The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 13, 2019

Allele Specific Expression of MICA Variants in Human Fibroblasts Suggests a Pathogenic Mechanism



Chunhua Shi 1, 2, §, Hongye Li 1, §, Jacob P Couturier 1, Karen Yang 1, Xinjian Guo 1, Dongyi He 3, Dorothy E Lewis 1, Xiaodong Zhou*, 1
1 Department of Internal Medicine, University of Texas Health Science Center at Houston, USA
2 Department of Internal Medicine, Jiangxi People’s Hospital, Nanchang, China
3 Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Guanghua Integrative Medicine Hospital, Shanghai, China

Abstract

The major histocompatibility complex class I chain-related gene A (MICA) is involved in immune responses of both nature killer (NK) cells and subsets of T cells with its receptor NKG2D. MICA is highly polymorphic in sequence which leads to MICA protein variants with distinct features. Specific polymorphisms of MICA have been associated with inflammatory diseases, including ankylosing spondylitis (AS), ulcerative colitis (UC) and Behçet’s disease. Studies herein characterize expression features of three MICA variants including MICA*008, a common variant in general population, and *MICA*007 and *019, which are associated with susceptibility to inflammatory diseases. MICA*019 was highly expressed on the surface of fibroblasts whereas expression of MICA*007 was the lowest in the culture supernatant. MICA*008 had low cell surface expression but was the only MICA allele in which exosomal material was detected. Surface or membrane-bound MICA activates NKG2D-mediated cytotoxicity, whereas soluble and exosomal MICAs down-regulate NKG2D. Therefore, comparisons of these three MICA variants in fibroblasts provides insight into understanding how MICA associated immune responses could be regulated to influence levels of inflammation.

Keywords: Exosome, fibroblasts, MICA, NKG2D, surface expression.


Article Information


Identifiers and Pagination:

Year: 2015
Volume: 9
First Page: 60
Last Page: 64
Publisher Id: TORJ-9-60
DOI: 10.2174/1874312901409010060

Article History:

Received Date: 8/5/2015
Revision Received Date: 1/6/2015
Acceptance Date: 19/6/2015
Electronic publication date: 26/8/2015
Collection year: 2015

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© Shi et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Department of Internal Medicine, University of Texas Medical School at Houston, 6431 Fannin Street, MSB5270, Houston Texas 77030, USA; Tel: 713-500-6900; Fax: 713-500-0580; E-mail: xiaodong.zhou@uth.tmc.edu§ First two authors contribute equally to the studies.





INTRODUCTION

The major histocompatibility complex class I chain-related gene A (MICA) is highly polymorphic. MICA with more than 100 identified alleles [http://www.ebi.ac.uk/ipd/ imgt/hla/]. Although, the functional significance of these alleles has not been fully defined, some have been associated with chronic inflammatory diseases. In particular, MICA*007 and *019 alleles were associated with ankylosing spondylitis (AS) [1Zhou X, Wang J, Zou H, et al. MICA, a gene contributing strong susceptibility to ankylosing spondylitis Ann Rheum Dis 2014; 73(8): 1552-7.
[http://dx.doi.org/10.1136/annrheumdis-2013-203352] [PMID: 23727634]
], MICA*007 also was associated with ulcerative colitis (UC) [2Orchard TR, Dhar A, Simmons JD, Vaughan R, Welsh KI, Jewell DP. MHC class I chain-like gene A (MICA) and its associations with inflammatory bowel disease and peripheral arthropathy Clin Exp Immunol 2001; 126(3): 437-40.
[http://dx.doi.org/10.1046/j.1365-2249.2001.01662.x] [PMID: 11737059]
], and MICA*019 with Behçet’s disease [3Muñoz-Saá I, Cambra A, Pallarés L, et al. Allelic diversity and affinity variants of MICA are imbalanced in Spanish patients with Behçet’s disease Scand J Immunol 2006; 64(1): 77-82.
[http://dx.doi.org/10.1111/j.1365-3083.2006.01780.x] [PMID: 16784494]
]. This association indicates that these two MICA alleles may be important in regulation of inflammation. Compared to the most common MICA*008 allele, several nucleotides differ in the MICA*007 and *019 alleles with the most prominent sequence variation at codon 293-297, encoding four (MICA-A4) or five (MICA-A5) alanine residues in the transmembrane domain of MICA, respectively. By contrast, the MICA*008 sequence contains an insertion of guanine at codon 295 that results in a premature stop codon at position 304, which in turn encodes a truncated MICA protein lacking part of the transmembrane domain and the whole cytoplasmic tail [4Mizuki N, Ota M, Kimura M, et al. Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behçet disease Proc Natl Acad Sci USA 1997; 94(4): 1298-303.
[http://dx.doi.org/10.1073/pnas.94.4.1298] [PMID: 9037047]
].

MICA protein is expressed as a membrane-bound protein in selective cells such as gut epithelial and fibroblasts. Under cellular stress conditions, such as infections, tissue injury, pro-inflammatory signals, and malignant transformation [5González S, López-Soto A, Suarez-Alvarez B, López-Vázquez A, López-Larrea C. NKG2D ligands: key targets of the immune response Trends Immunol 2008; 29(8): 397-403.
[http://dx.doi.org/10.1016/j.it.2008.04.007] [PMID: 18602338]
-1Zhou X, Wang J, Zou H, et al. MICA, a gene contributing strong susceptibility to ankylosing spondylitis Ann Rheum Dis 2014; 73(8): 1552-7.
[http://dx.doi.org/10.1136/annrheumdis-2013-203352] [PMID: 23727634]
], MICA interacts with its receptor NKG2D found on natural killer (NK) cells, NK T cells, γδ T cells, αβ CD8+ T cells, and a minor immune-regulatory subset of CD4+ T cells [10Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR, Spies T. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells Nat Immunol 2001; 2(3): 255-60.
[http://dx.doi.org/10.1038/85321] [PMID: 11224526]
-18González S, Groh V, Spies T. Immunobiology of human NKG2D and its ligands Curr Top Microbiol Immunol 2006; 298: 121-38.
[http://dx.doi.org/10.1007/3-540-27743-9_6] [PMID: 16329186]
]. Binding of MICA (membrane-bound MICA) with NKG2D triggers cell-mediated cytotoxicity and cytokine release from NK cells and T cells [9Das H, Groh V, Kuijl C, et al. MICA engagement by human Vgamma2Vdelta2 T cells enhances their antigen-dependent effector function Immunity 2001; 15(1): 83-93.
[http://dx.doi.org/10.1016/S1074-7613(01)00168-6] [PMID: 11485740]
, 10Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR, Spies T. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells Nat Immunol 2001; 2(3): 255-60.
[http://dx.doi.org/10.1038/85321] [PMID: 11224526]
, 19Rincon-Orozco B, Kunzmann V, Wrobel P, Kabelitz D, Steinle A, Herrmann T. Activation of V gamma 9V delta 2 T cells by NKG2D J Immunol 2005; 175(4): 2144-51.
[http://dx.doi.org/10.4049/jimmunol.175.4.2144] [PMID: 16081780]
, 20André P, Castriconi R, Espéli M, et al. Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors Eur J Immunol 2004; 34(4): 961-71.
[http://dx.doi.org/10.1002/eji.200324705] [PMID: 15048706]
]. On the other hand, the proteolytic cleavage of MICA proteins from expressing cells, termed as MICA shedding produces soluble MICA that may control the immune process by down-modulating NKG2D expression [21Salih HR, Rammensee HG, Steinle A. Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding J Immunol 2002; 169(8): 4098-102.
[http://dx.doi.org/10.4049/jimmunol.169.8.4098] [PMID: 12370336]
, 22Baragaño Raneros A, Suarez-Álvarez B, López-Larrea C. Secretory pathways generating immunosuppressive NKG2D ligands: New targets for therapeutic intervention OncoImmunology 2014; 3(3): e28497.
[http://dx.doi.org/10.4161/onci.28497] [PMID: 25050215]
], and facilitate expansion of an immunosuppressive CD4+ T-cell subset [15Groh V, Smythe K, Dai Z, Spies T. Fas-ligand-mediated paracrine T cell regulation by the receptor NKG2D in tumor immunity Nat Immunol 2006; 7(7): 755-62.
[http://dx.doi.org/10.1038/ni1350] [PMID: 16732291]
]. In addition, MICA can be excreted in exosomes which can also down-regulate NKG2D activity [23Ashiru O, Boutet P, Fernández-Messina L, et al. Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes Cancer Res 2010; 70(2): 481-9.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1688] [PMID: 20068167]
]. It was reported that MICA*008 protein was preferentially released from cells in exosomal form [23Ashiru O, Boutet P, Fernández-Messina L, et al. Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes Cancer Res 2010; 70(2): 481-9.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1688] [PMID: 20068167]
]. Therefore, the balance between membrane-bound MICA and soluble MICA/exosomal MICA may control the outcome of immune function via NKG2D regulation. Studies of MICA*007 and *019 protein variants in comparison with the most common allele, MICA*008 in expression and secretion in human fibroblasts may help understand potential functional significance of disease-associated MICA alleles.

MATERIALS AND METHODS

MICA Clones

The full length of MICA*007:01 was synthesized and inserted into pUC57 by GenScript (Piscataway, NJ). The full length of MICA*008:01 and 019:01 in pCDNA3.1 were gifts from Dr. Mar Vales-Gomez, Department of Immunology and Oncology Centro Nacional De Biotecnologia (CNB) Spain. All of three MICAs were subcloned into pEGFPC3 to form pEGFPC3-MICA clones by Xho I and BamH I sites. All clones of pEGFPC3-MICAs were confirmed by Sanger sequencing.

Fibroblast Cultures and Transfection

Primary human fibroblasts were grown in Hyclone DMEM/high glucose culture medium (GE Healthcare Life Sciences) plus 10% FBS (Gemini) and 1x penicillin-strep (Life Technologies) until 70-80% confluence. For transfection of each MICA clone, a total of 5x105 fibroblasts were suspended in 82ul neucleofector and 18ul supplement using nucleofector kit (Lonza, amaxa), and then mixed with 5ug of the pEGFPC3, pEGFPC3-MICA*007, pEGFPC3-MICA*008 and pEGFPC3-MICA*019 respectively. Amaxa biosystem Nucleofector II (program U23) was used for electroporation. The transfected fibroblasts were split into two small culture dishes (60x15mm) with 2 ml culture medium without any antibiotics, and were grown under standard culture conditions at 37°C in a humid atmosphere containing 5% CO2. The culture medium was changed after 24-hours transfection. The fibroblasts were harvested for the further analysis after 48-hours transfection. We also performed antibiotic screen for neomycin resistance as a dominant selectable marker for selection on the pEGFPC3. Amazingly, the results were very consistent.

Flow Cytometry Studies for Membrane-Bound MICA

Fibroblasts were rinsed with PBS and detached with Accutase solution (Sigma). Cells were then washed with PBS/2%FBS, and stained for either surface or intracellular MICA in conjunction with GFP expression. For surface staining, cells were incubated with MICA-APC monoclonal antibodies (Biolegend) for 30mins at 4°C, washed with PBS/2%FBS. For intracellular staining, cells were first fixed with Cytofix/Cytoperm solution (BD Biosciences) for 30mins at 4°C then washed with Perm/Wash buffer. Cells were then incubated with MICA-APC monoclonal antibodies for 30mins at 4°C then washed with Perm/Wash buffer. Data were acquired with Gallios Flow Cytometer and analyzed with Kaluza1.2 (Beckman-Coulter). For background subtraction, we examined two controls including the fibroblasts without transfection and transfected with pEGFPC3 only. Assays were done in triplicate.

ELISA Measurement for Soluble MICA

Each 0.4 ml of culture medium from cultured the fibroblasts alone and the fibroblasts transfected with pEGFPC3, pEGFPC3-MICA*007, pEGFPC3-MICA*008 and pEGFPC3-MICA*019 were collected, respectively. The supernatants were concentrated into 0.2 ml by Amicon@Ultra (Millipore UFC500324, 3K membrane) according to the manufactory instruction. The concentration of soluble MICAs with duplication were determined by the human MICA ELISA kit (RayBio, Catalog: ELH-MICA).

Exosomal MICA

A total of 4x106 fibroblasts were transfected with each MICA construct in pCDNA3.1. The media from the cultured fibroblasts were used to extract whole exosomes. Briefly, culture medium was centrifuged at 5,000 x g for 10 minutes to remove cell debris. The supernatant was mixed with the exosome isolation reagent (Life Technologies, Catalog: 4478359) and incubated overnight in 4°C. The samples were centrifuged at 10,000 x g for 1 hour at 4°C, and the supernatant discarded. The exosome pellets were re-suspended in PBS buffer and used for detecting MICA expression with ELISA and Western blots.

Western Blots

Cell lysates were prepared by incubation in TNE buffer (20mM Tris-HCl pH 7.5, 150mM NaCl and 5mM EDTA) that contained 1% NP40 and protease inhibitors. After centrifugation to remove nuclei and cell debris, samples were run on 8% SDS-PAGE gels under reducing conditions (Genscript, cat M00812), and then were transferred to Amersham Hybond-P (GE Healthcare Life Sciences) with above exosome suspension. The membrane was blocked using 5% nonfat dry milk in TBS–0.1% Tween 20, and then MICAs were detected by incubating the membrane with MICA antibody (Abgent, Catalog: AP8626c) at 4°C overnight and then followed by anti-Rabbit horseradish peroxidase–conjugated secondary antibodies at room temperature for 2 hours. MICA proteins were visualized using SuperSignal West Femto Maximum sensitivity substrate (Thermo, Catalog: 34095).

RESULTS

Flow cytometry showed differential expression of membrane-bound MICA (Fig. 1), however intracellular MICA was similar for the three constructs suggesting that an equivalent amount of MICA protein was produced, but increased cell surface expression was associated with specific alleles. The mean fluorescent intensity and standard deviation (MFI/SD) of membrane-bound MICA*008, *007:01 and *019 in three experiments of the transfected fibroblasts were 4.5 +/-1.33, 6.71+/-0.4 and 9.86+/-2.0, respectively. Student’s t test showed significant p-values in comparisons between MICA*008 and *007:01 (p = 0.026), and MICA*008 and *019 (p = 0.018) (Fig. 1).

Fig. (1)

A representative dot plot of three flow cytometry studies showed differential expression of membrane-bound (surface) MICA*008, *007 and *019 in cultured fibroblasts. A. Fibroblasts without transfection; B. Fibroblasts transfected with pEGFPC3 without MICA; C. Fibroblasts transfected with pEGFPC3- MICA*008; D. Fibroblasts transfected with pEGFPC3-MICA*007; E. Fibroblasts transfected with pEGFPC3-MICA*019; F. Relative expression levels of surface MICA in three assays. MFI: mean fluorescence intensity. Error bars indicate standard deviations.



Fig. (2)

ELISA showing soluble MICA*008, *007 and *019 from cultured media of the fibroblasts (a total of 2.5 x105 fibroblasts in 5 ml culture media). Fibroblasts were transfected with pEGFPC3-MICA*008, pEGFPC3-MICA*007 and pEGFPC3-MICA*019. After 48-hours transfection, culture media were collected for MICA ELISA. Error bars indicate standard deviations.



Fig. (3)

Western blot showing exosomal MICA only detected in MICA*008 transfected fibroblasts. A total of 4 x106 fibroblasts were transfected with three MICA clones (MICA*008, *007 and *019). After 48- hours transfection, exosomes of each transfected fibroblasts were extracted and examined.



ELISA measurement for soluble MICA*008, *007 and *019 also displayed different levels (Fig. 2). Among the three examined MICA variants, MICA*007 showed significantly less soluble MICA. Comparing soluble MICA*008 verses *007:01 and MICA*008 verses *019.

ELISA measurement for exosomal MICA indicated a high level in the MICA*008 transfected fibroblasts. By contrast, MICA*007 transfected fibroblasts had a marginal level (minimal standard level) in only one of three tests, and MICA*019 exosomes were not detected. Further confirmation with Western blots showed that exosomal MICA only appeared in MICA*008 transfected fibroblasts (Fig. 3).

DISCUSSION

MICA expression usually occurs under cellular stress conditions, and it is involved in an immunosurveillance mechanism aiding elimination of infected or transformed cells [24Smyth MJ, Swann J, Cretney E, Zerafa N, Yokoyama WM, Hayakawa Y. NKG2D function protects the host from tumor initiation J Exp Med 2005; 202(5): 583-8.
[http://dx.doi.org/10.1084/jem.20050994] [PMID: 16129707]
, 25Schrambach S, Ardizzone M, Leymarie V, Sibilia J, Bahram S. In vivo expression pattern of MICA and MICB and its relevance to auto-immunity and cancer PLoS One 2007; 2(6): e518.
[http://dx.doi.org/10.1371/journal.pone.0000518] [PMID: 17565371]
]. MICA controls the immune process through interaction with its receptor NKG2D. Expression of MICA on the cell surface (membrane-bound) activates NKG2D signaling. However soluble MICA (proteolytic product) and exosomal MICA (secreted form) down-regulate NKG2D [21Salih HR, Rammensee HG, Steinle A. Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding J Immunol 2002; 169(8): 4098-102.
[http://dx.doi.org/10.4049/jimmunol.169.8.4098] [PMID: 12370336]
-23Ashiru O, Boutet P, Fernández-Messina L, et al. Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes Cancer Res 2010; 70(2): 481-9.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1688] [PMID: 20068167]
]. Therefore, quantities of these three forms of MICA determine NKG2D mediated immune responses. Tumor-derived soluble MICA reduces NKG2D activity on CD8+ T and NK cells, and stimulates expansion of NKG2D+ CD4+ T cells with immune suppressor-like functions to evade NKG2D-mediated immune-surveillance [26Groh V, Wu J, Yee C, Spies T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation Nature 2002; 419(6908): 734-8.
[http://dx.doi.org/10.1038/nature01112] [PMID: 12384702]
]. By contrast, expression of MICA on the surface of synovial fibroblasts leads to up-regulation of MICA-NKG2D in local tissues that may cause auto-reactive T-cell stimulation, thus promoting the self-perpetuating pathogenic process in rheumatoid arthritis (RA) [27Groh V, Bruhl A, El-Gabalawy H, Nelson JL, Spies T. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis Proc Natl Acad Sci USA 2003; 100(16): 9452-7.
[http://dx.doi.org/10.1073/pnas.1632807100] [PMID: 12878725]
].

The studies herein compared expression of three MICA variants. We found that MICA*019 had the most cell surface expression followed by MICA*007, and MICA*008. This observation may reflect the level of activation of NKG2D signaling by each of these three MICA variants. Importantly, MICA*008 was the only variant found with an exosomal form, which together with its low presence on the surface of the fibroblasts may indicate that it has potentially a predominant inhibitory function on NKG2D signaling. By contrast, MICA*007 was found at the lowest level in soluble form among all three variants.

Three MICA variants displayed distinct expression on cell surface and proteolytic or exosomal forms suggesting their individual propensity in up- or down-regulation of NKG2D signaling. Therefore people carrying different MICA variants of these three alleles may respond to cellular stress with divergent paths after MICA-NKG2D mediated immune reactions. Previous genetic association studies indicated that the majority of AS patients carry MICA*007:01 and/or *019, while people carrying the most common MICA*008 allele showed significantly reduced risk of AS [1Zhou X, Wang J, Zou H, et al. MICA, a gene contributing strong susceptibility to ankylosing spondylitis Ann Rheum Dis 2014; 73(8): 1552-7.
[http://dx.doi.org/10.1136/annrheumdis-2013-203352] [PMID: 23727634]
]. In addition, MICA*007 also confer susceptibility to UC [2Orchard TR, Dhar A, Simmons JD, Vaughan R, Welsh KI, Jewell DP. MHC class I chain-like gene A (MICA) and its associations with inflammatory bowel disease and peripheral arthropathy Clin Exp Immunol 2001; 126(3): 437-40.
[http://dx.doi.org/10.1046/j.1365-2249.2001.01662.x] [PMID: 11737059]
], and MICA*019 to Behçet’s disease [3Muñoz-Saá I, Cambra A, Pallarés L, et al. Allelic diversity and affinity variants of MICA are imbalanced in Spanish patients with Behçet’s disease Scand J Immunol 2006; 64(1): 77-82.
[http://dx.doi.org/10.1111/j.1365-3083.2006.01780.x] [PMID: 16784494]
]. It is plausible to assume that patients who carry either MICA*007 or *019, and lack of MICA*008 may be more susceptible to an over-expression of MICA on the cell surface with greater activation of NKG2D leading to greater to cell-mediated cytotoxicity and inflammatory cytokine release from NK cells and T cells which is likely to produce more inflammation.

This is the first direct comparison of the expression of three MICA variants in primary human fibroblasts. The results of the studies together with previous reports of a high occurrence of MICA*007 and *019 in patients with chronic inflammatory diseases including AS, UC and Behcet’s disease indicated that over-presentation of these two MICA variants in patients may associate with a predominantly positive control for NKG2D mediated immune activation.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

This study was supported by the NIH NIAID 1U01AI09090-01.

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Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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