Main effects of IFN-β in circulating immune cells in MS.
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"},{slug:"intechopen-identified-as-one-of-the-most-significant-contributor-to-oa-book-growth-in-doab-20210809",title:"IntechOpen Identified as One of the Most Significant Contributors to OA Book Growth in DOAB"}]},book:{item:{type:"book",id:"10",leadTitle:null,fullTitle:"Coherence and Ultrashort Pulse Laser Emission",title:"Coherence and Ultrashort Pulse Laser Emission",subtitle:null,reviewType:"peer-reviewed",abstract:"In this volume, recent contributions on coherence provide a useful perspective on the diversity of various coherent sources of emission and coherent related phenomena of current interest. These papers provide a preamble for a larger collection of contributions on ultrashort pulse laser generation and ultrashort pulse laser phenomena. Papers on ultrashort pulse phenomena include works on few cycle pulses, high-power generation, propagation in various media, to various applications of current interest. Undoubtedly, Coherence and Ultrashort Pulse Emission offers a rich and practical perspective on this rapidly evolving field.",isbn:null,printIsbn:"978-953-307-242-5",pdfIsbn:"978-953-51-4538-7",doi:"10.5772/543",price:159,priceEur:175,priceUsd:205,slug:"coherence-and-ultrashort-pulse-laser-emission",numberOfPages:700,isOpenForSubmission:!1,isInWos:1,isInBkci:!0,hash:"e1bd25a76712d1cb8792820acf2ff001",bookSignature:"F. J. 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He is the author and editor of several well-known books on tunable lasers including Dye Laser Principles (Academic, New York, 1990) and Tunable Laser Optics (Elsevier Academic, New York, 2003). His most recent edited work is Tunable Laser Applications, 2nd Edition (CRC, New York, 2009).\r\nDr. Duarte has made key experimental and theoretical contributions to the field of narrow-linewidth tunable laser oscillators. These include original oscillator architectures and the generalized multiple-prism grating dispersion theory. He has also pioneered the use of Dirac’s quantum notation in the description of generalized N-slit interference and classical optics phenomena. Currently, his research focuses on further developments of dispersive narrow-linewidth laser oscillators and very large N-slit laser interferometers.\r\nDr. Duarte’s contributions are cited in some 130 laser and optics books including several classics. 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Salgad",authors:[{id:"104099",title:"Dr.",name:"Cynthya",middleName:"Elizabeth",surname:"González",fullName:"Cynthya González",slug:"cynthya-gonzalez"},{id:"108603",title:"Dr.",name:"Monika Inés",middleName:null,surname:"Hamann",fullName:"Monika Inés Hamann",slug:"monika-ines-hamann"},{id:"108606",title:"Prof.",name:"Cristina",middleName:null,surname:"Salgado",fullName:"Cristina Salgado",slug:"cristina-salgado"}]},{id:"30923",title:"Pathogenic Attributes of Non-Candida albicans Candida Species Revealed by SEM",slug:"pathogenic-attributes-of-non-candida-albicans-candida-species-revealed-by-sem",signatures:"Márcia Cristina Furlaneto, Célia Guadalupe Tardeli de Jesus Andrade, Luciana Furlaneto-Maia, Emanuele Júlio Galvão de França and Alane Tatiana Pereira Moralez",authors:[{id:"101952",title:"Prof.",name:"Marcia Cristina",middleName:null,surname:"Furlaneto",fullName:"Marcia Cristina Furlaneto",slug:"marcia-cristina-furlaneto"},{id:"109069",title:"Dr.",name:"Célia Guadalupe Tardeli De Jesus",middleName:null,surname:"Andrade",fullName:"Célia Guadalupe Tardeli De Jesus Andrade",slug:"celia-guadalupe-tardeli-de-jesus-andrade"},{id:"109070",title:"Dr.",name:"Luciana",middleName:null,surname:"Furlaneto-Maia",fullName:"Luciana Furlaneto-Maia",slug:"luciana-furlaneto-maia"},{id:"109071",title:"MSc.",name:"Emanuele Julio Galvão",middleName:null,surname:"França",fullName:"Emanuele Julio Galvão França",slug:"emanuele-julio-galvao-franca"},{id:"128748",title:"MSc.",name:"Alane Tatiana",middleName:null,surname:"Moralez",fullName:"Alane Tatiana Moralez",slug:"alane-tatiana-moralez"}]},{id:"30934",title:"Multimodal Microscopy for Ore Characterization",slug:"multimodal-microscopy-for-ore-characterization",signatures:"Otávio da Fonseca Martins Gomes and Sidnei Paciornik",authors:[{id:"99055",title:"Dr.",name:"Otavio",middleName:"Da Fonseca Martins",surname:"Gomes",fullName:"Otavio 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Saucedo-Muñoz, Victor M. Lopez-Hirata and Hector J. 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Otto, Wilhelm Habicht, Eckhard Dinjus and Michael Zimmerman",authors:[{id:"114899",title:"Dr.",name:"Thomas",middleName:null,surname:"Otto",fullName:"Thomas Otto",slug:"thomas-otto"}]},{id:"30938",title:"Fractal Analysis of Micro Self-Sharpening Phenomenon in Grinding with Cubic Boron Nitride (cBN) Wheels",slug:"fractal-analysis-of-self-sharpening-phenomenon-in-grinding-with-cubic-boron-nitride-cbn-wheel-",signatures:"Yoshio Ichida",authors:[{id:"105836",title:"Prof.",name:"Yoshio",middleName:null,surname:"Ichida",fullName:"Yoshio Ichida",slug:"yoshio-ichida"}]},{id:"30939",title:"Evolution of Phases in a Recycled Al-Si Cast Alloy During Solution Treatment",slug:"evolution-of-phases-in-a-recycled-al-si-cast-alloy-during-solution-treatment",signatures:"Eva Tillová, Mária Chalupová and Lenka Hurtalová",authors:[{id:"23964",title:"Prof.",name:"Mária",middleName:null,surname:"Chalupová",fullName:"Mária Chalupová",slug:"maria-chalupova"},{id:"100623",title:"Prof.",name:"Eva",middleName:null,surname:"Tillova",fullName:"Eva Tillova",slug:"eva-tillova"},{id:"135822",title:"Dr.",name:"Lenka",middleName:null,surname:"Hurtalová",fullName:"Lenka Hurtalová",slug:"lenka-hurtalova"}]},{id:"30940",title:"Strength and Microstructure of Cement Stabilized Clay",slug:"strength-and-microstructure-of-cement-stabilized-clay",signatures:"Suksun Horpibulsuk",authors:[{id:"103519",title:"Prof.",name:"Suksun",middleName:"-",surname:"Horpibulsuk",fullName:"Suksun Horpibulsuk",slug:"suksun-horpibulsuk"}]},{id:"30948",title:"FE-SEM Characterization of Some Nanomaterial",slug:"fe-sem-characterization-of-some-nanomaterials-",signatures:"A. Alyamani and O. M. 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Husain, H. Kishan, Ranjan Kumar and V.P.S. Awana",authors:[{id:"105419",title:"Mr.",name:"Shiva",middleName:null,surname:"Kumar Singh",fullName:"Shiva Kumar Singh",slug:"shiva-kumar-singh"},{id:"109865",title:"Prof.",name:"Mushahid",middleName:null,surname:"Husain",fullName:"Mushahid Husain",slug:"mushahid-husain"},{id:"109866",title:"Dr.",name:"V. P. S.",middleName:null,surname:"Awana",fullName:"V. P. S. Awana",slug:"v.-p.-s.-awana"},{id:"137474",title:"MSc.",name:"Devina",middleName:null,surname:"Sharma",fullName:"Devina Sharma",slug:"devina-sharma"},{id:"137475",title:"Dr.",name:"H.",middleName:null,surname:"Kishan",fullName:"H. Kishan",slug:"h.-kishan"},{id:"143941",title:"Dr.",name:"Ranjan",middleName:null,surname:"Kumar",fullName:"Ranjan Kumar",slug:"ranjan-kumar"}]},{id:"30952",title:"Morphological and Photovoltaic Studies of TiO2 NTs for High Efficiency Solar Cells",slug:"morphological-and-photovoltaic-studies-of-tio2-nanotubes-for-high-efficiency-solar-cells",signatures:"Mukul Dubey and Hongshan He",authors:[{id:"107873",title:"Prof.",name:"Hongshan",middleName:null,surname:"He",fullName:"Hongshan He",slug:"hongshan-he"},{id:"107874",title:"Mr.",name:"Mukul",middleName:null,surname:"Dubey",fullName:"Mukul Dubey",slug:"mukul-dubey"}]},{id:"30953",title:"Synthesis and Characterisation of Silica/Polyamide-Imide Composite Film for Enamel Wire",slug:"synthesis-and-characterization-of-spherical-silica-polyamide-imide-composite-film-for-enamel-wire",signatures:"Xiaokun Ma and Sun-Jae Kim",authors:[{id:"105601",title:"Prof.",name:"Sun-Jae",middleName:null,surname:"Kim",fullName:"Sun-Jae Kim",slug:"sun-jae-kim"},{id:"107938",title:"Dr.",name:"Xiaokun",middleName:null,surname:"Ma",fullName:"Xiaokun Ma",slug:"xiaokun-ma"}]},{id:"30954",title:"Scanning Electron Microscope for Characterising of Micro- and Nanostructured Titanium Surfaces",slug:"scanning-electron-microscope-for-characterising-of-micro-and-nanostructured-titanium-surfaces-",signatures:"Areeya Aeimbhu",authors:[{id:"99729",title:"Dr.",name:"Areeya",middleName:null,surname:"Aeimbhu",fullName:"Areeya Aeimbhu",slug:"areeya-aeimbhu"}]},{id:"30955",title:"Application of Scanning Electron Microscopy for the Morphological Study of Biofilm in Medical Devices",slug:"application-of-scanning-electron-microscopy-for-the-morphological-study-of-biofilm-in-medical-device",signatures:"R. M. Abd El-Baky",authors:[{id:"103658",title:"Dr.",name:"Rehab Mahmoud",middleName:null,surname:"Abd El-Baky",fullName:"Rehab Mahmoud Abd El-Baky",slug:"rehab-mahmoud-abd-el-baky"}]},{id:"30956",title:"Interrelated Analysis of Performance and Fouling Behaviors in Forward Osmosis by Ex-Situ Membrane Characterizations",slug:"interrelated-analysis-of-performance-and-fouling-behaviors-in-forward-osmosis-by-ex-situ-membrane-ch",signatures:"Coskun Aydiner, Semra Topcu, Caner Tortop, Ferihan Kuvvet, Didem Ekinci, Nadir Dizge and Bulent Keskinler",authors:[{id:"109299",title:"Associate Prof.",name:"Coskun",middleName:null,surname:"Aydiner",fullName:"Coskun Aydiner",slug:"coskun-aydiner"}]},{id:"30957",title:"Biodegradation of Pre-Aged Modified Polyethylene Films",slug:"biodegradation-of-pre-aged-modified-polyethylene-films",signatures:"Bożena Nowak, Jolanta Pająk and Jagna Karcz",authors:[{id:"103087",title:"Dr.",name:"Bożena",middleName:"Danuta",surname:"Nowak",fullName:"Bożena Nowak",slug:"bozena-nowak"},{id:"108409",title:"Dr.",name:"Jolanta",middleName:null,surname:"Pająk",fullName:"Jolanta Pająk",slug:"jolanta-pajak"},{id:"108412",title:"Dr.",name:"Jagna",middleName:null,surname:"Karcz",fullName:"Jagna Karcz",slug:"jagna-karcz"}]},{id:"30958",title:"Surface Analysis Studies on Polymer Electrolyte Membranes Using Scanning Electron Microscope and Atomic Force Microscope",slug:"surface-analysis-studies-on-polymer-electrolyte-membranes-using-scanning-electron-microscope-and-ato",signatures:"M. Ulaganathan, R. Nithya and S. Rajendran",authors:[{id:"102326",title:"Dr.",name:"M",middleName:null,surname:"Ulaganathan",fullName:"M Ulaganathan",slug:"m-ulaganathan"},{id:"102329",title:"Prof.",name:"S",middleName:null,surname:"Rajendran",fullName:"S Rajendran",slug:"s-rajendran"}]},{id:"30959",title:"Characterization of Ceramic Materials Synthesized by Mechanosynthesis for Energy Applications",slug:"characterization-of-ceramic-materials-synthesized-by-mechanosynthesis-for-energy-applications",signatures:"Claudia A. Cortés-Escobedo, Félix Sánchez-De Jesús, Gabriel Torres-Villaseñor, Juan Muñoz-Saldaña and Ana M. Bolarín-Miró",authors:[{id:"39070",title:"Dr.",name:"Ana Maria",middleName:null,surname:"Bolarin-Miro",fullName:"Ana Maria Bolarin-Miro",slug:"ana-maria-bolarin-miro"},{id:"106669",title:"Dr.",name:"Claudia Alicia",middleName:null,surname:"Cortés-Escobedo",fullName:"Claudia Alicia Cortés-Escobedo",slug:"claudia-alicia-cortes-escobedo"},{id:"107412",title:"Dr.",name:"Juan",middleName:null,surname:"Munoz-Saldana",fullName:"Juan Munoz-Saldana",slug:"juan-munoz-saldana"},{id:"107419",title:"Dr.",name:"Felix",middleName:null,surname:"Sanchez-De Jesus",fullName:"Felix Sanchez-De Jesus",slug:"felix-sanchez-de-jesus"},{id:"124602",title:"Prof.",name:"Gabriel",middleName:null,surname:"Torres-Villasenor",fullName:"Gabriel Torres-Villasenor",slug:"gabriel-torres-villasenor"}]},{id:"30960",title:"Scanning Electron Microscopy (SEM) and Environmental SEM: Suitable Tools for Study of Adhesion Stage and Biofilm Formation",slug:"scanning-electron-microscopy-sem-and-environnmental-sem-suitable-tools-for-study-of-adhesion-stage-a",signatures:"Soumya El Abed, Saad Koraichi Ibnsouda, Hassan Latrache and Fatima Hamadi",authors:[{id:"102518",title:"Dr.",name:"Soumya",middleName:null,surname:"El Abed",fullName:"Soumya El Abed",slug:"soumya-el-abed"},{id:"135701",title:"Prof.",name:"Saad",middleName:null,surname:"Koraichi Ibnsouda",fullName:"Saad Koraichi Ibnsouda",slug:"saad-koraichi-ibnsouda"},{id:"135703",title:"Prof.",name:"Latrache",middleName:null,surname:"Hassan",fullName:"Latrache Hassan",slug:"latrache-hassan"},{id:"135704",title:"Prof.",name:"Hamadi",middleName:null,surname:"Fatima",fullName:"Hamadi Fatima",slug:"hamadi-fatima"}]},{id:"30961",title:"Scanning Electron Microscopy Study of Fiber Reinforced Polymeric Nanocomposites",slug:"scanning-electron-microscopy-study-of-fiber-reinforced-polymeric-nanocomposites",signatures:"Mohammad Kamal Hossain",authors:[{id:"104713",title:"Dr.",name:"Mohammad",middleName:null,surname:"Hossain",fullName:"Mohammad Hossain",slug:"mohammad-hossain"}]},{id:"30962",title:"Preparation and Characterization of Dielectric Thin Films by RF Magnetron-Sputtering with (Ba0.3Sr0.7)(Zn1/3Nb2/3)O3 Ceramic Target",slug:"preparation-and-characterization-of-dielectric-thin-films-by-rf-magnetron-sputtering-with-ba0-3sr0-7",signatures:"Feng Shi",authors:[{id:"24821",title:"Dr.",name:"Feng",middleName:null,surname:"Shi",fullName:"Feng Shi",slug:"feng-shi"}]},{id:"30963",title:"Microstructural and Mineralogical Characterization of Clay Stabilized Using Calcium-Based Stabilizers",slug:"microstructural-and-mineralogical-characterization-of-clay-stabilized-using-calcium-based-stabilizer",signatures:"Pranshoo Solanki and Musharraf Zaman",authors:[{id:"20942",title:"Prof.",name:"Pranshoo",middleName:null,surname:"Solanki",fullName:"Pranshoo Solanki",slug:"pranshoo-solanki"},{id:"20945",title:"Prof.",name:"Musharraf",middleName:null,surname:"Zaman",fullName:"Musharraf Zaman",slug:"musharraf-zaman"}]},{id:"30964",title:"The Use of ESEM in Geobiology",slug:"the-use-of-esem-in-geobiology",signatures:"Magnus Ivarsson and Sara Holmström",authors:[{id:"109413",title:"Dr.",name:"Magnus",middleName:null,surname:"Ivarsson",fullName:"Magnus Ivarsson",slug:"magnus-ivarsson"},{id:"135734",title:"Dr.",name:"Sara",middleName:null,surname:"Holmström",fullName:"Sara Holmström",slug:"sara-holmstrom"}]},{id:"30965",title:"How Log Interpreter Uses SEM Data for Clay Volume Calculation",slug:"how-log-interpreter-uses-sem-data-to-estimate-a-reservoir-clay-volume-",signatures:"Mohammadhossein Mohammadlou and Mai Britt Mørk",authors:[{id:"103154",title:"PhD.",name:"Mohammadhossein",middleName:null,surname:"Mohammadlou",fullName:"Mohammadhossein Mohammadlou",slug:"mohammadhossein-mohammadlou"}]}]}],publishedBooks:[{type:"book",id:"3166",title:"Optoelectronics",subtitle:"Advanced Materials and Devices",isOpenForSubmission:!1,hash:"b7263978cf34e637a4b9592eb4975f3e",slug:"optoelectronics-advanced-materials-and-devices",bookSignature:"Sergei L. Pyshkin and John M. Ballato",coverURL:"https://cdn.intechopen.com/books/images_new/3166.jpg",editedByType:"Edited by",editors:[{id:"43016",title:"Prof.",name:"Sergei",surname:"Pyshkin",slug:"sergei-pyshkin",fullName:"Sergei Pyshkin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3365",title:"Adaptive Optics Progress",subtitle:null,isOpenForSubmission:!1,hash:"ddbbb55d13ae352a500c70d649c3a020",slug:"adaptive-optics-progress",bookSignature:"Robert K. Tyson",coverURL:"https://cdn.intechopen.com/books/images_new/3365.jpg",editedByType:"Edited by",editors:[{id:"95503",title:"Dr.",name:"Robert",surname:"Tyson",slug:"robert-tyson",fullName:"Robert Tyson"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3486",title:"Advances in Photonic Crystals",subtitle:null,isOpenForSubmission:!1,hash:"fa2245d09cc8fd5a8d7ae78b94afd698",slug:"advances-in-photonic-crystals",bookSignature:"Vittorio M.N. Passaro",coverURL:"https://cdn.intechopen.com/books/images_new/3486.jpg",editedByType:"Edited by",editors:[{id:"83905",title:"Prof.",name:"Vittorio",surname:"Passaro",slug:"vittorio-passaro",fullName:"Vittorio Passaro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3581",title:"Recent Optical and Photonic Technologies",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"recent-optical-and-photonic-technologies",bookSignature:"Ki Young Kim",coverURL:"https://cdn.intechopen.com/books/images_new/3581.jpg",editedByType:"Edited by",editors:[{id:"12009",title:"Dr.",name:"Ki Young",surname:"Kim",slug:"ki-young-kim",fullName:"Ki Young Kim"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3582",title:"Advances in Optical and Photonic Devices",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"advances-in-optical-and-photonic-devices",bookSignature:"Ki Young Kim",coverURL:"https://cdn.intechopen.com/books/images_new/3582.jpg",editedByType:"Edited by",editors:[{id:"12009",title:"Dr.",name:"Ki Young",surname:"Kim",slug:"ki-young-kim",fullName:"Ki Young Kim"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],publishedBooksByAuthor:[{type:"book",id:"915",title:"X-Ray Spectroscopy",subtitle:null,isOpenForSubmission:!1,hash:"4b9f46edd0253b7402917214be33475d",slug:"x-ray-spectroscopy",bookSignature:"Shatendra K. Sharma",coverURL:"https://cdn.intechopen.com/books/images_new/915.jpg",editedByType:"Edited by",editors:[{id:"90351",title:"Prof.",name:"Shatendra K",surname:"Sharma",slug:"shatendra-k-sharma",fullName:"Shatendra K Sharma"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},onlineFirst:{chapter:{type:"chapter",id:"77652",title:"Peripheral Biomarkers in Multiple Sclerosis Patients Treated with Interferon-Beta",doi:"10.5772/intechopen.99006",slug:"peripheral-biomarkers-in-multiple-sclerosis-patients-treated-with-interferon-beta",body:'Around 2.8 million people are diagnosed with multiple sclerosis (MS) worldwide. MS is an autoimmune demyelinating disease of the central nervous system (CNS) of unknown etiology. Hallmarks of MS include focal inflammatory infiltrates, demyelinating plaques, reactive gliosis, and axonal damage [1, 2].
The mechanism of MS pathology involves complex interactions between systems and cell types including neurons, glia, and immune cells, accompanied by permeability of the blood–brain barrier (BBB). Autoreactive T cells activated outside the CNS cross the BBB and are reactivated by local antigen-presenting cells. Secretion of proinflammatory cytokines stimulates microglial cells and astrocytes, recruits additional inflammatory cells, and induces antibody production by plasma cells [3].
Recombinant interferon-β (IFN-β) remains the most widely prescribed treatment for relapsing–remitting MS (RRMS) and a valid approach because of its good benefit/risk profile. Despite widespread use of IFN-β, its therapeutic mechanism is still partially understood. The efficacy of IFN-β treatment has been shown by a decreased annual relapse rate, disability progression and inflammatory brain lesions resulting in the approval of different IFN-β preparations [4].
IFN-β is a highly pleiotropic cytokine which antagonizes the proinflammatory milieu by inhibiting expression of proinflammatory molecules, while increasing production of anti-inflammatory factors. It inhibits leukocyte trafficking, regulates the adhesion molecule expression and inhibits matrix metalloproteinase activity. The mechanism of action of IFN-β is complex and multifactorial but has been shown to reduce the biological activity of RRMS in several clinical class I trials [5].
The identification of peripheral markers that could reflect the clinical course of MS and the efficacy of treatment is a stimulating field of research and debate. An ideal biomarker is characterized by high sensitivity and specificity as well as a simple, cost effective, reproducible, and non-invasive detection method [6]. For instance, there are reports focusing molecules and autoantibodies as potential biomarkers in the MS disease course. Our focus in this chapter is on circulating leucocytes that can be considered during the follow of RRMS patients in remission
MS is an autoimmune disease of the brain and the spinal cord characterized by chronic inflammation, demyelination, gliosis and neuronal loss. The demyelination consists of the damage of the myelin sheath surrounding nerves, consequently affects the function of the nerves. The pathological hallmark of chronic MS is the demyelinated plaque or lesions, which consists of a well-demarcated hypocellular area characterized by the loss of myelin sheaths or oligodendrocytes, relative preservation of axons, and the formation of astrocytic scars [1].
The etiology of MS remains elusive, with a complex multifactorial system implicated, in which environmental factors are hypothesized as interacting with genetically susceptible individuals. MS causes a heterogeneous array of symptoms and signs because of the differential involvement of motor, sensory, visual and autonomic systems with serious physical disability in young adults, especially women [2, 4, 7].
The CNS is frequently described as an immune-privileged site, evidence supports the notion that the CNS receives limited immune surveillance by peripheral lymphocytes under physiological conditions. New findings provide a mechanism by which large particles and immune cells can drain from the brain and interface directly with the peripheral immune system [8, 9].
MS is triggered in the periphery or in the CNS. The CNS-extrinsic (peripheral) model is the most widely accepted and is consistent with the method used to induce experimental autoimmune encephalomyelitis (EAE), the animal model for neuroinflammation. The autoreactive T cells from MS patients may become activated in the periphery as a result of a molecular mimicry, gain access to the CNS, and T cells generated against non-self-epitopes (viral or microbial antigens) cross-react with self-myelin epitopes of similar sequence [10, 11, 12].
85% of patients present a RR form of MS, characterized by discrete episodes of neurological dysfunction (relapses) separated by clinical stable periods with lack of disease progression (remissions). More than 30% remain in the RRMS form of the disease into old age [7, 11, 12, 13].
Relapse is the clinical result of an acute inflammatory focal lesion and is typically discernible using magnetic resonance imaging. Relapse is defined as newly appearing neurological symptoms in the absence of fever or infections that last for more than 24 hours and are separated from the previous event by at least one month. The frequency of relapses can vary widely among patients as well as during different periods during an individual patient’s disease. The relapse tends to be present for a limited time – days or weeks – and can lead to full recovery or can leave sequelae. At present time, no clinical features or biomarkers that are predictive of relapse rates have been identified. The signs and symptoms that occur during relapses are also diverse and unpredictable [3, 8, 11].
Immunological characteristics of MS lesions have been reflected in circulating immune cells of MS patients. Peripheral blood provides a ‘window’ into the immunopathogenesis of MS. The immunological disturbances that underlie MS can be observed not only in the CNS, but also through examination of peripheral immune cells [14].
IFN-β and glatiramer acetate have been used as first-line disease-modifying therapy for RRMS. More than two decades have passed since IFN-β was found to be effective in the management of MS. IFN-β treatment efficacy has been shown by a decrease in the annual relapse rate, in disability progression and in inflammatory brain lesions, resulting in the approval of different IFN-β preparations [15, 16, 17].
IFNs are naturally occurring cytokines, secreted by various cells such as fibroblasts, NK cells, leukocytes, and epithelial cells in response to pathogens such as bacteria, viruses, parasites, and tumor cells, as well as other foreign substances. They have a wide range in anti-inflammatory processes, regulation of cell growth and modulation of immune responses [18, 19].
IFN-β binds to the interferon receptor, activates the Janus kinase/signal transducer and the activator of transcription (STAT) pathway to phosphorylate STAT1 and STAT2. The activation of interferon-stimulated genes leads to the production of antiviral, antiproliferative, and antitumour products. The effectiveness of IFN-β in the treatment of MS may rely on both anti-viral and immunomodulatory aspects [26, 27].
IFN-β was the first immunomodulatory therapy approved by the U.S. Food and Drug Administration and is the most widely prescribed treatment for MS; it is generally well tolerated and overall reduces the relapse rate by 30% in patients with RRMS [4].
Several IFN-β preparations have been approved with differing structures (glycosylated IFN-β-1a vs. non-glycosylated IFN-β-1b), formulation (lyophilized vs. liquid), used excipients (e.g., containing serum albumin or not), modification (pegylation), dosage (protein load and bioactivity), route of administration (subcutaneous vs. intramuscular), or frequency of injection (ranging from bi-weekly to every other day). IFN-β shows high tissue distribution; however, it is not supposed to cross the BBB and exerts its immunomodulatory mechanism in the peripheral compartment. IFN-β is cleared via renal and hepatic pathways, in which catabolism seems to be important rather than simple excretion [15].
The therapeutic benefit of IFN-β in MS has been proven in several large clinical trials, with the effect of IFN-β therapy being more studied on T and B cells [20]. In spite of this, it is known that the biological functions of IFN-β act in both innate and adaptive immune responses and may influence phenotype and functions of all MS-relevant immune cells [21].
A biomarker is defined as a characteristic that can be objectively measured and evaluated and serves as an indicator of normal biological processes, pathological processes or pharmacological reactions to therapy. An ideal biomarker is characterized by high sensitivity and specificity as well as a simple, cost effective, reproducible, and non-invasive detection method [6].
In this section we synthesize and integrate the most relevant data regarding the characteristics of the selected immune cells that could be considered as IFN-β treatment-related biomarkers. The main goal of this work is an attempt to help researchers to perform a good assessment of immune cells in future studies. The presented data is a result of a compilation of several studies and findings.
Antigen presenting cells (APCs) are considered key players in the immune surveillance of CNS and, at the same time, they are critically involved in the pathogenesis of CNS autoimmune diseases. They are a morphologically and functionally diverse group of cells that links the innate and adaptive immune responses. These cells are specialized in the presentation of antigens to lymphocytes, particularly T cells. Included among such cells are dendritic cells (DCs), monocytes and macrophages (derived from monocytes that migrated from the blood stream to tissues). B lymphocytes that specifically capture antigens via their clonally expressed membrane immunoglobulin can also function efficiently as APCs to T cells [22].
In humans, DCs comprise two major subsets: plasmacytoid DCs (pDCs) and myeloid (mDCs). Through nucleic acid-sensing, pDCs activate toll-like receptors (TLR), such as TLR7 and TLR9, rapidly producing type I IFN. mDCs are dedicated APCs that have a characteristic dendritic morphology, express high levels of MHC class II molecules and recognize pathogen-derived lipids, proteins and nucleic-acids by TLR2, TLR4 and TLR3 respectively [23].
The DCs subsets may be helpful as biomarker between remission and relapse of RRMS patients treated with IFN-β. The circulating mDCs subset reduces in remission and increase in relapse RRMS patients. On the other hand, the pDCs frequency are maintain across the different phases of disease. Usually, these subsets present a low frequency in systemic circulation, so the mDCs/pDCs ratio is a good representative of the alteration observed in the DCs subsets. The mDCs/pDCs decreases in remission RRMS patients and is re-established in relapse RRMS patients, constituting a potential peripheral biomarker [24, 25].
The involvement of DCs in MS arises from studies that demonstrate the abundant presence of these cells in the inflamed CNS lesions and in the CSF of MS patients [21].
One of the immunomodulatory effects of IFN-β in the EAE model is the reduction in antigen presentation, particularly myelin-specific antigens, leading to reduced T-cell responses [23, 30]. In contrast with these effects, in remission phase it was observed that the DCs subsets increase the expression of HLA-DR and decrease in the relapse phase. The variation in HLA-DR expression is more evident in the mDCs subset. The same subset reduce the mRNA gene expression of CX3CR1; fractalkine is known to be upregulated and released in response to pro-inflammatory stimuli and induces adhesion, chemoattraction, and activation of leukocytes [25].
The activation status of the mDCs subset could discriminate between RRMS phases. This subset shown a highest activated status in remission than in relapse phase, through the increased HLA-DR expression and a reduced migratory capability, since reduce the mRNA gene expression of CX3CR1.
Monocytes represent a heterogeneous population of primary immune effector cells with distinct phenotypical and functional characteristics; their differential roles in steady-state immune surveillance and the pathogenesis of human CNS disease are poorly understood [26].
The differential expression of CD14 (part of the receptor for lipopolysaccharide) and CD16 (also known as FcγRIII) allows monocytes to be segregated into three subsets. The major subset designated “classical” monocytes (CD14++CD16−, cMo), corresponds to 80–90% of circulating monocytes. CD16 expressing monocytes are divided into a named “intermediate” monocyte (CD14++CD16+, iMo) and a subset classified as “non-classical” monocytes (CD14+CD16++, ncMo); each of these subsets corresponds to 5–10% of circulating monocytes [27, 28].
Patients with MS display high levels of monocyte-secreted inflammatory molecules in serum compared to healthy individuals, demonstrating a role for peripheral monocytes in the progression of the disease. Increased levels of serum tumor necrosis factor (TNF) α and β have been reported in MS relapse. Monocytes and microglia are known to act as major effectors in the demyelinating process through direct interaction and the production of proinflammatory cytokines and mediators (e.g., IL-1b, nitric oxide). CD16+ monocytes may contribute to the breakdown of the BBB by facilitating T cell trafficking into the CNS [22, 26, 29].
Research performed on monocyte pool in RRMS patients is scarce and ambiguous. A recent work achieved a significant decrease of the ncMo subset in both phases of RRMS patients, although in a higher extension in remission patients [25].
The frequency of monocytes subsets does not allow us to identify different phases of RRMS, but the HLA-DR expression could constitute a potential important biomarker between remission and relapse phases. A significant increase in HLA-DR expression in all monocyte subsets in the remission group when compared with healthy and relapse groups, has been described [25]. IFN-β enhances HLA-DR expression in circulating monocytes, but inside the CNS, one prominent model is based on the observation that IFN-β inhibits the IFNγ upregulation of MHC class II molecules on cell surface of macrophages and glial cells and therefore diminishes antigen presentation [30]. In the periphery, Kantor et al. report that the increase of MHC Class II expression in monocytes induced by IFN-β may contribute to the positive immunomodulatory effect in MS [31]. These findings were reinforced by the observation that when IFN-β-stimulated monocytes were used to stimulate autologous T cells, there was an increased secretion of anti-inflammatory cytokine IL-13 [32].
T cells are central regulators of the adaptive immune response, they help B lymphocytes to produce antibodies and secrete cytokines that provide efficient protection against pathogens. Distinct T helper (Th) cell subsets, producing one or more lineage-defining cytokines and expressing master transcription factors and homing receptors. Th subsets are differentiated from naive CD4+ T cells in response to a specific class of pathogenic microorganisms and to the cytokine milieu. This occurs in peripheral lymph nodes by mature DCs that present pathogen-derived peptides associated to MHC class II. With the involvement of their costimulatory molecules, DCs promote T cell proliferation and produce polarizing cytokines. In turn T cell was differentiated in distinct Th cell subsets, such as Th1, Th2, Th17, regulatory T (T reg) and T follicular helper (Tfh) [33].
The CD4+ T cells have been the most studied in the pathogenesis of MS, although CD8+ T cells are the dominant lymphocyte population in all stages of disease and lesions of MS patients. Naive CD8+ T cells follow a similar differentiation programme of CD4+ T cells [34, 35].
Th1 cells are described as being the pathogenic subset of T cells, whereas Th2 cells are reported to exert inhibitory effects [5]. Previous studies have pointed to a reduction in pro-inflammatory capability promoted by IFN-β therapy, consisting of a reduction of the expression of Th1-induced cytokines while enhancing Th2 responses [18]. Concerning the T cytotoxic (Tc) subsets, it has been reported the same behavior, in remission a downregulation of pro-inflammatory Tc1 responses and up-regulation of anti-inflammatory Tc2 with a beneficial effect on disease activity [36]. This dichotomy Th1, Th2 subsets and Tc1, Tc2 subsets could contribute to discriminate between remission and relapse phases.
The identification of Th17 cells helped to resolve some in adequacies of the original Th1/Th2 concept that had dominated T cell immunology research filed for almost 20 years. For a long time, it was thought that the IL-12/IFNγ pathway and Th1 cells were central to the development of autoimmune disease [37].
Both Th1 and Th17 cells have been implicated in the initiation and progression of disease in RRMS and its experimental model EAE [19]. The link between Th17 cells, IL-17 and MS relapses comes from the observation that in humans, Th17 cells are able to cross the BBB in MS lesions, enhancing neuroinflammation. In vitro studies have revealed that IL-17 blocks the differentiation and reduces the survival of oligodendrocyte lineage cells. In EAE model, it has been suggested that Th17 cells interact directly with neurons, forming antigen-independent, immune, synapse-like contacts [7, 38].
It is assumed that the inhibition of Th17 cells in RRMS patients attenuates the disease, however conflicting data have been published. Axtell et al. reported that IFN-β treatment effectively blocked disease symptoms in mice with EAE induced with Th1 cells. Otherwise, in EAE induced with Th17 cells the IFN-β treatment worsened disease [19].
In RRMS patients, it is not clear whether a more specific blockade of the Th17 pathway has beneficial effects in MS patients. Treatment with an antibody directed against IL-12p40 and therefore neutralizing both IL-12 and IL-23 did not result in a significant reduction of disease activity [39].
A meta-analysis pointed out several limitations across studies that assess the levels of peripheral Th17 cells and serum Th17-related cytokines. Like the severities of the disease and clinical subtypes in MS patients; the disease duration from relapse; and that the MS treatments were not consistent; and it was postulated that most studies selected MS patients with high disease activity. There were differences in experimental methods between studies and a lack of detailed standardized methods to identify the Th17 cells and Th17-related cytokines [40].
A recent in vivo study observed an increased frequency of circulating Th17 and Tc17 cells, accompanied by increased serum levels of IL-17 in remission RRMS patients treated with IFN-β [41]. This contradiction underlines the need to clarify the role of the IL-17-producing T cells in RRMS patients.
It has been demonstrated that a significant proportion of Th17 cells convert into IFN-γ-producing T cells and have chemokine receptors from both Th17 and Th1 subtypes, referred as Th17.1 cells. The enhanced potential of Th17.1 cells to infiltrate the CNS was supported by their predominance in CSF of early MS patients and their preferential transmigration across human brain endothelial layers [42, 43]. In remission RRMS patients, it was observed that Th17 and Tc17 cells exhibited a higher degree of Th1 plasticity since there were higher frequencies of those cells simultaneously producing intracellular IL-17 and IL-2 or IFNγ or TNFα [41].
Another subset of T cells, the Tregs, are characterized by high expression of CD25 and the transcription factor
In MS patients, both reduced or normal frequency of Tregs was observed. Libera et al. described a significant decrease in Treg cells in remission RRMS patients [45]. Haas et al. state that the frequency of Treg cells was normal in MS patients but with a lower suppressive function on autoreactive T cells [46]. Venken et al. described that RRMS patients treated with IFN-β showed restored naive Treg numbers as compared with age- and disease-duration-matched untreated patients [47].
Recently identified, the Tfh subset expresses the chemokine receptor CXCR5 as well as CD279 [48], is specialized in helping B cells to produce antibodies in the face of antigenic challenge and plays a crucial role in orchestrating the humoral arm of adaptive immune responses. Tfh cells have the unique ability to migrate into follicles in secondary lymphoid organs where they colocalize with B cells to deliver contact-dependent and soluble signals that support survival and differentiation of the latter cells. There is no complete and thorough understanding of how naïve Th cells differentiate into mature Tfh [49, 50].
Tfh cell levels are elevated in the blood of MS patients and this population is positively correlated with the progression of disability. One potential mechanism through which Tfh cells can contribute to disease is promoting the inflammatory B-cell activities, suggesting that Tfh cells cooperate with Th17 cells to induce inflammatory B cell responses in the CNS and increase disease severity [49].
The increased frequencies of Th1 cells, activated Tfh- and B-cells parallel findings from pathology studies, along with the correlation between activated Tfh- and B-cells, suggest a pathogenic role of systemic inflammation in progressive MS [51].
A similar frequency of Tfh cells between RRMS patients and healthy subjects was reported. However, this subset tend to exhibit a more proinflammatory activity, since higher frequencies of TNF-α+ Tfh cells have been observed [41]. It is well known that Tfh cells play an important role in T/B interactions in germinal centres (GC) and one potential mechanism through which Tfh cells can contribute to MS is in promoting inflammatory B-cell activities [49]. The Tfh subset and others follicular like T cells subsets, like Treg/follicular cells, are promising targets in the study of T cells in pathophysiology of MS.
γδ T cells develop in the thymus together with αβ T cells but rearrange a different TCR, consisting of a TCR-γ and TCR-δ chain. One of the most striking characteristics of γδ T cells is their inherent ability to secrete pro-inflammatory cytokines very rapidly, which influences adaptive immunity, they carry out immediate effector functions as well as mounting a memory response upon microbial reinfection. This fast response can be explained by γδ T cells exiting the thymus already with the functional competence to produce cytokines with no need of APCs cells [52, 53].
In MS, their potential importance is increased by the finding that γδ T cells accumulate in demyelinating CNS MS plaques; these cells show evidence of oligoclonal expansion indicating a local response to currently unknown antigens. γδ T cells have been shown to be present in both MS lesions and in CSF, and sequencing studies have shown that the major γδ T subsets present in the lesion differ from those in the CSF, suggesting specific functions for these cells in lesion development. In more chronic lesions, γδ T cells may become the most prevalent type of T cell in the lesion. γδ T cells isolated from the CNS can be expanded but only in patients with relapse disease, not chronic MS patients, suggesting that these cells may have differential roles during various phases of the disease [54, 55].
The frequency, the migratory pattern, the activation status of γδ T cells in RRMS patients are unclear. Between remission and relapse RRMS patients, the γδ terminally differentiated effector memory T cells (TEMRA) and the CCR5+ γδ TEMRA decrease in relapse when compared with remission RRMS patients [56], constituting a good biomarker between phases of the disease. Probably as a result of the migratory pattern describe for this phase of MS, preferentially toward RANTES and MIP-1α, whose expression is increased during relapses [57, 58].
The decrease of Eomesodermin and granzyme B mRNA expression in CD27− γδ T cells suggests a reduction in the cytotoxic potential of the circulating pool of γδ T cells, particularly in relapsing RRMS patients [56].
The most consistent immunodiagnostic feature and hallmark immunologic finding in MS patients is the presence of oligoclonal bands (OCB) in the CSF and their absence in peripheral circulation. Consequently, the pathogenic function of B cells in MS has been traditionally associated with antibody production. However, B cells have three putative biological roles: production of proinflammatory or regulatory cytokines, function as APCs and antibody production [59].
In MS, the memory B cells, plasmablasts and plasma cells preferentially cross the BBB and migrate into the CNS, where they dominate the B cell pool and exert different effector functions. B cells seem to be abnormally polarized toward a more proinflammatory phenotype [60].
More recent, somatic hypermutation studies have demonstrated that identical B cell clones can be shared between the CNS and the periphery in individual patients. These studies provide evidence of bidirectional trafficking of distinct B cell clones (both into and out of the CNS). The patterns suggest that B cells can travel back and forth across the BBB and commonly re-enter GC (in the meninges or cervical lymph nodes) to undergo further somatic hypermutations. These findings change our view of lymphocytic surveillance of CNS tissue and underline that B-cell trafficking is an important topic for future research and therapy strategies [60, 61, 62]. This news about recirculation of B cells through the BBB alters the perception of the role of B cells in MS.
B cells are released in the peripheral blood, recirculate between the secondary lymphoid tissues, and dying after a few days. According to phenotypic profile of B cell subsets, which also reflects their functional abilities and behavior, four major maturation-associated subsets can be identified in the human peripheral blood: immature/transitional, naive, memory and plasmablast [63].
In remission RRMS patients submitted to IFN-β, the percentage of immature/transitional B cells increases. This increase can be seen as an attempt to increase anti-inflammatory cytokines. Meanwhile, a decrease in the proportion of circulating class-switched memory B cells was reported [64, 65].
The relapsing RRMS patients exhibited distinct changes in B cell subsets homeostasis, resulting in a decrease in the total population of B cells, including a decrease of the immature/transitional and naïve B cell subsets when compared with remission RRMS patients. On the other hand, the plasmablast B cell subset presented an increase in relapse RRMS patients. The ratio between immature/transitional B cells and plasmablasts can thus be considered as a potential biomarker between phases of RRMS patients. The remission RRMS patients and the healthy subjects presented a similar ratio, and the relapse RRMS patients present a decreased ratio [66].
According to the new and recent data about the recirculation of B cells in RRMS, it seems that the increase of plasmablasts in circulation of relapsing episodes may be due to a migration of these cells from cervical lymph nodes and/or from B cell aggregates described in the meninges of MS patients to the blood marrow in an attempt to promote the immune response [67].
An ever-expanding body of literature, sometimes difficult to integrate, defines the intricate pathways by which IFN-β mediates its broad effects. To resume the effects of IFN-β in circulating immune cells a table listing the relevant studies and findings was performed (Table 1).
Effects of IFN-β | |
---|---|
Antigen presenting cells |
|
T cells |
|
B cells |
|
Main effects of IFN-β in circulating immune cells in MS.
A major role for IFN-β is the induction of a priming state through which production and regulation of mediators, including cytokines, are affected by synergistic or antagonistic interactions. In the treatment of MS, the most important IFN-β mechanisms of action appear to be mediated mainly by the increased expression and concentration of anti-inflammatory agents, in turn, down-regulating the inflammatory state observed in the patients both in the periphery and in the brain tissue (Figure 1) [21].
Main effects of IFN-β in RRMS patients (a) remission phase and (B) relapse phase. mDC – Myeloid dendtitic, pDC – Plasmacytoid dendtitic cell, cMO – Classical monocytes, iMo – Intermediate monocytes, ncMo – Non-classical monocytes.
The work from our group started with the selection of the RRMS patients and collected blood from each one after assigned an informed consent. By flow cytometry performed direct immunofluorescence membrane and intracytoplasmic staining protocols to identify and characterize the circulating subsets. To functional assessment of the cells was measured intracellular cytokines at single cell level, after in vitro stimulation. To evaluation of gene expression, RNA isolation and quantitative real-time reverse transcriptase-polymerase chain reaction was performed.
In our group publications, one can be find the flow strategy with the description of the antibodies used and the mRNA gene expression studies performed in APCs [25], in T cell subsets [41], in γδ T cells [56] and in B cell subsets [66].
The literature search was performed using the PubMed electronic bibliographic database. The search was restricted to English and publications between 2010 and 2021. The keywords used were: multiple sclerosis, IFN-β, antigen presenting cells, T cells and B cells alone or in conjugation. The bibliographies of retrieved articles and previous review articles were hand searched to obtain additional articles.
In demyelinating diseases, mainly in relapse phase of RRMS, the BBB suffer a profound disturbance, so as the exchanges and ultimately the CNS itself. Despite CNS suffered an immune response, immune abnormalities could be found in the peripheral immune compartment.
The periphery assumes an extremely important role in the study of MS. In remission phase is establish an equilibrium between CNS and systemic circulation. In this chapter we have attempted to contribute to highlight the more relevant data regarding circulating cell subsets that could potentially be considered as peripheral biomarkers in RRMS patients treated with IFN-β.
Some circulating immune cells assume differences between the remission and relapse phases of RRMS. These differences may be used as disease activity biomarkers to measure inflammatory and/or neurodegenerative components of disease and helpful to discriminate between phases of RRMS.
Technological advances of flow cytometry have greatly increased the strength of analysis achievable at the single-cell level. These developments can be applied to understand more clearly the immunopathology of MS and the identification of consistent, safe and reproducible biomarkers in the periphery.
This work was financed by the Foundation for Science and Technology (FCT), through funds from the State Budget, and by the European Regional Development Fund (ERDF), under the Portugal 2020 Program, through the Regional Operational Program of the Center (Centro2020), through the Project with the reference UIDB/00709/2020.
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Pal is Professor of Physics at Mahindra École\nCentrale Hyderabad India since July 1st 2014 after retirement\nas Professor of Physics from IIT Delhi; Ph.D.’1975 from IIT\nDelhi; Fellow of OSA and SPIE; Senior Member IEEE;\nHonorary Foreign Member Royal Norwegian Society for\nScience and Arts; Member OSA Board of Directors (2009-\n11); Distinguished Lecturer IEEE Photonics Society (2005-\n07).",institutionString:null,institution:{name:"Indian Institute of Technology Delhi",country:{name:"India"}}},{id:"69653",title:"Dr.",name:"Chusak",middleName:null,surname:"Limsakul",slug:"chusak-limsakul",fullName:"Chusak Limsakul",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Prince of Songkla University",country:{name:"Thailand"}}},{id:"23804",title:"Dr.",name:"Hamzah",middleName:null,surname:"Arof",slug:"hamzah-arof",fullName:"Hamzah Arof",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/23804/images/5492_n.jpg",biography:"Hamzah Arof received his BSc from Michigan State University, and PhD from the University of Wales. 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More specifically, I explored the consequences of the dynamics detected by the models on monetary policy implementation for 10 OECD countries. This study indicates that factors that may cause a rise in short-term interest rates with respect to the USA can lead to volatility in exchange rates and thus macroeconomic instability. It is also implied that sustaining macroeconomic growth and decreasing inflation can result in increased export performance, which in turn provides the amount of US dollars to curb volatility in US dollar quotations. Accordingly, this study reveals that high importance should be given to both monetary and non-monetary factors in the open-economy framework to detect the possible impacts on trade and capital flows by dynamic stochastic general equilibrium (DSGE) models. Due to their exchange rate risk of economic agents, I also suggest that the economic policy makers of these countries had better create a theoretical framework including financial frictions, economic agents’ preferences and different shocks to smooth the variations in exchange rates and minimise the negative outcomes of Brexit.",book:{id:"6487",slug:"trade-and-global-market",title:"Trade and Global Market",fullTitle:"Trade and Global Market"},signatures:"Oguzhan Ozcelebi",authors:[{id:"226325",title:"Prof.",name:"Oguzhan",middleName:null,surname:"Ozcelebi",slug:"oguzhan-ozcelebi",fullName:"Oguzhan Ozcelebi"}]},{id:"53827",title:"Malaysia and China: The Trade Balances, Foreign Exchanges and Crises Impacts",slug:"malaysia-and-china-the-trade-balances-foreign-exchanges-and-crises-impacts",totalDownloads:2047,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"China appears as the biggest trading partner for ASEAN economies, but it is inconclusive whether the complementarities between China and regional economies offset China’s competitive threat. This study tries to assess if real exchange fluctuations and the demand-supply channels determine the Malaysia-China trade balances in the global crises era, 1997–2010. The finding generally supports the complementary role of China in the Malaysia-China bilateral trading. However, despite the long-run effect of real exchange on trade balances, the Keynesian demand channel was not uphold during and after the global financial crisis—due to the contractionary effect on Malaysian output. The Chinese inflation impact is also not evident following the foreign exchange shocks. Meanwhile, currency devaluation for exports gains is insufficient to sustain Malaysia output expansion against China. Further productivity growth in real and tradable sectors is essentially needed.",book:{id:"5492",slug:"international-trade-on-the-brink-of-change",title:"International Trade",fullTitle:"International Trade - On the Brink of Change"},signatures:"Tze-Haw Chan",authors:[{id:"191390",title:"Dr.",name:"Chan",middleName:null,surname:"Tze-Haw",slug:"chan-tze-haw",fullName:"Chan Tze-Haw"}]},{id:"53059",title:"Brazil in the Twenty-First-Century International Trade: Challenges and Opportunities",slug:"brazil-in-the-twenty-first-century-international-trade-challenges-and-opportunities",totalDownloads:1731,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"This chapter discusses the impacts of globalization on international trade patterns and the required shifts in trade policies. Highlighting the effects of production fragmentation, geographic dispersion and the expansion of global value chains (GVCs), the chapter outlines the Brazilian experience to illustrate the difficulties that various countries face in acknowledging this economic reality and providing appropriate policy responses. It draws on the global value chains literature to analyze Brazil’s foreign trade policies implemented during the recent ruling of the Labor Party (PT) presidents Lula da Silva and Dilma Rousseff (2003 to 2015), discussing the Brazilian strategy (or the lack of one) to integrate into global value chains. Results of this exercise have led to the conclusion that a non–GVC-oriented trade policy has allowed Brazil to integrate only superficially into globalized international production and commercial flows. The chapter concludes providing an outlook on the policy shifts required for increasing Brazil’s insertion into global value chains and boosting a more prominent role in international trade.",book:{id:"5492",slug:"international-trade-on-the-brink-of-change",title:"International Trade",fullTitle:"International Trade - On the Brink of Change"},signatures:"Susan Elizabeth Martins Cesar de Oliveira",authors:[{id:"191481",title:"Dr.",name:"Susan",middleName:"Elizabeth Martins Cesar De",surname:"Oliveira",slug:"susan-oliveira",fullName:"Susan Oliveira"}]}],onlineFirstChaptersFilter:{topicId:"72",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:8,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:286,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:9,numberOfPublishedChapters:101,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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