Netherlands.
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Burgess STG, Greer A, Frew D, Wells B, Marr EJ, Nisbet AJ, Huntley JF. Transcriptomic analysis of circulating leukocytes reveals novel aspects of the host systemic inflammatory response to sheep scab mites. PLoS One 2012; 7:e42778. [PMID: 22880105 PMCID: PMC3411848 DOI: 10.1371/journal.pone.0042778] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Accepted: 07/11/2012] [Indexed: 11/18/2022] Open
Abstract
Infestation of ovine skin with the ectoparasitic mite Psoroptes ovis results in the development of a rapid cutaneous inflammatory response, leading to the crusted skin lesions characteristic of sheep scab. To facilitate the identification of novel diagnostic and therapeutic targets, a better understanding of the host-parasite relationship in sheep scab is essential. Although our knowledge of the host's local cutaneous inflammatory response to sheep scab has increased in recent years, we still know relatively little about the mechanisms of this response at the systemic level. This study used a combined network and pathway analysis of the in vivo transcriptomic response of circulating leukocytes to infestation with P. ovis, during a 6 week period. Network graph analysis identified six temporally-associated gene clusters, which separated into two distinct sub-networks within the graph, representing those genes either up or down-regulated during the time course. Functional and pathway analysis of these clusters identified novel insights into the host systemic response to P. ovis infestation, including roles for the complement system, clotting cascade and fibrinolysis. These analyses also highlighted potential mechanisms by which the systemic immune response to sheep scab can influence local tissue responses via enhanced leukocyte activation and extravasation. By analysing the transcriptomic responses of circulating leukocytes in sheep following infestation with P. ovis, this study has provided key insights into the inflammatory response to infestation and has also demonstrated the utility of these cells as a proxy of events occurring at local tissue sites, providing insight into the mechanisms by which a local allergen-induced inflammatory response may be controlled.
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Affiliation(s)
- Stewart T G Burgess
- Moredun Research Institute, Pentlands Science Park, Bush Loan, Edinburgh, Midlothian, Scotland, United Kingdom.
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Estecha A, Aguilera-Montilla N, Sánchez-Mateos P, Puig-Kröger A. RUNX3 regulates intercellular adhesion molecule 3 (ICAM-3) expression during macrophage differentiation and monocyte extravasation. PLoS One 2012; 7:e33313. [PMID: 22479382 PMCID: PMC3315569 DOI: 10.1371/journal.pone.0033313] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2011] [Accepted: 02/07/2012] [Indexed: 01/08/2023] Open
Abstract
The adhesion molecule ICAM-3 belongs to the immunoglobulin gene superfamily and functions as a ligand for the β2 integrins LFA-1, Mac-1 and αdβ2. The expression of ICAM-3 is restricted to cells of the hematopoietic lineage. We present evidences that the ICAM-3 gene promoter exhibits a leukocyte-specific activity, as its activity is significantly higher in ICAM-3+ hematopoietic cell lines. The activity of the ICAM-3 gene promoter is dependent on the occupancy of RUNX cognate sequences both in vitro and in vivo, and whose integrity is required for RUNX responsiveness and for the cooperative actions of RUNX with transcription factors of the Ets and C/EBP families. Protein analysis revealed that ICAM-3 levels diminish upon monocyte-derived macrophage differentiation, monocyte transendothelial migration and dendritic cell maturation, changes that correlate with an increase in RUNX3. Importantly, disruption of RUNX-binding sites led to enhanced promoter activity, and small interfering RNA-mediated reduction of RUNX3 expression resulted in increased ICAM-3 mRNA levels. Altogether these results indicate that the ICAM-3 gene promoter is negatively regulated by RUNX transcription factors, which contribute to the leukocyte-restricted and the regulated expression of ICAM-3 during monocyte-to-macrophage differentiation and monocyte extravasation.
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Affiliation(s)
- Ana Estecha
- Laboratorio de Inmuno-Oncología, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | | | - Paloma Sánchez-Mateos
- Laboratorio de Inmuno-Oncología, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Amaya Puig-Kröger
- Laboratorio de Inmuno-Oncología, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- * E-mail:
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Structure, Expression, and Function of ICAM-5. Comp Funct Genomics 2012; 2012:368938. [PMID: 22312318 PMCID: PMC3270525 DOI: 10.1155/2012/368938] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2011] [Revised: 09/20/2011] [Accepted: 10/07/2011] [Indexed: 01/28/2023] Open
Abstract
Cell adhesion is of utmost importance in normal development and cellular functions. ICAM-5 (intercellular adhesion molecule-5, telencephalin, TLN) is a member of the ICAM family of adhesion proteins. As a novel cell adhesion molecule, ICAM-5 shares many structural similarities with the other members of IgSF, especially the ICAM subgroup; however, ICAM-5 has several unique properties compared to the other ICAMs. With its nine extracellular Ig domains, ICAM-5 is the largest member of ICAM subgroup identified so far. Therefore, it is much more complex than the other ICAMs. The expression of ICAM-5 is confined to the telencephalic neurons of the central nervous system whereas all the other ICAM members are expressed mostly by cells in the immune and blood systems. The developmental appearance of ICAM-5 parallels the time of dendritic elongation and branching, and synapse formation in the telencephalon. As a somatodendrite-specific adhesion molecule, ICAM-5 not only participates in immune-nervous system interactions, it could also participate in neuronal activity, Dendrites' targeting signals, and cognition. It would not be surprising if future investigations reveal more binding partners and other related functions of ICAM-5.
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31
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Ohgomori T, Nanao T, Morita A, Ikekita M. Asn54-linked glycan is critical for functional folding of intercellular adhesion molecule-5. Glycoconj J 2011; 29:47-55. [PMID: 22187327 DOI: 10.1007/s10719-011-9363-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2011] [Revised: 11/21/2011] [Accepted: 11/28/2011] [Indexed: 11/24/2022]
Abstract
Intercellular adhesion molecule-5 (ICAM-5, telencephalin) is a dendritically polarized type I membrane glycoprotein, and promotes dendritic filopodia formation. Although we have determined the N-glycan structures of ICAM-5 in a previous report, their function is unknown. Here, we produced fifteen ICAM-5 gene constructs, in which each potential N-glycosylation site was mutated, to elucidate the function of the N-glycans of ICAM-5, and observed the effects of transfection of them on a neuronal cell line, Neuro-2a (N2a). Only the N54Q mutant, which is the mutant for the most N-terminal glycosylation site, failed to induce filopodia-like protrusions in N2a cells. Immunofluorescence staining and cell surface biotinylation revealed that N54Q ICAM-5 was confined to the ER and also could not be expressed on the cell surface. This is further supported by the biochemical evidence that almost all N-glycans of N54Q ICAM-5 were digested by Endo glycosidase H and peptide:N-glycanase, indicating that almost all of them retain high-mannose-type structures in ER. In additon, it also failed to form disulfide bonds or functional protein complexes. The stable transformants of N54Q ICAM-5 showed retarded cell growth, but it was interesting that there was no apparent ER stress, because the mutant was sequentially degraded via ER associated degradation pathway by comparing the susceptibilities of the responses to various inhibitors of this pathway in wild-type and N54Q ICAM-5 transfectants. Taken together, the Asn(54)-linked glycan is necessary for normal trafficking and function of ICAM-5, but is unassociated with ER-associated degradation of it.
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Affiliation(s)
- Tomohiro Ohgomori
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Yamazaki, Noda, Chiba, Japan.
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32
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Costantini C, Micheletti A, Calzetti F, Perbellini O, Tamassia N, Albanesi C, Vermi W, Cassatella MA. On the potential involvement of CD11d in co-stimulating the production of interferon-γ by natural killer cells upon interaction with neutrophils via intercellular adhesion molecule-3. Haematologica 2011; 96:1543-7. [PMID: 21712539 DOI: 10.3324/haematol.2011.044578] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Interaction between neutrophils and other leukocytes plays a variety of important roles in regulating innate and adaptive immune responses. Recently, we have shown that neu-trophils amplify NK cell/6-sulfo LacNAc(+) dendritic cells (slanDC)-mediated cytokine production, by potentiating IL-12p70 release by slanDC via CD18/ICAM-1 and directly co-stimulating IFNγ production by NK cells via ICAM-3. Herein, we have identified additional molecules involved in the interactions among neutrophils, NK cells and slanDC. More specifically, we provide evidence that: i) the cross-talk between neutrophils and NK cells is mediated by ICAM-3 and CD11d/CD18, respectively; ii) slanDC potentiate the production of IFNγ by NK cells via CD11a/CD18. Altogether, our studies shed more light on the role that adhesion molecules play within the neutrophil/NK cell/slanDC network. Our data also have potential implications in the pathogenesis of diseases driven by hyperactivated leukocytes, such as Sweet's syndrome, in which a neutrophil/NK cell co-localization is frequently observed.
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Affiliation(s)
- Claudio Costantini
- Department of Pathology and Diagnostics, Division of General Pathology, University of Verona, Verona, Italy
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Wipfler P, Oppermann K, Pilz G, Afazel S, Haschke-Becher E, Harrer A, Huemer M, Kunz A, Golaszewski S, Staffen W, Ladurner G, Kraus J. Adhesion molecules are promising candidates to establish surrogate markers for natalizumab treatment. Mult Scler 2010; 17:16-23. [PMID: 20937631 DOI: 10.1177/1352458510383075] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Natalizumab is the first monoclonal antibody therapy approved for multiple sclerosis (MS). Its therapeutic mechanism is the blockade of the α4-integrin subunit of the adhesion molecule (AM) very late activation antigen-4 (VLA-4), which leads to an inhibition of immune cell extravasation into the central nervous system (CNS). METHODS We investigated changes in the expression levels of unblocked α4-integrin and further AM (intercellular adhesion molecule-1, -2, -3 (cICAM-1, -2, -3), leukocyte function associated antigen-1 (LFA-1)) on peripheral blood mononuclear cells (PBMC) determined by flow cytometry from 25 patients with MS before the first natalizumab infusion and before the fourth infusion. In 15 MS patients AM expression was evaluated every 3 months over 1 year. RESULTS We found a significant decrease (p < 0.0001) of unblocked α4-integrin cell surface expression on all investigated PBMC subsets (T cells -61.7%, B cells -69.1%, monocytes/macrophages -46.4%) in the blood of MS patients after 3 months of natalizumab treatment. Moreover, a continuous decrease (p < 0.05) of unblocked α4-integrin expression levels was seen after 3, 6, 9, and 12 months. As a secondary effect, expression levels of the other investigated AM were differentially affected. CONCLUSIONS Results show a sustained decrease of unblocked α4-integrin expression not only in all patients but also in all investigated PBMC subsets. This probably results in a continuously decreasing transmigration of PBMC into the CNS and may explain the improved clinical efficacy in the second treatment year and also the increasing risk of progressive multifocal leukoencephalopathy during long-term natalizumab therapy. We conclude that AM expression profiles are promising candidates for the development of a biomarker system to determine both natalizumab treatment response and patients at risk for opportunistic CNS infections.
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Affiliation(s)
- P Wipfler
- Paracelsus Medical University, Christian-Doppler-Klinik, University Hospital of Neurology, Salzburg, Austria.
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Reuβ R, Schreiber V, Klein A, Infante-Duarte C, Filippi M, Pabst W, Pohl C, Oschmann P. No significant effect of orally administered chemokine receptor 1 antagonist on intercellular adhesion molecule-3 expression in relapsing—remitting multiple sclerosis patients. Mult Scler 2010; 16:366-9. [DOI: 10.1177/1352458509358188] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
We investigated the expression of intercellular adhesion molecules ICAM-1 and ICAM-3 on peripheral blood mononuclear cells in a subgroup of 34 patients with relapsing-remitting multiple sclerosis who were treated orally with the chemokine receptor 1 antagonist BX 471 in a 16-week, randomised, double-blind, placebo-controlled phase II study. ICAM-1 and ICAM-3 expression was measured by flow cytometry at different time points during and after therapy and compared using multivariate analysis of variance and non-parametric Mann Whitney test. ICAM-3 expression on CD14 + peripheral blood mononuclear cells was increased in the verum group under therapy, but did not differ significantly between the verum and placebo groups. Most likely, this trend represents a small epiphenomenon only mediated by receptor cross-talk and feedback mechanisms.
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Affiliation(s)
- R. Reuβ
- Department of Neurology, Justus Liebig University, Gieβen Germany, , Department of Neurology, Hospital Hohe Warte, Bayreuth, Germany
| | - V. Schreiber
- Department of Neurology, Justus Liebig University, Gieβen Germany
| | - A. Klein
- Department of Neurology, Justus Liebig University, Gieβen Germany
| | - C. Infante-Duarte
- Cecile Vogt Clinic for Neurology, Charité - Universitaetsmedizin Berlin and Max Delbrueck Centre for Molecular Medicine, Germany
| | - M. Filippi
- Neuroimaging Research Unit, Department of Neurology, San Raffaele Scientific Institute and University Milan, Italy
| | - W. Pabst
- Institute of Medical Informatics, Justus Liebig University, Gieβen Germany
| | - C. Pohl
- Department of Neurology, University Hospital of Bonn, Germany, Bayer Schering Pharma, Germany
| | - P. Oschmann
- Department of Neurology, Hospital Hohe Warte, Bayreuth, Germany
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35
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van Sorge NM, Bleumink NMC, van Vliet SJ, Saeland E, van der Pol WL, van Kooyk Y, van Putten JPM. N-glycosylated proteins and distinct lipooligosaccharide glycoforms ofCampylobacter jejunitarget the human C-type lectin receptor MGL. Cell Microbiol 2009; 11:1768-81. [DOI: 10.1111/j.1462-5822.2009.01370.x] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Structural study of the N-glycans of intercellular adhesion molecule-5 (telencephalin). Biochim Biophys Acta Gen Subj 2009; 1790:1611-23. [DOI: 10.1016/j.bbagen.2009.08.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2008] [Revised: 08/21/2009] [Accepted: 08/28/2009] [Indexed: 11/18/2022]
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Chavakis E, Choi EY, Chavakis T. Novel aspects in the regulation of the leukocyte adhesion cascade. Thromb Haemost 2009; 102:191-7. [PMID: 19652868 DOI: 10.1160/th08-12-0844] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Leukocyte recruitment plays a major role in the immune response to infectious pathogens and during inflammatory and autoimmune disorders. The process of leukocyte extravasation from the blood into the inflamed tissue requires a complex cascade of adhesive events between the leukocytes and the endothelium including leukocyte rolling, adhesion and transendothelial migration. Leukocyte-endothelial interactions are mediated by tightly regulated binding interactions between adhesion receptors on both cells. In this regard, leukocyte adhesion onto the endothelium is governed by leukocyte integrins and their endothelial counter-receptors of the immunoglobulin superfamily. The present review will focus on novel aspects with respect to the modulation of the leukocyte adhesion cascade.
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Gahmberg CG, Fagerholm SC, Nurmi SM, Chavakis T, Marchesan S, Grönholm M. Regulation of integrin activity and signalling. Biochim Biophys Acta Gen Subj 2009; 1790:431-44. [PMID: 19289150 DOI: 10.1016/j.bbagen.2009.03.007] [Citation(s) in RCA: 135] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2008] [Revised: 03/05/2009] [Accepted: 03/10/2009] [Indexed: 01/09/2023]
Abstract
The ability of cells to attach to each other and to the extracellular matrix is of pivotal significance for the formation of functional organs and for the distribution of cells in the body. Several molecular families of proteins are involved in adhesion, and recent work has substantially improved our understanding of their structures and functions. Also, these molecules are now being targeted in the fight against disease. However, less is known about how their activity is regulated. It is apparent that among the different classes of adhesion molecules, the integrin family of adhesion receptors is unique in the sense that they constitute a large group of widely distributed receptors, they are unusually complex and most importantly their activities are strictly regulated from the inside of the cell. The activity regulation is achieved by a complex interplay of cytoskeletal proteins, protein kinases, phosphatases, small G proteins and adaptor proteins. Obviously, we are only in the beginning of our understanding of how the integrins function, but already now fascinating details have become apparent. Here, we describe recent progress in the field, concentrating mainly on mechanistical and structural studies of integrin regulation. Due to the large number of articles dealing with integrins, we focus on what we think are the most exciting and rewarding directions of contemporary research on cell adhesion and integrins.
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Affiliation(s)
- Carl G Gahmberg
- Division of Biochemistry, Faculty of Biosciences, University of Helsinki, Viikinkaari 5, 00014, Finland.
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Binding of the Streptococcus gordonii DL1 surface protein Hsa to the host cell membrane glycoproteins CD11b, CD43, and CD50. Infect Immun 2008; 76:4686-91. [PMID: 18678668 DOI: 10.1128/iai.00238-08] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Infective endocarditis is frequently attributed to oral streptococci. The mechanisms of pathogenesis, however, are not well understood, although interaction between streptococci and phagocytes are thought to be very important. A highly expressed surface component of Streptococcus gordonii, Hsa, which has sialic acid-binding activity, contributes to infective endocarditis in vivo. In the present study, we found that S. gordonii DL1 binds to HL-60 cells differentiated into monocytes, granulocytes, and macrophages. Using a glutathione S-transferase (GST) fusion to the NR2 domain, which is the sialic acid-binding region of Hsa, we confirmed that the Hsa NR2 domain also binds to differentiated HL-60 cells. To identify which sialoglycoproteins on the surface of differentiated HL-60 cells are receptors for Hsa, intrinsic membrane proteins were assessed by bacterial overlay and far-Western blotting. S. gordonii DL1 adhered to 100- to 150-kDa proteins, a reaction that was abolished by neuraminidase treatment. These sialoglycoproteins were identified as CD11b, CD43, and CD50 by GST pull-down assay and immunoprecipitation with each specific monoclonal antibody. These data suggest that S. gordonii DL1 Hsa specifically binds to three glycoproteins as receptors and that this interaction may be the initial bacterial binding step in infective endocarditis by oral streptococci.
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40
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Lapalombella R, Zhao X, Triantafillou G, Yu B, Jin Y, Lozanski G, Cheney C, Heerema N, Jarjoura D, Lehman A, Lee LJ, Marcucci G, Lee RJ, Caligiuri MA, Muthusamy N, Byrd JC. A novel Raji-Burkitt's lymphoma model for preclinical and mechanistic evaluation of CD52-targeted immunotherapeutic agents. Clin Cancer Res 2008; 14:569-78. [PMID: 18223233 DOI: 10.1158/1078-0432.ccr-07-1006] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE To date, efforts to study CD52-targeted therapies, such as alemtuzumab, have been limited due to the lack of stable CD52 expressing transformed B-cell lines and animal models. We describe generation and utilization of cell lines that stably express CD52 both in vitro and in vivo. EXPERIMENTAL DESIGN By limiting dilution, we have established several clones of Raji-Burkitt's lymphoma cell line that express surface CD52. Immunophenotype and cytogenetic characterization of these clones was done. In vivo usefulness of the CD52(high) cell line to evaluate the therapeutic efficacy of CD52-directed antibody was investigated using a SCID mouse xenograft model. RESULTS Stable expression of CD52 was confirmed in cells cultured in vitro up to 52 weeks of continuous growth. The functional integrity of the expressed CD52 molecule was shown using alemtuzumab, which induced cytotoxic effects in vitro in the CD52(high) but not the CD52(low) clone. Compared with control antibody, alemtuzumab treatment in CD52(high) inoculated mice resulted in significantly increased median survival. Comparable levels of CD52-targeted direct cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cytotoxicity and anti-CD52 immunoliposome-mediated delivery of synthetic oligodeoxyribo nucleotides in CD52(high) clone and primary B-chronic lymphocytic leukemia cells implicated potential in vivo application of this model for evaluation of CD52-targeted antibody and immunoliposomes encapsulating therapeutic agents. CONCLUSIONS These results show the in vitro utility of the cloned Raji cell lines that stably express high levels CD52. The disseminated leukemia-lymphoma mouse model described herein using these stable cell lines can serve as an excellent system for in vivo therapeutic and mechanistic evaluation of existing and novel antibodies directed against CD52 molecule.
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MESH Headings
- Alemtuzumab
- Animals
- Antibodies, Monoclonal/immunology
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Humanized
- Antibodies, Monoclonal, Murine-Derived
- Antibodies, Neoplasm/immunology
- Antibodies, Neoplasm/therapeutic use
- Antigens, CD/immunology
- Antigens, CD/metabolism
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/metabolism
- Antineoplastic Agents/immunology
- Antineoplastic Agents/therapeutic use
- Burkitt Lymphoma/drug therapy
- Burkitt Lymphoma/immunology
- CD52 Antigen
- Cell Line, Tumor
- Genes, p53
- Glycoproteins/immunology
- Glycoproteins/metabolism
- Humans
- Immunotherapy
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/immunology
- Liposomes/metabolism
- Mice
- Mice, SCID
- Mutation
- Rituximab
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Rosa Lapalombella
- Division of Hematology-Oncology, Department of Internal Medicine, Ohio State University, Columbus, OH 43210, USA
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41
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Boschelli DH. Inhibitors of leukocyte-endothelial cell interactions as anti-inflammatory therapeutics - update. Expert Opin Investig Drugs 2008. [DOI: 10.1517/13543784.3.8.861] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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42
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Aarnoudse CA, Bax M, Sánchez-Hernández M, García-Vallejo JJ, van Kooyk Y. Glycan modification of the tumor antigen gp100 targets DC-SIGN to enhance dendritic cell induced antigen presentation to T cells. Int J Cancer 2008; 122:839-46. [PMID: 17957800 DOI: 10.1002/ijc.23101] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Dendritic cells (DC) have gained much interest in the field of anticancer vaccine development because of their central function in immune regulation. However, the clinical application of ex vivo cultured DC has significant disadvantages. A vaccine that targets dendritic cells in vivo and enhances antigen presentation would be of great benefit. Because of its DC-restricted expression pattern, and its function as an antigen uptake receptor, DC-SIGN is an interesting candidate target structure for human immature DC. Here, we studied whether modification of the melanoma differentiation antigen gp100 with DC-SIGN-interacting glycans enhances targeting to human DC. A high-mannose form of gp100, as protein or as tumor lysate, not only interacted specifically with DC through DC-SIGN but also resulted in an enhanced antigen presentation to gp100-specific CD4(+) T cells. Our results indicate that glycan modification of tumor antigens to target C-type lectin receptors, such as DC-SIGN, is a new way to develop in vivo targeting DC strategies that simultaneously enhance the induction of tumor-specific T cells.
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Affiliation(s)
- Corlien A Aarnoudse
- Department of Molecular Cell Biology and Immunology, VU Medical Center, Amsterdam, The Netherlands
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43
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Malcherek G, Mayr L, Roda-Navarro P, Rhodes D, Miller N, Trowsdale J. The B7 homolog butyrophilin BTN2A1 is a novel ligand for DC-SIGN. THE JOURNAL OF IMMUNOLOGY 2007; 179:3804-11. [PMID: 17785817 DOI: 10.4049/jimmunol.179.6.3804] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The MHC-encoded butyrophilin, BTN2A1, is a cell surface glycoprotein related to the extended family of B7 costimulatory molecules. BTN2A1 mRNA was expressed in most human tissues, but protein expression was significantly lower in leukocytes. An Ig-fusion protein of BTN2A1 bound to immature monocyte-derived dendritic cells. Binding diminished upon MoDC maturation and no binding was detected to Langerhans cells. Induction of the counterreceptor was IL-4 dependent and occurred early during dendritic cell differentiation. The interaction required the presence of Ca2+ and was mediated by high-mannose oligosaccharides. These properties matched DC-SIGN, a DC-specific HIV-1 entry receptor. This was confirmed by binding of soluble BTN2A1 to DC-SIGN-transfectants and its inhibition by a specific Ab. DC-SIGN bound to native BTN2A1 expressed on a range of tissues. However, BTN2A1 was not recognized on some normal cells such as HUVECs despite a similar expression level. The BTN2A1 of tumor cells such as HEK293T have more high-mannose moieties in comparison to HUVECs, and those high-mannose moieties are instrumental for binding to DC-SIGN. The data are consistent with tumor- or tissue-specific glycosylation of BTN2A1 governing recognition by DC-SIGN on immature monocyte-derived dendritic cells.
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Affiliation(s)
- Georg Malcherek
- Department of Pathology, Division of Immunology, University of Cambridge, Cambridge, United Kingdom.
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44
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Thibault S, Tardif MR, Barat C, Tremblay MJ. TLR2 Signaling Renders Quiescent Naive and Memory CD4+T Cells More Susceptible to Productive Infection with X4 and R5 HIV-Type 1. THE JOURNAL OF IMMUNOLOGY 2007; 179:4357-66. [PMID: 17878330 DOI: 10.4049/jimmunol.179.7.4357] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
It has been recently demonstrated that circulating microbial products are responsible for a systemic immune activation in individuals infected with HIV-type 1. Bacterial products carry structural conserved motifs recognized by TLRs. Some TLR members are expressed in primary human CD4+ T cells but the precise functional role played by these pattern recognition receptors is still imprecise. In this study, we report that engagement of TLR2 in quiescent naive and memory CD4+ T cells leads to the acquisition of an effector-like phenotype. Interestingly, engagement of TLR2 renders both cell subsets more susceptible to productive infection with X4 virions and a higher virus production was seen with R5 viruses. It can be proposed that exposure of resting CD4+ T cells to pathogen-derived products that can engage TLR2 induces the acquisition of an effector-like phenotype in naive and memory CD4+ T lymphocytes, a phenomenon that might result in an acceleration of virus replication, immune dysregulation, and HIV-type 1-mediated disease progression.
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Affiliation(s)
- Sandra Thibault
- Centre de Recherche en Infectiologie, Centre Hospitalier de l'Université Laval, and Faculté de Médecine, Université Laval, Québec, Canada
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45
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Toivanen A, Ihanus E, Mattila M, Lutz HU, Gahmberg CG. Importance of molecular studies on major blood groups--intercellular adhesion molecule-4, a blood group antigen involved in multiple cellular interactions. Biochim Biophys Acta Gen Subj 2007; 1780:456-66. [PMID: 17997044 DOI: 10.1016/j.bbagen.2007.09.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2007] [Revised: 09/05/2007] [Accepted: 09/06/2007] [Indexed: 11/18/2022]
Abstract
Several blood groups, including the LW-blood group were discovered in the first part of last century, but their biochemical characteristics and cellular functions have only more recently been elucidated. The LW-blood group, renamed ICAM-4 (CD242), is red cell specific and belongs to the intercellular adhesion molecule family. ICAM-4 binds to several integrin receptors on blood and endothelial cells and is thus able to form large cellular complexes containing red cells. Its physiological function(s) has remained incompletely understood, but recent work shows that macrophage integrins can bind red cells through this ligand. In this article we discuss molecular properties of major blood group antigens, describe ICAM-4 in more detail, and show that phagocytosis of senescent red cells is in part ICAM-4/beta(2)-integrin dependent.
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Affiliation(s)
- Anne Toivanen
- Division of Biochemistry, Faculty of Biosciences, P.O. Box 56, Viikinkaari 5, 00014 University of Helsinki, Finland
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46
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Madsen CD, Ferraris GMS, Andolfo A, Cunningham O, Sidenius N. uPAR-induced cell adhesion and migration: vitronectin provides the key. ACTA ACUST UNITED AC 2007; 177:927-39. [PMID: 17548516 PMCID: PMC2064291 DOI: 10.1083/jcb.200612058] [Citation(s) in RCA: 175] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Expression of the membrane receptor uPAR induces profound changes in cell morphology and migration, and its expression correlates with the malignant phenotype of cancers. To identify the molecular interactions essential for uPAR function in these processes, we carried out a complete functional alanine scan of uPAR in HEK293 cells. Of the 255 mutant receptors characterized, 34 failed to induce changes in cell morphology. Remarkably, the molecular defect of all of these mutants was a specific reduction in integrin-independent cell binding to vitronectin. A membrane-tethered plasminogen activator inhibitor-1, which has the same binding site in vitronectin as uPAR, replicated uPAR-induced changes. A direct uPAR–vitronectin interaction is thus both required and sufficient to initiate downstream changes in cell morphology, migration, and signal transduction. Collectively these data demonstrate a novel mechanism by which a cell adhesion molecule lacking inherent signaling capability evokes complex cellular responses by modulating the contact between the cell and the matrix without the requirement for direct lateral protein–protein interactions.
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Affiliation(s)
- Chris D Madsen
- FIRC Institute of Molecular Oncology (IFOM), 20139 Milan, Italy
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47
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Chiang SC, Chang CC, Lin YC, Ng HP, Lee ST. Loop 1 structure of the leishmanial ICAM-L molecule is crucial for parasite binding and infection of host macrophages. Int J Parasitol 2007; 37:1001-11. [PMID: 17306804 DOI: 10.1016/j.ijpara.2007.01.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2006] [Revised: 01/03/2007] [Accepted: 01/04/2007] [Indexed: 10/23/2022]
Abstract
The binding of each intercellular adhesive molecule (ICAM) molecule fragment from Leishmania amazonensis (ICAM-L) to host macrophages was investigated using an indirect immunofluorescent sandwich technique, based on the observation that ICAM-L can block the uptake of L. amazonensis on the macrophage surface and all prepared ICAM-L fragments can react with rabbit anti-ICAM-L antiserum. The ICAM-L fragments lacking the loop 1 (LI) structure failed to bind to macrophages, and the disruption of the LI structure by mercaptoethanol led to the failure of binding. The fragments containing the LI structure functioned similarly to ICAM-L, by temporarily retarding host cell growth and cell cycle progression, and inhibiting the Leishmania infection of host macrophages. These results suggest that LI constitutes the main determinant of the ICAM-L molecule in binding to, and infection of, host macrophages.
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Affiliation(s)
- Su-Chi Chiang
- Division of Infectious Diseases and Immunology, Institute of Biomedical Sciences (IBMS), No. 128, Academia Road Section 2, Nankang, Taipei 11529, Taiwan, ROC
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48
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Chan KYK, Ching JCY, Xu MS, Cheung ANY, Yip SP, Yam LYC, Lai ST, Chu CM, Wong ATY, Song YQ, Huang FP, Liu W, Chung PH, Leung GM, Chow EYD, Chan EYT, Chan JCK, Ngan H, Tam P, Chan LC, Sham P, Chan VSF, Peiris M, Lin SCL, Khoo US. Association of ICAM3 genetic variant with severe acute respiratory syndrome. J Infect Dis 2007; 196:271-80. [PMID: 17570115 PMCID: PMC7202406 DOI: 10.1086/518892] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2005] [Accepted: 02/16/2007] [Indexed: 12/12/2022] Open
Abstract
Genetic polymorphisms have been demonstrated to be associated with vulnerability to human infection. ICAM3, an intercellular adhesion molecule important for T cell activation, and FCER2 (CD23), an immune response gene, both located on chromosome 19p13.3 were investigated for host genetic susceptibility and association with clinical outcome. A case-control study based on 817 patients with confirmed severe acute respiratory syndrome (SARS), 307 health care worker control subjects, 290 outpatient control subjects, and 309 household control subjects unaffected by SARS from Hong Kong was conducted to test for genetic association. No significant association to susceptibility to SARS-CoV infection was found for the FCER2 and the ICAM3 single nucleotide polymorphisms. However, patients with SARS homozygous for ICAM3 Gly143 showed significant association with higher lactate dehydrogenase levels (P=.0067; odds ratio [OR], 4.31 [95% confidence interval [CI], 1.37–13.56]) and lower total white blood cell counts (P=.022; OR, 0.30 [95% CI, 0.10–0.89]) on admission. These findings support the role of ICAM3 in the immunopathogenesis of SARS.
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Affiliation(s)
- Kelvin Y. K. Chan
- Department of Pathology, Hong Kong Jockey Club Clinical Research CentreHong Kong
| | - Johannes C. Y. Ching
- Department of Pathology, Hong Kong Jockey Club Clinical Research CentreHong Kong
| | - M. S. Xu
- Department of Pathology, Hong Kong Jockey Club Clinical Research CentreHong Kong
| | - Annie N. Y. Cheung
- Department of Pathology, Hong Kong Jockey Club Clinical Research CentreHong Kong
| | - Shea-Ping Yip
- Department of Health Technology and Informatics, Hong Kong Polytechnic UniversityHong Kong
| | | | | | | | | | - You-Qiang Song
- Department of Biochemistry, Hong Kong Jockey Club Clinical Research CentreHong Kong
- Genome Research Center, Hong Kong Jockey Club Clinical Research CentreHong Kong
| | - Fang-Ping Huang
- Department of Pathology, Hong Kong Jockey Club Clinical Research CentreHong Kong
| | - Wei Liu
- Department of Pathology, Hong Kong Jockey Club Clinical Research CentreHong Kong
| | | | - G. M. Leung
- Department of Community Medicine, Li Ka Shing Faculty of Medicine, University of Hong KongHong Kong
| | | | - Eric Y. T. Chan
- Department of Pathology, Hong Kong Jockey Club Clinical Research CentreHong Kong
| | - Jane C. K. Chan
- Hospital Authority Severe Acute Respiratory Syndrome Collaborative Group, Hong Kong Hospital Authority Head OfficeHong Kong
| | - Hextan Ngan
- Department of Obstetrics and Gynecology, Hong Kong Jockey Club Clinical Research CentreHong Kong
| | - Paul Tam
- Department of Surgery, Hong Kong Jockey Club Clinical Research CentreHong Kong
- Genome Research Center, Hong Kong Jockey Club Clinical Research CentreHong Kong
| | - Li-Chong Chan
- Department of Pathology, Hong Kong Jockey Club Clinical Research CentreHong Kong
| | - Pak Sham
- Department of Psychiatry, Hong Kong Jockey Club Clinical Research CentreHong Kong
| | - Vera S. F. Chan
- Department of Biosurgery and Surgical Technology, Imperial College LondonLondon, United Kingdom
| | - Malik Peiris
- Department of Microbiology, Hong Kong Jockey Club Clinical Research CentreHong Kong
| | - Steve C. L. Lin
- Department of Biosurgery and Surgical Technology, Imperial College LondonLondon, United Kingdom
| | - Ui-Soon Khoo
- Department of Pathology, Hong Kong Jockey Club Clinical Research CentreHong Kong
- Reprints or correspondence: Dr. Ui-Soon Khoo, Rm. 324, 3/F, University Pathology Bldg., Dept. of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam Rd., Hong Kong ()
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49
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Biggins JE, Biesinger T, Yu Kimata MT, Arora R, Kimata JT. ICAM-3 influences human immunodeficiency virus type 1 replication in CD4(+) T cells independent of DC-SIGN-mediated transmission. Virology 2007; 364:383-94. [PMID: 17434553 PMCID: PMC1973158 DOI: 10.1016/j.virol.2007.03.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2006] [Revised: 01/08/2007] [Accepted: 03/12/2007] [Indexed: 11/18/2022]
Abstract
We investigated the role of ICAM-3 in DC-SIGN-mediated human immunodeficiency virus (HIV) infection of CD4(+) T cells. Our results demonstrate that ICAM-3 does not appear to play a role in DC-SIGN-mediated infection of CD4(+) T cells as virus is transmitted equally to ICAM-3(+) or ICAM-3(-) Jurkat T cells. However, HIV-1 replication is enhanced in ICAM-3(-) cells, suggesting that ICAM-3 may limit HIV-1 replication. Similar results were obtained when SIV replication was examined in ICAM-3(+) and ICAM-3(-) CEMx174 cells. Furthermore, while ICAM-3 has been proposed to play a co-stimulatory role in T cell activation, DC-SIGN expression on antigen presenting cells did not enhance antigen-dependent activation of T cells. Together, these data indicate that while ICAM-3 may influence HIV-1 replication, it does so independent of DC-SIGN-mediated virus transmission or activation of CD4(+) T cells.
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Affiliation(s)
| | | | | | | | - Jason T. Kimata
- *Corresponding Author: Department of Molecular Virology and Microbiology, BCM385, Room 811D, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA Tel: 713-798-4536, FAX: 713-798-4435,
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50
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Ihanus E, Uotila LM, Toivanen A, Varis M, Gahmberg CG. Red-cell ICAM-4 is a ligand for the monocyte/macrophage integrin CD11c/CD18: characterization of the binding sites on ICAM-4. Blood 2006; 109:802-10. [PMID: 16985175 DOI: 10.1182/blood-2006-04-014878] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Intercellular adhesion molecule 4 (ICAM-4) is a unique member of the ICAM family because of its specific expression on erythroid cells and ability to interact with several types of integrins expressed on blood and endothelial cells. The first reported receptors for ICAM-4 were CD11a/CD18 and CD11b/CD18. In contrast to these 2, the cellular ligands and the functional role of the third beta2 integrin, CD11c/CD18, have not been well defined. Here, we show that ICAM-4 functions as a ligand for the monocyte/macrophage-specific CD11c/CD18. Deletion of the individual immunoglobulin domains of ICAM-4 demonstrated that both its domains contain binding sites for CD11c/CD18. Analysis of a panel of ICAM-4 point mutants identified residues that affected binding to the integrin. By molecular modeling the important residues were predicted to cluster in 2 distinct but spatially close regions of the first domain with an extension to the second domain spatially distant from the other residues. We also identified 2 peptides derived from sequences of ICAM-4 that are capable of modulating the binding to CD11c/CD18. CD11c/CD18 is expressed on macrophages in spleen and bone marrow. Inhibition of erythrophagocytosis by anti-ICAM-4 and anti-integrin antibodies suggests a role for these interactions in removal of senescent red cells.
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Affiliation(s)
- Eveliina Ihanus
- Faculty of Biosciences, Division of Biochemistry, PO Box 56, Viikinkaari 5, University of Helsinki 00014, Finland
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