Clinical phenotypes associated with SLC25A46 mutations.
\r\n\t
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Nahhas",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11534.jpg",keywords:"Solar Energy, Water Energy, Biomass Energy, Hydro Energy, Wind Energy, PV, Solar, Smart Grid, Wind Generators, Power Electronics, Pumped Hydroelectric, Natural Gas Storage",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 9th 2022",dateEndSecondStepPublish:"April 6th 2022",dateEndThirdStepPublish:"June 5th 2022",dateEndFourthStepPublish:"August 24th 2022",dateEndFifthStepPublish:"October 23rd 2022",remainingDaysToSecondStep:"a month",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Prof. Nahhas is an official reviewer of journals such as the American Journal of Nanomaterials—USA, many International conferences, and holds the Associate Professor position at several Saudi Universities. Professor Nahhas served in many prestigious leading positions including Dean of the College of Engineering at Al-Lith, head of the Department, Vice Dean at Umm Al Qura University, Makkah. He is also a member of IEEE.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"140058",title:"Prof.",name:"Ahmed",middleName:"M.",surname:"Nahhas",slug:"ahmed-nahhas",fullName:"Ahmed Nahhas",profilePictureURL:"https://mts.intechopen.com/storage/users/140058/images/system/140058.jpg",biography:"Ahmed M. Nahhas received his Master’s degree in Computer Engineering from Illinois Institute of Technology, Chicago, Illinois, USA in 1996 and a Ph.D. in Electrical Engineering (Electronics) from the University of Pittsburgh, Pittsburgh, Pennsylvania, USA in 2001. Professor Nahhas’s research has been centered on developing new photonic and electronic devices at micro and nano-scales involving various functional materials such as rare-earth-doped oxides, wideband gap semiconductors, and nanostructured materials. Prof. Nahhas’s research investigates epitaxial growth and fabrication of ZnO and GaN optical devices. Fabrication of MSM photo-detectors has been developed on a macro-scale area of wafer surface using a directed self-organization method and has been investigated as an interaction medium in optical, electrical, chemical, and biological domains. Surface-Plasmon phenomena occurring in structures are of particular interest since many novel properties can be derived from those and can be incorporated into an on-chip configuration for interaction. Professor Nahhas has participated in reviewing several academic articles and dissertations in the area of electrical, electronics, communications, control engineering, and e-learning. He is an official reviewer of journals such as the American Journal of Nanomaterials—USA, many International conferences, and holds the Associate Professor position at several Saudi Universities. Professor Nahhas served in many prestigious leading positions including Dean of the College of Engineering at Al-Lith, head of the Department, Vice Dean at Umm Al Qura University, Makkah. Currently, he works at the College of Engineering and Islamic Architecture, Umm Al Qura University, Makkah, Kingdom of\nSaudi Arabia.",institutionString:"Umm al-Qura University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Umm al-Qura University",institutionURL:null,country:{name:"Saudi Arabia"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"453622",firstName:"Tea",lastName:"Jurcic",middleName:null,title:"Ms.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"tea@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"8446",title:"Zinc Oxide Based Nano Materials and Devices",subtitle:null,isOpenForSubmission:!1,hash:"7c1d14eb8eac769093f8d7a219a3884f",slug:"zinc-oxide-based-nano-materials-and-devices",bookSignature:"Ahmed M. 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They produce ∼90% of neuronal adenosine triphosphate (ATP), which is continuously required for maintaining the complex morphology and specialized functions of neurons, including electrical excitability and synaptic transmission [1], and are regenerated continuously in postmitotic neurons through biogenesis. In addition to undergoing the dynamic processes of mitochondrial fission and fusion, mitochondria are transported bidirectionally within neurites, in which they are distributed purposefully, facilitating energy transmission over long distances to meet local demands and, when necessary, undergo controlled degradation by mitophagy [2, 3]. Thus, mitochondrial dynamics play critical roles in neuronal homeostasis and survival.
Recent evidence suggests that abnormal mitochondrial dynamics may contribute to both familial and sporadic neurodegenerative diseases [4]. Most proteins related to mitochondrial dynamics are encoded by genes in the nucleus. Mutations in such nuclear-encoded genes can cause monogenic disorders in which mitochondrial dysfunction is unequivocally central to the pathogenesis of the disease. For example, mutations in
Recent studies have implicated the 46th isoform of subfamily A of the solute carrier (SLC) family 25, termed SLC25A46, in mitochondrial dysfunction pathology. SLC25A46 is a mitochondrial outer membrane protein that was shown recently to be involved in mitochondrial dynamics, either playing a role in mitochondrial fission or serving as a regulator of mitofusin (MFN)1/2 oligomerization [17, 18]. Disorders caused by recessive
SLC25A46 belongs to the solute carrier family 25 (SLC25), a superfamily that contains 53 nuclear-encoded mitochondrial carrier proteins in humans [27]. SLC25 members are characterized by the presence of three tandem repeats of about 100 amino acids, each containing two transmembrane alpha helices linked by a large loop [28]. The mature carrier protein thus consists of six transmembrane helices that form an aqueous pore and have a highly conserved consensus sequence, P-X-[D/E]-X-X-[R/K], at the C-terminal ends of the three odd-numbered transmembrane alpha helices, whose charged residues form salt bridges that close the pore on the matrix side [29]. SLC25 proteins may shuttle a variety of solutes across the mitochondrial membrane to participate in various metabolic pathways [30]. Although common mechanisms of substrate translocation have been proposed, SLC25 members vary greatly in their size, the nature of substrates they transport, the modes of transport employed, and the driving forces they employ [30, 31, 32].
A number of genetic conditions associated with SLC25 mitochondrial transporters have been characterized biochemically and genetically [33]. SLC25 members mediate a variety of cellular functions, and mutations in SLC25 genes have been linked to various defects, such as carnitine/acylcarnitine carrier deficiency (OMIM 212138), HHH syndrome (OMIM 238970), aspartate/glutamate isoform 1 and 2 deficiencies (OMIM 612949, 603471, 605814), congenital Amish microcephaly (OMIM 607196), neuropathy with bilateral striatal necrosis (OMIM 613710), congenital sideroblastic anemia (OMIM 205950), neonatal epileptic encephalopathy (OMIM 609304), and citrate carrier deficiency (OMIM 190315) [33]. These disorders are characterized by specific metabolic dysfunctions related to the role of the particular carrier that has been affected. Most disease-related SLC25 members have been characterized in terms of substrate identification and associated metabolic pathways, with the exception of two orphan SLC25 members, namely SLC25A38 and SLC25A46 [33].
Given the typical SLC25 molecular structure, the primary sequence of the SLC25A46 protein has been predicted to form six conserved transmembrane alpha helices, TM1–TM6, spanning a region between amino acids 100–418 (Figure 1) [22]. However, the otherwise highly conserved P-X-(D/E)-X-X-(R/K) consensus sequence characteristic of SLC25 proteins is altered in SLC25A46. Moreover, the N-terminus of SLC25A46 is about five times longer than that of other members of the family (∼100 vs. <20 amino acids). These unusual characteristics suggest that SLC25A46 is unlikely to have a conventional metabolite carrier function. Recently, studies have proposed that unlike most SLC25 members that are located in the inner mitochondrial membrane, SLC25A46 may be anchored to the outer mitochondrial membrane where it may act as a regulator of mitochondrial dynamics rather than as a substrate transporter.
Schematic diagram of SLC25A46 structure and its interactions. (A) SLC25A46 consists of six conserved transmembrane alpha helices. (B) 3D structure of SLC25A46. (C) Potential interactions of SLC25A46 with dynamic proteins.
In 2015, recessive mutations in
ID | SLC25A46 mutations | SLC25A46 proteins | Age of onset | Age of death | Optic atrophy | Peripheral neuropathy | Cerebellar or brainstem atrophy | Hypotonia or myopathy | Ataxia | Lactate | Other features | Mitochondrial dynamics |
---|---|---|---|---|---|---|---|---|---|---|---|---|
UK family Abrams et al. [17] | c.165_166insC; c.746G>A | p.His56fs*94; p.Gly249Asp | 5 y/8 y | Alive (40 y/43 y) | + | + | − | − | − | Normal | Normal CSF examination, oxidative enzyme activity, no ragged red fibers. | n.k. |
PL family Abrams et al. [17] | c.1005A>T | p.Glu335Asp | 1 y/2 y | Alive (13 mo/11.5 y) | + | + | + | + | + | ↑ | Developmental delay, 3-MG ↑ in urine. | Increased mitochondria. |
IT family Abrams et al. [17] | c.1018C>T | p.Arg340Cys | 2 y | Alive (51 y) | + | + | + | + | + | ↑ | CK ↑(225, NR<170 U/L), lactic acid at upper end of normal range. | Hyperfilamentous. |
US family Abrams et al. [17] | c.882_885dupTTAC; c.998C>T | p.Asn296fs*297; p.Pro333Leu | Prenatal | 105 d | + | + | + | + | n.k. | n.k. | Facial and hand dysmorphism, meconium aspiration. | n.k. |
Moroccan family Nguyen et al. [21] | c.283+3G>T | p.? | Prenatal | 7 d | + | n.k. | + | + | n.k. | ↑ | Club foot posture, lactate-to-pyruvate ratio ↑ and all individual complexes ↓ in fibroblasts. | Mitochondrial fragmentation. |
Pakistani origin family Charlesworth et al. [19] | c.413T>G | p.Leu138Arg | n.k. | Alive (15 y/20 y) | + | + | + | + | + | n.k. | Comprised exotropia, difficulty initiating saccades, spasticity, scoliosis. Old brother with mild phenotypes. | n.k. |
Saudi family Sulaiman et al. [26] | c.775C>T | p.Arg259Cys | 28 y | Alive | + | − | − | + | n.k. | Normal | No ragged red fiber or cytochrome c deficiency, intact sensation and coordination, unremarkable acylcarnitine profile, amino acids, CK and urine organic acids. | Occasional enlarged mitochondria. |
Tunisian family Hammer et al. [23] | c.1018C>T | p.Arg340Cys | 1 y/6 y | Alive (22 y/19 y) | + | + | ± | n.k. | + | n.k. | Dysarthria, gait instability, Babinski sign, abolished Achilles reflexes, finger-nose dysmetria, severe sensorimotor demyelination. | n.k. |
Algerian family 1 Hammer et al. [23] | c.1018C>T | p.Arg340Cys | 2 y | Alive (31 y) | + | + | ± | n.k. | + | n.k. | Subtle white matter changes in cerebellum, increased tendon reflexes, no Achilles reflex, positive Hoffmann sign, no Babinski sign. | n.k. |
Algerian family 2 Hammer et al. [23] | c.479G>C | p.Trp160Ser | 23 y | Alive (26 y) | − | n.k. | n.k. | n.k. | + | n.k. | Abolished vibration sense, at ankles, nystagmus and saccadic pursuit, scoliosis. | n.k. |
Family 1 Wan et al. [22] | c.1022T>C | p.Leu341Pro | Prenatal | 14 d/28 d | n.k. | n.k. | + | + | n.k. | Normal | PCH, severe global developmental delay, normal respiratory chain enzymes in muscle and liver. | Increase in mitochondrial length. |
Family 2 Wan et al. [22] | g.chr5:110738771_ 11074670del | p.? | Prenatal | 42 d | + | + | + | + | n.k. | ↑ | PCH, occasional myoclonic jerks; EEG: generalized slowing with abnormal theta rhythm, no epileptic discharges, sibling with same phenotype. | n.k. |
Dutch family Dijk et al. [25] | c.691C>T g.chr5:110742638_ 110745029del | p.Arg231*; p.? | Prenatal | 1 d | + | n.k. | + | + | n.k. | n.k. | PCH, all three children died within 1 day after birth, lack of spontaneous respiration, profound muscle weakness. Convulsion, spinal motor neuron degeneration. | n.k. |
German family Braunisch et al. [24] | c.736A>T | p. Arg 246 * | Prenatal | 1 d/23 d | n.k. | n.k. | + | + | n.k. | ↑ | PCH, seizures, EEG: low amplitudes with sharp waves, epileptiform discharges without clinical equivalents, thrombocytes ↑, lung hypoplasia, bradycardia at birth, green amniotic fluid. | n.k. |
Italian family Braunisch et al. [24] | c.42C>G; c.462+1G>A | p.Tyr14 *; P. ? | Prenatal | 1 d/18 d | n.k. | n.k. | + | + | n.k. | n.k. | PCH, floppy infant, little respiratory effort and voluntary movements; EMG: neurogenic lesion; loss of spinal motor neurons, normal CK levels, serum transferrin IEF, two siblings were hypotonic and died immediately after birth. | n.k. |
French Canadian family Janer et al. [20] | c.425C>T | p.Thr142Ile; (instable protein) | Birth | 15 mo | + | n.k. | + | + | n.k. | ↑ | Leigh syndrome, psychomotor delay, growth retardation, mild spastic diplegia; motor delay; fever, convulsion, gasping respirations, bilateral intranuclear ophthalmoplegia, hyperreflexia, mild spasticity. | Mitochondrial hyperfusion in fibroblast. |
Clinical phenotypes associated with SLC25A46 mutations.
Note: y, year; mo, month; d, day; n.k., not known; ↑, increase.
A recent study reported the identification of
PCH is a rare, heterogeneous group of prenatal onset neurodegenerative disorders, mainly (but not exclusively) affecting the cerebellum and pons. The current PCH classification scheme includes 10 distinct PCH subtypes defined by clinical features and genetic etiology. PCH1 is distinguished from the other PCH subtypes by its association with spinal muscular atrophy due to spinal motoneuron degeneration; it often leads to early death. All patients with obvious loss-of-function
Cerebellar and brainstem atrophy are shared phenotypic features of PCH, Leigh syndrome, and most variant
To sum up,
The
Schematic diagram of reported pathogenic SLC25A46 variants. Exons 1–8 are represented by blue blocks. Mutations are color coded as follows: red, nonsense and missense mutations that would be expected to destabilize the protein; blue, micro-deletions/insertions/duplications; orange, splice-site mutations; and black, regular missense mutations.
A systemic genotype-phenotype analysis of all available cases indicates that phenotype severity correlates strongly with the magnitude of SLC25A46 protein level reduction caused by each mutation. As shown in Table 1, very severe
In conclusion, the main molecular causes of
In the last 2 years, a series of experiments aiming at resolving the function of SLC25A46 and the pathogenesis of
Animal species | SLC25A46 mutations | SLC25A46 proteins | Age of onset | Age of death | Optic atrophy | Peripheral neuropathy | Ataxia | Degeneration in cerebellum /brainstem | Other features | Mitochondrial dynamics |
---|---|---|---|---|---|---|---|---|---|---|
Bovine Duchesne et al. [43] | c.376C>T | p. R126C | 1 mo. | Euthanasia around 2–3 mo. | — | + | + | + | Degenerative lesions both in gray matter and white matter; demyelination in certain peripheral nerves. | Elongated mitochondria with abnormal cristae. |
Tg−/− FVB/N mouse Duchesne et al. [43] | Tg18: indel 12 bp; Tg26: del 75 bp | p.Val122Leu123delinsATIIYI; p.Ala108fs*159 | 2 w | 3–4 w | — | ± | + | ± | Impaired growth, small intestine, thymus, spleen and liver, severe hypoglycemia; low plasma iron concentrations combined with high ferritin. | Elongated mitochondria with abnormal cristae. |
atc/atc C57BL/6 J mouse Terzenidou et al. [42] | c.283C>T | p.Gln95fs* | 2 w | 5 w | + | + | + | + | Growth retardation, severe thymic and splenic hypoplasia, compromised Purkinje cell dendritic arborization and reduced synaptic connectivity, RGC aberrations, improper neuromuscular junction. | Atypical mitochondria in Purkinje cells. |
Slc−/− B6D2 mouse Li et al. [39] | c.992_1037del | p.Leu331fs*346 | 2 w | 2–8 w | + | + | + | + | Purkinje cell loss and dendritic abnormalities, degeneration in striatum, corpus callosum and spinal cord; axon degeneration and demyelination. | Enlarged or ring/C-shaped mitochondria. |
Clinical phenotypes associated with mutant SLC25A46 animal models.
Note: mo represents month; w the week.
Knock down of SLC25A46 in various cell lines by different research groups caused mitochondrial hyperfusion and abnormal cristae architecture visualized with fluorescent staining and electron microscopy [17, 20, 22]. In concordance, in an ultrastructural study of a SLC25A46 knock-out mouse model, we observed enlarged mitochondria with swollen cristae in Purkinje cell (PC) dendrites and sciatic nerves (Table 2) [39]. Hyperfused mitochondria consequent to SLC25A46 loss was unexpected because loss of Ugo1 function usually results in mitochondrial fission; however, it should be noted that strikingly similar cristae architecture abnormalities from loss of function are common to both genes [38, 40, 41]. Interestingly, in SLC25A46 mutant Purkinje cell bodies, ring-shaped or C-shaped mitochondria (a rarely reported morphology) were more commonly observed than hyperfused mitochondria [39, 42]. Furthermore, mitochondria were found to have an abnormal distribution and impaired movement within mutant Purkinje cells in a primary culture of mouse cerebellar cells [39]. These findings confirm that SLC25A46 plays an important role in the regulation of mitochondrial dynamics, including mitochondrial fusion/fission, distribution, and movement, as well as the maintenance of cristae architecture. Regarding the molecular actions of SLC25A46 in the balance of mitochondrial dynamics, recent research findings present three possible explanations: (1) SLC25A46 may act as an independent pro-fission factor; (2) SLC25A46 may serve as a regulator by interacting with mitochondrial fusion machinery, such as through an association with MFN1/2 oligomerization; and (3) SLC25A46 may regulate mitochondrial dynamics through its functions in lipid transfer between the endoplasmic reticulum (ER) and mitochondria.
In an inter-institution collaborative exploratory study employing immunoprecipitation assays and mass spectrometry analysis, there was no evidence of SLC25A46 interacting with MFN2 or OPA1 in HEK293T cells, but rather SLC25A46 was observed forming a complex with mitofilin that was independent of MFN2 [17]. Furthermore, overexpression of wild-type SLC25A46 protein led to mitochondrial fragmentation and disruption of the mitochondrial network. Thus, SLC25A46 was proposed to act as a pro-fission factor [17]. In contrast, two subsequent studies using similar immunoprecipitation approaches in patient fibroblasts and two cell lines (HEK293T with stable wild-type SLC25A46 expression and LAN5 neuronal cells) showed SLC25A46 interactions with proteins involved in fission and fusion, including MFN1/2 and OPA1, as well as with components of the MICOS (mitochondrial contact site and cristae organizing system) complex (Figure 1) [18, 20]. Moreover, decreased expression of SLC25A46 resulted in increased stability and oligomerization of MFN1 and MFN2 in association with mitochondria, thus promoting mitochondrial hyperfusion [18]. In SLC25A46 knock-out mice, two independent mass spectrometry studies yielded opposite results regarding the interaction between SLC25A46 and common dynamic proteins [42, 43]. Hence, although it seems reasonable that SLC25A46 would have interaction relationships with MFN1/MFN2 and the MICOS complex similar to those of Ugo1, further studies are needed to resolve its molecular mechanisms given the current conflicting results in the literature.
MFN2 tethers the ER to the mitochondrial network, suggesting that the ER may have a physical relationship with the mitochondrial network [44]. SLC25A46 has also been shown to interact with all nine components of the endoplasmic reticulum membrane complex (EMC) [18, 20], an ER protein complex recently shown to be necessary for phospholipid transfer from the ER to mitochondria in yeast. Most mitochondrial phospholipid species were altered dramatically by the loss of SLC25A46, indicating that SLC25A46 provides direct coupling of lipid flux between the ER and mitochondria at outer-inner mitochondrial membrane contacts [20]. Meanwhile, endoplasmic reticulum chaperone BiP (a.k.a. 78 kDa glucose-regulated protein), which acts at the ER-mitochondria interface under stress conditions and is considered as a major regulator of the ER, was down-regulated in
Studies implicating OPA1 and the MICOS complex in the maintenance of cristae architecture are compelling, but it is unclear how they may interact [45]. The observation that SLC25A46 interacts with OPA1 and MIC60, the major MICOS organizer, provides a molecular link that may integrate their functions in modulating cristae architecture [18, 20].
It now seems likely that SLC25A46 may possess multiple homeostatic functions in mitochondrial dynamics. Further studies are expected to reveal more refined details of the pathophysiological functions of SLC25A46, such as which domain interacts with dynamic proteins and which domain recognizes and communicates with the ER.
Disorganization of cristae leads to disruption of the assembly of the respiratory supercomplexes that mediate oxidative phosphorylation, which reduces the activity of their components (i.e., respiratory complexes I–V) and, thus, diminishes respiration efficiency [46, 47]. Mitochondrial metabolism is disrupted in both patients with mutant
Mitochondrial pathobiology has long been linked to the pathogenesis of neurodegenerative diseases, in part because neurons are highly dependent upon mitochondrial metabolism. Autopsy on a pair of deceased siblings who died due to
For now, most anatomical and histological analyses for
Three SLC25A46 knock-out mouse models with different genetic backgrounds, including FVB/N, C57BL/6J, and B6D2, were generated, respectively (Table 2). In spite of various mutation positions and sizes, three mouse lines displayed very similar phenotypes, including growth delay, progressive ataxia, optic atrophy, short life span, which recapitulated the pathological state in human. Further histopathologic studies have shown tissue- and cell-specific lesions in both the central nervous system and peripheral nervous system (Table 2).
Although macroscopic examination showed no overt abnormalities in the gross anatomy of mutant brain, histological staining revealed markedly reduced cerebellums, with Purkinje cells (PCs) that had stunted dendrites and were reduced in number. Degeneration (evidenced by Fluoro-Jade C dye) was selectively present in mutant PCs [39]. Examination via electron microscopy (EM) revealed that degenerated PC dendrites exhibited disorganized cytoskeleton, often containing remnants of mitochondria and other organelles. Numerous atypical mitochondria with cytoplasmic inclusions were found both in the soma and dendrites of PCs. In addition, a significant reduction in vGlut1 and vGlut2 immunoreactivity both in PCs and molecular layer indicated a paucity of glutamatergic synapses in mutant mice [42]. Apart from PCs, degenerative signals were also aggregated in the vestibular nucleus of brainstem, deep cerebellar nuclei, the striatum, the corpus callosum, and the spinal cord, but not in other parts of the brain [39]. The neurodegeneration was associated with astrogliosis and microgliosis in the cerebellum and spinal cord, indicating high levels of neuroinflammation [39, 42]. These observations suggest that although
Aged SLC25A46 mutant mice displayed enhanced hind limb clasping reflex and muscle atrophy, suggesting potential peripheral neuropathy. Acquiring compound muscle action potentials (CMAPs) reduced in mutant sciatic nerve measured by electromyography (EMG)
Optical coherence tomography (OCT) scanning on retina for live mice revealed that although the optic discs were grossly normal in terms of retinal appearance, retinas were thinner in aged SLC25A46 mutant mice [39]. Further quantitative measurements indicated that ganglion cell complex (GCC) thicknesses, which includes the nerve fiber layer (NFL), ganglion cell layer (GCL), and inner plexiform layer (IPL), were significantly reduced in adult mutant mice. Retinal and these reductions were associated with retinal ganglion cell loss and atypically small optic nerve axons with reduced neurofilament expression, as well as some axons that exhibited signs of degeneration and demyelination [39, 42]. Pax6+ and GAD65+ GABAergic amacrine cells—both of which form synapses with retinal ganglion cells—were also significantly reduced. These pathological changes are in line with the phenotypic features of ADOA.
Ultrastructural studies revealed dysmorphic mitochondria in both the central and peripheral nervous systems. Numerous enlarged and round mitochondria with abnormal cristae were found in Purkinje cell dendrites, while ring- or C-shaped mitochondria were commonly observed in soma. Peripheral nerve axons also had abnormal round, fused, and aggregated mitochondria in myelinated and non-myelinated fibers [39, 43].
Given the degeneration in long peripheral axons and distal optic nerves of SLC25A46 knock-out animal models, the aforementioned findings support the idea that neurons with long axons or complicated dendrites are more sensitive to abnormal mitochondrial dynamics. Similar to the findings in mutant Purkinje cells, this sensitivity could also be due to the impaired transport of hyperfused mitochondria along axons and dendrites, probably due to their abnormal size and/or reduced ATP availability in the distal portions of long axons secondary to mitochondrial dysfunction. Further studies are needed to clarify this point.
SLC25A46 plays a critical role in mitochondrial dynamics and the maintenance of mitochondrial cristae, which are particularly important in neurodevelopment and neurodegeneration. Loss of SLC25A46 function causes a wide spectrum of neurodegenerative diseases, including optic atrophy, peripheral neuropathy, progressive ataxia, Leigh syndrome, and lethal congenital pontocerebellar hypoplasia. In SLC25A46-related neurodegenerative diseases, phenotype severity correlates strongly with the magnitude of SLC25A46 level deficit observed.
This work was supported by the Center for Pediatric Genomics at the Cincinnati Children’s Hospital, a grant from the National Institutes of Health (1R01EY026609-01) to Taosheng Huang, and a grant from the National Natural Science Foundation of China (81470299) to Zhuo Li.
The authors declare that they have no conflicts of interest.
HLA-DQ2 antigen is a surface receptor of antigen-presenting cells (APC), it is composed of two polypeptide subunits: the α chain (of 32–34 kD) and the β chain (of 29–32 kD) [1]. Each one presents a peptide-binding domain, an Ig-like domain, and a transmembrane region with a cytoplasmic tail (\nFigure 1\n). These structures are bind by non-covalent association leadings. Unlike Major Histocompatibility Complex (MHC) class I molecules, both polypeptide chains are encoded by genes in the HLA-DQ regions strictly located on chromosome 6 (\nFigure 2\n). The pocket for the bond with the peptide is constituted for half by one chain and half by the other; each one contributes with an α-helix and 4 filaments of the β sheet.
\nLabel: The structure of the MHC-II molecule [
Label: Chromosomal origin of HLA class I and class II [
In the extracellular portion, each chain has an Ig domain (α2 and β2) of which, β2 contains the binding site for lymphocyte helper CD4+. In HLA-DQ2 both the α-chains and the β-chains are polymorphic, as a result, unique DQ molecules can be formed, with α- and β-chains encoded on the same chromosome (encoded in cis) or on opposite chromosomes (encoded in trans). However, evidence suggests that not every α- and β-chain pairing will form a stable heterodimer. It is generally considered that alleles of DQα- and DQβ-chains pair up predominantly in cis rather than in trans. However, the occurrence of trans-encoded HLA class II molecules is well documented in the literature, such as in the case of type 1 diabetes (T1D), where the trans encoded HLA molecules may play a role in pathogenesis [4].
\nEach MHC molecule has only one antigen pocket that can bind one peptide at once, but different peptides at different times. Peptides that can bind to MHC-II molecules reach 30 or more, while class I MHC molecules can accommodate peptides with 8–11 amino acids. The peptide–MHC binding is created during its assembly and is used to stabilize the complex to allow its expression on the cell surface and for this reason, the dissociation rate is very slow. This naturally provides a very long half-life that allows T lymphocytes to meet the antigen. Between MHC and peptide, a non-covalent connection is formed among the residues in the pocket. Once the binding has occurred, the peptide and the water molecules that solubilize it fill the pocket, making contact with the walls and the floor that make it up.
\nT cells activated by class II molecules are CD4+ helper cells that: activate cytokine production, control antibody synthesis, and regulate cellular response. DQ is also involved in the common recognition of auto-antigens; the presentation of these antigens to the immune system provides tolerance at a young age. When this tolerance is lost DQ can be involved in autoimmune diseases such as celiac disease (CD), type 1 diabetes, and many others as we will see more details afterward [5].
\nAs mentioned before, there are many potential DQ isoforms, as a result of the combination of cis- and trans haplotypes and those with cis-pairing are more common. Typically individuals can produce 4 isoforms, but only HLA-DQ2.5 and HLA-DQ2.2 tend to be predominantly represented.
\nHLA-DQ2.5 is composed of the allele HLA-DQA1*0501 (or DQA1*0505) encoding the alpha chain and the allele HLA-DQB1*0201 (or DQB1*0202) encoding the beta chain. HLA-DQ2.2 consists of the HLA-DQA1*02 alpha chain allele and the HLA-DQB1*0202 beta chain allele [6].
\nVery important concerning isoforms is that different subunit matches can cause the binding of different foreign or self-antigens. Generally, MHC molecules have slots at the pocket level that can interact with specific amino acids or be complementary to certain amino acid side chains. The importance of polymorphism is detected here: only the ability of MHC to bind specifically to a peptide permits it to be recognized by lymphocytes and to trigger the immune response to it.
\nThe molecule HLA-DQ2 has a peculiar ligation system with three binding sites, preferably for negatively charged residues and different peptide-binding motifs. The binding motifs associated with HLA-DQ2 consist of truncated variants of eight different peptides with a length of 9–19 amino acids.
\nData from the pooled sequencing and the biochemical binding analyses of synthetic variants of a ligand indicate that the side chains of amino acid residues at relative position P1 (bulky hydrophobic), P4 (negatively charged or aliphatic), P6 (Pro or negatively charged), P7 (negatively charged) and P9 (bulky hydrophobic) are important for binding of peptides to DQ2 (\nFigure 3\n).
\nLabel: Analysis of the HLA-DQ2 protein: (A) the 3D structure; (B) the binding sites; (C) the amino acids residues and the α helix and the β sheet domains [
Computer modeling of the DQ2 with variants of the ligand in the groove suggests that peptides bind to DQ2 through the primary anchors P1, P7, and P9 and making additional advantageous interactions using the P4 and P6 positions [8].
\nDQ2.5 refers to both a protein isoform and a genetic haplotype. DQ2.5 isoform or heterodimer is shorthand for the cell surface receptor HLA-DQ α5β2 (\nFigure 4\n).
\nLabel: The crystal structure of HLA-DQ2.5-CLIP1 [
DQ2.5 and the linked DR3 are associated with probably the greatest frequency of autoimmune occurrence relative to any other haplotypes. A genome-wide survey of markers linked to celiac disease, reveals that the highest linkage is for a marker within the DQA1*0501 allele of the DQ2.5 haplotype. The association of DQB1*0201 is almost as high. Greatly elevating risk is the ability of the DQ2.5 haplotype encoded isoforms to increase abundance on the cell surface in DQ2.5 double homozygote. While the frequency of DQ2.5 haplotype is only 4 times higher than the general population, the number of DQ2.5 homozygotes is 10 to 20 times higher than the general population. Of the approximately 90% of celiacs that bear the DQ2.5 isoform, only 4% produce DQ2.5trans and differs slightly, one amino acid, from DQ2.5cis.
\nMultiple copies of the DQ2.5 haplotype do not cause apparent increases of severity in celiac disease, but the 25% of celiac patients homozygous DQ2 (DQ2.5/DQ2) tend to show increases risk of life-threatening complications and more severe histological findings. The HLA-DQ2.5 molecule preferentially binds peptides with negatively charged amino acids at anchor positions [10, 11]. Whereas gluten peptides contain few negative charges, these charges can be introduced by the enzyme tissue transglutaminase (tTG) that selectively deamidates glutamine residues in gluten peptides [12, 13, 14]. DQ2.5cis is the major factor in adaptive immunity by frequency and efficiency in alpha-gliadin presentation and its responses can be differentiated from other DQ isoforms. Specifically, this DQ2 heterodimer is responsible for presenting the α2-gliadin that most effectively stimulates pathogenic T-cells.
\nAs mentioned before, the DQ2.5 haplotype is linked to DR3, which is not linked to DQ2.2. Using either serotyping or genotyping DQ2.5 can be distinguished from DQ2.2 or DQ2.3 [5].
\nHLA-DQ2.2 is shorthand for the DQ α2β2 heterodimeric isoform (\nFigure 5\n). DQ2.2 homozygotes represent about 1.1% of the celiac population. While HLA-DQ2.5 is strongly associated with the disease, HLA-DQ2.2 is not [5].
\nLabel: The crystal structure of HLA-DQ2.2 [
Whereas the molecular surfaces of the antigen-binding clefts of HLA-DQ2.5 and HLA-DQ2.2 are very similar, there are important differences in the nature of the peptides presented. These peculiarities in peptide motif binding cause differences in responding to T cell repertoires and in the disease penetrance [16].
\nDQ2.2 individuals can mount an antigluten response but bear a lower risk of celiac disease. The reason is fewer gluten peptides would bind stably to this HLA molecule. The results give insight into processes important for the establishment of T-cell responses to antigen in HLA-associated diseases. Patients with celiac disease with DQ2.2 have gluten-reactive T cells in their small intestine [17].
\nDQ2.3 is the shorthand for the heterodimeric DQ α3β2 isoform and is encoded by the DQA1*03:DQB1*02 haplotype (\nFigure 6\n). The receptor coded for the haplotype is a DQ2.3cis isoform, which is genetically linked to DR7 [5]. The gluten epitope, which is the only known HLA-DQ2.3-restricted epitope, is preferentially recognized in the context of the DQ2.3 molecule by the T-cell clones of a DQ8/DQ2.5 heterozygous celiac patient.
\nLabel: The crystal structure of HLA-DQ2.3 [
The DQ2.3 molecule combines the peptide binding signatures of the DQ2.5 and DQ8 molecules. This results in a binding motif with a preference for negatively charged anchor residues at both the P1 and the P4 positions. In this way, some epitopes can be presented even more effectively in the context of the trans-encoded DQ2.3 molecule. This has relevance for understanding how the trans-encoded DQ2.3 molecule is predisposing to type 1 diabetes [4].
\nThe analysis of the structure of DQ2.3 together with all other available DQ crystals shows that the P1 pocket in DQ2.3 is significantly different from that of DQ2.5 due to the polymorphic MHC residues found in this region. Additionally, DQ2.3 presents a gluten epitope to T-cells much more efficiently than DQ2.5 [4].
\nDQ2 beta chains can combine with trans chains to other alpha chains. However, there is no preference in cis isoforms for DQ2 alpha chains, 4, 7, 8, or 9 bindings to DQ1 alpha chains (DQA1*01). The DQA1*03, *05 chains process nearly identical alpha chains. The *04 chain can potentially combine with DQ2 to form DQ2.4. There is the possibility of DQ2.6 resulting from coupling with DQA1*0601 [5].
\nCeliac disease is a genetically determined immune-mediated disorder in which individuals carrying HLA DQ2 and/or DQ8 haplotypes develop an immunologic response to gluten ingestion that leads to a wide range of clinical signs and symptoms.
\nThe Humoral nature, the hereditary and the polygenic CD have great influence in triggering the disease. The assessment of HLA-DQ2/DQ8 is relevant from a diagnostic aspect to detect celiac disease; in fact, about 95% of patients with CD present the HLA-DQ2 genotype [19].
\nIn celiac patient inflammatory T cell responses to HLA-DQ2-bound gluten peptides are thought to cause disease. Gluten-reactive T cells can be isolated from small intestinal biopsies of celiac patients. T cells derived from the lesion mainly recognize gluten deamidate peptides. There are several distinct T cell epitopes within gluten. DQ2 and DQ8 bind the epitopes so that the glutamic acid residues created by deamidification are placed in compartments that have a preference for negatively charged side chains. Evidence indicates that in vivo deamidation is mediated by the enzyme tissue transglutaminase (tTG) that can also cross-link glutamine residues of peptides with lysine residues in other proteins, including tTG itself. This can lead to the formation of gluten-tTG complexes. These complexes may allow gluten-reactive T-cells to provide aid to tTG-specific B-cells through an intramolecular aid mechanism, thus explaining the presence of gluten-dependent tTG autoantibodies which is a characteristic feature of active CDs.
\nIdeally, all patients with CD carry alleles encoding for the DQ2 and/or DQ8 molecules or at least one chain of the DQ2 heterodimer. The presence of CD in the absence of these DQ risk factors is extremely rare. The presence of these molecules does not accurately predict that CD will develop, as they are present in 25–50% of the general population, although the fact that the vast majority of these individuals will never develop the disease. About 90% of individuals with CD carry HLA-DQ2.5, while individuals with CD who do not express these haplotype usually express either HLA-DQ2.2 or HLA-DQ8; very few coding for HLA DQ7.5 (DQA1*05:05–DQB1*03:01), DQ2.3 or DQ8.5 (DQA1*05–DQB1*03:02).
\nDifferences in CD risk between haplotypes are related to gluten peptide binding and subsequent T-cell response. The effect of gene dose is related to the level of peptide binding to homozygous and heterozygous HLA-DQ2 and its subsequent presentation to T cells. Individuals homozygous for DQ2.5 and DQ8 have an increased risk of the disease. Gluten presentation by HLA-DQ2 homozygous was superior to HLA-DQ2/non-DQ2 in terms of T cell proliferation and cytokine secretion (\nFigure 7\n).
\nLabel: Haplotypes and different class risk for celiac disease [
HLA-DQ2.5 predisposes to celiac disease respect to DQ2.2, because the first one presents a large repertoire of gluten peptides, whereas the second one presents only a subset of these. HLA-DQ2.2 does not predispose to CD unless it is expressed in combination with HLA-DQ2.5. Gluten presentation by HLA-DQ2.5/2.2 induces intermediate T-cell stimulation. However, individuals homozygous for HLA-DQ2.5 or heterozygous HLA-DQ2.2/2.5 have the highest risk of developing CD. In HLA-DQ2.5/2.2 heterozygous individuals have properties identical with HLA-DQ2.5 dimers. In contrast, HLA-DQ2.5/non-DQ2.2 heterozygous individuals have an only slightly increased risk (\nFigure 8\n).
\nLabel: Genotypes and celiac disease prevalence [
Considering even more in detail, it has been demonstrated that differences in conferred risk associated with CD are the result of the polymorphism in the α chain between HLA-DQ2.5 and HLA-DQ2.2.
\nHLA-DQ2.2 is virtually identical to the peptide-binding properties of HLA-DQ2.5. Both are highly homologous except for a single polymorphic residue (HLA-DQ2.5-Tyr22α and HLA-DQ2.2-Phe22α). The role of the Phe22α variant in HLA-DQ2.2 is to influence peptide binding preferences and to decide how DQ2.2 TCRs engage the DQ2.2-gluten complex.
\nCrystal structure studies revealed a docking strategy, where the TCR HLA-DQ2.5 gliadin epitopes complexes were notably distinct from the HLA-DQ2.2-glut TCR complex [22].
\nHLA-DQ2.5 and HLA-DQ2.2 binds and presents gluten peptides with glutamate residues at anchor positions P4, P6, or P7). Three HLA-DQ2.2 epitopes (DQ2.2-glut-L1, DQ2.2-glia-α1, and DQ2.2-glia-α2) have sequences similar to HLADQ2.5 binding peptides, with the exception that they all carry serine at P3. As seen for HLA-DQ2.5 epitopes, the HLA-DQ2.2 ones display a hierarchy with DQ2.2-glut-L1 being the epitopes recognized by most T cells [23].
\nHLA-DQ2 is influenced by interaction with Ag presentation cofactors, invariant chain (Ii), HLA-DM (DM), a peptide exchange catalyst for MHC class II (\nFigure 9\n).
\nLabel: Localization of HLA-DM on the MHC class II region [
DM can enhance or suppress the presentation of specific MHCII peptide complexes. In general, MHCII–peptide complexes with lower intrinsic stability are DM susceptible, but not all high-stability complexes are DM resistant. HLA-DQ2 is relatively resistant to DM because DQ2 has a natural deletion in the region involved in the interaction with DM, compared with most other alleles.
\nThe role of DQ2/DM concerns interaction in the DQ2-restricted gliadin epitopes, relevant to celiac disease, or DQ2-restricted viral epitopes, relevant to host defense. DM activity has different consequences on DQ2 presentation of epitopes to T cell clones, with suppression of gliadin presentation and enhancement of viral peptide presentation. These results imply key differences in DQ2 Ag presentation pathways.
\nDM-resistant feature of DQ2 likely contributes to the escape of gliadin peptides from extensive DM editing. Also, DQ2 has the special ability to stably bind proline-rich gliadin peptides that use TG2-deamidated residues as DQ2-binding anchors. Together, these unique features of DQ2 may allow gliadin presentation to disease-driving CD4+ T cells and contribute to the uniquely selective DQ2 presentation of DM-sensitive gliadin epitopes.
\nIn contrast, the presentation of DM-resistant epitopes that form more-stable complexes with DQ2 likely relies less on the above mechanisms, as DM editing positively affects the presentation of these epitopes. The elevation of DM expression in peripheral APC (particularly during infection) may benefit self-tolerance by attenuating the presentation of DM-sensitive epitopes while boosting the presentation of DM-resistant pathogen-derived epitopes and aiding in host defense [25].
\nRefractory celiac disease (RCD) is defined by persistent mal-absorptive symptoms and villous atrophy despite strict adherence to a GFD for at least 6–12 months in the absence of other causes of non-responsive treated celiac disease.
\nThe pathology can be classified as type 1 (normal intraepithelial lymphocyte phenotype), or type 2 (defined by the presence of abnormal [clonal] intraepithelial lymphocyte phenotype). RCD 1 usually improves after treatment with a combination of aggressive nutritional support, adherence to GFD, and alternative pharmacologic therapies. By contrast, clinical response to alternative therapies in RCD 2 is less certain and the prognosis is poor. Severe complications such as ulcerative jejunity and Enteropathy T-cell lymphoma (ETL) may occur in a subgroup of patients with RCD [26].
\nETL is a T-cell non-Hodgkin lymphoma arising in the gastrointestinal tract that shows a differentiation of tumor cells toward the phenotype of intestinal intraepithelial T cells. The clinical course of ETL is highly aggressive, with most patients dying from the disease within months of diagnosis. Enteropathy T-cell lymphoma comprises two morphologically, clinically, and genetically distinct lymphoma entities: the ETL type 1 and 2.
\nETL arises in individuals with the DQA1*0501, DQB1*02 CD-predisposing genotype. The HLA typing found in these patients revealed that more than 95% have an HLA-DQ2/-DQ8 genotype [27]. Comparing studies of HLA-DQB1 genotyping in celiac disease and ETL have detected that the overall HLA-DQB1 genotype pattern observed in type 1 ETL closely resembled those for ETL, whereas those of type 2 ETL are not significantly different from that of normal Caucasian controls.
\nETL1 patients show significantly more frequent expression of HLA-DQB1*02 than the type 2 ones [28]. Lymphoma type 1 may arise and be pathogenetically linked to refractory celiac disease by a stepwise acquisition of genetic alterations. Contrary given the genetic alterations and HLA-DQB1 genotype patterns, celiac disease may not be causal to type 2 ETL. At least 47% of patients with type 2 ETL are very likely to never have had celiac disease [29].
\nThe highly significant correlation between HLA-DQ2 homozygosity and the development of RCD II and ETL, suggests that the strength of the gluten-specific T-cell response in the laminapropria directly or indirectly influences the likelihood of RCD II and lymphoma development. As already mentioned in the chapter, also in this case, the higher T-cell proliferation and cytokine secretion induced by HLA-DQ2 homozygous APC, than HLA-DQ2 heterozygous APC, may explain the strongly increased risk for disease development in HLA-DQ2/DQ2 individuals [30]. This would indicate that adherence to a gluten-free diet is particularly important for CD patients who are HLA-DQ2 homozygous.
\nThese observations suggest that specific tests, such as those for lymphocyte typing for T cells, should be indicated in all patients with CD who are not responding to a gluten-free diet. The availability of a simple and reliable immune histochemical method can make the distinction between CD and RCD feasible. HLA-DQ typing is doable and it may be an efficient test to recognize individuals at risk for these conditions with a poor prognosis, particularly now that some evidence has been given to support the hypothesis that autologous hematopoietic stem-cell transplantation can alter disease progression in severe [29].
\nLiver and gastrointestinal diseases have many etiologies that are poorly understood. Whether due to genetic abnormalities, psychological factors, or other environmental variables, functional disorders can be complex and difficult cases to resolve. A strongest evidence of an association with
Known immunological associations between IBD and DR7, which is linked to both DQ2 and DQ8 haplotype have been established. The relation between DQ2/8 and IBD/IBS was analyzed in particular in two studies from an Italian and a Danish group and both demonstrated that the proportion of IBS was lower among HLA DQ2/8 positive individuals. However the Italian group also found that IBD and liver diseases were more prevalent among HLADQ2/8 subjects, but it is not confirmed in the Danish study. Prior prevalence data though suggest that IBD, particularly Crohn’s disease, is lower in individuals with the DQ2/8 linked celiac disease.
\nIBS has also been linked to HLA DQ2/8 haplotypes and intestinal transit rates [31]. Approximately 46% of patients with diarrhea-predominant IBS (IBS-D) have accelerated colonic transit. Some patients with IBS report an association of symptoms with specific foods, suggesting a role for food hypersensitivity. One such food is gluten in the absence of overt celiac disease. The spectrum of gluten sensitivity ranges from minimal histological changes such as increased intraepithelial lymphocytes without villous atrophy, increased immunoglobulin A (IgA) deposits in intestinal villi, gluten-sensitive diarrhea, and immunological mucosal response to gluten exclusion in patients with celiac disease. Typically, one or more of these findings are seen in individuals who are positive for HLA-DQ2 or HLA-DQ8. Wahnschaffe et al. demonstrated that, among patients with IBS-D, response of diarrhea to a gluten-free diet was influenced by HLA-DQ2 positivity and the presence of IgG tissue transglutaminase (TTG) antibody in duodenal aspirates. Symptom response to gluten withdrawal occurred in 62% of patients positive for both HLA-DQ2 and IgG-TTG; in contrast, only 12% of patients negative for HLA-DQ2 and TTG-IgG responded; suggesting that symptom generation in this subset of patients is immune-mediated. Is demonstrated that patients with IBS-D, positive for either HLA-DQ8 or both HLA-DQ2/DQ8 genotypes that are associated with gluten sensitivity, have an accelerated colonic transit time [32].
\nThe HLA DQ2 in association with HLA-DR3 is also associated with another GI disease; in fact, this combination is linked with a more rapid progression of primary sclerosing cholangitis (PSC) [33].
\nType 1 diabetes (T1D) is an autoimmune disease attacking pancreatic Langerhans islets. The islets are composed of several types of cells: α, β, δ, ε, and pancreatic polypeptide (PP). Each type plays a different role in the secretory function of the pancreas and, among others, α and β cells produce glucagon and insulin, respectively. The interplay between these two compounds provides proper glucose level administration in blood.
\nIt has been already shown that auto aggression in T1D starts in mutations in the MHC system. HLA-DQ molecules have the role to bind and present beta-cell autoantigen derived peptides in T1D. The combinations of DR4-DQ8 and DR3-DQ2 antigens occur in 90% of people with diabetes. However, the homozygous state for an allele does not further increase the risk. Indeed it is well established that individuals heterozygous for HLA-DQ2 and HLA-DQ8 have almost 5 fold higher risk than homozygous to development of T1D [1, 13, 14]. This has been linked to the formation of trans dimers between the HLA-DQ2 α chain and the HLA-DQ8 β chain (HLA-DQ8 trans) [19, 22, 26, 34]. In particular, the HLA DQ8 trans heterodimer confers the highest risk for the development of T1D. This indicates that such HLA-DQ trans dimers can bind and present a unique autoantigen derived peptide that leads to beta-cell destruction in the pancreas and the development of T1D [35].
\nJuvenile diabetes has a high association with DQ2.5. A combination of DQ2.5 and DQ8 significantly increases the risk of type 1 onset of adult diabetes, while the presence of DQ2 with DR3 reduces the age of onset and severity of the autoimmune disease.
\nThe formation of trans encoded molecules DQ8.5 (DQA1*05:01/DQB1*03:02) and DQ2.3 (DQA1*03:01/DQB1*02:01), which could present one or a few specific diabetogenic epitopes to CD4+ T-cells, possibly inducing an immune response that leads to the destruction of insulin-producing pancreatic β islet cells [12]. A strong argument for the involvement of the DQ2.3 heterodimer in type 1 diabetes comes from trans racial gene mapping studies that have found that this heterodimer, which is typically found in the trans configuration among Caucasian subjects, exists and is over-represented in the cis configuration among type 1 diabetes patients of African origin [16, 17]. The increased diabetes risk of the African DQ2.3 (DQA1*03:01/DQB1*02) carrying DR7 haplotype is contrasted by a protecting effect of the DQ2.2 (DQA1*03:01/DQB1*02) carrying DR7 haplotype of European origin [17].
\nPatients with homozygous type 1 DQ2 diabetes have a marked prevalence of IgA anti-transglutaminase autoantibodies. The great excess of positive transglutaminase autoantibodies among homozygous DQ2 diabetics is related to both the presence of DQ2 and its addition to all genetic or environmental factors associated with type 1 diabetes. These additional factors may be related to abnormalities in mucosal immunity that increases the risk of both type 1 diabetes and celiac disease.
\nType 1 diabetes is an autoimmune disease attacking pancreatic Langerhan’s islet. The islet is composed of several types of cells: α, β, δ, ε, and pancreatic polypeptide (PP). Each type plays a different role in the secretory function of the pancreas and, among others, α and β cells produce glucagon ad insulin, respectively [36]. Interplay between these two compounds provides proper glucose level administration in blood.
\nIt has been already shown that auto aggression in T1D starts in mutation in the MHC system. HLA-DQ molecules have the role to bind and present beta cell autoantigens derived peptides in T1D. The combinations of DR4-DQ8 and DR3-DQ2 antigens occur in 90% of people with diabetes. However, the homozygous state for an allele does not further increase the risk. It is well established that individuals heterozygous for HLA-DQ2 and HLA-DQ8 have an almost 5 fold higher risk than those who are homozygous for either of the DQ variants for the development of T1D, and this has been linked to the formation of trans dimers between the HLA-DQ2 α chain and the HLA-DQ8 β chain (HLA-DQ8 trans). This indicates that such HLA-DQ trans dimers can bind and present a unique auto antigen-derived peptide that leads to beta-cell destruction in the pancreas and the development of T1D. In particular, HLA DQ8 trans heterodimer confers the highest risk for the development of T1D.
\nIndeed diabetes has a high association with DQ2.5. A combination of DQ 2.5 and DQ8 significantly increases the risk of type 1 onset of adult diabetes, while the presence of DQ2 with DR3 reduces the age of onset and severity of the autoimmune disease.
\nThe formation of trans encoded molecules DQ8.5 (DQA1*05:01/ DQB1*03:02) and DQ2.3 (DQA1*03:01/DQB1*02:01), which could present one or a few specific diabetogenic epitopes to CD4+ T cells, possibly inducing an immune response that leads to the destruction of insulin-producing pancreatic β islet cells. Moreover, a strong argument for the involvement of DQ2.3 heterodimer in type 1 diabetes comes from transracial gene mapping studies that have found that this heterodimer, which is typically found in the trans-configuration among Caucasian subject, exists and is over-represented in the cis configuration among type 1 diabetes patients of African origin. The increased diabetes risk of the Africans DQ2.3 carrying DR7 haplotype is contrasted by a protecting effect of the DQ2.2 carrying DR7 haplotype of European origin, speaking to the functional importance of α chain in the DQ2.3 molecule.
\nPatients with homozygous type 1 DQ2 diabetes have a marked prevalence of IgA anti-transglutaminase autoantibodies. The great excess of positive transglutaminase autoantibodies among homozygous DQ2 diabetics is related to both the presence of DQ2 and its addition to all genetic or environmental factors associated with type 1 diabetes. These additional factors may be related to abnormalities in mucosal immunity that increases the risk of both type 1 diabetes and celiac disease. In T1D the risk associates with the HLA-DQ2/8 heterozygous haplotype was found to be increased compared with homozygous HLA-DQ2 or HLA-DQ8 individuals, suggesting an epistatic or synergic effect [37].
\nThe term autoimmune thyroid disease (AITDs) encompasses several different entities characterized by varying degrees of thyroid dysfunction and the presence of serum auto-antibodies against thyroid tissue-specific components, such as thyroglobulin (TG) and thyroid peroxidase (TPO) [34].
\nHashimoto’s thyroiditis (HT) and Graves’ disease (GD) are AITDs with different physiopathology, being traditionally regarded as two different disease entities. More recent views, in contrast, have considered the hypothesis that there might be a continuum between HT and GD.
\nGenes of, or closely associated with, the HLA complex are assumed to contribute to the genetic predisposition to AITDs. Genetics plays a prominent role in both the determination of thyroid hormone and thyrotropin (TSH) concentrations and susceptibility to autoimmune thyroid disease. Heritability studies have suggested that up to 67% of circulating thyroid hormone and TSH concentrations are genetically determined, suggesting a genetic basis for narrow intra-individual variation in levels [34]. Until today the mechanisms leading to thyroid autoimmunity are largely unknown.
\nIn 30%–40% of healthy individuals, DQ2, and DQ8 are associated with diseases such as Hashimoto’s Thyroiditis. In patients with a CD instead, autoimmune thyroid disease was observed in 14% and 30.3% in adults, while thyroid abnormalities were described in 37.6% and 41.1% in pediatric age.
\nNoteworthy was the presence of high titers of serum TPO antibodies [11] and serum TG antibodies [12] in the celiac pediatric patients without a gluten-free diet (GFD), these values were reported to return to normal after 2 or 3 years on a GFD. This finding suggests that these antibodies are gluten dependent.
\nFurthermore has been analyzed the association between Hashimoto’s thyroiditis and celiac disease in the Dutch population and it has been demonstrated that HLA DQ2.5 was associated with higher TSH levels. This correlation is not been found for the other thyroid markers (TPO, FT4). A reason could be that TSH is a more sensitive marker for hypothyroidism, as well as the fact that TSH is a quantitative parameter measured in all participants of that study, giving more power to detect differences.
\nMore than doubled GD rates are correlated to the genetic association to the DR3-DQ2 haplotype [38]. A study of Asian Indian patients with Graves’ disease revealed a significant increase in the frequency of HLA-DQW2 as compared to the control population [37]. HLA-DQA1*0501 was also shown to be associated with GD in a Caucasian family study [37] but, the primary susceptibility allele in GD is indeed HLA-DR3 [37]. Further analyses have shown that these variants are almost always inherited together in Caucasian populations, so they act as a single genetic factor. These haplotypes are among the crucial genetic factors of celiac disease in European descendants, confirming a strong connection between gluten intolerance and autoimmune thyroid conditions. This theory is confirmed by studies on a large UK Caucasian case–control population, which have shown that the contribution of the HLA class II region to the genetic susceptibility of Graves’ disease is due to the haplotype DRB1*0304-DQB1*02-DQA1*0501, with no independent association of any individual allele. However, as a result of strong linkage disequilibrium within the MHC region, it is difficult to assess which loci are acting as primary etiological determinants. The same HLA haplotype is associated with the large multifunctional proteasome 2 loci (LMP-2). The LMP molecules are overexpressed in thyrocytes, the target cells of Graves’ disease and the LMP genes are found within the MHC class II region. The LMP genes may therefore play a role in susceptibility to Graves’ disease [39].
\nDermatitis herpetiformis (DH) is a chronic, pruritic, papulovesicular skin disease of unknown origin. The characteristic rash is symmetrically distributed over the extensor surfaces and buttocks and, also, most patients with DH have asymptomatic gluten-sensitive Enteropathy [40].
\nAll patients with DH had typical clinical and histologic features, as well as granular deposits of IgA at the dermal-epidermal junction. The gastrointestinal lesions are essentially identical to those seen in patients with ordinary CD, although less severe and more patchy. A pathophysiologic link between CD and DH has been suggested by the observation that the skin lesions of DH as well as the abnormalities of the jejunal mucosa regress on a gluten-free diet.
\nDH is associated with a markedly increased frequency of the HLA class II antigens DR3 and DQ2. The primary HLA association is HLA-DQ2 (expressed in 100% of DH patients), whereas the HLA-DR3 is code in 95% of cases [41]. HLA-DQ8 may therefore be a second HLA susceptibility molecule in DH; all the DH patients carrying DQ2 plus a DR4 haplotype also carried DQ8.
\nAn increased frequency of DR3, DQ2 homozygosity, and a slightly increased frequency of DR3, DQ2 heterozygosity were found among the DH patients. It is, therefore, possible that a gene dosage effect of DQB1*02 may be present also in DH patients.
\nDH and CD both are primarily associated with the same DQ (α1*0501, β1*02) heterodimers, and in both diseases most of the few remaining patients not carrying this heterodimer instead carry the DQ (α1*03, β1*0302) heterodimers.
\nIn patients where a jejunal biopsy has been performed have been detected abnormal biopsies both among the DQ (α1*0501, β1*02) positive and negative patients. No significant differences in the frequency of abnormal biopsies were observed between the two groups of patients.
\nCD and DH have different HLA associations; CD being primarily associated with genes in the DQ/DR region, while DH was more strongly associated with genes in the complement region. Anyway, the very similar associations in CD and DH to the same cis or trans associated DQ2 heterodimer, or the DQ8 heterodimer, can be taken as an argument against differences in primary HLA associations in these two diseases [41].
\nRecurrent pregnancy loss (RPL) is diagnosed when three or more consecutive spontaneous abortions occur. RPL occurs in about 2–3% of clinically diagnosed pregnancies of reproductive-aged women.
\nAt present, accepted etiologies for RPL include parental chromosomal abnormalities, untreated hypothyroidism, uncontrolled diabetes mellitus, certain uterine anatomic abnormalities, antiphospholipid antibody syndrome, thrombophilias, infections, and environmental factors [42].
\nIn RPL women, an increased risk of immune abnormalities, such as increased antinuclear antibodies (ANA) and thyroid antibody is been observed [43].
\nHowever, in 40% of cases, the cause is unknown.
\nA significant association between RPL and celiac disease is been demonstrated. Various pathogenic mechanisms underlying the pregnancy failure in CD have been suggested: among them the ability of anti-transglutaminase antibodies to impair the trophoblast invasiveness and endometrial endothelial cells differentiation and disrupt early placentation. A higher proportion of individuals HLA DQ2/DQ8 positive in women with RPL compared to controls is found, (52.6% vs. 23.6%), with 3.6 times higher odds of DQ2/DQ8 positivity.
\nWhether a similar mechanism to that of CD can be linked to this obstetric complication needs to be investigated. This model might appear a simplification of all the complex mechanisms underlying RPL.
\nThe HLA-DQ2/DQ8 alleles by themselves, outside of CD, are found more frequently in RPL women. A possible pathogenic link of HLA-DQ2/DQ8 positivity, in presence of exogenous still unknown stimuli, may favor an immune condition with detrimental effects during the early stages of pregnancy.
\nA statistically significant association between HLA-DQ2/DQ8 and ANA positivity in RPL women is demonstrated. There is a significantly higher prevalence of ANA positivity in RPL women compared to control (~ 50% vs. 8.3%–27%).
\nANA are a group of autoantibodies found both in the serum of patients with autoimmune and rheumatic diseases and in the general population.
\nAs serological markers, ANA show diagnostic and prognostic significance, while their clinical utility in normal individuals is still unclear. Even if many serologically positive individuals will never develop an autoimmune disease, others may be in a pre-autoimmune state.
\nFurther studies are needed to better understand the possible pathogenic mechanism to this observation; the clinical and therapeutic implications of our observation to provide a new approach to RPL couples [44].
\nHLA class-II alleles are associated with some allergies indicating that these alleles might confer susceptibility to the respective allergens. HLA plays a role in antigen/allergen presentation and IgE deregulations.
\nFew studies have associated HLA DQ2/DQ8 with allergy and other ones have analyzed the association between HLA class II antigens and the specific IgE response to purified allergens. One of these studies found an association between DQ8 and have in specific IgE immune response in individuals with a latex allergy, while others found DQ2 to be associated with olive pollen. However, the association of HLA DQ2/8 with allergy remains unclear.
\nThere is a significant difference between HLA DQ2/8-positive and -negative individuals for dust mite allergy.
\nA significant association between the IgE antibody response to a highly purified allergen from olive tree pollen and HLA class II antigens DR7 and DQ2 in Spanish patients with seasonal allergic pollenosis is reported. The HLA-DQ2 phenotypic frequency is greater in patients with IgE antibodies olive tree pollen compared with the control group.
\nThe combined involvement of DR and DQ in the allergen response has only been described in the study of reactive T-cell repertoire in a mite sensitized patient. It’s identified HLA-DR and DQ restricted T-cell epitopes, one of which can bind to both DR and DQ molecules.
\nThese results empathize the importance of genetic factors in the allergic response. As described in several reports, antigen-specific and non-specific factors are involved in genetic restriction.
\nUntil now none of these factors can be considered as the exclusive determinant of the restriction. It is necessary to perform more studies with T-cell lines and peptides of this protein to determine which is the main region implicated in this response, and clarify this complex response [45].
\nInfection with human immunodeficiency virus type 1 (HIV-1) and progression to acquired immune deficiency syndrome (AIDS) are controlled by both host genetic factors and viral factors.
\nThe HLA region controls immune response functions and tissue rejection and influences susceptibility to infectious diseases including HIV. There are HLA class II alleles associated with susceptibility to and protection from HIV-1 infection and that these differences between ethnic groups.
\nIn the HIV+ Caucasian group, a poor prognosis was associated with HLA-DQ2 and a preferable prognosis was associated with HLA-DQ3.
\nThe HLA-DQ3 association appears to be linked with the development of Toxoplasmic Encephalitis (TE) in AIDS. An association of HLA-DQ2 with the occurrence of opportunistic infections in AIDS patients is been confirmed [46]. Of interest was the absence of difference in the frequencies of the HLA-DQ2 antigen between TE patients and controls.
\nThe development of TE in HIV infected patients is regulated by genes in or near the HLA complex and suggests that HLA-DQ typing may help in decisions regarding TE prophylaxis.
\nAn immune response gene in the DQ region may control the progression of HIV infection in adults. The rapidly progressive DQ-associated peptide might block the progression of HIV if given as a novel vaccine [47].
\nAlthough DQ2 is associated with vigorous antigluten T cell responses, DQ2 also is associated with poor responses to several vaccines and failure to control hepatitis virus C and hepatitis virus B.
\nStudies analyses the association between HLA class II alleles and haplotypes with antibody response to recombinant HBsAg vaccination in Iranian healthy adult individuals. The results, in parallel with other reports, confirm the association of certain HLA class-II alleles with a lack of antibody response to HBsAg vaccine [48].
\nDiscordant HLA/peptide binding and cytokine production patterns observed in genetically identical monozygotic twins vaccinated with HBsAg suggest the involvement of post genetic and environmental factors influencing the T cell repertoire.
\nHowever, APC from non-responders can present HBsAg to HLA class II-matched T-cells of responders. This indicates that defective HBsAg-specific T-cell repertoire rather than APC dysfunction could be involved in vaccination failure [49].
\nSeveral studies have established significant associations between DQ2, primary sclerosing cholangitis, and hepatitis C virus recurrence after transplant. A significant relationship between the individual scores of HLA mismatches HLA-DQ2 and the recurrence of HCV was observed.
\nThe large proportion of DQ2/8 positive viral hepatitis patients agrees with the hypothesis that these haplotypes may be involved in certain liver disease pathogenesis. DR3-DQ2 haplotype is the principal risk factor for the disease [50].
\nAnalyses by restriction fragment length polymorphism do not implicate a single susceptibility gene at the DQ locus. The unique factor that allows patients with autoimmune hepatitis to be distinguished from normal subjects or those with viral hepatitis is the DR3-DQ2 haplotype.
\nThe association of DQ2 with suboptimal responses to some viruses raised the possibility that its reduced interaction with DM might also lead to the presentation of moderate-affinity viral peptides, whose unstable binding to DQ2 would reduce the surface of the DQ2/peptide complex and compromise CD4+ T cell responses [51].
\nHLA genes also play a role in reproduction, pregnancy maintenance, in parental recognition and have been associated with over 100 diseases and disorders including autism.
\nAutism remained a poorly understood pathology for several decades. It is important to note that the diagnostic criteria have been modified over the years to include a broader category of symptoms, thus increasing the number of children diagnosed with the disorder, now referred to as Autism Spectrum Disorder (ASD) [52].
\nIt has been reported that ASD subjects often have associations with HLA genes or haplotypes, suggesting underlying deregulation of the immune system mediated by HLA genes.
\nA significant number of autistic children have serum levels of IgA antibodies against the enzyme tissue transglutaminase II (TG2) above normal, and the expression of these antibodies is linked to the HLA-DR3, DQ2, and DR7, DQ2 haplotypes [53].
\nTG2 is expressed in the brain, where it is important in cell adhesion and synaptic stabilization.
\nThese children constitute a subpopulation of autistic children who fall within the autism disease spectrum, and for whom autoimmunity may represent a significant etiological component of their autism.
\nMultiple sclerosis is a chronic disease in young adults. It is caused by the demyelination of the central nervous system cells. It is considered a T-cell-mediated autoimmune disease that is likely caused by exogenous events, such as infectious agents, in susceptible individuals [54].
\nPopulation, family, and twin studies indicate that genetic factors and most likely several genes are associated with the disease, but genetic backgrounds as well as exogenous or somatic events are required to develop the disease. The strongest genetic association with disease among the many candidate genes that were analyzed was demonstrated for HLA-DR15, HLA-DQ2, and HLA-DQ6 [55]. HLA-class II haplotypes such as DR2/DQ6, DR3/DQ2, and DR4/DQ8 show the strongest linkage with the disease.
\nA positive connection of primary progressive MS with DR4-DQ8 and DR1-DQ5 and an association of “bout onset” MS with DR17-DQ2 is be found, while an HLA association with disease severity was not found [56].
\nIt is currently unclear how the expression of a particular HLA class II gene would result in susceptibility to develop an organ-specific autoimmune disease.
\nThe HLADQ2 associated disease risk is known to be modified across individuals or populations varying in ethnic background, geography, or gender.
\nThe presence of genes coding for DQ2 and DQ8 molecules explains up to 40% of the occurrence of celiac disease in European populations. DQ2 is most common in Western Europe; higher frequencies are observed in parts of Spain and Ireland. In European celiac patients, the frequency of the HLA DQ2 is up by 90% e the HLA DQ8 is between five and 10% like was described in Dutch, UK, and Irish cases.
\nDifferences in the frequencies of the HLA genotypes DQ2 and DQ8 in non-European populations have already been described. Patients of Indian origin had a lower frequency of HLA DQ2 than those of British origin. Lower frequencies of HLA DQ2 and higher frequency of HLA DQ8 than Europe have also been described among CD patients in the United States (82% DQ2 and 16% DQ8 only) and in Cuba (86% DQ2) In Chilean celiac patients the genotype DQ8 predominates. The genotypes DQ2 and DQ8 were present in 93.2% of patients with CD in the Northeast of Brazil. The HLA DQ2 was present in 75.6% and DQ8 in 17.8% of these patients.
\nAnother finding from this group is that 79% of the unaffected control families carried genotype DQ2 and/or DQ8, which is one of the highest frequencies so far described among first-degree relatives. Most studies on HLA among first-degree relatives found that no more than 59.5% of first-degree relatives in Europe presented HLA DQ2 and DQ8. Since the frequencies of genetic markers among populations of first-degree relatives reflect and amplify those among the general population of which they form part, in this region, a large proportion of the general population may carry these markers.
\nThe frequencies of the different isoforms of DQ2 were also analyzed. The Eurasian geographic distribution of DQ2.2 is slightly greater than DQ2.5. Compared to DQ2.5, the frequency in Sardinia is low, but in Iberia, it is high reaching a maximum frequency of ~30% in Northern Iberia, and half that in the British.
\nCases of DQ2.2 patients with CD without DQ2.5 are in some populations, particularly in the south of Europe. It extends along the Mediterranean and Africa at relatively high frequency and is found in high frequencies in some Central Asian, Mongolians, and Han Chinese. It does not appear to have an indigenous presence in the West Pacific Rim and DQ2.2 presence in South-east Asia and Indonesia is likely the result of gene flow from India and China in the past. The haplotype shows considerable diversity in Africa. The expansion of DQ2.2 into Europe appears to have been slightly later. DQ2.5 is generally highest in northern, Icelandic Europe, and Basque in northern Spain. Phenotype frequency exceeds 50% in parts of Ireland, which overlaps one of three global nodes of the DQ2.5 haplotype in Western Europe [57].
\nThis work is designed to provide a quick overview of the HLA-DQ2 molecule, analyzing the main points such as molecular structure, gene variants, and the role played by the molecule in the clinical context; dealing not only with the most known autoimmune diseases to which it is linked but also with less known areas of development.
\nThis work aimed to offer a new point of view on the subject, although aware of having only skimmed the topic, we hope to have offered a starting point for any new analysis of the molecule.
\nThis chapter allowed us to analyze HLA in a different context from the most known of compatibility in hematopoietic stem cell transplantation, confirming once again the enormous complexity of the HLA system and its many facets and applications.
\n"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nOAI-PMH
\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\nPeer Review Policies
\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\\n\\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
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The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
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Lipids of seeds are essentially composed of TAG; it would be interesting to describe their synthesis during the maturation of the seeds. Some plants contain in their reserve lipids unconventional fatty acids such as gamma linolenic acid in Borrago officinalis L., short-chain fatty acids C: 12 and C: 10, fatty acids with very long chains, and fatty acids that are cyclical. 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She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. 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He is also Member of the Laboratory of genetic, animal and feed resource and member of Animal science Department of INAT. He graduated from Higher School of Agriculture of Mateur, University of Carthage, in 2002 and completed his masters in 2006. Dr. M’HAMDI completed his PhD thesis in Genetic welfare indicators of dairy cattle at Higher Institute of Agronomy of Chott-Meriem, University of Sousse, in 2011. 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He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. 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She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}},{id:"441116",title:"Dr.",name:"Jovanka M.",middleName:null,surname:"Voyich",slug:"jovanka-m.-voyich",fullName:"Jovanka M. Voyich",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Montana State University",country:{name:"United States of America"}}},{id:"330412",title:"Dr.",name:"Muhammad",middleName:null,surname:"Farhab",slug:"muhammad-farhab",fullName:"Muhammad Farhab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"349495",title:"Dr.",name:"Muhammad",middleName:null,surname:"Ijaz",slug:"muhammad-ijaz",fullName:"Muhammad Ijaz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}}]}},subseries:{item:{id:"20",type:"subseries",title:"Animal Nutrition",keywords:"Sustainable Animal Diets, Carbon Footprint, Meta Analyses",scope:"An essential part of animal production is nutrition. Animals need to receive a properly balanced diet. One of the new challenges we are now faced with is sustainable animal diets (STAND) that involve the 3 P’s (People, Planet, and Profitability). We must develop animal feed that does not compete with human food, use antibiotics, and explore new growth promoters options, such as plant extracts or compounds that promote feed efficiency (e.g., monensin, oils, enzymes, probiotics). These new feed options must also be environmentally friendly, reducing the Carbon footprint, CH4, N, and P emissions to the environment, with an adequate formulation of nutrients.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/20.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11416,editor:{id:"175967",title:"Dr.",name:"Manuel",middleName:null,surname:"Gonzalez Ronquillo",slug:"manuel-gonzalez-ronquillo",fullName:"Manuel Gonzalez Ronquillo",profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",biography:"Dr. Manuel González Ronquillo obtained his doctorate degree from the University of Zaragoza, Spain, in 2001. He is a research professor at the Faculty of Veterinary Medicine and Animal Husbandry, Autonomous University of the State of Mexico. He is also a level-2 researcher. He received a Fulbright-Garcia Robles fellowship for a postdoctoral stay at the US Dairy Forage Research Center, Madison, Wisconsin, USA in 2008–2009. He received grants from Alianza del Pacifico for a stay at the University of Magallanes, Chile, in 2014, and from Consejo Nacional de Ciencia y Tecnología (CONACyT) to work in the Food and Agriculture Organization’s Animal Production and Health Division (AGA), Rome, Italy, in 2014–2015. He has collaborated with researchers from different countries and published ninety-eight journal articles. He teaches various degree courses in zootechnics, sheep production, and agricultural sciences and natural resources.\n\nDr. Ronquillo’s research focuses on the evaluation of sustainable animal diets (StAnD), using native resources of the region, decreasing carbon footprint, and applying meta-analysis and mathematical models for a better understanding of animal production.",institutionString:null,institution:{name:"Universidad Autónoma del Estado de México",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,series:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517"},editorialBoard:[{id:"175762",title:"Dr.",name:"Alfredo J.",middleName:null,surname:"Escribano",slug:"alfredo-j.-escribano",fullName:"Alfredo J. 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