\r\n\tEngineering Geology studies can be conducted during different stages of the project, as it can be conducted during the planning process, or the environmental impact analysis process, or the structural design process, or during construction operations in public and private projects, in addition to the stages of economic engineering, and the type of studies after completing construction of the facility. Geological engineering includes the following areas: geological risk assessment, geotechnical engineering, material properties, land slippage and slope risk, erosion, floods, seismic studies, and water displacement.
",isbn:"978-1-83881-894-4",printIsbn:"978-1-83881-864-7",pdfIsbn:"978-1-83881-898-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"2f650c6c80cd6fb768152350964432e8",bookSignature:"Dr. Essa Georges Lwisa and Prof. Hasan Arman",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8157.jpg",keywords:"Rocks, Plate Tectonic, Geo Hazards, Ground Subsidence, Land Slide, Mass Fabric, Ground Mass Description, Engineering Geophysics, Seismic Methods, Grout Treatment, Bentonite Suspension, Water Reservoirs",numberOfDownloads:164,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 29th 2020",dateEndSecondStepPublish:"June 19th 2020",dateEndThirdStepPublish:"August 18th 2020",dateEndFourthStepPublish:"November 6th 2020",dateEndFifthStepPublish:"January 5th 2021",remainingDaysToSecondStep:"10 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Technical assessor in the Emirates National Accreditation System (ENAS), a trainer at H&A Professional Development Advisory, a member of the American Society of Testing and Materials (ASTM), Society of Petroleum Engineers (SPE), and Society of Core Analysis.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"272012",title:"Dr.",name:"Essa",middleName:"Georges",surname:"Lwisa",slug:"essa-lwisa",fullName:"Essa Lwisa",profilePictureURL:"https://mts.intechopen.com/storage/users/272012/images/system/272012.jpg",biography:"Dr. Essa Georges Lwisa is an expert in core analysis, rock properties, formation evaluation, and enhanced oil recovery. He works at the United Arab Emirates University- Chemical and Petroleum Engineering department since 2009 as a core analysis lab engineer. \n•\tTechnical assessor in Emirates National Accreditation System (ENAS).\n•\tAffiliations: \t\no\tAmerican Society of Testing and Materials (ASTM) \no\tInternational Register of Certificated Auditors (IRCA)\no\tSociety of Petroleum Engineers (SPE) \no\tSociety of Core Analysis. \no\tSociety of Petrophysicists and Well Log Analysts (SPWLA)\n•\tReviewer at the Journal of Petroleum Science and Engineering \n•\tEditorial board member: \no\tInternational Journal of Petro Chemistry and Research\no\t Journal of Chemistry and Applied Chemical Engineering\no\tJournal of Petroleum Science and Engineering \n•\tBooks Editor: Engineering Geology \n•\tBook chapters:\no\tIntroduction to Engineering Geology. \no\tEnhanced oil recovery by nitrogen and carbon dioxide injection followed by low salinity water flooding for tight carbonate reservoir\no\tPropellant Stimulation and Hydraulic Fracturing\no\tChemical Enhanced Oil Recovery\n•\tHe has participated in many conferences and published 17 scientific papers in respected journals. \n•\tRecently, Dr. Essa is working on a new research about using polar salts in enhanced oil recovery and water treatment. \n•\tFar from engineering, Essa is a co-founder and a lead player at the United Arab Emirates Music Orchestra.\nAwards\nThe second place at the Abu Dhabi Ports HSE week for the research: “A Novel Risk Management Approach in Enhanced Oil Recovery Industry”; 2019\nUnited Arab Emirates University Chancellor Innovation Award for the research: “Enhanced oil recovery by treated low salinity water flooding”; 2019\nHonored with IAAM Scientist Medal of year 2017 for notable research in the Advanced Material Science and Technology during award ceremony of International Association of Advanced Materials, Stockholm, Sweden, 23rd, August 2017; for the research: “Innovation in oil, A sustainable EOR technique by green water flooding”",institutionString:"United Arab Emirates University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"United Arab Emirates University",institutionURL:null,country:{name:"United Arab Emirates"}}}],coeditorOne:{id:"143532",title:"Prof.",name:"Hasan",middleName:null,surname:"Arman",slug:"hasan-arman",fullName:"Hasan Arman",profilePictureURL:"https://mts.intechopen.com/storage/users/143532/images/system/143532.jpg",biography:"Dr. Hasan Arman is a Professor at Geology Department, College of Science, United Arab Emirates University since August 2008. In 2018 August, he was appointed as head of the Geology Department. He received his undergraduate degree from Hacettepe University, Turkey in 1984 and his Ph.D. degree from the University of Arizona, USA in 1992. From 1992 to 1993, he was a Postdoc at the University of Nevada, Reno, USA. Between 1993 and 2008, he was a faculty member at Sakarya University, Civil Engineering Department, Turkey as Assistant and Associate Professor. He became a Professor at the same university in 2006. Dr. Arman has been teaching several different courses in undergraduate and graduate levels related to geology, environment, engineering, and energy. His research interests include soil and rock mechanics, engineering and environmental geology, environmental degradation, water resources, global warming, climate change, renewable and sustainable energy sources. Dr. Arman's publications have appeared in different peer-reviewed journals and he is an editorial board member in several international journals, also acting as a scientific reviewer in many others.",institutionString:"United Arab Emirates University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"United Arab Emirates University",institutionURL:null,country:{name:"United Arab Emirates"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:[{id:"75858",title:"Time-Dependent Behavior of Rock Materials",slug:"time-dependent-behavior-of-rock-materials",totalDownloads:32,totalCrossrefCites:0,authors:[null]},{id:"74968",title:"Introductory Chapter: Engineering Geology",slug:"introductory-chapter-engineering-geology",totalDownloads:54,totalCrossrefCites:0,authors:[{id:"272012",title:"Dr.",name:"Essa",surname:"Lwisa",slug:"essa-lwisa",fullName:"Essa Lwisa"}]},{id:"73111",title:"Neotectonics and Stressed State Patterns of the Sakhalin Island",slug:"neotectonics-and-stressed-state-patterns-of-the-sakhalin-island",totalDownloads:79,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"184402",firstName:"Romina",lastName:"Rovan",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/184402/images/4747_n.jpg",email:"romina.r@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, copyediting 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:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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1. Introduction
\n
Systemic lupus erythematosus represents the prototype of autoimmune diseases and is characterized by an unparalleled variety of clinical and laboratory manifestations. From a pathogenetic perspective, a breakdown of immune tolerance will lead to the proliferation and functional differentiation of certain effector cells of the innate and adaptive immunity, such as neutrophils, dendritic cells (DCs), macrophages, and auto‐reactive lymphocytes [1, 2]. The net result will be the production of pro‐inflammatory cytokines and autoantibodies, formation of immune‐complexes and, eventually, tissue damage driven by the deposition of these complexes onto certain tissues and the activation of the complement cascade; other mechanisms have also been described, such as autoantibody‐ and cell‐mediated toxicity. Tissue damage will, in turn, provide the substrate for neo‐epitope formation or the revealing of cryptic epitopes; this will further amplify the autoimmune response. Given the clinical diversity of SLE, several studies investigating the molecular mechanisms of the disease have yielded contradictory findings regarding multiple cellular subpopulations or soluble mediators. These findings seem to be influenced by disease duration, global disease activity, therapeutic variables, and other confounders [2]. Among them, an impairment of the mechanisms of the peripheral immune tolerance, mainly represented by the T regulatory cells (Tregs), has been universally documented in SLE and considered to be a crucial factor in disease pathogenesis.
\n
1.1. T regulatory cells
\n
Tregs represent a subpopulation of the CD4+ T lymphocytes which were first described in the 1970s [3] as suppressor cells since their primary function was the suppression of the immune response [4]. At that time, the term ‘infectious tolerance’ was introduced to describe the acquisition of suppressive capacity of non‐suppressor cells from Tregs with an, as yet, unknown mechanism [5]. The study of this cellular subpopulation was initially abandoned due to technical difficulties with regard to the isolation and analysis of these cells because of the lack of specific surface markers [6, 7].
\n
Research interest in suppressor T cells re‐emerged in 1995, when Sakaguchi et al. described the intense expression of the α chain of the IL‐2 receptor (IL‐2Rα, CD25) on their surface [8]. These cells were then called regulatory T cells since their function was the multifaceted regulation of the immune response and the maintenance of immune homeostasis [9]. During the next few years, several investigators showed that these cells are characterized by a unique functional phenotype, which is marked, not only by the over‐expression of the CD25, but also from decreased responsiveness after polyclonal stimulation of their T cell receptor (TCR) [10, 11]. These studies suggested that their regulatory/suppressive capacity against the effector T cells was irrespective of the antigen that generated the initial activation of the effector cells (non‐antigen specific and, thus, non‐MHC restricted).
\n
The demonstration of the high surface expression of the CD25 molecule led to the characterization and distinction of Tregs from other subsets of T lymphocytes, as well as to the discovery of their thymic origin and initial functional differentiation [12]. However, it was later shown that CD25 is not exclusively expressed in Tregs. Other recently activated T lymphocytes and all T cells with regulatory function in vitro were also expressing this molecule [13]. As might be expected, Tregs do express the highest levels of CD25 (CD25high) as compared to the conventional CD4+ T cells, in which its expression is transient and of low intensity. Based on flow cytometric analysis, it has been shown that, among CD4+CD25+ cells, only those at the upper 2% of CD25 expression possess suppressive capacity [14].
\n
In 2001, the gene FOΧP3 (Forkhead Box P3) was discovered in mice; its mutations were leading to the spontaneous development of autoimmune phenomena [15]. Mutations of the human FOXP3 have been associated with two distinct systemic autoimmune syndromes, namely the IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X‐linked syndrome) and XLAAD (X‐linked, autoimmunity, allergy, dysregulation) [16–18]. In 2003, it was proven that FOΧP3 is the master regulator for the functional differentiation of Tregs and is required for their proliferation [19]. It is found in the Χ chromosome (Xq11.23‐Xq13.3) and consists of 11 exons that code a 48‐kDa protein with 431 amino acids [18]. FOXP3 is mainly expressed in the T lymphocytes (mainly those that bear the αβTCR), whereas it is hardly detectable in B cells, γδ T cells, NK, macrophages, and dendritic cells. It is considered the lineage‐specification factor of the natural T regulatory cells (nTregs).
\n
The respective transcription factor FOXP3 is highly expressed in the CD4+CD25high T cells, while its early activation in the naive T cells drives their differentiation toward a regulatory phenotype. This is particularly detected under inflammatory conditions where CD4+CD25‐ T cells overexpress FOXP3, which in turn leads to the increased surface expression of other molecules, such as CTLA‐4 (cytotoxic T lymphocyte‐associated antigen 4, CD152) and GITR (glucocorticoid‐induced TNF receptor‐a family‐related protein) [20, 21]. These cells now possess suppressive capacity; they secrete less IL‐2 and proliferate slowly.
\n
Further research revealed that, like CD25, the expression of FOXP3 is not confined to naturally occurring Tregs; actually, it could be induced in recently activated cells (in low intensity) and CD4+ T cells that acquire suppressive properties afterward [22]. However, based on its critical importance, all cells bearing the FOXP3 key regulator are considered to be regulatory in function. FOXP3+ Tregs are divided in natural and inducible cells, according to their origin (thymus and/or periphery, respectively). The most well‐studied subgroups of the inducible Tregs (iTregs) are the Tr1, Th3, and CD8+ Tregs (Figure 1).
\n
Figure 1.
Natural (thymus derived) and inducible (peripheral) Tregs.
\n
\n
1.2. Natural Tregs (nTregs)
\n
Thymic‐derived Tregs or natural Tregs are characterized by the CD4+CD25highFOXP3+ phenotype and range between 1 and 3% of the peripheral CD4+ T lymphocytes [13, 23]. They are considered to maintain an anergic state (based on the findings of decreased responsiveness to antigen stimulation and limited proliferation capacity), nTregs have remarkable proliferative potential, both in vitro and in vivo, upon antigen stimulation in the presence of dendritic cells [24]. Reciprocally, Tregs are able to induce tolerogenic DCs, further complicating their interactions with these cells [7, 12].
\n
nTregs express the same αβTCR as the conventional T lymphocytes but they comprise a distinct clone [25]. They derive from pluripotent stem cells and differentiate in the thymic cortex through a positive selection process after the linkage of their TCR with self‐antigens with intermediate affinity [26, 27]. These antigens are presented through MHC II molecules from the thymic cortical cells [28]. Co‐stimulation via the CD28 molecule induces the FOXP3 promoter either directly or through other genes that increase its activation [29]. It seems that the selection of these CD25+ cells occurs according to a predefined ratio to the respective CD25− cells, which have been generated earlier. They are long‐lived cells capable of producing anti‐apoptotic molecules that protect them from the process of negative selection [26, 27].
\n
Upon migration to the periphery, nTregs maintain their regulatory phenotype and suppressive capacity, which are mediated through cell‐to‐cell contact. This mechanism involves certain surface molecules, and it is independent of secreted cytokines [13, 26]. Survival in the periphery is facilitated by CD28 and its respective ligands (CD80, CD86), transforming growth factor β (TGF‐β) and IL‐2 [12].
\n
Several surface molecules have been considered to allow the laboratory isolation from other cellular subpopulations and are crucial for their function. The most important such molecules are the CD4, CD25high, CD127low, CD45RO and CD45RBlow, providing a phenotype of activated memory cells [30].
\n
Moreover, nTregs express other activation markers, such as CD28, CTLA‐4, GITR and chemokine receptors, which are implicated in their migration and trafficking [30, 31]. They also express several Toll‐like receptors (TLRs), TGF‐β, neuropilin‐1, perforin and granzymes, L‐selectin (CD62L), LAG‐3 (lymphocyte activation gene‐3, CD223) and the folate receptor FR4 [32–35]. Multiple adhesion molecules are also abundantly expressed on their surface, such as CD11a, CD44, CD54, and CD103 [36]. All the aforementioned markers have been described in other cell types, which are not exclusively expressed in nTregs and cannot be used as differentiation markers.
\n
Other markers that are thought to be highly specific for nTregs were discovered from the Ikaros gene family; the respective transcription factor is called Helios and is preferentially expressed in nTregs as compared to other CD4+ T cells [37].
\n
Recently, it has been demonstrated that certain epigenetic mechanisms are implicated in the regulation and maintenance of FOXP3 expression [38]. In this regard, the methylation state of the Treg‐specific demethylated region (TSDR, a conserved non‐coding sequence in the CNS2 region of the FOXP3 gene) plays a crucial role. Current isolation techniques require this method since only CD4+CD25+FOXP3+ T cells with demethylated TSDR were capable of strongly and permanently expressing FOXP3 and suppressing effector cells [39]. TSDR is incompletely hypomethylated in Tregs that are induced in the periphery and completely methylated in all other CD4+CD25+ T cells [38]. Helios+FOXP3+ Tregs have increased suppressive potential and are fully demethylated at the TSDR region [37].
\n
\n
1.3. Inducible or adaptive Tregs (iTregs)
\n
These Tregs subgroups are not derived from the thymus but they are induced from naive CD4+ T cells in the periphery in response to the occasional micro‐environmental conditions, Figure 1 [40]. Inducible Tregs regulate the immune response against self and non‐self antigens and are implicated in the pathophysiology of infections, neoplasias and organ transplantation. Their mechanism of action is usually dependent on the secreted cytokines and not on direct cellular contact. Their characterization is based on the aforementioned surface markers (CD25, CD127, CTLA‐4, GITR, etc.), the intensity of intracellular FOXP3 expression as well as their suppressive capacity [13]. As mentioned above, their TSDR is incompletely hypomethylated; thus, FOXP3 expression is transient and unstable. The most important subgroups include the Tr1 and Th3 lymphocytes, the CD4+CD25+ Tregs that are induced from the CD4+CD25− activated T cells, CD103+ Tregs, CD8+ Tregs and the double negative Tregs (CD4−CD8−DN).
\n
Tr1 cells are antigen‐specific CD4+ T regulatory lymphocytes that are induced in the presence of IL‐10 [41]. They derive from CD4+CD25− naive T lymphocytes after antigenic stimulation with certain costimulatory molecules, such as CD3 and CD46 [42, 43]. Apart from the epigenetic differences, they are phenotypically indistinguishable from natural Tregs, but they secrete large amounts of IL‐10. The intensity of the surface expression of CD25 and intracellular FOXP3 is lower than that of nTregs; however, their suppressive capacity is as intense [44]. Their regulatory function is mediated mainly through IL‐10 and, secondarily, through TGF‐β. They play a major role in the pathophysiology of certain infections and the regulation of allergic reactions [45].
\n
Th3 lymphocytes are CD4+ Tregs that were called helper T cells (T helper 3), although their function is primarily suppressive [46]. Their cardinal characteristic is the secretion of large amounts of TGF‐β [47]. The ex vivo expansion of the Th3 cells was one of the first reports of clonal expansion of Tregs using an orally administered antigen in mice [48]. Th3 cells are generated and activated through an antigen‐specific process but their suppressive function is not specific and mediated through TGF‐β. Even in the absence of inflammation, TGF‐β secretion induces the expression of FOXP3 in the activated T cells and maintains Tregs’ survival in the periphery [49].
\n
Other types of Tregs include the CD4+CD25+ Tregs deriving from CD4+CD25− T lymphocytes under specific conditions, the CD103+ Tregs (expressing integrin alpha‐E beta‐7), the CD8+CD28− Tregs and the CD4−CD8− double negative Tregs [13]. All these subpopulations express FOXP3 upon activation and are able to suppress immune responses in a non‐antigen specific fashion.
\n
Further research using certain surface markers revealed the existence of novel subpopulations of iTregs, including the CD4+CD25−FOXP3+ T cells, the CD4+CD45RA+FOXP3+ Tregs, the CD4+CD161+ Tregs, and the CD4+CXCR5+FOXP3+ Tregs [50–52]. Although the CD25−FOXP3+ T cells could suppress effector cells in vitro, it is still uncertain if they represent dysfunctional Tregs or, simply, activated T cells. The CD161+ Tregs represent an excellent paradigm of T cell plasticity, as they are capable of producing pro‐inflammatory cytokines such as IL‐2, IFN‐γ, and IL‐17, behaving like Th1 or Th17 cells under proper cytokine microenvironment [53]. In spite of their cytokine‐producing properties, these cells also retain their regulatory functions and have the already mentioned demethylated TSDR in the FOXP3 locus, like the nTregs. Finally, the CXCR5+ Tregs are follicular T cells, which are able to gain access into the germinal centres (through the CXCR5) and directly suppress the B cells that undergo hypermutation and isotype switch at those sites. These cells are decreased in active and new onset SLE, seemingly allowing for the activation of B cells [54].
\n
\n
\n
2. Mechanisms of action
\n
The mechanisms of action of Tregs have been studied mostly in in vitro systems. Thus, it is not clear how accurately these studies may reproduce Treg activity in vivo. Tregs delete auto‐reactive T cells and induce tolerance and dampen inflammation, while their cellular targets include CD4+CD25− T cells, CD8+ T cells, B cells, monocytes, DCs, and NK cells [55]. These cells appear to inhibit the target cells via IL‐2 deprivation, cell‐to‐cell contact and cytolysis, secretion of inhibitory cytokines, metabolic disruption and modulation of DC maturation and function [56–60], Figure 2.
\n
Figure 2.
Treg mechanisms of action.
\n
IL‐2 is not required for the thymic development of nTregs; however, in the periphery, it acts as a growth factor, essential for their survival and functional integrity. Tregs have more requirements in IL‐2 than conventional T cells. IL‐2 drives the production of IL‐10, CTLA‐4, TGF‐β, and the activation of FOXP3 [61]. Simultaneously, CD25 expression is induced, further amplifying the affinity of Tregs for IL‐2. In co‐cultures of Tregs and T effector cells, addition of exogenous IL‐2 led to active proliferation and activation of Tregs [62]. In addition, Tregs inhibit the function of other T helper cells or cytotoxic cells by deprivation of other cytokines that share the common γ chain, such as IL‐4 and IL‐7; this leads to apoptosis of the effector cells [63]. Moreover, the prioritized usage of IL‐2 may modify the function of Tregs by the increased IL‐10 production [64].
\n
The suppressive function of nTregs is mediated through direct cell‐to‐cell contact and is not dependent on the presence of inhibitory cytokines like IL‐10 and TGF‐β [13, 56, 57]. Surface molecules that are involved in this process include CTLA‐4 [65, 66], membrane‐bound TGF‐β [67, 68], LAG‐3 (lymphocyte activation gene‐3, CD223) [69], GITR (glucocorticoid‐induced TNFR‐a family‐related protein) [70, 71], PD‐1 (programmed death‐1, CD279) [72] and perforin and granzymes, which lead to cytolysis of the target cell [73].
\n
Granzyme B, in particular, has been implicated as an effector mechanism in Treg‐mediated suppression, since its up‐regulation was associated with the killing of target cells in a granzyme B‐dependent, perforin‐independent manner [73]. Granzyme B‐deficient Tregs display reduced suppressive activity [74]. Other studies proved that the activated Tregs could lyse CD4+, CD8+ T cells and B cells through granzyme A and perforin [56–58].
\n
The intracellular signal transduction pathways have not been elucidated yet; however, it has been demonstrated that CTLA‐4 induces the expression of ICER (inducible cAMP early repressor) and, subsequently, inhibition of IL‐2 signals to target cells [75]. Membrane‐bound TGF‐β activates the Smad proteins and inhibits genes that are required for the functional differentiation of the effector cells [68].
\n
Suppression by inhibitory cytokines is an important mode of action utilized by iTregs. The most important cytokines with regulatory/suppressive capacity are TGF‐β [76, 77], primarily produced by the Th3 cells and IL‐10 [78, 79] by the Tr1 cells. IL‐10 activates the JAK/STAT intracellular pathway and the MAP kinases [78]. The net result is the inhibition of genes that control the synthesis and secretion of pro‐inflammatory cytokines. Another regulatory cytokine that is produced from Tregs is the IL‐35 [80]. This cytokine is assembled by two chains, IL‐12α and EBI3, and is required for the suppressive capacity of Tregs in vivo, since inability to express these chains results in uncontrolled expansion of T effector cells in systemic autoimmune diseases [81]. Other anti‐inflammatory cytokines that have been implicated in the mechanisms of action of Tregs include IL‐27 and IL‐37 [82]; more recently, it has been shown that fibrinogen‐like protein 2 is also secreted by Tregs and mediates immune suppression [38].
\n
Metabolic disruption of the target cells is another mechanism utilized by Tregs to regulate immune responses. nTregs possess large amounts of cAMP (cyclic adenosine monophosphate), which exerts potent inhibitory action against the proliferation and differentiation of the effector T cells and the expression of genes that control the synthesis of IL‐2 and IFN‐γ [83]. Gene expression is inhibited through the suppression of the protein kinase A of NF‐κB or through activation of ICER. Tregs induce intracellular cAMP within the effector T cells with cell‐to‐cell cAMP transfer through the gap junctions. Neutralization of cAMP or blockage of the gap junctions led to significant weakening of Tregs’ suppressive function [83]. In addition, co‐expression of CD39 and CD73 on the surface of Tregs induces the secretion of large amounts of adenosine that suppresses T effectors [84]. The linkage of adenosine to its receptor A2A on Tregs induces TGF‐β secretion and inhibits IL‐6, generating appropriate circumstances for new Treg development [85, 86].
\n
Tregs seem capable of limiting the capacity of DCs to stimulate effector cells. In this context, their interaction with the dendritic cells and the inhibition of their maturation is of particular importance [87, 88]. Tregs induce the production of regulatory molecules from DC, such as indoleamine‐2,3‐dioxygenase (IDO), IL‐10 and TGF‐β, through interactions between CTLA‐4 and CD80/CD86 [89, 90]. The same investigators showed that Tregs reduce the expression of the costimulatory molecules CD80 and CD86 on DCs. Moreover, the catabolism of tryptophan and arginine through IDO leads to Tregs activation and induction of regulatory phenotype in naive T cells and T effector cell apoptosis [91].
\n
\n
3. Homeostasis of Tregs
\n
3.1. Functional differentiation of Tregs in the periphery
\n
Certain transcriptional factors are implicated in the process of maturation and functional specialization of the CD4+ T cells. The most important factors are T‐bet for Th1 cells, GATA‐3 for Th2 cells, RORγt for Th17 cells, Bcl6 for follicular T helper cells (Tfh), and FOXP3 for Tregs [92]. For Tregs, in particular, their functional integrity depends on the dynamic interaction of different transcriptional regulators, which is shaped by the occasional micro‐environmental circumstances. These regulators include members of the nuclear factor of activated T (NFAT) cell family, the NF‐κB, the activator protein‐1 (AP‐1) and STAT5 [93]. Furthermore, functional specialization of Tregs has been documented; for instance, these cells are using Th‐related transcription factors during Th1, Th2 or Th17 immune responses. In this context, T‐bet+ Tregs migrate into the inflamed tissue in cases of Th‐1‐mediated inflammation and suppress the Th1 effectors [94]. Accordingly, the expression of IRF4 in Tregs is required for the suppression of Th2 responses, while the deletion of STAT3 is linked to uncontrolled Th17 responses [95]. The precise mechanisms by which these transcription factors control Tregs differentiation are unknown. However, the experimental inhibition of these factors was associated with impaired expression of certain surface chemokine receptors, such as CXCR3 (for Th1), CCR8 (for Th2) and CCR6 (for Th17 immune response) [96]. Moreover, deletion of the respective genes of these chemokine receptors led to decreased Tregs activity and renders Tregs incapable of migrating into the site of Th‐1‐mediated inflammation [97]. Based on these data, it seems possible that phenotypically and functionally distinct Tregs may be active against different effector arms of the immune response.
\n
\n
3.2. Clonal expansion of Tregs
\n
The question if nTregs numbers remain stable through life or if their pool is constantly enriched with new cells was based on the findings of stable numbers of CD4+CD25+ T cells in mice from the age of 2 weeks up to 1 year. In thymectomized mice with no T cells, adoptive transfer of Tregs was followed by an expansion of these cells to the extent of the nonthymectomized animals of similar age [98].
\n
In humans, it has demonstrated that nTregs, after they leave thymus, are constantly proliferating after cytokine (TGF‐β, IL‐2, IL‐10) stimulation and in the presence of tissue antigens. DCs can also induce Tregs in the presence of IL‐2 [99].
\n
\n
3.3. Tregs recruitment at the site of inflammation
\n
Natural Tregs are generated in the thymus and migrate into the periphery where their population will be enriched with inducible Tregs. The precise site of their clonal expansion (peripheral lymphoid organs or the site of inflammation) is not known. Apart from the thymus, Tregs have been found in the bone marrow, lymph nodes, intestine, liver, synovial fluid, skin, vessel wall, etc.
\n
More than 25% of the total CD4+ T cells residing in the bone marrow have regulatory phenotype and properties [100]. In this regard, the bone marrow acts as a reservoir for Tregs that is able to release them upon inflammation. Bone marrow Tregs express CXCR4 (the CXCL12 receptor), which is crucial for their migration and their return to the bone marrow after suppression [100]. Integrins are also implicated in their migration; intense expression of CD62L and CCR7 along with poor expression of CD103 (integrin αEβ7) allows for penetration into the lymph nodes. On the contrary, strong expression of CD103 is required for migrating into the inflamed tissues [94].
\n
Integrins are crucial for the homeostasis of iTregs; integrin α4β7 tissue expression (usually in the mucosal vessels) attracts Tr1 cells, whereas the α4β1 (on the endothelium of inflamed tissues) engages the Th3 cells [101]. Furthermore, it has been showed that when Tregs migrate to the T‐zone of lymph nodes, they utilize the CCL19/CCR7 ligation, while when they migrate to the B‐zone, they utilize the CXCL13/CXCR9 interaction [102].
\n
\n
3.4. How effector cells escape Treg‐mediated suppression
\n
Tregs are also regulated by the immune system in a fashion that allows the control of their action either through negative feedback or through the development of escape mechanisms for the effector cells [103, 104]. The negative feedback is maintained through various mechanisms, such as TLR activation on DCs [104] and the direct regulation by cytokines like IL‐21, IL‐7, IL‐15, TNF‐α and IL‐6. In particular, IL‐21 increases the resistance of the effector T cells against Tregs in experimental diabetes [105]. DC‐derived IL‐6 renders CD4+ T cells resistant to Tregs suppression [106]. Additional mechanisms include the amplification of co‐stimulatory molecule expression on the surface of T effectors and DCs, such as the CD80 and CD86 molecules, CD28, NFATc1, c2, c3 and TRAF6, which protect the integrity of intracellular signal transduction [10].
\n
\n
\n
4. Tregs in systemic lupus erythematosus
\n
4.1. A matter of numbers and function?
\n
SLE is characterized by the breakdown of immune tolerance against self‐antigens. The net result is the induction and proliferation of auto‐reactive lymphocytes, the production pro‐inflammatory soluble mediators, the formation of pathogenic autoantibodies and immuno‐complexes that cause tissue damage [1]. Tregs are thought to play a critical role before and during this pathophysiological process. Most studies in lupus‐prone mice and humans demonstrated quantitative and/or qualitative defects of these cells [14, 107–113]. Other reports present insignificant variations in Tregs numbers between lupus patients and healthy controls [50, 114, 115] or even higher numbers [116], probably as a result of significant differences in protocol designs. With regard to the functional capacity of these cells, studies are again controversial with reportedly defective [110, 111] or normal [14, 114, 115] function. In the latter case, T effectors showed decreased sensitivity to the suppressive function of Tregs [117].
\n
In a seminal paper, Miyara et al. described the characteristics of Tregs kinetics and the strongly inverse the correlation with SLE disease activity [14]. They found that Tregs (CD4+CD25bright) were globally depleted from the periphery of active lupus patients. They provided evidence that these cells do not accumulate in involved organs (by kidney biopsies) or lymphoid tissue (by lymph node biopsies). In fact, Tregs were found to be more sensitive to Fas‐mediated apoptosis although they were still functionally intact. Moreover, they were the first to show that Tregs are increased after the successful treatment of disease flare. FOXP3 expression was found in 85.6% of the CD4+CD25high compartment.
\n
The issue of functional integrity of Tregs within the lupus inflammatory microenvironment was questioned later by the findings of Valencia et al. [110] and Lyssouk et al. [111]. These groups reported that CD4+CD25high Tregs were defective in terms of both proliferation and suppression against CD4+ and CD8+ T effector cells. They also showed that FOXP3 expression was decreased in Tregs from active lupus patients, generating doubt about the appropriate immunophenotype that should be used for cell isolation and study. These findings were confirmed later by using the mean fluorescence intensity (MFI) in newly diagnosed, untreated lupus patients [118].
\n
At the same time, Barath et al. were the first to utilize the CD4+CD25highFOXP3+ immunophenotype for Tregs characterization [112]. They found these cells in significantly lower levels as compared to healthy controls, whereas the inducible CD4+IL‐10+ Tregs did not display any significant quantitative differences. At the tissue level, CD4+CD25+FOXP3+ Tregs were found in decreased numbers in the skin lesions of active cutaneous lupus as compared to other inflammatory skin diseases, such as psoriasis, atopic dermatitis, and lichen planus [119].
\n
In 2008, a new subpopulation was described, namely the CD4+CD25−FOXP3+ T cells [50]. These cells were found in increased numbers in newly diagnosed SLE patients and were associated with other indices of disease activity, such as low complement C3 and C4 [51]. Their function was primarily regulatory as they were able to suppress the effector T cell proliferation but not IFN‐γ production [51]. Other investigators opposed these findings by performing the measurements in untreated lupus patients, reaching the conclusion that not all FOXP3 expressing T cells are Tregs [120].
\n
The association of Tregs with SLE disease activity was tested in several studies with a small number of patients. Most of them reported a strongly inverse correlation [14, 113], whereas others found insignificant correlations [109, 112].
\n
In the first large‐scale (n = 100 patients), longitudinal (mean follow up of 5 years) study of CD4+CD25highFOXP3+ Tregs as a biomarker of disease activity, we found that these cells are gradually decreased from healthy controls to patients with inactive, mild, or severe disease [113]. Moreover, we observed inverse alterations in cases of changing disease activity; these cells were reduced during disease flare and increased upon remission, while numbers remained stable during stable disease activity. Their sensitivity and specificity to assess a clinically significant change in global disease activity was 88 and 74%, respectively. Their positive and negative predictive values were 85 and 79%, respectively. In the same study, we reported decreased Tregs numbers in active lupus nephritis and active neuropsychiatric involvement, whereas no differences were observed in patients with active antiphospholipid syndrome (APS). The ability of CD4+CD25highFOXP3+ Tregs to predict disease flares was low (positive predictive value 17%).
\n
Concerning the influence of certain therapeutic approaches, we prospectively showed that Tregs’ numerical restoration after treatment is independent of the occasional medication administered [121]. In that study, patients achieved remission after administration of various immunomodulatory agents, including glucocorticoids (oral and intravenous), cyclophosphamide, intravenous immuno globulins, azathioprine and hydroxy chloroquxine. In all cases, a significant increase of CD4+CD25highFOXP3+ Tregs was observed. That restoration was faster with the intravenous regimens as compared to oral therapies. Cyclophosphamide pulse therapy, in particular, led to a significant increase of Tregs after the fourth pulse in patients with active lupus nephritis and/or neuropsychiatric involvement [122]. Of note, an even faster response (shortly after the first infusion) was documented after treatment with intravenous tocilizumab in patients with rheumatoid arthritis [123].
\n
\n
4.2. Novel theories for Tregs in the pro‐inflammatory environment of SLE
\n
As mentioned above, most studies on Tregs have been conducted in vitro; thus, their reliability and accuracy pertaining to the actual function of these cells in vivo are questionable. After the discovery that a fully demethylated TSDR is required for intense and sustained expression of FOXP3, the hallmark of regulatory function, many beliefs have been revised [39]. In this context, Helios+FOXP3+ T cells, with a fully demethylated TSDR, were found in increased numbers in active lupus patients; their function was intact [124]. It is not yet known if Helios represents a unique marker for Tregs; however, the epigenetic change is believed to differentiate between natural and inducible Tregs. Nevertheless, there is disequilibrium between Tregs and effector cells that is more prominent in the pro‐inflammatory environment of SLE.
\n
Several studies have reported on altered ratios between Tregs and T effectors in lupus patients [125]. The most striking feature, among other findings, was that there is plasticity between Tregs and Th17 populations, and the latter may derive from the former under certain circumstances [126]. In this regard, the presence of TGF‐β alone will drive naive CD4+ T cells towards Tregs differentiation, while the simultaneous presence of IL‐6 will lead to Th17 proliferation [127]. Other transitions have also been described between Th1 and Th17 cells, based on the presence of IL‐12 receptors on the surface of Th17 cells; upon activation with IL‐12, these cells are capable of producing IFN‐γ [125, 127]. Of note, it has been documented that some Tregs down‐regulate FOXP3 expression and act as effectors, promoting inflammation through the secretion of IL‐17 and IFN‐α [39]. These cells are called ex Tregs and believed to derive from the Tregs lineage prior to natural Tregs commitment. They acquire pro‐inflammatory characteristics in the periphery, probably in the context of a generalized immune response.
\n
The concept of Tregs/Th17 imbalance, in particular, seems of paramount importance in SLE. It has been demonstrated that disease relapses may occur as a consequence of an impaired Tregs/Th17 ratio, in favour of the latter, in animal models [128]. Those findings were later confirmed in lupus patients, in whom the altered Tregs/Th17 ratio was documented even in clinically quiescent disease; this may represent a hallmark of SLE [129, 130]. In this context, it is believed that the sole targeting of the Th17 arm of the immune response will not render meaningful results; approaches aiming at the restoration of the Tregs/Th17 balance will be more likely to exert beneficial effects [125, 131].
\n
The disturbed balance between T effectors (Th1, Th2, Th17) and Tregs is driven by a relative IL‐2 deficiency in SLE [132]. Treatment with low doses of IL‐2 re‐established the equilibrium between Tregs and T effectors in animal models of the disease; accordingly, IL‐2 neutralization or CD25 depletion accelerated disease onset [39]. Studies in lupus patients showed that FOXP3+Helios+ Tregs were capable of proliferating despite the reduced IL‐2 levels; however, the integrity of their suppressive function has not been confirmed [124]. Apart from IL‐2, other cytokines, such as IL‐6, IL‐21 and IFN‐α may inhibit the Tregs function and/or render T effectors resistant to regulation. All these cytokines are found in abundance in SLE and are positively correlated to disease activity. On the other hand, the main regulatory cytokine, TGF‐β, is lower in active disease, generating hypotheses that the cytokine disequilibrium drives the imbalance of Tregs and T effectors. The exact mechanisms by which these cytokines increase the T effectors’ resistance to Tregs suppression have not been elucidated yet [39].
\n
\n
4.3. Epigenetics and Tregs
\n
Latest studies revealed that certain epigenetic mechanisms, such as methylation, histone modification and miRNAs, play a significant role in Tregs biology [38]. In this regard, the methylation status of the TSDR is of paramount importance for the sustained expression of FOXP3 and, hence, the intensity of Treg suppressive function. Histone modification is another mechanism involved in Tregs functional differentiation. The acetylation of histones H3 and H4 has been shown to reliably differentiate Tregs than FOXP3+ effectors [133]. Modification of the FOXP3 promoter by other genes influenced dramatically the rate of differentiation of iTregs in the periphery [38]. Finally, miRNA‐155 is associated with less Tregs, though functionally intact, in mice, while miRNA‐126 up‐regulates Tregs and enhances their function [134].
\n
Epigenetic regulation of the FOXP3 gene has been reported in lupus patients. In this context, decreased peripheral Tregs were associated with hypermethylation of the promoter of the FOXP3 gene [135]. Genome‐wide studies have shown that virtually all immune cells in SLE, including Tregs, had severe hypomethylation in interferon‐type I‐related genes [38]. Treatment with a histone modification inhibitor the enhanced Tregs number and function in lupus‐prone mice [136]; the same results were reached with an inhibitor of the protein kinase IV [137]. It is believed that these approaches will soon be tested in lupus patients [38].
\n
\n
\n
5. Tregs-based therapeutic approaches in SLE
\n
5.1. Adoptive transfer of ex vivo expanded Tregs
\n
Based on the aforementioned data, Tregs may represent a promising target in SLE therapeutics. Several groups have tried to manipulate this cellular subpopulation in order to restore the defective immune tolerance that is a crucial component of disease pathophysiology [138]. Early experiments in mice models showed that adoptive transfer of ex vivo expanded Tregs was capable of ameliorating the disease [139, 140]. In the first experiment, T cells treated with IL‐2 and TGF‐β lost their ability to induce a graft‐versus‐host disease and prevented other effector T cells from activating B cells [139]. In addition, when transferred to animals with high titers of anti‐dsDNA antibodies, they led to a significant reduction of their titers and doubled survival. In New Zealand black/New Zealand white mice, a well‐studied lupus model, transfer of thymic Tregs (CD4+CD25+CD62Lhigh) decreased the rate of glomerulonephritis, the severity of proteinuria and improved survival [140]. The precise mechanism by which these Tregs suppress the autoimmune response has not been elucidated; however, it was demonstrated that the induction of tolerogenic DCs plays a critical role [141]. These DCs were also able to expand the recipient’s CD4+FOXP3+ Tregs (infectious tolerance).
\n
Studies in humans also showed that in vitro expanded Tregs, both polyclonal [142] and antigen‐specific [143] may display enhanced regulatory activity. These encouraging results led to the implementation of this strategy in phase I and II clinical trials in other autoimmune diseases. Seminal studies in type 1 diabetes (T1D) proved the feasibility of generating purified iTregs for therapeutic purposes [144, 145]. Bluestone et al. demonstrated that Tregs could survive for more than 1 year after infusion in 14 patients with T1D; although there were no significant reactions to infusion, from an efficacy standpoint there was no significant improvement in C‐peptide levels and HbA1c [144]. In another study of 12 children with T1D, adoptive transfer of Tregs led to significant reduction in exogenous insulin needs and improvement in C‐peptide levels. Of note, two children were insulin independent after 12 months [145]. In chronic graft‐versus‐host disease (GVHD), adoptive transfer of Tregs ameliorated symptoms in two out of five patients, while the remaining patients did not show any deterioration after 21 months of follow‐up [146]. In another study, where umbilical cord‐derived Tregs were used in 11 patients, there was a significant reduction in the rate of severe acute GVHD, whereas chronic GVHD at 1 year was 0% in Treg‐treated patients and 14% in patients who received the conventional therapy with immunosuppressives (sirolimus and mycophenolate mofetil) [147]. All the aforementioned studies reported a purity of approximately 90%, demonstrating that this approach is feasible; on the other hand, survival of Tregs in vivo (after infusion) was limited with a dramatic decline after 14 days from infusion. There are several currently ongoing clinical trials based on adoptive Treg transfer mainly in solid organ transplantation [147]. Such therapeutic approaches have not been published yet in lupus patients; one phase I clinical trial aiming to assess Treg efficacy in cutaneous lupus started in 2015 [148].
\n
\n
5.2. Hematopoietic and mesenchymal stem cell transplantation
\n
Hematopoietic and mesenchymal stem cell transplantation (HSCT and MSCT, respectively) aim at immune reconstitution after intensive chemotherapy and have been implemented in cases with refractory autoimmune diseases.
\n
In the context of SLE, HSCT has been shown to induce long‐term remission for approximately 5 years in half patients, whereas relapse was usually mild [149, 150]. On the other hand, MSCT exerts potent immunosuppressive capacity since mesenchymal stem cells do not require MHC (major histocompatibility complex) restriction for their function [151]. The effects of these therapeutic approaches on Tregs numbers and function have a critical role with respect to their efficacy. Zhang et al. showed that CD4+CD25highFOXP3+ Tregs were reconstituted in levels comparable to those of normal individuals after autologous HSCT in 15 SLE patients [152]. In addition, a novel Tregs subset (CD8+LAPhighCD103high) was induced and capable of maintaining remission through TGF‐β mediated suppression. On the contrary, Szodoray et al. did not find any significant differences in Tregs numbers (pre‐ and post‐transplant) in 12 patients with various systemic autoimmune diseases; only three lupus patients were enrolled in that study [153].
\n
Concerning MSCT, a report on nine patients with refractory SLE showed good safety profile after 6 years; unfortunately, Tregs were not assessed in this study [154]. Limited case reports demonstrated a significant increase of peripheral Tregs in three lupus patients; however, clinical remission was not achieved [155, 156]. Of note, mesenchymal stem cells were shown to increase Tregs in 30 active lupus patients, in a dose‐dependent fashion, even after 1 week after transplantation, and this was sustained for 1 and 3 months after transplant [157]. In the same study, Th17 cells were accordingly reduced after 3 months.
\n
\n
5.3. IL‐2‐based approaches
\n
Extensive research on IL‐2 and IL‐2 receptor (IL‐2R) biology has shed light on its critical importance for the maintenance of immune tolerance by influencing Tregs number and function [132]. Administration of low doses of IL‐2 led to remission and decreased glucocorticoid dose in lupus patients [158], while it was shown that Tregs expansion (CD4+CD25highCD127low) and a decrease in T effectors/Tregs ratio were the primary mechanism [159]. The same results were observed in other diseases, such as GVHD and HCV‐related vasculitis [160]. Interestingly, IL‐2/anti‐IL‐2 immunocomplexes were capable of reducing the severity of renal inflammation in NZB/W F1 mice by inducing CD4+CD25+FOXP3+ Tregs. With regard to proteinuria, this approach was superior to the combination of glucocorticoids and mycophenolate mofetil, the current standard of care for LN [161].
\n
\n
5.4. All‐trans retinoic acid (atRA)
\n
This approach has been used in various autoimmune diseases with inconsistent and contradictory results, possibly due to the small sample sizes [162]. Limited data in lupus patients showed that Tregs could be induced by atRA [163]; however, these results were not confirmed [164]. In a more recent study, retinoic acid increased Treg numbers (and decreased Th17 cells) in lupus patients with low levels of vitamin A [165].
\n
\n
5.5. Tolerogenic peptides
\n
The rationale behind the use of tolerogenic peptides in SLE therapeutics is that a dysregulated immune system can be modified by inducing tolerance against a specific antigen. This is a crucial component of this approach since non‐specific tolerance may lead to generalized immune suppression and secondary immunodeficiency. In this context, such different molecules (hCDR1, pCons, P140, etc.) have been administered in lupus prone mice with subsequent expansion of Tregs and suppression of effector cells and pro‐inflammatory cytokines [166, 167]. These encouraging results led to the first peptide‐based randomized controlled trial in SLE with 149 patients [168]. Although the effect on Tregs was not assessed, approximately 62% of the peptide‐treated patients achieved the primary clinical end‐point as compared to 38.6% of the placebo arm (all patients received standard of care therapy).
\n
\n
5.6. Effect of other medications on Tregs
\n
Apart from the aforementioned approaches that implicate Tregs in their mechanism of action, medications commonly used in SLE patients have been demonstrated to increase their numbers and/or restore their function. Several studies have demonstrated a significant Tregs expansion after treatment with glucocorticoids [121, 122, 169–171]. Moreover, intravenous methylprednisolone pulses led to a dramatic and sustained increase in CD4+CD25highFOXP3+ Tregs numbers, regardless of the initial clinical indication [121]; this was noted even from the first few days after the pulses [172]. The mechanism by which these medications lead to Treg proliferation is yet unknown; however, a steroid‐mediated up‐regulation of FOXP3 has been described [171].
\n
Immunosuppressive drugs have also been shown to affect Tregs in active SLE. Cyclophosphamide pulse therapy led to a significant increase in Tregs numbers after the 4th month of administration, which reflected clinical remission [121], although the effect of concomitant glucocorticoid treatment may have a role. Similar results were obtained with azathioprine and hydroxychloroquine [121]. Of note, polyclonal intravenous immunoglobulins (IVIGs) also led to Tregs increase, possibly through up‐regulation of FOX3 and intracellular IL‐10 and TGF‐β [173]. Rituximab was demonstrated to enhance the Tregs numbers and function in lupus patients whereas the increased and sustained FOXP3 mRNA expression was associated with favourable outcome [174]. In general, in vivo expansion of Tregs after treatment might be the result of a change of Th1/Th17 to Th2 balance, which could lead to disease remission and not a direct drug‐specific reaction [121].
\n
Other medications that are increasingly used in lupus patients and may affect Tregs include statins. These drugs display multiple beneficial effects in atherosclerosis through different mechanisms among which immune modulation is critical [175]. Several experiments in animal models showed that statins increase the numbers and suppressive capacity of Tregs as well as their accumulation in the atherosclerotic plaque [176]. Atorvastatin, in particular, exerted similar results in human Tregs [177].
\n
All the pre‐mentioned therapeutic interventions are summarized in Table 1.
\n
Therapy
Mechanism
Approach
Efficacy
Notes
Adoptive transfer of ex vivo expanded Tregs
Increase of Tregs pool
Experimental and clinical trials in other immune‐mediated diseases
Moderate
High purification rates, low Tregs survival
HSCT/MSCT
Immune system reconstitution
Limited clinical trials
Moderate
Inconsistent clinical results
IL‐2
Enhanced survival and function of Tregs
Limited clinical trials
Moderate
IL‐2/anti‐IL‐2 complexes provided favourable results in LN
Retinoids
Induction of Tregs
Limited clinical trials
Inconsistent
Mainly in patients with low vitamin A
Tolerogenic peptides
Induction of Tregs
Experimental studies and one RCT
Moderate
Ongoing phase III clinical trials
Glucocorticoids
Up‐regulation of FOXP3
Limited observational trials
Good
Rapid induction of Tregs
Immunomodulating agents
Induction of Tregs
Limited observational trials
Good
Regardless of the agent used, probably an epiphenomenon to disease remission
Statins
Enhanced numbers and function of Tregs
Experimental and limited observational trials
Good
Accumulation of Tregs in the atherosclerotic plaques
Table 1.
Therapeutic approaches targeting Tregs in SLE.
\n
\n
5.7. Barriers in Tregs‐based therapeutic approaches
\n
Although the above‐mentioned data are encouraging for SLE patients, several challenges still exist. The multiple phenotypes that have been used to characterize Tregs in the different studies have demonstrated that all Tregs are not functionally capable of suppressing autoimmune responses [160]. In the chronic inflammatory environment of SLE, it cannot be predicted which regulatory cells are likely to function more beneficially; furthermore, effector cells are more capable of escaping regulatory mechanisms under these circumstances [106]. Furthermore, tissue distribution of Tregs, after infusion, is unknown, while their survival and maintenance of regulatory capacity have not been precisely defined in the context of SLE. Other considerations include technical aspects, such as the purity and cost‐effectiveness of these approaches.
\n
\n
\n
6. Conclusion
\n
Most well‐designed studies have concluded that Tregs are significantly depleted from the periphery of active lupus SLE patients and this reduction is in accordance with disease activity. Moreover, Tregs follow alterations in disease activity (with inverse changes) quite reliably; numeric increase is not drug specific but characterizes disease remission. Their value as an activity biomarker has been demonstrated and may be helpful in assessing disease status in controversial circumstances. Their potential to be used for therapeutic purposes, either by direct adoptive transfer or by approaches aiming to increase their numbers, is quite promising in the field of SLE.
\n
\n',keywords:"regulatory T cells, systemic lupus erythematosus, SLE immunopathphysiology, Treg therapy",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/54773.pdf",chapterXML:"https://mts.intechopen.com/source/xml/54773.xml",downloadPdfUrl:"/chapter/pdf-download/54773",previewPdfUrl:"/chapter/pdf-preview/54773",totalDownloads:1196,totalViews:594,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,dateSubmitted:"October 17th 2016",dateReviewed:"March 13th 2017",datePrePublished:null,datePublished:"May 31st 2017",dateFinished:"May 11th 2017",readingETA:"0",abstract:"Systemic lupus erythematosus (SLE) is one of the most diverse autoimmune diseases, regarding clinical manifestations and therapeutic management. Visceral involvement is often and is generally associated with increased mortality and/or permanent disability. Thus, a reliable assessment of disease activity is required in order to follow‐up disease activity and apply appropriate therapy. Several serological indexes have been studied due to their competence in assessing disease activity in SLE. Apart from conventional and currently assessed serological indexes, regulatory T cells (Tregs), a CD4+ cellular population of the acquired immune compartment with homeostatic phenotype, are currently under intense investigation in SLE. In this chapter, Tregs ontogenesis and subpopulations are discussed focusing on their implications in immunopathophysiology of SLE. The authors present data indicating that this CD4+ population is highly associated with disease activity and response to treatment, concluding that Tregs are a promising biomarker in SLE. Future prospective includes Tregs implication in SLE therapeutic interventions.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/54773",risUrl:"/chapter/ris/54773",book:{slug:"lupus"},signatures:"Konstantinos Tselios, Alexandros Sarantopoulos, Ioannis\nGkougkourelas and Panagiota Boura",authors:[{id:"51005",title:"Prof.",name:"Panagiota",middleName:null,surname:"Boura",fullName:"Panagiota Boura",slug:"panagiota-boura",email:"boura@med.auth.gr",position:null,institution:{name:"Saint Michael's College",institutionURL:null,country:{name:"United States of America"}}},{id:"90664",title:"Dr.",name:"Alexandros",middleName:null,surname:"Sarantopoulos",fullName:"Alexandros Sarantopoulos",slug:"alexandros-sarantopoulos",email:"alexsar@med.auth.gr",position:null,institution:{name:"Aristotle University of Thessaloniki",institutionURL:null,country:{name:"Greece"}}},{id:"198461",title:"Dr.",name:"Konstantinos",middleName:null,surname:"Tselios",fullName:"Konstantinos Tselios",slug:"konstantinos-tselios",email:"tselioskostas2@gmail.com",position:null,institution:null},{id:"203002",title:"Dr.",name:"Ioannis",middleName:null,surname:"Gkougkourellas",fullName:"Ioannis Gkougkourellas",slug:"ioannis-gkougkourellas",email:"igkougkourelas@gmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1. T regulatory cells",level:"2"},{id:"sec_2_2",title:"1.2. Natural Tregs (nTregs)",level:"2"},{id:"sec_3_2",title:"1.3. Inducible or adaptive Tregs (iTregs)",level:"2"},{id:"sec_5",title:"2. Mechanisms of action",level:"1"},{id:"sec_6",title:"3. Homeostasis of Tregs",level:"1"},{id:"sec_6_2",title:"3.1. Functional differentiation of Tregs in the periphery",level:"2"},{id:"sec_7_2",title:"3.2. Clonal expansion of Tregs",level:"2"},{id:"sec_8_2",title:"3.3. Tregs recruitment at the site of inflammation",level:"2"},{id:"sec_9_2",title:"3.4. How effector cells escape Treg‐mediated suppression",level:"2"},{id:"sec_11",title:"4. Tregs in systemic lupus erythematosus",level:"1"},{id:"sec_11_2",title:"4.1. A matter of numbers and function?",level:"2"},{id:"sec_12_2",title:"4.2. Novel theories for Tregs in the pro‐inflammatory environment of SLE",level:"2"},{id:"sec_13_2",title:"4.3. Epigenetics and Tregs",level:"2"},{id:"sec_15",title:"5. Tregs-based therapeutic approaches in SLE",level:"1"},{id:"sec_15_2",title:"5.1. Adoptive transfer of ex vivo expanded Tregs",level:"2"},{id:"sec_16_2",title:"5.2. Hematopoietic and mesenchymal stem cell transplantation",level:"2"},{id:"sec_17_2",title:"5.3. IL‐2‐based approaches",level:"2"},{id:"sec_18_2",title:"5.4. All‐trans retinoic acid (atRA)",level:"2"},{id:"sec_19_2",title:"5.5. Tolerogenic peptides",level:"2"},{id:"sec_20_2",title:"5.6. Effect of other medications on Tregs",level:"2"},{id:"sec_21_2",title:"5.7. Barriers in Tregs‐based therapeutic approaches",level:"2"},{id:"sec_23",title:"6. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Tsokos GC. Systemic lupus erythematosus. The New England Journal Medicine. 2011;365:2110–2121. DOI: 10.1056/NEJMra1100359'},{id:"B2",body:'Scheinecker C, Bonelli M, Smolen JS. Pathogenetic aspects of systemic lupus erythematosus with an emphasis on regulatory T cells. Journal of Autoimmunity. 2010;35:269–275. 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Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, University of Toronto Lupus Clinic, Toronto, ON, Canada
Clinical Immunology Unit, 2nd Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
Clinical Immunology Unit, 2nd Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
Clinical Immunology Unit, 2nd Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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1. Introduction
The sun is a nuclear fusion reactor that contains gravity. It produces unimaginable quantities of energy. Solar energy is a very perfect source of power. It can be captured passively by solar panels or other collectors. When the collectors have been produced, there will be no carbon emissions or waste products [1]. There are no moving parts to hurt wildlife. There is no dependence on foreign entities. The energy is produced and delivered for free by the sun [2]. The uranium division begins progressing with the absorption of the smooth-moving neutron from the non-strong U-235 isotope. The obtained U-236 is split into Ba-139 and Kr-94 as well as three unfastened neutrons. The mass deficiency of approximately 20% of atomic mass units has also been converted into 210 MeV energy units [3, 4]. There were 447 nuclear fission power stations in service globally, 55 in construction and 111 in the design processes [5].
In the United States in 2018, 19.3% of the electricity supply was produced by 97 nuclear power plants. This amounts from zero percent to the other countries, for example, in New Zealand, and 71.7% in the European Union; the total global energy demand in 2018 was 10.3% [6].
With 11 new reactors under development, China has the most quickly expanding nuclear power program. Pakistan aims to construct three to four nuclear power stations by 2030 [7].
Several countries had nuclear installations in the past, but they still do not have nuclear plants in operation. Italy closed all the nuclear power stations between them by 1990, and, as a consequence of the referendums established by the Italians in 1987, nuclear power already has stopped [8]. A number of nations currently run nuclear power stations but are considering the process of nuclear technology. These countries are Belgium, Germany, Switzerland, and Spain [3]. Also according to the U.S. Energy Information Administration (EIA), solar power increased by 39% in the United States from 2014 to 2017 [4]. Starting at 10 GW and ending at 27, this growth trend for the field is very encouraging. In addition, carbon dioxide emissions have decreased by a few percent, the lowest since 1991 [5]. If it continues down this path, more study is likely to be carried out as a result of the growth in the market for efficient, cheap solar energy, in order to attempt to develop even more carbon-free or low-carbon fuels such as wind and nuclear power [6]. There are two big issues relating to nuclear plants: waste disposal and potential failure. Nuclear power plants produce dangerous wastes; for example, a 1-GW nuclear power plant can produce 300 kg of nuclear waste, with a half-life of almost 24,000 years, and cause environmental issues. The current methods for disposing of these kinds of waste are inadequate. The complete reprocessing of all radioactive waste and the chemical transformation of long fission products will be an ideal option. However, trends in this area have not progressed extensively [7]. The first and most critical problem is its disparity; the amount of solar energy that can be harvested depends widely on the time, location, season, weather, and several other factors. In order to improve this topic, engineers are exploring the development of new storage methods for large quantities of energy generated [5]. One of these storage techniques suitable for mountainous areas is pumped hydroelectric storage (PHES) that also uses excess energy generated during nonpeak hours of the day to pump water from a reservoir in a much high elevation. PHES is just one of the several potential storage methods used by many people, and it is so essential because it provides a clean, efficient use of solar energy when normally none is generated by replacing it with hydroelectricity [8]. Because of the good use and storage of solar energy, it becomes more difficult to determine whether to use solar energy or some other form of renewable energy for power companies and individuals. Despite the obvious cost of installing solar power, this is a higher investment opposed to the use of fossil fuels due to much lower maintenance and occasional overproduction of energy.
Solar energy is a key player in the sustainable power plan. In sunny places, many residents built panels on their roofs to support air-conditioning, heating, and other household needs and the panels were set up by themselves. Study in the collection and storage of solar energy should be a major effort worldwide [9]. But in less sunny areas, there are a few expensive homes which run 100% on solar power, using large battery banks to power them through the nights.
Solar energy has the capacity to boost everything we need; however our ability to turn the energy of the sun into electrical power and also to store energy is simply not fully developed. Energy storage in particular has proven to be challenging, as solar panels have a very irregular energy intake because it depends on season, climate conditions, time of day, and so on. The inability to use all solar power harvested efficiently is an issue that is likely to force even more development in the field to come soon after it has been resolved. The industry is full of possible innovations that have yet to be made and which can be recognized if time is taken to develop the innovative technology. Therefore, when looking at potential ways of storing the energy produced, PHES may not be the most cost-effective, but it is proven to be safe and can be added to some existing infrastructure at the same time as analysis seeks to make it more efficient.
2. Solar energy
Solar technology, i.e., renewable wind, offers a reliable and stable supply of solar energy during the year. As our natural resources are likely to decline in the years to come, it is necessary for the entire world to shift toward sustainable sources. Solar power is a reactive electromagnetic sunlight energy that can be used for a wide range of still-evolving applications, such as solar heating, photovoltaics, solar electricity, solar thermal processing, artificial molten, salt power plants, and photosynthesis.
Solar energy is a significant source of green energy, and its techniques are generally characterized as either passive solar energy or active solar energy based on whether solar energy is absorbed and transmitted or transformed into solar energy. Strong solar technologies involve the use of photovoltaic devices, concentrating solar power and solar water heaters to harvest electricity. Passive methods include the alignment of a system or building to the sun, the use of products with desirable light properties or thermal mass, and the construction of spaces that automatically disperse air.
2.1 Advantages of solar energy
The biggest advantage of solar energy is that it can be quickly installed by both home and business consumers, because it does not involve any major construction, such as in the case of wind and geothermal power stations. Solar energy not only benefits individual owners but also benefits the environment. Figure 1 shows a simple model of a solar thermal system.
No pollution: Solar energy is a safe, nonpolluting, efficient, and green energy resource. This does not pollute the environment by producing poisonous pollutants, such as carbon dioxide, nitrogen oxide, and sulfur oxide. Solar energy does not need power and thus prevents the problems of shipping power or handling radioactive materials.
Long-lasting solar cells: Solar cells have two special features: first the lack of drive systems and second the minimal maintenance requirements. Then they have already got a longer life and they’re more noticeable.
Renewable source: Solar energy is a sustainable energy source that can continue to generate power as long as there is light. While solar energy cannot be generated during the night and rainy days, it can be used again and again throughout the day. Solar energy from the sun is a steady and continuous source of electricity which can be used to harvest strength in remote areas.
Low maintenance: Generally, solar cells do not need upkeep and operate for a long time. More solar panels can be installed from time to time if desired. While solar panels have an initial expense, there are no recurrent costs. The initial expense, which is paid once, may be recovered in the long run. Apart from this, solar panels do not create any noise and do not emit an unpleasant scent.
Easy installation: There is no need to install equipment such as cables, power supply, pipes, etc.; solar panels make solar tracking simpler. Unlike wind and geothermal energy harvesting systems that need land drilling equipment, solar panels do not need them and can be easily mounted on rooftops to insure that no additional infrastructure is needed, so residential home users can easily use this technology to supply electricity. In addition, they can be installed in a dispersed manner, meaning that no large-scale installations are required.
Figure 1.
Solar thermal system [10].
The technology of solar cells is developing, and as our nonrenewable supply decreases, it is necessary for the world to transition into renewable energy sources. There are, though, a range of issues that prohibit solar energy from being used more widely. Solar energy drawbacks are likely to be resolved as technology advances, and their use grows as people continue to realize the benefits of solar energy.
2.2 Disadvantages of solar energy
Solar energy can either be thermal or photovoltaic. The photovoltaic type is one of the most stable types of converting radiant energy into electrical energy. It really is suitable in many countries with adequate sunlight, such as Iran, and countries close to the equator, in terms of the quantity and availability of this technology. The energy source does not relate to someone and requires permission to use it. This feature has given rise to solar energy becoming special among renewable energy sources. Solar energy from ancient times is used by people using a magnifying glass to light the fire. Throughout this way, the sunlight was concentrated on dark wooden surfaces, and the fire became ignited. Also, solar photovoltaic (SPV) cells convert solar energy directly into DC electricity. This power source may be used to power solar clocks, calculators, or signals. These are also found in areas which are not linked to the power grid. Figure 2 shows a concentrated solar power (CSP) plant. Solar heat energy (SHE) can be used to heat water or air, which requires ventilation of the room inside the house.
Figure 2.
Concentrated solar power (CSP) plant [10].
Solar energy can be broadly categorized as active or passive solar energy depending on how they are captured and utilized. For active solar power, specific solar heating equipment is used to transform solar power into thermal energy, but there is no specialized equipment for passive solar power [11]. Active solar requires the use of mechanical devices such as photovoltaic panels, solar trap fans, and solar thermal collectors or reservoirs. Passive solar solutions transform solar energy into thermal energy without the usage of active mechanical devices. It is primarily a method to use curtains, doors, plants, positioning of buildings, and other basic methods to catch or block the sun for usage. Passive solar heating is a smart way to save electricity and optimize its consumption. An example of passive solar heating is what happens to your car on a hot summer day.
2.3 Environmental impacts of solar power systems
Although solar energy is recognized to be one of the cleanest and most renewable sources of energy today, it also has several environmental impacts. Solar energy uses photovoltaic panels to generate solar electricity. Nevertheless, the processing of photovoltaic cells to generate the energy includes silicon and to produce other waste products. Inappropriate handling of such materials can result in hazardous exposure to humans and the environment [12]. Installing solar power plants will entail a significant portion of land that may have an effect on established habitats. Solar energy does not pollute the air when converted to electricity by solar panels. It is found in abundance and does not help in global warming.
2.4 Solar energy’s potential
Solar power is now expected to play a greater position in the future due to recent developments that will result in lower costs and better efficiency. In fact, the solar photovoltaic industry is preparing to supply half of all future US power generation by 2025. More and more architects understand the importance of active and passive solar power and know how to successfully integrate it into building designs. Solar hot water systems can compete economically with conventional systems in some areas. Shell has predicted that by 2040, 50% of the world’s electricity supply would come from sustainable resources. Over recent years, the rate of generating photovoltaic cells has declined by 3% per year while policy subsidies have increased. While certain other information about solar energy is meaningless, this renders solar energy an even more efficient source of electricity. Solar energy is projected to be used by millions of households across the world in the next several years, as seen by developments in the United States and Japan. Aggressive financial incentives in Germany and Japan and China have made these countries global leaders in solar deployment for years [13].
A renewable resource that can be used to generate power is solar. The sun itself is a source of radiant, daylight, and other energy sources on Earth. Steam engines are a perfect illustration of radiant energy, by having sunrays magnified by mirrors guided to the turbine to heat water and produce steam, which in effect drives the turbine and causes steam to escape, and this pushes the piston. Calculators often work on solar power by storing light rays and transmitting energy to enable the calculator to function even though no light is present. Trevor Smith1 notes that “solar rays can be used to fuel or cool houses, supply hot water and produce steam for turbines generating energy. Sunlight can be converted directly into energy by photovoltaics, a fast-growing branch of solar technology.” This allows people to generate energy from renewable resources. James Bow notes that in 1977, 1 W of solar power costs $76.67. In 2014, the cost dropped to around $0.60. This suggests that modern solar power projects are far more economical, which means that renewable energy has come a long way and will continue to grow. One of the greatest declines in solar power is that, first, the sun is still growing and dropping, ensuring that the energy provided and processed is confined to the location of solar panels. Second, the batteries used to store electricity generated by the sun are expensive and produce a large amount of emissions. Third, in order to allow the best of the light, wide quantities of solar panels or mirrors need to be installed, which could be a function of restricted resources. The energy generated by the solar is a type of renewable energy used by today’s society.
3. Nuclear energy
Nuclear power is the energy of an atom. Atoms are very tiny objects which make up a single body in the universe. There is enormous power in the links that connect the nucleus unchanged. Power is generated when the ties are disbanded. Nuclear energy may be used to create electricity, but it must be produced first. Nuclear power can be produced by both nuclear fusion and nuclear fission. In nuclear fission, atoms are separated into smaller atoms, which generate steam. Nuclear power stations have been used for electricity generation. Another method of generating nuclear energy is through nuclear fusion. The combination of atoms to each other and the creation of heavier atoms are established. When atoms are coupled, a lot of energy is released. These reactions occur together in the sun to generate thermal energy to radiation. Numerous studies are currently underway, although this technique has not yet been commercialized and it is not known if it is possible to generate electricity from this method. Uranium (U-235) is the most commonly produced nonrenewable material for nuclear fission. Plants use a particular type of U-235, as the atoms are readily isolated. During nuclear fission, the neutron hits and splits the uranium atom, releasing a large sum of energy in the form of heat and radiation. More neutrons are also released as the uranium atom is separated. Some neutrons proceed to hit other uranium atoms, and the process begins over and over again. It’s a chain reaction, too. Although uranium is around 100 times more common than silver, U-235 is extremely scarce. Most of the US uranium is extracted in the western United States, but only 17 percent of the plutonium reactors is generated abroad. Uranium provided to US reactors in 2013 arrived from a number of nations, including Russia, Australia, and several other African countries. Figure 3 displays the map of uranium mines in the world [14].
Figure 3.
Map of uranium mines in the world.
There are 648 nuclear power stations in the world. There are 61 nuclear power stations and 99 research facilities in the United States. Nuclear plants are found in 30 states, and 46 are situated east of the Mississippi River. After 1990, nuclear power has supplied around one-fifth of US electricity annually. Nuclear power provides as much electricity as all the fuel consumed in California, New York, and Texas together. Nuclear energy plants supply more than 20% of US energy. Figure 4 shows the map of nuclear power stations in the world.
Figure 4.
Map of nuclear power stations in the world.
3.1 Nuclear power is the result of nuclear fission
Uranium fission occurs with the capture of the slow neutron by the non-isotope U-235. The resultant U-236 generates three free neutrons and separates into Kr-94 and Ba-139. The mass defect of roughly 0.2 atomic mass units is converted into 210 MeV energy units. U = 1.66 × 10−27 gk for the atomic mass unit, and eV equals 1.60 × 10−27J, the radioactive energy unit.
Many power stations, like nuclear power plants, use heat to produce electricity. Power plants rely on steam from hot water to drive massive turbines, which then produce electricity. Because of using fossil fuels to produce electricity, nuclear power plants employ nuclear fission energy. The fission occurs in the nuclear power plant reactors. Nuclear reactors are devices which contain and regulate nuclear chain reactions while releasing heat at a regulated rate. The nucleus of the device, which includes nuclear fuel, is at the top of the plant. The uranium fuel is constructed of ceramic pellets. Each ceramic pellet contains at about the same amount of energy as 150 gallons of gasoline. Such energy-rich pellets are packaged in 12 foot wire fuel pipes. The array of fuel rods, sometimes hundreds of them, is called a burn unit.
The heat generated during the fission at the center of the reactor is used to boil water to steam, which turns the turbine blades. The energy can be generated while the rotor blades rotate. Afterwards, the steam is pumped back into the atmosphere in a different power plant system called a cooling tower. The product will be collected.
Nuclear power plants do not emit carbon dioxide emissions during operation compared to fossil fuel-fired power stations. Methods for the extraction and refining of uranium oxide and the processing of nuclear fuel, however, require a large amount of power. Nuclear power stations supply large quantities of metal and concrete which also require a substantial amount of energy to be produced. When fossil fuels are used for the production and refining of uranium oxide or for the installation of a nuclear power plant, the emissions generated by the burning of these fuels may be associated with the energy emitted by nuclear power plants. The main environmental concerns linked to nuclear power include the processing of toxic waste such as uranium mine tailings, expended reactor fuel, and other nuclear waste. These materials can stay radioactive and dangerous to human health for thousands of years. Animals are subject to strict laws governing their care, delivery, preservation, and treatment for the protection of human health and the environment. The US Nuclear Regulatory Commission (NRC) regulates the operations of nuclear power plants. Nuclear waste is classified as small and large rates of emissions. Radioactivity of these materials may range from just over natural background rates, including in mill tailings, to much higher amounts, such as spent nuclear fuel or sections of a nuclear plant. Radioactivity of toxic waste is decreased as time passes by a process called nuclear decay. The period of time taken to reduce the radioactivity of hazardous material to half of the original level is considered the contaminated half-life of the substance. Short-lived radioactive waste is also treated permanently prior to disposal in order to mitigate the future danger of contamination to staff handling and carrying waste, as well as to the amount of pollution at production sites.
Nuclear waste stored in tanks is very dangerous. These vessels are kept under special conditions in the water with safety shields until their half-life exceeds the standard of security. Various countries have specific laws on the processing of nuclear waste. The United States has set out strict rules on the storage and management of radioactive fuel and waste. Some nuclear power plant fuels can be stored in dry storage tanks. In this way, nuclear fuel tanks are stored in separate rooms with cement or steel air-conditioning devices.
Typically, once a nuclear reactor stops, it shifts. It involves the controlled extraction of the reactor and other devices that have been damaged from operation and the elimination of radioactivity to a degree that permits other uses of the site. The United States Nuclear Regulatory Commission (NRC) has stringent regulations regulating the decommissioning of nuclear power facilities, including the washing up of radioactively polluted reactor processes and equipment, including the disposal of atomic waste.
Uncontrolled nuclear reactions in a nuclear reactor will potentially contribute to extensive pollution of air and water. The probability of this occurring at nuclear power plants in the United States is known to be very low due to the complex and robust safeguards and multiple protection measures in effect at nuclear power plants, the preparation and expertise of reactor workers, the monitoring and service operations, and the legislative standards and oversight of the United States. A wide-field near nuclear power plant is controlled and supervised by trained security forces. Some of the reactors have containment vessels that are designed to withstand extreme weather events and earthquakes.
3.2 Advantages of nuclear energy
According to the laws of physics, energy is neither produced nor destroyed, but it can be converted from one kind to another, including the transfer of electrical energy into mechanical energy of electric motors. From the structure of the atom, much of its mass exists in a part called the core, and this mass contains protons with a positive electric field and neutrons with an ineffective or neutral electric field. Studies and experiments have indicated that neutrons weigh a lot more than protons. Nuclear energy is the energy generated by a nuclear explosion or a nuclear fusion under the specific conditions of the nucleus of an atom. A lot of energy can be released as nuclear fission or nuclear fusion happens. Once the heavy element, uranium, was exploded with neutrons, it was found that something special occurred instead of causing radioactivity as other materials. This cycle has been called fission. When nuclear fusion or nuclear fission happens as a product of neutron impacts, not only are two lighter elements produced and many radiations released, but more neutrons are generated, as can be seen in Figure 5. It is therefore obvious that concurrently released neutrons can start a chain reaction by acting on released light atoms, increasing the intensity of the reaction. This reaction may spread throughout uranium.
Figure 5.
Uranium-235 radioactive fission.
A lot of energy would be produced through the fission of the uranium-235 nucleus (see Figure 5). To consider the amount of this energy, it’s enough to remember that this amount is around 60,000,000 times greater than when a carbon atom burns. During a nuclear fission reaction, the atom decomposes and releases a lot of kinetic energy into the environment. Obviously, kinetic energy is directly related to the generation of heat. The first reactors to generate a functional volume of electricity were installed in the Calder Hall in England. Atomic bombs may be produced of mere fissionable material. Of the two bombs dropped on Japan to end the World War 2, one contained plutonium and the other very highly enriched uranium-235.
3.3 Advantages of nuclear energy
Lower greenhouse gas emissions: As recorded in 1998, the production of greenhouse gasses has been projected to have declined by almost half owing to the success of the usage of nuclear power. Nuclear processing has by far the lowest environmental impacts, because it does not release greenhouse gasses such as carbon dioxide, a fuel that is largely responsible for the greenhouse effect. Thanks to its application, there is no harmful impact on water, soil, or other environment, although certain greenhouse gasses are emitted when shipping fuel or harvesting uranium oil.
Powerful and efficient: The other major benefit of having nuclear technology is that it is more effective and efficient than other potential forms of electricity. Technology advances have rendered it more competitive than most. That is one of the reasons that many nations are spending extensively in nuclear power. At least, a tiny part of the world’s energy is flowing into it.
Reliable: In comparison to conventional energy sources such as solar and wind, which involve sun or wind to generate electricity, nuclear energy may be generated from nuclear power plants even under extreme weather conditions. They also can provide 24/7 power and need to be shut down for maintenance purposes only.
Cheap electricity: Similar to traditional energy sources such as sun and wind, which require solar or wind power production, nuclear electricity may be produced from nuclear power plants even under severe weather conditions.
Low fuel cost: The key factor behind the low cost of fuel is that it takes a limited amount of uranium to generate oil. When a nuclear reaction happens, it produces millions of times more hydrogen than normal energy sources.
Supply: There are other economic benefits of building up nuclear power stations and utilizing renewable electricity instead of traditional oil. It’s one of the nation’s biggest producers of energy. The greatest part of it is that this electricity has a constant availability. This is readily accessible, has large supplies, and is projected to last about 100 years, whereas electricity, oil, and natural gas are small and are likely to disappear early.
Easy transportation: Electrical power generation requires much fewer raw contents. This implies that just 28 g of U-235 produces as much energy as 100 metric tons of coal. As it is needed in limited amounts, the transport of fuel is much simpler than that of fossil fuels. Optimal use of natural resources in energy production is a rather careful approach for every country. This not only strengthens the socioeconomic climate but provides a precedent for other countries as well.
There is no question that nuclear technology has found its way into the future; however, like most electricity forms, it still suffers from certain significant disadvantages.
3.4 Disadvantages of nuclear energy
Radioactive waste: Waste generated by nuclear reactors must be disposed of in a secure location because it is highly dangerous and may leak radiation if it is not properly treated. Any kind of pollution releases radiation from tens to hundreds of years. Collection of toxic waste has become a significant obstacle in the growth of nuclear programs. Nuclear waste includes radioisotopes with lengthy half-lives. This ensures that the radioisotopes exist in one shape or another in the atmosphere. Such aggressive radicals pollute the sand or the sea. It’s classified as mixed waste. Mixed waste induces toxic chemical reactions, which create harmful problems. Radioactive waste is normally covered beneath sand and is classified as proof, although the material is going to be used to produce atomic weapons or chemical bombs.
Nuclear accidents: While too many modern measures have been placed in motion to insure that such a tragedy will not arise again as Chernobyl or, more recently, Fukushima, the danger associated with it remains fairly high. Just slight radiation exposure may have disastrous consequences. There are some symptoms that induce fatigue, vomiting, diarrhea, and exhaustion. Many operating in nuclear power plants that live in these areas are at risk of obtaining the toxic radiation on what they are consuming.
Nuclear radiation: There are power reactors that are called breeders. They’re making plutonium. It is an element that is not present in nature but is a fissionable product. It is a by-product of a chain reaction which, once added in nature, is very toxic. It is mainly used for the development of nuclear weapons. Very definitely, it’s considered a dirty gun.
High cost: Another realistic drawback to utilizing nuclear technology is that a lot of money is required to put up a nuclear power plant. This is not often feasible for developed nations to support such an expensive renewable energy source. Nuclear power plants usually take 5–10 years to build, because there are a variety of legal formalities to be done, so they are often protested by those residing nearby.
National risk: Nuclear technology has provided humanity the ability to create more bombs than to generate anything that will render the planet a safer community to stay in. They ought to be more cautious and diligent when utilizing nuclear technology to prevent any big incidents of any sort. They are soft sites for terrorists and extremist groups. Health is a big concern here. A little weak protection will prove to be deadly and barbaric to humans and even to this world.
Impact on aquatic life: Eutrophication is another consequence of nuclear waste. There are several workshops and conferences that take place every year to find a common answer. As of yet, there is no result. Studies claim the nuclear waste requires nearly 10,000 years to return to its original state.
Big impacts on health and medicine: We still remember the horror that unfolded during the World War 2, after the atom bombs dropped on Nagasaki and Hiroshima. Still after five decades of mishap, children were born with defects. This is partly due to the nuclear influence. Will we have some treatments for that? The response is no.
Availability of fuel: Given the abundance of fossil fuels in most countries around the planet, uranium deposits are so hazardous that they are only available in a few countries, as the map of accessibility to uranium resources depicts in Figure 3. Permissions from a variety of foreign bodies are needed before anyone would even conceive about constructing a nuclear power plant.
Nonrenewable: Nuclear technology requires plutonium, which is a limited resource that has not been produced in many nations. Most countries depend on other countries for the continuous supply of this gasoline. It’s extracted and shipped like any other tool. Supply should be secure as long as demand is accessible. Once all the nuclear reactors have been dismantled, they would not be of much benefit. Due to its dangerous effects and restricted availability, it cannot be identified as renewable.
Various nuclear energy projects are ongoing in both developed and emerging countries, such as India. Not to note, the benefits of nuclear technology are well ahead of the drawbacks of fossil fuels. That’s why energy generation technology has been the most preferred technology.
4. Conclusions
By concatenating uranium extraction from seawater, manifestly safe breeding reactor technology, and borehole disposal of nuclear waste, a viable, planetary-scale nuclear energy network can be developed, i.e., another that is capable of supplying such an enormous quantity of energy at such a high degree of intensity that it can be relied on to sustain much—and possibly much—of the human society in virtually much possible scenarios of significant concern. For that way, nuclear technology is qualitatively distinct from other consumable technology options and must be assumed to be completely renewable in other respects. Throughout the immediate future, it is possible that the opportunity to build and demonstrate manifest protection for the latest generation of modern nuclear plants would be necessary to establish the basis for a prosperous future focused on nuclear technology.
Human civilization needs fossil energy because of its current facilities and its basic needs. This need and the high use of fossil fuels in the industrial, commercial, and residential sectors have contributed to major rapid climate change. The challenge of global warming is one of the massive problems confronting governments around the world. Earth heating may change the ecosystems and create many long-term problems. Greenhouse gasses like carbon dioxide are rising water levels in the oceans. Some droughts are in risk of extinction. These concerns are so significant that crisis analysts have described the modern century as a fuel for sustainability and protection of the planet.
Many countries have adopted official targets for the share of renewable energy in their grids, and others are considering them (Figure 6). Now that the governments of the world have a common issue, human beings will take collaborative action. Global organizations have been set up to manage this issue. The usage of renewable resources is one of the proposals created by global organizations to manage this crisis. Those alternative sources of energy include renewable energy and nuclear power. Countries must make decisions based on the long-term future to determine and improve the energy structures of the nation and calculate the various costs. At present, taking into account the cost factor, it is not possible to fulfill all energy demand from clean energy sources. But the good news is that this is possible with the cooperation of nuclear and renewable energy. Several countries have, in their perspective, made the energy demand share dependent on renewable and nuclear energy. Specific planners engage in predicting future projects and their costs. Figure 6 constitutes some of the OECD-calculated costs. The key competition today is between solar and nuclear energy. The cost of using solar energy over active nuclear energy continues to be substantial and significant. They are also ideal for all levels of challenging electricity. Costs for involvement in the energy market are assessed by the OECD per year. In Figure 6, the authors made the data comprehensible. Six countries pioneered the use of nuclear energy and renewable energy sources. Figure 6 shows that the United States has been able to keep the cost of participating energy resources low, with the highest level of technology.
Figure 6.
Costs of combining nuclear technology with renewable energy.
If the nuclear energy program is properly and sustainable way installed and the cost limit is eliminated, supplying electricity from nuclear energy resources will be reasonable and resolve these critical challenges for decades to come. It therefore seems necessary that we, as founders and citizens of a global society, begin to lay down the technological and structural foundations that will enable a viable, full-scale nuclear energy network to become operational in the immediate future while at the same time doing the same with regard to other realistic types of renewable energy supply on a scale [14].
One of the problems for nuclear power plants, as discussed earlier, is the difficulty of supplying 100 percent of electricity through these power plants. If we allow the setup and control share to be 10 percent and that share is given by solar energy, then the problem will be solved. However, if their share is assumed to be relatively large, then the cost of the system will increase, presenting another challenge.
These are rather heroic calculations given the paucity of sources, but they do indicate plausible effects. Increasing the penetration of renewable has small effect on backup costs since they tend to increase in direct proportion to the renewable capacity (MW) that needs backup and the increased capacity adds proportional MWh. However, balancing costs increase because more spinning reserve capacity is required at lower load factors. Since research is lowering the price of the solar-connected grid, the next problem is network costs. When renewable sources of energy such as photovoltaic systems manage to meet a district or village’s full demands, then there will be a crisis. Power plants continue to use energy for spending networks indefinitely, and it is not clear how cost-effective these networks are. In this case, it would be illogical to establish and to develop a network [15]. (As a side note, backup and balancing are less costly in the United States because the dispatchable power is typically gas fired, which is less costly there.)
Another inference can be drawn from these results: the marginal cost of the system will generally increase with increased penetration of renewables, essentially due to their intermittentness and tendency toward remote locations. In addition to marginal system cost per MWH, there is another critical metric: marginal cost per ton of CO2 emissions reduced by increased deployment of renewables. After all, that is a primary policy driver for renewable targets.
The United States has set ambitious targets for renewable penetration: 33% by 2020, not including hydro. Further consideration (up to 51% in the legislative proposal) has been given for the future. The 33% level is thought to result in an implicit cost of $50/ton carbon reduction. Some energy companies have carried out important research on target utilization of 50% nuclear power and 50% solar energy. This research includes researching this topic in both scientific and economic terms. It was represented in Figures 6 and 7. If the target is 50%, the lowest cost is $403, and the lowest cost is $340 for 40%. When energy storage technologies, such as nighttime high-altitude storage, are planned for solar energy, then the scenario will be more complex. This scenario shows that the size of large power plants can be utilized with good systems. For plants larger than 5000 mW, $636 per ton saves economic power [16]. Figure 7 shows the costs involved with combining nuclear and renewable energy.
Figure 7.
The cost of getting a combination of nuclear energy and renewable energy paid by different countries.
The next challenge is solar and nuclear energy competition. Although solar power plants will fall in price each day, in most countries the price of renewable energy is still higher than in nuclear power plants. The cost of integrating and merging systems is also important. Currently, the value of building nuclear power plants in many countries is very high due to the companies concerns of moment, technology, sanctions, security, and safety hazards. It is possible to eliminate those limitations in solar energy. The same problems may not be as wide for state-owned companies or regulated markets that services have ready access to cheap capital, and that partly explains why Asia’s enthusiasm for nuclear reactors is far stronger than it is in the United States or Europe. Researchers are working to reduce the costs of technology, but the nuclear industry is not strong, although that could improve small modular reactors if they can be developed in the process. According to Figure 7, given the right facilities, the United States has to pay the lowest costs for involvement in nuclear and solar energy. South Korea also has the right structure to take this scenario forward.
Nuclear and renewable energies qualify for subsidies that vary from country to region. Some subsidies are direct, such as feed-in imports for renewable energy sources, while others shift the risks from utilities to customers.
The final guidelines would help to better compensate for nuclear and renewable costs and could help to reduce the costs of both:
Comparisons of nuclear and renewables costs should account for systems integration and differences in capacity factors.
In order to estimate nuclear costs, more attention should be given to the choice sensitivity of discount rate, as the discount rate drastically impacts the relative economic attractiveness of a nuclear project.
Findings on problems that may restrict the use of a nuclear reactor in “load-following” phase are important and should be given high priority.
Priority should be given to new reactor technologies like SMRs and regulatory reform in order to reduce nuclear capital costs. The final results of this section will include the following explanation. These explanations will help in choosing and policy making in the field of solar and nuclear energy. The outlook for these results is for the next 10 years. This outlook may change by changing conditions and creating critical conditions such as dramatically lower fossil fuel prices.
Nuclear power is dirty, dangerous, expensive, and not carbon-free and encourages nuclear proliferation. The nuclear power plant itself does not release toxic gasses such as CO2. Nevertheless, nuclear power leads to climate change; for any phase in the fuel chain used to produce electricity at the end of the day, a lot more energy is required, such as uranium extraction and uranium enrichment, which are highly energy-intensive methods. The life study of the whole fuel chain clearly indicates the relation to nuclear electricity to climate change. In a pioneering study [17], more than 100 studies have identified important but simple results, analyzing the life cycle of greenhouse gas emissions equivalent to greenhouse gasses produced at nuclear power plants around the world. The results show that if the life expectancy of a plant is equal to the greenhouse gas emission equivalent to that energy production, then the emission equals 1.4 g of carbon dioxide per kilowatt hour (gCO2e/kWh) up to 288 gCO2e/kWh is variable. The mean greenhouse gas emissions equate to 66 gCO2e/kWh.
As a first conclusion, the extensive use of solar energy services for at least the next decade may be out of the issue. Photovoltaic and solar thermal systems, especially large thermal, wind, and biomass systems, will enter and expand energy networks quickly. Other renewable energy systems will be developed and priced to reduce consumption, such as biogas (wastewater, landfills, and livestock), geothermal, and possibly wave and tidal energy. This growth will be high in the next 10 years, but market with conventional systems will still take time [18]. Nuclear power is also an option when contemplating a transition from the dirtiest of fossil fuels, and thus nuclear power should be debated together with renewables. Nuclear time for building, risk, waste, and, in particular, costs must be tracked, because nuclear costs are increasing when solar energy costs are dropping. Small- and large-scale renewable energy projects and emerging storage systems are being increasingly developed by communities and nations. Also China, probably the most ambitious nation in terms of nuclear power, is introducing more wind and solar power relative to nuclear power—and not just nameplate capacity—which is actually produced. Last year alone, China installed 20.72 GW of wind (4.8 GW of production while its power factor is just 23%) and 28 GW of renewable energy (10.6 GW of production), with about 90% of its solar installations coming from utilities. In the same year, more than five nuclear plants (5.7 GW output) were added to the existing wind and solar power. China is only one example of how wind and solar power can be installed quickly while producing more electricity. At the period (and if) China finishes its 28 nuclear power plants (many are still behind schedule), with an estimated potential of 34 GW, further wind and solar power would be installed around the same timeframe—again, taking into account efficiency factors [19].
For the coming 10 years, here in the United States, the five US nuclear power facilities are 2 years behind track and have a budget of billions of dollars. Once live, they will produce 5.1 GW while renewables would produce a rather modest 131 GW.
The other two factors are systems for the energy, safety and security systems. In a nuclear power plant, when things go awry, it can be really bad because of accidents, threats, or critical situations that happen. It should be noted that the smallest incident in a nuclear power plant can often incapacitate or destroy a city or a country. Is it likely? Who knows for sure? Could you foresee the next earthquake in Southern California or somewhere else in the United States or Japan or the rest of the world? What about the next wave washing down a coastline? How about the next cyber threat or the Middle East militant organization? Compare a tragedy for a nuclear power plant against a solar power plant. When you ask me why I’m against constructing new reactors, it’s about economy, health and protection, and the reality that we can expand on current hydro and nuclear power facilities with all the renewables—and we can do it quicker.
\n',keywords:"solar energy, nuclear energy, renewable, power plants, technology",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/72177.pdf",chapterXML:"https://mts.intechopen.com/source/xml/72177.xml",downloadPdfUrl:"/chapter/pdf-download/72177",previewPdfUrl:"/chapter/pdf-preview/72177",totalDownloads:135,totalViews:0,totalCrossrefCites:0,dateSubmitted:"January 20th 2020",dateReviewed:"April 14th 2020",datePrePublished:"December 7th 2020",datePublished:"February 24th 2021",dateFinished:"May 15th 2020",readingETA:"0",abstract:"Both solar energy and nuclear energy face significant economic challenges. Sustainable energy costs have traditionally been greater than any of those associated with the growth of fossil fuel power generation, although the costs of renewable energy technologies (especially photovoltaic) have dropped. Furthermore, capital costs remain a big challenge in the nuclear generation. In many nations, the cost of building small nuclear power plants is quite large due to time, technology, and environmental and safety challenges for consumers. Such problems might not be as big for state-owned corporations or controlled industries for which utilities have quick access to cheap resources, and this partially explains why the interest for nuclear reactors in Asia is far greater than in the United States or Europe. Learning could help decrease costs for both types of technologies, but the track record for learning-by-doing in the nuclear sector is not good.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/72177",risUrl:"/chapter/ris/72177",signatures:"Mostafa Esmaeili Shayan and Farzaneh Ghasemzadeh",book:{id:"9888",title:"Nuclear Power Plants",subtitle:"The Processes from the Cradle to the Grave",fullTitle:"Nuclear Power Plants - The Processes from the Cradle to the Grave",slug:"nuclear-power-plants-the-processes-from-the-cradle-to-the-grave",publishedDate:"February 24th 2021",bookSignature:"Nasser Awwad",coverURL:"https://cdn.intechopen.com/books/images_new/9888.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"145209",title:"Prof.",name:"Nasser",middleName:"S",surname:"Awwad",slug:"nasser-awwad",fullName:"Nasser Awwad"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"317852",title:"Ph.D.",name:"Mostafa",middleName:null,surname:"Esmaeili Shayan",fullName:"Mostafa Esmaeili Shayan",slug:"mostafa-esmaeili-shayan",email:"mostafa.esmaeili@modares.ac.ir",position:null,institution:{name:"Tarbiat Modares University",institutionURL:null,country:{name:"Iran"}}},{id:"319145",title:"Prof.",name:"Farzaneh",middleName:null,surname:"Ghasemzadeh",fullName:"Farzaneh Ghasemzadeh",slug:"farzaneh-ghasemzadeh",email:"fgh.7192@yahoo.com",position:null,institution:{name:"Iran University of Science and Technology",institutionURL:null,country:{name:"Iran"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Solar energy",level:"1"},{id:"sec_2_2",title:"2.1 Advantages of solar energy",level:"2"},{id:"sec_3_2",title:"2.2 Disadvantages of solar energy",level:"2"},{id:"sec_4_2",title:"2.3 Environmental impacts of solar power systems",level:"2"},{id:"sec_5_2",title:"2.4 Solar energy’s potential",level:"2"},{id:"sec_7",title:"3. Nuclear energy",level:"1"},{id:"sec_7_2",title:"3.1 Nuclear power is the result of nuclear fission",level:"2"},{id:"sec_8_2",title:"3.2 Advantages of nuclear energy",level:"2"},{id:"sec_9_2",title:"3.3 Advantages of nuclear energy",level:"2"},{id:"sec_10_2",title:"3.4 Disadvantages of nuclear energy",level:"2"},{id:"sec_12",title:"4. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'Esmaeili Shayan M, Najafi G, Ahmad BA. Power quality in flexible photovoltaic system on curved surfaces. Journal of Energy Planning and Policy Research. 2017;3:105-136'},{id:"B2",body:'Esmaeili MS, Najafi G. Energy-economic optimization of thin layer photovoltaic on domes and cylindrical towers. International Journal of Smart Grid. 2019;3:84-91'},{id:"B3",body:'Ogland-Hand JD, Bielicki JM, Wang Y, et al. The value of bulk energy storage for reducing CO2 emissions and water requirements from regional electricity systems. Energy Conversion and Management. 2019;181:674-685'},{id:"B4",body:'Norman C. Nuclear Safety. Butterworth Heinemann. Elsevier Ltd.; 1974'},{id:"B5",body:'Alonso G. Desalination in Nuclear Power Plants. UK: Woodhead Publishing; 2020'},{id:"B6",body:'Yu Q , Zhang T, Peng X, et al. Cryogenic energy storage and its integration with nuclear power generation for load shift. In: Storage and Hybridization of Nuclear Energy: Techno-economic Integration of Renewable and Nuclear Energy. Elsevier Ltd.; 2018. pp. 249-273'},{id:"B7",body:'Ojovan MI, Lee WE, Kalmykov SN. An Introduction to Nuclear Waste Immobilisation. Elsevier Ltd.; 2013. pp. 1-362'},{id:"B8",body:'Biberian J-P. Cold Fusion Advances in Condensed Matter Nuclear Science. Elsevier Ltd.; 2020'},{id:"B9",body:'Murray RL, Holbert KE. Nuclear Energy: An Introduction to the Concepts, Systems, and Applications of Nuclear Processes. Elsevier Ltd.; 2019'},{id:"B10",body:'Esmaeili Shayan M, Najafi G, Gorjian S. Design Principles and Applications of Solar Power Systems (In Persian). 1st ed. Tehran: ACECR Publication-Amirkabir University of Technology Branch; 2020'},{id:"B11",body:'Aleixandre-Tudó JL, Castelló-Cogollos L, Aleixandre JL, et al. Renewable energies: Worldwide trends in research, funding and international collaboration. Renewable Energy. 2019;139:268-278'},{id:"B12",body:'Kerlin TW, Upadhyaya BR. Dynamics and Control of Nuclear Reactors. Elsevier Ltd.; 2019. pp. 95-125'},{id:"B13",body:'Fundamentals of Thermal and Nuclear Power Generation. Elsevier Ltd.; 2020'},{id:"B14",body:'Sanders MC, Sanders CE. Nuclear waste management strategies: An international perspective. 2019'},{id:"B15",body:'Zhong RZ, Cheng L, Wang YQ , et al. Effects of Anthelmintic Treatment on Ewe Feed Intake, Digestion, Milk Production and Lamb Growth. Singapore: Springer Verlag; 2017'},{id:"B16",body:'Suman S. Hybrid nuclear-renewable energy systems: A review. Journal of Cleaner Production. 2018;181:166-177'},{id:"B17",body:'Lima MA, Mendes LFR, Mothé GA, et al. Renewable energy in reducing greenhouse gas emissions: Reaching the goals of the Paris agreement in Brazil. Environmental Development. 2020;33:105-115'},{id:"B18",body:'Azadbakht M, Esmaeilzadeh E, Esmaeili-Shayan M. Energy consumption during impact cutting of canola stalk as a function of moisture content and cutting height. Journal of the Saudi Society of Agricultural Sciences. 2015;14:147-152'},{id:"B19",body:'Review and outlook of world energy development. Non-Fossil Energy Development in China. 2019:1-36'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Mostafa Esmaeili Shayan",address:"mostafa.esmaeili@modares.ac.ir",affiliation:'
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He worked as a researcher in the Nippon Oil Company from 1996 to 2000. He was an assistant professor and then a research associate professor at Tokyo University of Agriculture and Technology from 2000 to 2005. He attained his current position of associate professor and full professor at Tokyo Institute of Technology in 2005. He has published more than 170 papers in scientific journals. His interests are microelectronics, metallurgy, surface finishing, chemical engineering, and liquid crystal and polymer science. His recent topic of interest is material design and the evaluation of electroplated gold alloys for high-sensitivity CMOS-MEMS accelerometers.",institutionString:"Tokyo Institute of Technology",profilePictureURL:"https://mts.intechopen.com/storage/users/157966/images/system/157966.png",totalCites:0,totalChapterViews:"0",outsideEditionCount:0,totalAuthoredChapters:"1",totalEditedBooks:"1",personalWebsiteURL:null,twitterURL:null,linkedinURL:null,institution:{name:"Tokyo Institute of Technology",institutionURL:null,country:{name:"Japan"}}},booksEdited:[{type:"book",slug:"novel-metal-electrodeposition-and-the-recent-application",title:"Novel Metal Electrodeposition and the Recent Application",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6870.jpg",abstract:"Gold and noble metals have been attractive to humans from ancient times because of their beautiful features. In modern society, noble metals, especially gold, play important roles as components in electronic devices because of their high electrical conductivity, chemical stability, and density. In the field of MEMS devices, the demand for continuous miniaturization and sensitivity enhancement is always high. Especially for MEMS accelerometers, sensitivity is affected by Brownian noise, and components with sufficient mass are needed to suppress this noise. Therefore, it is difficult to reduce the dimensions of components to allow further miniaturization of the device. 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OASPA
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The Open Access Scholarly Publishers Association (OASPA) was established in 2008 to represent the interests of Open Access (OA) publishers globally in all scientific, technical and scholarly disciplines. Its mission is carried out through exchange of information, the setting of standards, advancing models, advocacy, education, and the promotion of innovation.
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STM
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COPE
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Creative Commons
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Creative Commons (CC) is a nonprofit organization that enables the sharing and use of creativity and knowledge through free legal tools. IntechOpen uses the CC BY 3.0 license for chapters, meaning Authors retain copyright and their work can be reused and adapted as long as the source is properly cited and Authors are acknowledged.
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Crossref
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Altmetric and Dimensions from Digital Science
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Digital Science is a technology company serving the needs of scientific and research communities at key points along the full cycle of research. They support innovative businesses and technologies that make all parts of the research process more open, efficient and effective. IntechOpen integrates tools such as Altmetric to enable our researchers to track and measure the activity around their academic research and Dimensions, to ease access to the most relevant information and better understand and analyze the global research landscape.
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DORA
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iThenticate
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Enago
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Amazon
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DHL
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IntechOpen has partnered with DHL since 2011 to ensure the fastest delivery of Print on Demand books.
The Association of Learned and Professional Society Publishers (ALPSP) is the largest association of scholarly and professional publishers in the world. Its mission is to connect, inform, develop and represent the international scholarly and professional publishing community. IntechOpen has been a member of ALPSP since 2016 and has consequently stayed informed about industry trends through connecting with peers and developing jointly.
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OASPA
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The Open Access Scholarly Publishers Association (OASPA) was established in 2008 to represent the interests of Open Access (OA) publishers globally in all scientific, technical and scholarly disciplines. Its mission is carried out through exchange of information, the setting of standards, advancing models, advocacy, education, and the promotion of innovation.
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STM
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The International Association of Scientific, Technical and Medical Publishers (STM) is the leading global trade association for academic and professional publishers. As a member, IntechOpen has not only made a commitment to STM's Ethical Principles.
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COPE
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The Committee on Publication Ethics (COPE) provides advice to editors and publishers on all aspects of publication ethics and, in particular, how to handle cases of misconduct in research and publication. IntechOpen has been a member of COPE since 2013 and adheres to the COPE Code of Conduct and Best Practice Guidelines, ensuring that we maintain the highest ethical standards.
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Creative Commons
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Creative Commons (CC) is a nonprofit organization that enables the sharing and use of creativity and knowledge through free legal tools. IntechOpen uses the CC BY 3.0 license for chapters, meaning Authors retain copyright and their work can be reused and adapted as long as the source is properly cited and Authors are acknowledged.
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Crossref
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Crossref is the official Digital Object Identifier (DOI) Registration Agency for scholarly and professional publications with a goal of making scholarly communications more effective. IntechOpen deposits metadata and registers DOIs for all content using the Crossref System. IntechOpen also deposits its references and uses the Crossref Cited-by service that enables researchers to track citation statistics.
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Altmetric and Dimensions from Digital Science
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Digital Science is a technology company serving the needs of scientific and research communities at key points along the full cycle of research. They support innovative businesses and technologies that make all parts of the research process more open, efficient and effective. IntechOpen integrates tools such as Altmetric to enable our researchers to track and measure the activity around their academic research and Dimensions, to ease access to the most relevant information and better understand and analyze the global research landscape.
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CLOCKSS
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CLOCKSS preserves scholarly publications in original formats, ensuring that they always remain available and openly accessible to everyone.
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Counter
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COUNTER provides the Code of Practice that enables publishers and vendors to report usage of their electronic resources in a consistent way. This enables libraries to compare data received from different publishers and vendors.
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DORA
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DORA is a worldwide initiative covering all scholarly disciplines which recognizes the need to improve the ways in which the outputs of scholarly research are evaluated and seeks to develop and promote best practice. To date it has been signed by over 1500 organizations and around 14,700 individuals.
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iThenticate
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Enago
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IntechOpen collaborates with Enago, through its sister brand, Ulatus, one of the world’s leading providers of book translation services. Their services are designed to convey the essence of your work to readers from across the globe in the language they understand.
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SPi Global
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Amazon
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Amazon is the world’s largest online retailer and cloud services provider. IntechOpen books have been available on Amazon since 2017, guaranteeing more visibility for our Authors and Academic Editors.
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DHL
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IntechOpen has partnered with DHL since 2011 to ensure the fastest delivery of Print on Demand books.
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