\r\n\tBasic science studies have provided new insights into the pathophysiology of β-thalassemia. Studies of genotypic and phenotypic heterogeneity among patients and a better understanding of the control of erythropoiesis have provided new targets for designing novel agents that can be tailored to individual patient needs. JAK-2 kinase inhibitors and agents targeting the GDF-11/SMAD pathway are in clinical trials.
\r\n\r\n\tThis book will attempt to discuss the historical background of the disease and present the most up-to-date material regarding disease management in today's world for the reader to be updated on the best practice management of the disease.
",isbn:"978-1-83969-158-4",printIsbn:"978-1-83969-157-7",pdfIsbn:"978-1-83969-159-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"23abb2fecebc48a2df8a954eb8378930",bookSignature:"Dr. Akshat Jain",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10727.jpg",keywords:"History of Gene Mutation, Genetic Counselling, Anemia, Genotyping, Hemoglobin Electrophoresis, HLA typing, Hemolysis, Aplastic Anemia, Blood Transfusion, Laboratory Testing, Fetal Hemoglobin Modifiers, Gene Therapy",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 4th 2021",dateEndSecondStepPublish:"March 4th 2021",dateEndThirdStepPublish:"May 3rd 2021",dateEndFourthStepPublish:"July 22nd 2021",dateEndFifthStepPublish:"September 20th 2021",remainingDaysToSecondStep:"a month",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"A board-certified pediatrician with a specialization in pediatric hematology-oncology and stem cell transplantation. In collaboration with Harvard Medical School, he studied and reported the outcomes of a global hemophilia collaboration. He is a member of the American Board of Pediatrics, Hematology, and American Board of Pediatrics, also he is a Committee member for the American Society of Pediatric Hematology-Oncology Special Interest Group in Global Pediatric Hematology oncology.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"344600",title:"Prof.",name:"Akshat",middleName:null,surname:"Jain",slug:"akshat-jain",fullName:"Akshat Jain",profilePictureURL:"https://mts.intechopen.com/storage/users/344600/images/system/344600.jpg",biography:"Akshat Jain M.D. M.P.H.\n11175 Campus Street \nLoma Linda, California 92354\nPhone: (917) 331-3216\nakshatjainusa@gmail.com \n\nMEDICAL EDUCATION \n●\tS.S.R. Medical College, Belle Rive, Mauritius - MBBS, Bachelor of Medicine Bachelor of Surgery, 2007\n●\tPediatrics Residency Training ,The New York Medical College, Metropolitan Hospital , Dec2008-Dec 2011\n●\tPediatric Hematology Oncology and Stem Cell Transplant Fellowship, Cohen’s Children's Hospital of New York at LIJ-North Shore Health system. July 2012- September 2015\n●\tMaster’s in Public Health ,Hofstra University School of Public Health ,New York , August 2015\n\n\nHONORS/ AWARDS \n●\tThe New York Academy of Medicine Honorary Associate Award , December 2009\n●\tProgram Leadership Award - Committee of Interns and Residents (C.I.R./SIEU), April 2010\n●\tAmerican Academy of Pediatrics Program Delegate Award, New York Medical College, December 2010.\n●\tCitation of Honor from New York County for Excellence in Medicine and Service to Long Island, New York,Nassau county executive chambers , August 15,2015 \n●\tTimes of India N.R.I. ( Non Resident Achiever ) award , August 2015 \n●\tCertificate for academic excellence –Hofstra University School of Health Science & Human Services, New York August 26, 2015\n●\tAmerican Society of Hematology Leadership Institute Award , April 2016\n●\tGlobal Health Speaker Award , convener of Global Health Symposium, Hofstra NorthWell School of Medicine and School of Public health , May 2016\n●\tInternational Pediatric Lymphoma Meeting ,Session Chairperson of Pediatric Lymphoma , Indian Society of Hematology and Oncology , November 2016\n●\tContent Leader Award for Hematology perspective’s in the Global CoronaVirus Pandemic Preparedness Response for Medical Association of physicians of Indian Origin, April 2020.\n●\tConvener and Chairperson International Webinar for COVID 19 Coagulopathy, May 2020. \n●\tFeatured in the Top Doctors magazine 2020, ranked top pediatric Hematologist Oncologist for Southern California.\n\nNATIONAL/INTERNATIONAL POSITIONS \n●\tHofstra University Dean Advisory Board for the School of Health Professions, December 2017\n●\tEditorial Board – American Society of Pediatric Hematology Oncology Communications Committee, International Journal of Hematology Research (ISSN 2409-3548)\n●\tReviewer - JAMA Pediatrics (ISSN: 2168-6203), British Medical Journal (ISSN, 1468-5833), JAMA Oncology (ISSN: 2374-2437), International Journal of Hematology Research (ISSN 2394—806X), Journal of Pediatric Hematology and Oncology (ISSN: 1536-3678), New England Journal of Medicine (Resident 360). \n●\tMember – Core committee: American Cancer Society (A.C.S.) and American Academy of Pediatrics (A.A.P.) - Joint global pediatric Oncology taskforce.\n●\tAdvisor -World Health Organization, South East Asia for maternal and child health initiatives.( 2013-Ongoing) , Ministry of Health and Family Welfare ,Government of India ( 2014- Ongoing ) , American Academy of Pediatrics &American Cancer Society Global Taskforce on Pediatric Cancers.( 2014-Ongoing )\n●\tEditor – AAPI journal (American Association of Physicians of Indian Origin. Circulation -40,000)\n●\tVisiting Professorship in Hematology Oncology and Stem Cell Transplantation, Rajasthan University of Medical Sciences, India. ( 2009-Ongoing )\n●\tIndustry Advisor – Bayer, UniQure, Sanofi-Genzyme, Takeda, CSL Behring\n●\tDirector of International Bone Marrow Failure Consortium- India, part of the Global Hematology Initiative of Cohen Children’s Medical Center, New York, August 2015-2017. \n●\tCommittee member for the American Society of Pediatric Hematology Oncology Special Interest Group in Global Pediatric Hematology oncology. ( 2016- Ongoing)\n\n\n WORK EXPERIENCE \nNov 2017- Current Loma Linda University Children’s Hospital \n Director Division of Pediatric Hematology \n Director, Comprehensive Hemophilia Program\n Director, Comprehensive Sickle Cell Program \n Division of Pediatric Hematology Oncology and Stem Cell Transplantation\n Professor of Public Health, Loma Linda University School of Public Health \n\nMar 2017– Oct 2017 Pediatrics and Pediatric Hematology Oncology Practice \n Adventist Health Ukiah Valley, California \n\nSept 2015 –Aug 2016 Assistant Professor Pediatrics, Hofstra North Shore LIJ School of Medicine \n Section Head –Global Pediatric Hematology Oncology and Stem Cell Transplantation\n North Shore LIJ Health system.\n Associate Adjunct Faculty, Hofstra University School of Public Health.\n\nJuly 2012 – Sep 2015 The Steven and Alexandra Cohen’s Children's’ Hospital of New York at LIJ-North Shore \n Hofstra University - Pediatrics Hematology Oncology and Stem Cell Transplant Fellowship \n Chief - Jeffrey Lipton MD\n\nDec 2011- April 2012 Global Health : SMS Medical College and Group of Hospitals, Government of India \n Project Director for Project A.G.N.I. - Set up a regional Lead Poisoning prevention and \n anemia nodal center \n \n Course Director - Pediatric Subspecialty training module for Pediatricians at J.K. Lone \n Children’s Hospital for Government of India. \n\nDec 08- Dec 2011 The New York Medical College, Residency in Pediatrics \n Metropolitan Hospital, NY\n Maria Fareri Children's Hospital at Westchester.\n The Memorial Sloan Kettering Hospital. NY\n House staff on Stem Cell Transplantation service.\n \nApril – August 2008 Oklahoma State Medical Association (O.S.M.A.) Externship Program\n The Integris Baptist Teaching Hospital and Nazih Zuhdi Transplant Center\n\nRESEARCH EXPERIENCE \nNov 2017 – Ongoing: Current and ongoing – Director, Inherited Bleeding Disorder Experimental Therapeutics Program, Loma Linda University School of Medicine\nJan 2014 –July 2015 - Hofstra University School of Public Health \n Needs Assessment to barriers in cancer care for newly diagnosed patients in a resource \n Limited setting. \n Principal Investigator - Akshat Jain, Co-PI -Corrine Kyriacou \n\nJune 2012- July 2015 - Steven and Alexandra Cohen Children’s Medical Center \n Study – Non Invasive assessment of endothelial dysfunction in children with Sickle cell \n Disease. \n Co-Principal Investigator – Banu Aygun MD\n Study – Multicenter study assessing outcome of Reduced Intensity Conditioning for \n patients undergoing hematopoetic stem cell transplantation for Sickle cell disease . \n Co-Principal Investigator – Indira Sahdev MD\n \nJan 2012- Mar12 A.G.N.I. (Anterograde Growth Normalization Initiative) \n Project Director, Project of Government of India for establishment of Universal Lead \n Independent Pilot project to study effects of Elevated Blood Lead levels in children \n suffering from Developmental disorders- Adapted by W.H.O. 2014 for a National Level \n Lead Screening program, India \n \nJan 2009- Dec11 The New York Medical College, Metropolitan Hospital Center. NY\n Resident Physician – Hypothalamic volumes in patients with Growth Hormone deficiency.\n Maria Fareri Children's hospital / Dr.Richard Noto - Pediatric Endocrinology\n \nApril 2008-Dec 08 Nazih Zuhdi Transplant Institute, Integris Baptist Hospital, Oklahoma City\n Project – Single institution outcome study for Solid organ transplants\n Research Assistant Department of Hepatology\n \nOct 2007 – Dec07 Mount Sinai School of Medicine, New York, NY\n Project- Arterio-venous fistula post liver transplantation.\n Research mentor-Dr. Charissa Chang, Assistant Professor in Department of Liver Diseases. \n\nCERTIFICATION\n\n1.\tCalifornia State Medical License 8/2016- Present , New York State Licensure 8/2013-12/16\n2.\tAmerican Board of Pediatrics - Board certified, 11/14- Present\n3.\tAmerican Board of Pediatric Hematology Oncology – Board Certified , 06/2018- Present\n4.\tNeonatal Advanced Life Support 06/2009-Present \n5.\tPediatric Advanced Life Support 06/2009-Present \n6.\tECFMG Certification 12/2007-Present \n\nORAL PRESENTATIONS \n\n\n1.\tLeukemia and Lymphoma Society of America C.M.E. Symposium presentation – Leukemia and Beyond: Advances in Cancer Care and Blood Disorders in the 21st Century, October 2019\n2.\tLoma Linda University School of Medicine – Grand Rounds, Advances in the Management of Sickle Cell Disease, March 2019.\n3.\tLoma Linda University School of Medicine – Experimental Therapeutics in Sickle Cell Disease – New Horizons at Loma Linda , November 2018 .\n4.\tAdventist Health Ukiah , California - Neurological Defects of Iron Deficiency and Lead Poisoning in Humans , October 2017\n5.\tHofstra NorthWell School of Medicine - National Public Health Symposium on Global Public Health , Convener and Moderator ,April 2016 \n6.\tCleveland Clinic Children’s Medical Center, Ohio – Non BCR-ABL Myeloproliferative syndromes of childhood, January 19, 2016.\n7.\tChildren’s Hospital at SMS Medical College ,India – Pediatric Hematology Oncology Emergencies for the Tropics, November 13, 2015 \n8.\tHarvard Medical School, Boston Children’s Hospital Division of Pediatric Hematology – Advances in Global Hematology, Annual Hemophilia Twining symposium, August 2, 2015.\n9.\tNew York Medical College as Grand Rounds, Division of Pediatrics – Emergencies in Pediatric Hematology and Oncology, April 2015.\n10.\tMaurice A. Deane School of Law, Hofstra University, New York - Healthcare Access to Undocumented immigrants: Immigration reform and its impact, March 2015.\n11.\tPediatric Academic Society/Society of Pediatric Research (PAS/SPR) as platform presentation, Vancouver, BC - Global Child Health in Rich & Poor Countries Lessons Learned from Indigenous Health, May 3 2014.\n12.\tDepartment of Medicine and Medical Oncology, as Guest International faculty , SMS Medical College, India - Advances in Stem Cell Transplantation – January 2014.\n13.\tInternational health conference, Global Association of physicians of Indian Origin , New Jersey – Impact of Lead Intoxication in Low to middle income countries , August 2012.\n14.\t139st APHA Annual Meeting and Exposition 2011, Boston - Use of decision support in a Harlem pediatric emergency department to increase prescription of controller medicines to patients with poorly controlled asthma - Wilson Wang, Carolina Valez, Nicole Falanga, Vikas Bhambhani , Akshat Jain , Farhad Gazi, David Spiller, Paper no-227188 , November 2011 \n15.\tThe New York Academy of Medicine, Resident award night - False negative result in newborn screening for Congenital Adrenal hyperplasia - July 2009.",institutionString:"Loma Linda University Children's Hospital",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Loma Linda University Children's Hospital",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"280415",firstName:"Josip",lastName:"Knapic",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/280415/images/8050_n.jpg",email:"josip@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copy-editing and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. Mauricio Barría",coverURL:"https://cdn.intechopen.com/books/images_new/6550.jpg",editedByType:"Edited by",editors:[{id:"88861",title:"Dr.",name:"R. Mauricio",surname:"Barría",slug:"r.-mauricio-barria",fullName:"R. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"59914",title:"Cytokines and Interferons: Types and Functions",doi:"10.5772/intechopen.74550",slug:"cytokines-and-interferons-types-and-functions",body:'\nCytokines are a cell-signaling group of low molecular weight extracellular polypeptides/glycoproteins synthesized by different immune cells, mainly, by T cells, neutrophils and macrophages, which are responsible to promote and regulate immune response (i.e. activity, differentiation, proliferation and production of cells and other cytokines). These polypeptides act on signaling molecules and cells, stimulating them toward sites of inflammation, infections, traumas, acting on primary lymphocyte growth factors and other biological functions. Cytokines may act in the site where they are produced (autocrine action), in nearby cells (paracrine action) or in distant cells (endocrine action). In this sense, they are important in the development and regulation of immune system cells. Different types of cytokines had been discovered, including chemokines, interferons (IFN), interleukins (IL), lymphokines and tumor necrosis factor (TNF) [1, 2, 3, 4].
\nIn this chapter, we describe and review different cytokines. They will be categorized according to their type, followed by presentation of their function and a brief scope: IFN (IFN-α, β and γ), IL (IL-1, IL-2 and others), TNF (TNF-α and TNF-β) and others. A brief explanation of different cytokines activities also will be done, comprising pro- and anti-inflammatory action, cellular immune responses and performance in hematopoiesis. Methods to reach these objectives include a literature search in the most relevant sources of information, including PubMed/Medline, Scopus and Web of Science databases.
\nAs key results, this chapter will provide a better understanding on cytokines types and functions, with organized concepts about this subject. As we aim to provide a comprehensive review of the available data regarding cytokines, this chapter will be a valuable source of information for readers who seek a thorough and structured synthesis on this topic.
\nInterferon family represents a widely expressed group of cytokines. It includes three main classes, designated as type I IFNs, type II IFN and type III IFNs. The two main type I IFNs includes IFN-α (further classified into 13 different subtypes such as IFN-α1, -α2, -α4, -α5, -α6, -α7, -α8, -α10, -α13, -α14, -α16, -α17 and -α21), and IFN-β. The term
Interferon was the first described member of the class of protein molecules now known as cytokines. Nowadays, interferons are well known to participate in innate immune system, mediating responses against viral infections. This role of the IFNs was first described in the 1930s, when a research conducted by Hoskins demonstrated that rabbits previously infected by the herpes simplex virus were protected against subsequent infections by the same type of virus. In 1937, a few years after Hoskins’ experiment, Findlay and MacCallum showed that the virus-infected animals were also resistant to infections caused by antigenically different viruses, corroborating and complementing the existing evidence regarding IFNs functions at that time. Their findings, however, were only confirmed in 1957, when Isaacs and Lindenmann, through cell cultures research, demonstrated that cells infected by a virus had the ability to produce a protein that could make other cells resistant to other viruses. Glasgow, in 1966, theorized that the interferon production was not limited to primary infection by viruses, and that this cytokine might play a role following re-infection. Therefore, the concept of “immune induction” of interferon became well established by the end of the 1960s. The early 1970s were marked by two milestone studies, which confirmed the existence of two different categories of interferons, which differed physicochemically and biologically: the immune-induced interferon (currently known as type II IFN) and the classical virus-induced interferon (currently known as type I IFN). In 1980, the terms IFN-α and IFN-β arose to designate the “classical interferons”, which had been obtained in pure forms exhibiting homogeneity. Albeit the “immune-induced interferon” had not been obtained in pure form at that time, it was recognized that this molecule was different from IFN-α and IFN-β, being, therefore, designated as IFN-γ. Despite the markedly difference of this cytokine when compared to IFN-α and IFN-β, IFN-γ was originally classified in the IFN family due to its ability to ‘interfere’ with viral infections, which characterizes the original definition of IFNs. In the last decade, a third type of IFN (type III IFN) has been described, the IFN-λ. This type is also referred as interleukins IL-28A and B (IFN-λ2 and IFN-λ3, respectively), and IL-29 (IFN-λ1) [8, 9, 10, 11].
\nThere are several isotypes of type I IFNs. In humans, there are multiple forms of IFN-α, only one type of IFN-β and additional isotypes, as IFN-δ, IFN-ε, IFN-κ, IFN-τ and IFN-ω (IFN-δ and IFN-τ have been only described in pigs and cattle). This sort of cytokines presents similar structure, binding to the same cell surface receptor, and they are coded by a family of linked genes located on the human chromosome 9 [7, 12].
\nType I IFN synthesis is induced by microbial challenge (i.e., viral and bacterial infections or microbial nucleic acids exposure) when the pattern recognition receptors (PRRs) sense these microorganisms. These receptors can be found in the cytosol or in the endosome. Once a virus infects a cell, the cell activates signals that lead to phosphorylation, dimerization and passage to the nucleus of the interferon response factor 3 (IRF3). Along with IRF3, other transcription factors, such as nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1), activate the transcription of IFN-β gene. After this process, secreted IFN-β binds to the interferon receptor (IFNAR) on the surface of the infected cell, producing an autocrine signaling to mobilize other interferon response factors and alter gene expression patterns to provide interferon response. Besides autocrine signaling, IFN-β also binds to the interferon receptor expressed by neighboring non-virus infected cells, acting in a paracrine manner to promote interferon response in order to help these cells to resist viral infection [5, 13, 14].
\nInterferon response comprises a series of reactions that alter the expression of a variety of human genes. These reactions are mediated by the binding with type I interferon receptors, which consists of the IFNAR1 and IFNAR2 transmembrane proteins, and two associated cytoplasmic tyrosine kinases, the Janus kinase 1 (Jak1) and tyrosine kinase 2 (TyK2). In addition to IRF3, another transcription factor induced by interferon response is interferon response factor 7 (IRF7), which is responsible to initiate IFN-α transcription without the need of NF-κB and AP-1. The canonical pathway that mediates the biological effects of IFNs corresponds to the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Both the antiviral and inflammatory effects of IFN-α/IFN-β are specifically mediated by STAT1 and STAT2. This pathway, however, does not work in isolated manner. It extensively communicates with other signal transduction pathways, therefore recruiting several effector molecules to promote a potent effect against viral infections, antiproliferative and antitumor activities, in addition to the immunomodulatory effects. In healthy individuals, these type I IFN genes are strictly regulated, with almost no constitutive IFN-α production [7, 15, 16].
\nA high number of cells produce IFN-α and IFN-β, including macrophages, fibroblasts, and endothelial cells, specialized leukocytes, called interferon-producing cells (IPCs), or natural interferon-producing cells, secrete up to 1000 times more interferon than the others after microbial challenge. These cells, also known as plasmacytoid dendritic cell (pDCs), are present in the blood, comprising less than 1% of the total peripheral blood mononuclear cells. In terms of morphology, they are similar to plasmocytes, another type of cell responsible for the massive production of this cytokine. IPCs express toll-like receptors (TLRs) 6, 7, 9 and 10, which are critical components of innate immunity, acting as pathogen sensors. Toll-like receptors act on innate immunity cells by detecting conserved patterns of pathogenic microorganisms. These cells, when activated by these receptors, lead to maturation of antigen-presenting cells and production of inflammatory cytokines. Hence, IPCs become responsive to a variety of viral infections through quick secretion of massive amounts of type I IFN. In other words, these cells can produce substantial amounts of type I IFN in response to stimulation with a wide range of DNA and RNA viruses, which signal through TLR9 and TLR7, respectively. During an antiviral immune response, therefore, IPCs are able to promote the function of NK cells, B and T cells, and myeloid dendritic cells through type I IFN. IPCs still differentiate into a unique type of mature dendritic cell, which allows the direct regulation of the function of T cells and links innate and adaptive immune responses. This process occurs at a later stage of viral infection [11, 17, 18, 19, 20].
\nThe whole process mentioned above can be summarized through the following explanation. On the first day after stimulation by viral infection (microbial challenge), IPCs produce massive amounts of type I IFN. On the following 2 days, IPCs differentiate into a type of dendritic cell called a plasmacytoid dendritic cell, which maintains the ability to produce interferon. During the infection process, these cells cluster into the T cell areas of the draining lymph nodes. Although there is some similarity between plasmacytoid dendritic cells and myeloid dendritic cells (known as conventional dendritic cells), it is believed that plasmacytoid dendritic cells do not have a substantial involvement in T cell activation in adaptive immunity, which is the main function of conventional dendritic cells. Therefore, in the context of innate immunity, conventional dendritic cells produce relatively small amounts of type I IFN, but produce large amounts of IL-12, a cytokine that interacts with type I IFN to activate the NK cell response to viral infection [7, 11].
\nIFNs, besides being first line of defense against viral infections, play important roles in immunosurveillance for malignant cells. More specifically, type I interferons present a potent antiviral activity, which is associated with several physiological changes. For ease of understanding, the role of type I interferons, in which IFN-α and IFN-β are the major actors, can be divided in three main functions. Firstly, these cytokines stimulate resistance to viral replication in all cells through cellular genes activation, with the consequent destruction of the viral mRNA and inhibition of the viral proteins translation. Secondly, they promote an increase in ligands to NK cell receptors expression in virus-infected cells. Thirdly, they lead to NK cells to eradicate virus-infected cells [8, 21, 22].
\nNK cells are lymphocytes of innate immune system, which provide defense against viral infections by secreting cytokines (mainly IFN-γ) and killing infected cells. When IFN-α or IFN-β bind to interferon receptors on circulating NK cells, these are activated and directed to infected tissues, where they attack virus-infected cells. It is possible to say that NK cells play, in innate immune response, similar functions than cytotoxic T cells in adaptive immune response [23, 24].
\nType II and type III IFNs do not share homogeneity with type I IFN in terms of induction, and the signaling pathways are, therefore, through their own receptors. Nevertheless, the signal pathways involved with type I IFN and type II IFN, as well as the target genes used by these cytokines, somewhat overlap. IFN-γ receptor (IFNGR) is composed by two structurally homologous polypeptides that belong to the type II cytokine receptor family, named IFN-γR1 and IFN-γR2. IFN-γ (originally designated as macrophage-activating factor) binds and induces dimerization of the two receptor chains. This process leads to the activation of JAK1 and JAK2 kinases and, subsequently, to the phosphorylation and dimerization of STAT1, which stimulates the transcription of several genes. The genes induced by this cytokine encode several different molecules that mediate the biological activities of IFN-γ [5, 14, 25].
\nUnlike IFN-α or IFN-β, the gene that encodes IFN-γ is located on the human chromosome 12. This unique specimen of type II IFN is the primary cytokine involved in macrophage activation (named as classical activation) and plays a critical role in immunity against intracellular microorganisms. In innate immune system, IFN-γ is the main cytokine produced by NK cells, acting as a mediator of innate immunity. Despite belonging to the
Regarding biological activities, both type I and type II IFN are essential in the immediate cellular response to viral infections. IFN-γ acts on immune cell activation and induction of the major histocompatibility complex (MHC) molecules, which is important at a later stage of the response. Thus, this cytokine establishes an antiviral state for long-term control, coordinating the transition from innate to adaptive immunity. IFN-γ plays a role in macrophage activation, triggering microbicide effector functions in these cells. Macrophages activated by IFN-γ promote more intensive pinocytosis and phagocytosis, in addition to an improved microbial killing ability. Furthermore, IFN-γ acts as a cell growth inhibitor and presents the ability of triggering apoptosis [25, 26].
\nIn summary, in the early stages of infection, NK cells are the main producers of IFN-γ, whose major role is macrophage activation. Once activated, macrophages release cytokines that participate in T cells activation, therefore initiating the adaptive immune response. After being produced and entering the infected site, the effector T cells become, in turn, the main source of IFN-γ and cell-mediated cytotoxicity. Besides the effects on host defense, IFN-γ is also involved in the protection against tumor development [5, 26].
\nType III IFN (IL-28/29 or IFN-λ), likewise type I IFN, present antiviral activity. Type III IFN is subdivided in IFN-λ1 and IFN-λ2/3, which are expressed in identical patterns. The signaling pathway related to IFN-λ is similar to IFN-α/IFN-β, involving mechanisms relying on IRFs and NF-κB actions, with the last one playing an essential role in regulating type III IFN expression. Nevertheless, the expression of IFN-λ is more flexible when compared to type I IFN, once it also involves independent actions of NF-kB and IRFs, allowing the production of this cytokine in response to a wider range of stimuli. Most classes of virus and some bacterial products induce IFN-λ expression, and almost all cell types, mostly pDCs, produce type III IFN after virus infection. However, different from the other types of IFN, macrophages are not involved in IFN-λ expression. Regarding biological activities, IFN-λ acts as the first line in host defense against viral infections, besides regulating innate and adaptive immune responses. Recently, a new member of the Interferon Lambda family was identified, the IFN-λ4. This cytokine presents strong antiviral activity and has been recently described to be related to hepatitis C treatment failure. Several
The first sign that type I IFN was somehow involved with human autoimmune diseases came from the observation of an increased incidence of autoantibodies and autoimmune diseases after type I IFN treatment. Hence, when considering the indication of IFN-α therapy for some conditions (e.g., hepatitis C virus infection), it is important to scrutinize the presence of autoantibodies in the patient, since they may increase the risk for autoimmune disease development with this kind of treatment [14]. As previously mentioned, pDCs are responsible for producing high levels of type I IFN in response to nucleic acid-containing immune complexes through the activation of TLRs 7 and 9 [11]. These immune complexes are prevalent in autoimmune conditions, such as systemic lupus erythematosus (SLE), which makes this process highly relevant for the development of autoimmunity. It has been described that, in autoimmune diseases, several key immune effector cells, such as B cells, T effector cells and regulatory T cells are modulated by IFN-α. Hence, type I IFN plays a substantial role in this kind of condition [16].
\nRegarding type II IFN, IFN-γ may contribute to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis and type I diabetes mellitus. The role of this cytokine in autoimmune diseases (both in promoting and suppressing the condition) has been shown in several mouse models. The administration of IFN-γ at very early stages of experimental autoimmune encephalomyelitis exacerbates the disease, while its administration at a later stage reduces disease severity. Hence, the absence of biomarkers that could indicate the best stage of the disease to initiate IFN-γ treatment consists in a limiting factor for its therapeutic use [25, 26, 30]. This subject will be reported in the topic “Cytokines and autoantibodies”.
\nDue to the ability to increase immune response, type I and type II IFN have been explored in clinical trials as treatments for several conditions. It has been found that these cytokines are involved with the improvement of several conditions, such as hepatitis B and C virus infections, autoimmune diseases and certain types of leukemia and lymphomas. Hence, this class of cytokines, which play a paramount role in the immune system, consist of valuable treatment strategy. Still, in order to obtain full advantage of the therapeutic potential of interferons, further researches are needed to elucidate the core mechanisms of their effects [31, 32].
\nTumor necrosis factor (TNF) is a cytokine that had the name derived from it discovery in 1975 as a molecule that caused in vitro necrosis of tumors. Shortly thereafter, it was observed that TNF expression was promoted by immune system cells. These discoveries were important to a posterior characterizing of the TNF superfamily and the TNF receptor superfamily, which has more than 40 members, being the most outstanding TNF-α (commonly named as TNF) and TNF-β (also named Iymphotoxin), but also including cytokines and membrane proteins that have similar sequence homologies and a homotrimeric pyramidal structure (e.g. CD40 ligand, FAS ligand, OX40 ligand, GITR ligand and other several proteins). The binding of this family of cytokines with their respective receptors triggers especially inflammatory reactions [33, 34, 35, 36, 37] .
\nTNF-β, a type II transmembrane protein, is an important key in the development of lymph nodes and Peyer’s patches, and also for the maintenance of secondary lymphoid organs. The expression of TNF-β is mainly stimulated by lymphocytes. TNF-α will be better described in the following topics [38, 39].
\nAlthough it were discovered many receptors along the decades, two are best known: TNFR1 (55 kD) and TNFR2 (75 kD). Both receptors are plasma membrane trimmers, while TNFR1 is expressed by most human cells and TNFR2 is mainly produced by immune system cells. It is important to mention that TNFR2 have a higher affinity to TNF. They are related to inflammatory reactions, so that a cytokine bind to the receptor, it induces the recruitment of proteins that are important for the process [35, 40] .
\nThe production of this cytokine is performed by different cells from the immune system, which includes T cells, NK cells, macrophages and monocytes. The stimulus for TNF expression includes different factors, such as bind to pathogen lipopolysaccharide (LPS) and other parts with toll-like receptors (TLRs), and also by other cytokines, highlighting IFN-y [33, 35].
\nIt is primary secreted as a nonglycosylated type II membrane protein arranged as homotrimer. TNF membrane releases a trimeric soluble cytokine (a polypeptide that weighs around 17-kDa with triangular pyramid shape) through proteolytic cleavage by metalloprotease TNF-converting enzyme, and this is the circulating form that is found in blood plasma, and that allows a potent capacity to displacement in the body, thus it endocrine function. It is not well defined but from three of these circulating TNF it is possible to polymerize them forming one 51-kD polypeptide which facilitates the binding of the cytokine with three receptors simultaneously [37, 41, 42].
\nTNF have a lot of physiologic multifunction including immune and inflammatory roles and the survival and death of different cells. The main function of cytokine is to attract and activate immune cells to sites of infections and to destroy pathogens, such as bacteria and virus. In this context, TNF stimulate vascular endothelial cells to express adhesion molecules (e.g. selectins and ligands for leukocyte integrins) that allows immune system cells to connect the wall of blood vessels. Additionally, complementing the inflammatory response, TNF induces the production of chemokines that increase the affinity of leukocyte to their ligands, the expression of IL-1 and to activate microbicidal functions of immune system cells. For all TNF importance in the inflammatory reaction, if low quantities of this cytokine are presented in the local, the containment of the infection may be impaired [33, 37, 41, 42, 43].
\nTNF is also well known to act in inflammatory reaction of some autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease. Errors in this production are responsible for a considerable number of autoimmune, neoplastic and other diseases. Under these conditions, the treatment of these diseases are based on biologic agents targeting TNF, and thus looking for reducing the number of available TNF molecules or to block it receptors [33, 35, 40].
\nTNF also promotes necrosis of tumor cells by inducing programmed cell death, a cytolytic potential. The activation of apoptosis mechanism is mediated by TNFR1, by stimulating the recruitment of death signaling proteins, such as Fas-associated protein with death, TNFR-associated factor (TRAF)-1 and TNFR-associated death domain protein (TRADD). These intracellular proteins are responsible for the release of other proteins such as pro-caspase-8, which in it activated form activate caspase-3, caspase-6, caspase-7 and other cytosolic substrates. These proteins induce genomic DNA degradation and cell death through interacting with latent DNAse. Evidences also suggest that TNF have the capacity to induce carcinogenesis and to stabilize tumors, an event that it is opposite of the previous explained, by DNA mutations and it mechanism of repair (i.e. genotoxic potential). This is possible due to the activation of NF-κB in tumor cells and by promoting production of IL-6 (a tumor-promoting cytokine), both facilitate metastasis and cancer cells to escape from immune system defense [35, 40, 41, 42].
\nThere are other biological events and actions caused by TNF. When this cytokine is produced in large scale, such as in severe infection, it may induce shock or decrease of blood pressure due to reducing vascular muscle tone and myocardial contractility. Additionally, in high concentrations TNF can reduce blood glucose concentration, and cause intravascular thrombosis (by decreasing anticoagulant capabilities of the endothelium). TNF is also known as an endogenous pyrogen because it promotes fever by stimulating hypothalamus cells to produce prostaglandins [33, 40].
\nInterleukins (ILs) are a group of secreted proteins with diverse structures and functions. These proteins bind to receptors and are involved in the communication between leukocytes. They are intimately related with activation and suppression of the immune system and cell division. The interleukins are synthesized mostly by helper CD4+ T lymphocytes, monocytes, macrophages and endothelial cells [5, 44, 45].
\nInterleukins are named as IL plus a number. Previously, different names were used to refer to the same IL. For instance, IL-1 was called lymphocyte-activating factor, mitogenic protein or T cell replacing factor III. In order to standardize the nomenclature, in 1979, during the Second International Lymphokine Workshop, the term interleukin was introduced. After that, the interleukins started being named consecutively according to the date of their discovery [44, 46, 47].
\nThere have been identified 40 interleukins so far and some of them are further divided into subtypes (e.g. IL-1α, IL-1β). These ILs are grouped in families based on sequence homology and receptor chain similarities or functional properties [5, 44, 48, 49].
\nIn this section, a brief description of various ILs will be presented. Focus will be given to the families of interleukins 1 and 2.
\nInterleukin-1 family is composed by 11 cytokines: 7 ligands with agonist activity (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β and IL-36γ), 3 receptor antagonists (IL-1Ra, IL-36Ra and IL-38) and 1 anti-inflammatory cytokine (IL-37) [44, 50].
\nThe interleukin-1 family started with only two components: IL-1α, IL-1β. Over the years, new IL with similar behavior and/or structure were discovered and added to the family. All the agonists members of this family show pro-inflammatory activity. These cytokines share a common C-terminal three-dimensional structure with a typical β-trefoil fold consisting of 12-β-strands connected by 11 loops, and have identical positioning of certain introns. Considering that, it is plausible to affirm that they probably arose from the duplication of a common ancestral gene [45, 51, 52].
\nAll members of the family except IL-18 and IL-33 have genes encoding on chromosome 2 in a 400 kb region in human species. Despite the fact that all the cytokines are extracellular, they are synthesized without a hydrophobic leader sequence and are not secreted via reticulum endoplasmic-Golgi pathway, with the exception of IL-1Ra. The secretion mechanism of the other members of the family is still not known. These cytokines bind to closely related receptors, and many of the encoding genes are clustered in a short region of chromosome 2. The receptors contain extracellular immunoglobulin domains and a toll/IL-1 receptor (TIR) domain in the cytoplasmic portion [45, 52].
\nIn order to become active, both IL-1α and IL-1β bind to the ligand-binding chain type I (IL-1R1). Then, the co-receptor, termed the accessory protein (IL-1RAcP), is recruited, and together they form a heterodimeric complex. The signaling that will culminate in a variety of inflammatory activities is initiated by the recruitment of the adaptor protein MyD88 to the toll-IL-1 receptor (TIR), which is followed by the phosphorylation of kinases, the translocation of the nuclear factor kappa B (NF-κB) to the nucleus and the expression of inflammatory genes [50, 51].
\nBoth IL-1α and IL-1β have precursor forms. The precursor of IL-1α is present in the epithelial layers of the gastrointestinal tract, lung, liver, kidney, endothelial cells and astrocytes; and it is capable of binding to the IL-1R1 and initiating the signaling cascade, essentially after cell death by necrosis (e.g. myocardial infarction and stroke). On the other hand, the precursor of IL-1β is not active and does not bind to the receptor. It requires a cleavage to become in the active form [44, 50, 51].
\nIL-1β is highly involved with autoimmune, infectious, degenerative and, especially, with autoinflammatory diseases. An important part of autoinflammatory diseases is caused by genetic defects in innate inflammatory pathways, and usually show their signals early in life. The first disease classified as autoinflammatory was tumor necrosis factor receptor associated periodic syndrome (TRAPS). Other examples are familial Mediterranean fever and adult and juvenile Still disease. This group of diseases promptly responds to the treatment with IL-1β blockade, with few exceptions. In many autoinflammatory diseases, there is a state of increased release of IL-1β. The precursor is converted to the active form through the action of Caspase-1. This enzyme is also found in the inactive form in tissue macrophages and dendritic cells, and requires conversion by autocatalysis to become active. However, it is in the active form in circulating human blood monocytes. The release of IL-1β from blood monocytes in highly controlled and takes several hours in healthy subjects. In patients with an autoinflammatory disease, more mature IL-1β is released when compared to healthy subjects, which leads to exacerbated inflammation. Despite of this group of diseases being characterized by severe inflammation, the amount of IL-1β released is not much greater than that released from healthy subjects. Currently, human anti-IL-1β monoclonal antibody is being developed to treat autoinflammatory diseases. Canakinumab was approved by Food and Drug Administration (FDA) in 2009 for the treatment of cryopyrin-associated periodic syndromes (CAPS). In 2016, Canakinumab was also approved for treating TRAPS, hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD) and familial Mediterranean fever (FMF) [50, 51].
\nIL-1Ra is a receptor antagonist. It is synthetized by the same cells that produce IL-1α and IL-1β (monocytes, macrophages, dendritic cells and others). The binding of IL-1Ra to the receptor does not involve conformational change and, hence, the co-receptor IL-1RAcP is not recruited. IL-1Ra regulates the activity of IL-1. However, to efficiently block the IL-1 response, it has to be in an amount approximately 100-folds greater than the agonists cytokines. Anakinra is a recombinant version of IL1-Ra used in the treatment of rheumatoid arthritis [44, 53].
\nIL-18 is synthetized as an inactive precursor, and, similarly to IL-1β, it needs cleavage by caspase-1 to become in the active form. The precursor form is present in almost all cells of the human body, likewise IL-1α. Usually diseases related to IL-18 appear when there is an imbalance between the amount of IL-18 and IL-18 binding protein, which is responsible for limiting the level of activity of IL-18. This cytokine is released usually from dying cells, once again like IL-1α [51, 54].
\nIL-18 was first described as “IFN-γ-inducing factor”, because it was discovered as an inducer of IFN-γ production. However, alone, IL-18 does not induce the production of considerable amounts of IFN-γ. For that to happen, it has to act in association with IL-12. IL-18 promotes TH1 and Th2 cells responses, and also induces IL-13 production in T cells and NK cells together with IL-2. It also enhances NK toxicity by promoting the expression of Fas ligand in NK cells. IL-18 is involved in several autoimmune diseases, in myocardial infarction, metabolic syndromes and others [44, 55].
\nIL-33 is an alarmin cytokine, rapidly released upon cellular damage. It is involved mainly in type 2 immunity and inflammation. It acts in Th2, in innate lymphoid cell-2 (ILC2), and in activated M2 polarized macrophages. This cytokine is expressed by keratinocytes, epithelial and endothelial cells, and monocytes. IL-33 is produced as a precursor, but, contrary to IL-1, caspase-1 transforms it in an inactive cytokine. The precursor is active and other proteases can cleavage it in more potent forms. IL-33 induces Th2 response binding to ST2 and next recruiting IL-1RacP. The activity of IL-33 is controlled essentially by the binding to soluble ST2 and soluble IL-1RAcP. Levels of increased soluble ST2 are present in various inflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis [44, 50, 56].
\nIL-36α, IL-36β and IL-36γ are receptor agonists, while IL-36Ra is a receptor antagonist that blocks the activation of the receptor and competes with IL-36, acting as a regulator. These cytokines are included in the interleukin-1 family because they share homology to the first members of the family. Their homology to IL-Ra and IL-1β varies from 20 to 52%. Furthermore, IL-36β and IL-36γ have the core 12-fold, β-trefoil structure and lack a signal peptide, particular features of IL-1 family. All these cytokines need an N-terminal processing to become in the active form, but the enzyme responsible for this process is still not known. IL-36 cytokines are predominantly found in skin cells, and that is why they are related with several skin disorders, such as psoriasis. After binding to the receptor (IL-36R and IL-1RAcP co-receptor), dendritic cells are activated and participate in the polarizing of T-helper responses [50, 52, 57].
\nDifferent from the other members of the family, IL-37 is an anti-inflammatory cytokine, and reduces innate inflammation as well as acquired immune responses. Its presence has already been reported in skin, tonsils, esophagus, placenta, breast, prostate and colon. There are five different isoforms of IL-37: IL-37a, IL-37b, IL-37c, IL-37d and IL-37e, expressed in different locations of the human body. So far, IL-37b, which contains a 12β-strand trefoil, typical of the IL-1 family, appears to be the most biologically active, and therefore the object of the majority of studies. IL-37 suppresses the production of pro-inflammatory cytokines, such as IL-1A, IL-6, CC chemokine ligand (CCL-12), colony-stimulating factors (CSF-1 and CSF-2), chemokine ligand-13 (CXCL-13), IL-1β, IL23-A and IL1RA, and also inhibits dendritic cell activation [58, 59, 60].
\nIL-38 is the most recent member of the Interleukin-1 family, identified in 2001. It binds to the same receptor that the IL-36 cytokines, IL-36R. However, it acts as an antagonist, similarly to IL-36Ra. Therefore, IL-38 acts reducing inflammatory response. IL-38 shares 41% homology with IL-1Ra and 43% with IL-36Ra. This cytokine is present in skin, tonsil, thymus, spleen, fetal liver and salivary glands. The properties and biological activities of IL-38 are still being studied [52, 61, 62].
\nThe IL-2 cytokine family, also known as the common γ-chain family, is composed by ILs 2, 4, 7, 9, 15 and 21. All these ILs bind to the common γc receptor, also called CD132. These cytokines act as growth and proliferation factors for progenitors and mature cells [44, 63].
\nIL-2 is the first member of the common γ-chain family, previously known as T cell growth factor. This cytokine is mainly produced by CD4+ and CD8+ T cells, but can be also expressed by dendritic cells and NKs. The IL-2R is composed by three subunits (CD25, CD122 and common γc), all necessary to binding to IL-2. IL-2 acts in the development of regulatory T (Treg) cells, as a B cell growth factor, stimulates antibody synthesis and promotes proliferation and differentiation of NK cells and T helpers. IL-2 has been extensively used as an anti-cancer therapy [44, 63, 64, 65].
\nIL-4 is produced by Th2 cells, basophils, eosinophils and mastocytes. It has two receptors: IL4-R type I, which binds only to IL-4 and is composed by CD124 (IL-4rα) and CD 132; and type II, which binds to IL-4 and to IL-13, and it consists in IL-4Rα and IL-13Rα1. These receptors are spread all over the human body. IL-4 is known to play several different roles, regulating allergic conditions and activating the immune response against extracellular parasites (B cell class switching to IgE). It is the main cytokine to stimulate development of Th2 cells. Dupilimab is an IL-4 receptor antagonist approved in 2017 by FDA for treatment of eczema [44, 66, 67].
\nIL-7 is a homeostatic cytokine. It can be found essentially in T cells, progenitors of B cells and bone marrow macrophages. As the other members of the family, its receptor (IL-7R) consists in the common γ-chain fraction, along with another unit, the IL-7Rα (CD127). IL-7 is involved in the survival and proliferation of thymocytes and in the development of naïve and memory B and T cells, mature T cells and NKs. Deficiencies related to IL-7 result in immunodeficiency, autoimmune diseases and leukemia [44, 68].
\nIL-9 is mainly produced by Th2 cells, but it is also expressed in less amounts by eosinophils and by mastocytes of asthmatic patients. Its receptor, IL-9R, is composed by the CD132 and IL-9Rα units. IL-9 is a potent growth factor for T cells and mastocytes, and some of it activities include the inhibition of cytokine production by Th1 cells, IgE production, and mucus secretion by bronchial epithelium. Recently, a new subset of effector T cells was discovered, Th9, and it is believed that it is intimately related with IL-9 production. IL-9 is associated to allergic diseases and protection from helminthic infections. This cytokine can be found in elevated amounts in Hodgkin lymphoma, hence, IL-9 antagonists are being studied as a potential treatment for this disease [44, 69, 70].
\nIL-15 is structurally homologous to IL-2. The receptor, IL-15R, is composed by the CD132 subunit common to the family, and also by IL-15Rα and IL-2Rβ chains. IL-15 is produced by keratinocytes, skeletal muscle cells, monocytes and activated CD4+ T cells, in response to signals that trigger innate immunity. IL-15 has some identical functions to IL-2, such as T cell activation and stimulation of NK cell proliferation, but it also involved with CD8+ memory cell, NK cell, and NKT-cell homeostasis. Increased levels of IL-15 were reported in autoimmune disorders, such as rheumatoid arthritis, psoriasis and celiac disease [44, 71].
\nIL-21 is produced by T cells, NKT cells and Th17. The receptor, IL-21, is present in various parts of the human body and consists in CD132 and IL-21R. This cytokine is involved with B cells functions, and also increases the proliferation of CD8+ T cells, NK cells and NKT. IL-21 is currently being studied as anti-cancer therapy [44, 64].
\nIn addition to the aforementioned cytokines, other also deserves attention, such as chemokines. The chemokines represent a large family of structurally homologous cytokines that stimulate leukocytes movement and regulate the migration of them from the blood to tissues, in a process named chemotaxis. They control homeostatic immune cells, such as neutrophils, B cells, and monocytes, trafficking between the bone marrow, blood and peripheral tissues. Therefore, they can be classified as chemotactic cytokines [33, 72].
\nThere are about 50 human chemokines, classified into 4 families according to the location of N-terminal cysteine residues. The two major families are CC and CXC chemokines, in which the cysteine residues are adjacent on CC family, and are separated by one amino acid on CXC family. In general, members of CC chemokines are chemotactic for monocytes, and a small subset of lymphocytes, while CXC chemokines are more specific for neutrophils. The best-known chemokine is IL-8, or CXCL8, which belongs to the CXC chemokine family, and is responsible for neutrophil recruitment and for the maintenance of the inflammatory reaction. On the other hand, the monocyte chemoattractant protein-1 (MCP-1) or CCL2, and CCL11 or eotaxin, are examples of CC chemokines, which acts on recruitment of a variety of leukocytes, but especially monocytes, and eosinophils, respectively [33, 73, 74].
\nThe chemokines receptors are expressed on all leukocytes and are divided in two groups: G protein-coupled receptors with seven-transmembrane α-helical segments, and atypical receptors, which appear to attenuate inflammation by scavenging chemokines, independently of G protein. Each receptor subtype is capable of binding to various chemokines of the same family, and a single chemokine can bind to more than one receptor. Despite of this factor, a lot of chemokines presents a great tissue and receptor specificity [72, 73].
\nChemokines can be produced constitutively in various tissues, and are responsible for regulating the traffic of leucocytes, especially lymphocytes, through peripheral lymphoid tissues. However, the best-known activity of chemokines is the involvement on inflammatory reactions. Recruitment of macrophages, neutrophils and T cells to the site of inflammation is strongly stimulated by chemokines. In fact, they represent a secondary pro-inflammatory mediator that is induced by primary pro-inflammatory mediators, such as IL-1 or TNF. In general, members of the chemokines family induce recruitment of well-defined leukocyte subsets, differently of the classic leukocyte chemoattractants. They induce the movement of leukocytes, and consequently promote their migration to a specific local, by stimulating actin filaments [33, 72, 73, 74].
\nBeyond the involvement of the chemokines on acute inflammatory reactions, and the regulation of the traffic of leukocytes through peripheral lymphoid, independently of the presence of inflammation, some kind of chemokines can promote angiogenesis and wound healing, associated mostly with CXC family, while other are involved in the development of diverse nonlymphoid organs [73, 74]. They also have an important role in the priming of naive T cells, in effector and memory cell differentiation, and in regulatory T cell function [72].
\nBesides chemokines, there are cytokines that stimulates hematopoiesis, such as the colony-stimulating factors (CSFs), which contributes to the growth of progenitors of monocytes, neutrophils, eosinophils and basophils, as well as activating macrophages. Immune and inflammatory reactions uses leukocytes, due to the recruitment induced by some kinds of cytokines, so new must be produced [73, 74]. Additionally, the GM-CSF (granulocyte-macrophage colony-stimulating factor) and M-CSF (macrophage colony-stimulating factor) have, like some other cytokines, a pro-inflammatory action, and exhibit a connexon between the expression of them and TNF, IL-1, IL-23 and IL-17 [75].
\nFinally, other cytokines can be highlighted: TGF-β, LIF, Eta-1 and oncostatin M. The TGF-β is responsible for the chemoattraction of monocytes and macrophages, but also it has an anti-inflammatory effect, by inhibiting the lymphocyte proliferation. LIF and oncostatin M induce the production of acute-phase protein, while Eta-1 stimulates the production of IL-2, and inhibits the production of IL-10 [73].
\nOn this topic, the association between the cytokines and autoimmune diseases will be reviewed, but emphasis will be given to these ones: systemic lupus erythematosus, type 1 diabetes mellitus, multiple sclerosis, vitiligo and heart failure.
\nThe impossibility of differentiating between own and non-own (strange) could result in the synthesis of antibodies against the components of the organism (autoantibodies), which could be extremely deleterious [73]. The organism is characterized by a failure of the normal mechanism of self-tolerance, resulting in reactions against one’s cells, in the absence of any present infection or another cause, known as autoimmunity, and the diseases caused by this phenomenon are referred as autoimmune diseases [33, 76].
\nThe pathogenesis of autoimmune diseases involves mainly the genetic susceptibility, and previous infections. In relation to infections, it is observed a recruitment of leukocytes into the affected tissue, resulting in the activation of tissue antigen-presenting cells (APC). Consequently, these APCs express costimulators and secrete T cell-activating cytokines, contributing to the breakdown of T cell tolerance. Therefore, the infection promotes the activation of T cells that are not specific for the pathogen, in a process called bystander activation. Additionally, microbes may engage toll-like receptors (TRLs) on dendritic cells, resulting on production of lymphocyte-activating cytokines, leading to the autoantibody production. This process was demonstrated in mouse models, and its influence in human autoimmune diseases remains unclear [33].
\nThe systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by the involvement of immune complexes formed from autoantibodies and their specific antigens that are responsible for the clinical manifestation, especially glomerulonephritis, arthritis and vasculitis. The peripheral blood lymphocytes of patient presents an excessive production and response to type 1 IFNs, but the involvement of this cytokines on the development of the diseases is still uncertain [33]. In these patients, for instance, serum IFN-α and IFN-α-induced gene expression are frequently observed, implying that the molecular pathogenesis of this condition is mediated by type I IFN. It has also been shown that IFN-γ serum levels are increased in SLE patients, and in mouse models, the receptor of this cytokine was necessary to the disease development. The massive amount of circulating IFN correlates to disease severity, which is likely to be triggered by excessive pDC activation. Recently, clinical trials evaluating anti-IFN-α monoclonal antibodies for SLE have been conducted, exhibiting promising results. Moreover, a trial evaluating a monoclonal antibody that binds IFN-γ was conducted, but no significant improvements in the efficacy outcome measures were observed. Additionally, a recent study demonstrated that keratinocytes may participate on the pathophysiological of the cutaneous manifestation of the SLE, by increasing cell apoptosis and producing pro-inflammatory cytokines, especially IL-23, IL-12, IL-6, IL-17, (Th17-related cytokines), IL-10 and TFG-β [16, 30, 77, 78].
\nIn parallel, another autoimmune disease widely studied that involves cytokines, besides several other factors, is the type 1 diabetes mellitus. This disease is characterized by pancreatic β cells destruction, which it is due to hypersensitivity reactions mediated by CD4+ TH 1 cells reactive with islet antigens, the effect of cytotoxic T lymphocyte on lysis of islet cells, and local production of cytokines, especially TNF, IL-1, IL-21 and IFN-α. In some cases, the islets show cellular necrosis and lymphocytic infiltration, consisted of both CD4+ and CD8+ cells. Remaining islet cells often express class II MHC molecules, an effect of local production of INF-γ by the T cells [33, 73, 79]. The onset of young age of this disease may be associated with upregulation of growth factors, especially GM-CSF and IL-7. Other mediators overexpressed are the pro-inflammatory cytokine IL-1β, the regulatory cytokine IL-10, IL-27, and some Th17 cytokines (IL-17, IL-21, IL- 23). Additionally, patients that involve to ketoacidosis, a serious complication of the disease, have a tendency for higher IL-8 and IL-10 levels [80].
\nIn the same way, it stands out the rheumatoid arthritis, a chronic and systemic autoimmune disease described as a progressive disability on joints, particularly of the fingers, shoulders, elbows, knees and ankles that can promote systemic consequences like cardiovascular, pulmonary and skeletal disorders. It is characterized by the production of autoantibodies, like rheumatoid factor, cytokines, chemokines, hyperplasic synovium, osteoclastogensis and angiogenesis. The pro-inflammatory cytokines IL-1α/β, IL-8, IL-6, TNF-α, INF-y and some CSFs are responsible for the pathogenesis of this disease, and are involved with the intracellular molecular signaling pathway that causes chronic inflammation on synovial membrane. These cytokines, especially TNF-α, activates the leukocytes endothelial cells and synovial fibroblasts, and stimulates the production of collagenases that are responsible for the destruction of the cartilage, ligaments and tendons of the joints. Therefore, monoclonal antibody drugs, such as anti-TNF are approved for treatment of this disease [33, 75, 76, 81].
\nIt is also believed that bone destruction in rheumatoid arthritis is due to overexpression of the TNF family cytokine receptor activator of nuclear factor KB (RANK), an essential mediator that promotes maturation and activation of osteoclasts [33, 76]. Therefore, the cytokines on rheumatoid arthritis promote the autoimmunity, the destruction of joint tissue and maintain the synovial inflammation [82].
\nThe multiple sclerosis is a neurodegenerative autoimmune disease of high mortality in adults, characterized by a chronic inflammation in the central nervous system with secondary demyelination due to leukocyte and cytokines infiltration of brain tissue and spinal cord. Clinical manifestations are weakness, paralysis and ocular symptoms [33, 73]. A recent study proposed the role of Th1 lymphocytes in the pathogenesis of the brain inflammation, with several cytokines involvement. Th1 lymphocytes produces mainly IFNγ (type II IFN) that is responsible for the production of other pro-inflammatory cytokines, and chemoattractants, such as IL-2, IFNγ, CC chemokines, like CCL5, CCL11 and CCL27 and CXC chemokines, especially CXCL1 and CXCL10. On the other hand, lower levels of circulating type I IFN are observed. Therefore, unlike SLE, multiple sclerosis treatment involves the administration of IFN-β. Additionally, an upregulation of CCL27 was found in cerebrospinal fluid of multiple sclerosis patients, demonstrating the possibility of its involvement on activation and migration of autoreactive immune effectors in the brain, and consequently a potential contribution for the pathogenesis of this disease [83].
\nVitiligo, is another autoimmune disease, characterized by the skin depigmentation, which is associated to the production of antibodies against the melanocytes, and it is more frequent in patients that have other autoimmune diseases, like Grave’s disease [73]. A variety of cytokines are increased in vitiligo patients in relation to healthy people. A recent systematic review demonstrated an association between the expression of some kind of cytokines in vitiligo skin, especially INF-y, TGF-β, IL-1β, IL-17, and the chemokines CXCL9, CXCL10 and CXCL12. IFN-y and IL-1β are closely related to the pathogenesis of vitiligo, but serum TGF-β and IL-17 are more abundantly expressed in relation to the others [84].
\nFinally, another disease that has the participation of cytokines on its pathogenesis is the heart failure, a chronic disease characterized by a cardiac impairment due to hypertension, myocardial infarction, arrhythmias and other heart diseases. A recent evidence showed the involvement of the adaptive immune system in the development and progression of heart failure, which is related to high mortality in adults. T cells, particularly TH1, and TH17 and B1 lymphocyte, contribute to the pathologic chronic inflammation, and cell migration. The inflammatory component of this disease, which has a closely relation to the morbidity and mortality, are the cytokines, including TNF-α, TNF-β, IL-1, IL-6, IL-7, IL-10 and IFN-y, chemokines and cardiac autoantibodies. Those factors are associated with cardiomyocyte death and tissue remodeling by fibrosis, contributing to the left ventricle dysfunction, and consequently to disease progression. In detail, initially the dendritic cells and other antigen-presenting cells can process specific proteins of the myocardial tissue and theirs contact with memory B cells promotes the release of autoantibodies, and consequently activates pro-apoptotic pathways, by antigen-dependent cell cytotoxicity, and complement-mediated cell cytotoxicity in health myocytes. Another characteristic of the pathogenesis of heart disease is the production of inflammatory mediators by B cells, such pro-inflammatory cytokines (TNF-α and IL-6) and chemokines, which recruit monocytes involved with inflammation and heart remodeling, beyond the activation of T lymphocytes, leading to the production of other specific inflammatory cytokines (IFN-y and IL-2) [73, 85].
\nSelective immunosuppression of B-lymphocytes may be a promising therapeutic on acute and chronic heart failure, as the blockage of the immune mediators, such cytokines, once they are involved to the propagation of the disease [85].
\nIn sum, different kinds of cytokines are involved on autoimmune diseases, which plays an important role especially on inflammatory process, and contributing to the pathogenesis, in most cases. Studies have been performed, in order to establish the association between cytokines and the evaluation of these diseases, with the objective of developing therapeutic strategies, such as anti-TNF for rheumatoid arthritis.
\nIn this chapter, the main aspects regarding the different types of cytokines and their main functions were reviewed. Hence, the comprehensive and fundamental role of cytokines in the immune system could be thoroughly investigated. Additionally, the contribution of these molecules to the development of diseases, particularly related to autoimmunity, as well as its use as treatment approach for some clinical conditions was explored.
\nDuring the last decades, the nonlinear optical (NLO) materials have gained significant role because of their various applications in medicine, molecular switches, luminescent materials, laser technology, spectroscopic and electrochemical sensors, data storage, microfabrication and imaging, modulation of optical signals, and telecommunication [1, 2, 3]. Organic materials are distinguished by the fact that they exhibit strong nonlinear optical (NLO) properties [4, 5, 6, 7, 8]. In the last years, researchers have based on the synthesis of the target organic molecules with particular geometries and certain electronic molecular parameters, in order to have the desired nonlinear optic properties [9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31].
\nThe changes of optical properties (absorption coefficient, index of refraction), through the increasing intensity of the input light, led to the discovery of the nonlinear optical phenomenon, second harmonic generation (SHG), detectable only after the improvement of the laser in 1962 [32]. Thus, nonlinear optics developed as a tremendous field of research, especially after the profound understanding of nonlinear optic phenomena (NLO) and the structure-property relations of chromophores, after the development of different tools to accurately measure and calculate hyperpolarizabilities [33].
\nRecent literature highlights the increased interest in organic materials in recent decades, as an alternative to their inorganic counterparts, and having several advantages, such as their low cost, low toxicity, ease of solution processability, flexibility for device fabrications [34], and modulation of their optical, electronic, and chemical properties by adapting their molecular structure. Field effect transistors, photovoltaic devices, organic light-emitting diodes (OLEDs), and white light sources for indoor and outdoor lighting are some of the applications of organic materials [33].
\nThe deposition of organic materials in thin films, required for the design of new, successful devices, implied the precise monitoring of their chemical, structural, and morphological properties [35]. The deposition of organic substances in thin films has to meet the requirements of the market: (1) good uniformity of simple or multilayer structures of organic, polymeric, or composite materials—in the electronics industry; (2) thickness control, film uniformity of coating, and good interfacing properties—in OLED polymer applications; (3) conformal coatings required to modify the interior surfaces of porous materials (membranes, foams, textiles) or irregular geometries of surfaces—for optoelectronic and medical devices [36].
\nSeveral classes of organic compounds, including conjugated molecules, fullerenes, polymers, perylenes, dyes, and thiophenes, have been studied as materials and investigated for their NLO responses [5]. Conjugated organic polymers with large nonlinear responses correlated with rapid response time have been observed as NLO materials with great expectations [37]. Although organic compounds have been considered as frail, the experiments showed, with the optical damage, threshold for polymeric materials can be greater than 10 GW/cm2 [37].
\nTwo deposition techniques, physical and chemical, are used in order to obtain
Many articles report the synthesis of the novel organic molecules or polymers with highly active chromophores and superior optical activity, as response to the demand of substances with NLO properties for various applications [83, 84, 85, 86].
\nThis chapter refers to synthesis of organic compounds with nonlinear optical properties in one of the techniques mentioned above, laser-deposited films.
\nThe optical response is due to a transition of the dipole moment from the ground state to the excited state due to the transition of an electron between frontier orbitals, from the highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO). The chemical activity of the molecule and the availability of the internal charge transfer are due to the balance between the redox ability of HOMO (as reducing agent) and LUMO (as oxidizing agent), which reveals the internal charge transfer responsible for the non linear optical properties. Nonlinear materials are defined as optical media in which the refractive index depends on light intensity [87]. So, the HOMO-LUMO gap energy is involved in molecular electrical transport properties.
\nThe designing and obtaining (synthesis) of the new molecules with high first hyperpolarizability β (theoretical and experimental) is central in discovery of the second-order and higher-order nonlinear optical materials and is quantified by the induced dipole moment under an intense light field E in Eq. (1):
\nwith μi the ith component of the induced dipole moment, Ej the corresponding component of the applied electromagnetic field, and αij, βijk, γijkl, the components of the linear polarizability, the first hyperpolarizability, and the second hyperpolarizability. In case of an ensemble of molecules, the macroscopic polarization is defined by Eq. (2):
\nwith χs\n(1), (2), (3) the macroscopic susceptibilities of the first (1), second (2), and third (3) order, which can be directly related to the density of the organic chromophore [88]. Recent advances in chromophore design report some features for classic dipolar organic structures with good nonlinear optic properties [89]: (1) presence of a π-conjugated systems with π electron delocalization, (2) a “push-pull” system, which is a couple donor-acceptor or connected to a system that contributes to the delocalization of the π electrons; (3) presence of a strong electron donor groups (e.g., ─NR2, ─NHR, ─OR, ─OH), and strong electron withdrawing groups (e.g., ─CF3, SO2CF3, ─SO3H, ─NO2, ─CN), positioned at opposite ends of a conjugated molecule in case of dipolar molecules; (4) great values of dipole moment and polarizability; (5) small HOMO-LUMO energy gap; (6) planarity of the molecule for neutral, polar, and zwitterionic resonance structures. Dipole organic molecules have an intrinsic matter: the dipoles prefer to align antiparallel with each other in the solid-state film to nullify the bulk effect. Octupolar molecules, alternative NLO materials, present more advantages compared with dipole molecules [90]: (1) the second harmonic response (SHG) does not depend on the polarization of the incident light because they are more isotropic than the dipolar molecules; (2) β values of the octupoles can be increased by increasing of intramolecular charge transfer; (3) octupoles form noncentrosymmetric crystals; and (4) they are less likely to undergo relaxation due to the lack of ground-state dipole moment.
\nIn the last decades, literature reveals some classes of organic compounds suitable for organic electronic devices, such as organic photovoltaics (OPVs) and organic thin-film transistors (OTFTs), which possess certain characteristics, such as high molecular hyperpolarizability coefficients (β), special geometry, and in most cases, small HOMO-LUMO energy gaps [25, 26, 27]. Among these classes of organic compounds, there are highlighting fullerenes, perylenes, thiophene compounds, polymers, and dyes.
\nFurthermore, the polymers represent one of the most used classes of substances in pulsed laser deposition (PLD), but also in the other methods for preparing thin films. Organic compounds with nonlinear optical properties and organic compounds reported in laser deposition (PLD) will be presented in the following two sections.
\nCanulescu group [91] studied thin films of fullerenes (C60)
Fullerenes with NLO properties [
Thin films of
Kamanina highlights that there are two reasons for the importance of fullerenes: their unique energy levels and high value of electron affinity energy (0.65–0.7 eV). This value is larger than the one for most dyes and organic molecules with intramolecular acceptor fragment and can stimulate the efficient intermolecular charge transfer complex formation in the fullerene-doped organic conjugated materials [94].
\nAlthough fullerene acceptors were the predominant choice in the acceptor materials for two decades, the limited tunability of electronic properties and weak absorption of fullerene derivatives in visible range prevent further development of organic solar [95]. Therefore, other classes of organic molecules have been researched to obtain the desired properties of the electronic materials.
\nPerylene compound
Perylene
Perylene diimides (PDIs) are a new class of nonfullerene electron acceptors for organic solar cells with many attracting features, like low cost; significant thermal, chemical, and light stability; good electron-accepting ability; and excellent electron mobility [96]. Carlotti et al. investigated PDI dimers as nonfullerene electron acceptors [96] for organic solar cells. Two isomers
Perylene isomers
Small-molecule semiconductors with an A-D-A core structure (D is an electron-rich unit and A is an electron-deficient unit) function as an electron donor or electron acceptor in organic photovoltaic cell devices [97].
\nThiophenes are one of the most studied heterocyclic compounds for D-π-A systems due to their relatively low resonance energies, the facile and cheap preparation of chromophores with high stabilities, and good nonlinearities [98]. The hyperpolarizabilities β of derivatives
Thienyl compounds with nonlinear optical properties [
Small-molecule semiconductors based on an A-D-A structure [
Chemical structure of fused-ring electron acceptor
Raposo et al. reported the synthesis of the 2,2′-bithiophene-conjugated dyes
Azo-dyes as NLO chromophores
Porphyrins
Pascal et al. obtained the push-pull dyes
A review of all the compounds deposited by MAPLE, including organics, with their applications was carried out by Caricato et al. [33]. Consequently, here we point out the newest structures reported in the literature with the most notable nonlinear optical properties mentioned.
\nMariano et al. combine spin coating with the MAPLE technique, to realize polymeric multilayered thin films using three polymers
Polymers deposited by MAPLE technique [
Recent works reported new conjugated copolymers with different donor (D)-acceptor (A) motifs (see \nFigure 10\n) for optoelectronic devices [113]. Authors synthesized a series of four DAA copolymers
Donor (D)-acceptor (A) motifs along with magnetic moment and LUMO energy variations [
Structures of DAA copolymers isoindigo-based acceptors and thiophene donors
Other classes of heterocyclic compounds were reported to have nonlinear optical properties, and some of them are presented below. 1,2,3,4,5,6,7,8-Octahydroacridine (OHA)
Structures of compounds
The main method used to obtain thin laser films is matrix-assisted pulsed laser evaporation (MAPLE). Most organic compounds deposited by matrix-assisted pulsed laser evaporation reported so far are polymers, so they are very important for this chapter. There are three important advantages of the MAPLE technique compared to solution cast techniques: (1) the control of thickness; (2) possibility to deposit multilayers; and (3) fabrication of thin films on nonplanar substrates with good surface coverage [110].
\nThe fact that method pulsed laser ablation is not convenient for the deposition of soft materials (almost all polymers, proteins, and other materials are chemically and/or thermally modified or destroyed) has led to the invention of a new improved method to remove these limitations. Two researchers McGill and Chrisey gave birth to matrix-assisted pulsed laser evaporation (MAPLE) technique [33] in order to deposit thin and uniform films of polymers and carbohydrates. The new method is suitable for the deposition of the complex organic materials, such as polymers, bioorganic molecules, and coordination compounds [118]. Fabrication of thin films from such materials is very important for new devices with many applications, including light-emitting diodes (LEDs) [110], field-effect transistors, sensors, photovoltaic devices, and white light sources for indoor and outdoor lighting [13, 110, 114, 115].
\nThree steps are necessary in the MAPLE technique:
dissolving the substance (solute) of interest in a volatile solvent (matrix) to form a diluted homogeneous solution (concentration of the order of 1 wt%);
freezing the solution at the temperature of the liquid nitrogen; and
placing the solution in the vacuum chamber to act as a target for laser-assisted deposition and irradiation of the frozen solution with a pulsed laser beam.
Matrix-assisted pulsed laser evaporation deposition of the desirable molecules is effectuated in a light manner, which implied the passing of the condensed phase to the gas phase. A low kinetic energy is implied in MAPLE process, in advantage to laser ablation with a high level of kinetic energy [110].
\nIn the MAPLE method, the laser pulse energy is absorbed by the solvent and converted into thermal and kinetic energy, enabling the solvent to evaporate and carry in the gas phase the solute molecules onto the deposition substrate where they adhere as a thin film. A very volatile solvent is required to be pumped during the flight from target to substrate, and thus, the deposited film is made up of the dissolved material only.
\nMost of the laser energy is absorbed by the volatile matrix, not the dissolved molecules, which minimize the photochemical decomposition of the precursor solution. In addition, the use of low fluences prevents or reduces thermal damage and decomposition of molecules, so deposition can take place at low fluctuations (0.05–0.5 J/cm2) compared to conventional pulsed laser deposition (PLD) (typically few J/cm2).
\nParticularly important in this technique is the choice of solvent because it has a great impact on the deposition of organic matter, it can interact with the dissolved substance, it can lead to the production of secondary products from it, or it can be present in the deposited films [33]. The role of solvent in MAPLE technique is central; we can say that the solvent (1) must dissolve the solute without interacting with it; (2) has to be volatile; (3) must absorb laser radiation; and (4) must transport the dissolved substance from the target to the substrate.
\nThe experimental setup of MAPLE deposition technique for thin-film fabrication is showed in \nFigure 13\n. The solution concentration must be of 0.1–2.0% (mass) because of the hard laser interaction with the frozen solid. The solvent is desirable to have a freezing point as high as possible. Only the solvent (also named matrix) absorbed the radiation when the laser reaches the target, so the matrix evaporates, the “solid” is ablated, and only the material’s molecules are deposited on the substrate [119].
\nScheme of the MAPLE setup [
Interactions of electromagnetic fields in various media produce new fields changed in frequency, phase, amplitude, or other characteristics of the incident fields resulting nonlinear optical (NLO) properties [89]. The parameter used to evaluate the NLO susceptibility is the total hyperpolarizability (βtot), meaning that a compound with large βtot value is predicted to be a potential NLO active one and vice versa [11]. Literature shows that experimental determination of the βtot value and therefore the NLO susceptibility is an expensive and laborious process, which led to using the quantum mechanical calculations including the DFT methods for the designing of NLO materials. The mean polarizability α, the total static dipole moment μtot, the quadrupole moment Q, and the mean first polarizability βtot may be calculated by using DFT theory. The x, y, z components are defined as follows:
\nTherefore:
\nThe larger hyperpolarizability value of one component over the other components means that the electronic charge delocalization is larger in that direction [11]. There are a lot of factors that contribute to enhance the NLO properties of the compounds, which are cumulated with the prospective βtot calculated values [3].
\nExperimental setup used to investigate the SHG behavior [117] in thin-film samples is represented in \nFigure 14\n. The component parts of the system used for the determination of second harmonic generation (SHG) are a sapphire laser (“Tsunami,” from Spectra-Physics; 780 nm, 60–100 fs pulse duration, 80 MHz repetition rate); an optical system made of a half-wave plate and a Glan-Taylor polarizing prism that allows the variation of beam intensity; a microscope\'s objective is to focus the laser beam onto the thin-film samples and collect the emitted SHG radiation. A dichroic mirror (DM) separated the excitation radiation, and the SHG intensity is measured by a camera spectrograph [117].
\nExperimental setup for determining second harmonic generation.
The experimental second harmonic generation of MAPLE-grown 1,2,3,4,5,6,7,8-octahydroacridine (OHA)
The SHG experimental spectra of MAPLE-grown OHA thin films (adapted with the permission from reference [
The synthesis of the most important classes of the nonlinear optical organic compounds, fullerenes, perylenes, thiophene, azo-dyes dyes, thienes, polymers, and other compounds, along with the techniques employed for the deposition of these compounds, was presented. For the synthesis of the new compounds with nonlinear optical applications, important reactions, like Stille, Suzuki, Knoevenagel, Huisgen, Vilsmeier-Haack-Arnold, click, were employed.
\nAmong the simpler and more sophisticated techniques, the matrix-assisted pulsed laser evaporation (MAPLE) technique that permits making organic films with different morphologies, on different types of substrates, is the main method used to obtain thin laser films, with three basic advantages: the control of thickness; possibility to deposit multilayers; and fabrication of thin films on nonplanar substrates with good surface coverage. Crystallization growth mechanisms in MAPLE-deposited conjugated polymer films that determine specific structure, therefore the carrier transport properties, were discussed in relation with second harmonic generation (SHG) behavior of the thin films.
\nOrganic compounds are cheap, low toxicity, ease of solution processability; therefore, their applications as NLO materials are growing.
\nThe author has no conflict of interest to declare.
This is a brief overview of the main steps involved in publishing with IntechOpen Compacts, Monographs and Edited Books. Once you submit your proposal you will be appointed a Author Service Manager who will be your single point of contact and lead you through all the described steps below.
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