MOG prophylactic procedures in EAE.
\r\n\tb) how a concentrated attention focus on screens (i.e., tablets and smartphones) could result in a total activity absorption and a flow experience;
\r\n\tc) teens' preference for media social interaction appears to be closely associated with impaired modes of mood regulation;
\r\n\td) the web activities as factors of externalized and/or internalized risks;
\r\n\te) the implementation of health promotion interventions by Internet Apps; finally,
\r\n\tf) the cross-cultural differences and similarities about teen approaches to the web around the world.
\r\n\tThis book intends to provide the reader with an overview of studies with a research topic that is crucial today: the need to integrate teens' use of the web into the processes contributing to determine adolescents' developmental trajectories and Quality of Life.
",isbn:"978-1-83969-594-0",printIsbn:"978-1-83969-593-3",pdfIsbn:"978-1-83969-595-7",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"f005179bb7f6cd7c531a00cd8da18eaa",bookSignature:"Prof. Massimo Ingrassia and Prof. Loredana Benedetto",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10671.jpg",keywords:"Media Multitasking, Brain Development, Optimal-Experience Conditions, Digital Media Use, Mood Self-Regulation, Social Networking, Health Risk Behaviors, Internalizing/Externalizing Risk, Health Behaviors, Prevention, Cross-Cultural Research, Teen",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 25th 2021",dateEndSecondStepPublish:"March 24th 2021",dateEndThirdStepPublish:"May 23rd 2021",dateEndFourthStepPublish:"August 11th 2021",dateEndFifthStepPublish:"October 10th 2021",remainingDaysToSecondStep:"a month",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Massimo Ingrassia is Director of the Post-graduate Advanced Studies in Palliative care and pain management for psychologists and a scientific advisor in research projects assessing psychological adjustment and therapeutic adherence in chronic illness. He was the author or co-author of several articles, and editor of the books on Parenting.",coeditorOneBiosketch:"Loredana Benedetto, Ph.D., is a psychologist and professor of Developmental and Educational Psychology at the Department of Clinical and Experimental Medicine, University of Messina. She was a scientific consultant for projects supporting families of the disabled and interventions in pediatric palliative care.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"193901",title:"Prof.",name:"Massimo",middleName:null,surname:"Ingrassia",slug:"massimo-ingrassia",fullName:"Massimo Ingrassia",profilePictureURL:"https://mts.intechopen.com/storage/users/193901/images/system/193901.png",biography:"Massimo Ingrassia, PsyD, is an Associate Professor of Developmental and Educational Psychology at Messina University, Italy, where he teaches graduate and postgraduate courses in Health Psychology. He is the Director of the postgraduate advanced studies in Palliative Care and Pain Management for Psychologists. His research interests include risk behaviors in adolescence and emerging adulthood, childhood development and digital technologies, pediatric palliative care and family resilience, and quality of life and chronic diseases. Dr. Ingrassia is also a scientific advisor for research projects assessing psychological adjustment and therapeutic adherence in chronic illness. 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She has been a scientific consultant for projects supporting families of disabled children and interventions in pediatric palliative care. Her research interests focus on parenting assessment, self-efficacy and parental cognition, digital parenting and problematic use of the Internet in children, metacognition and childhood disorders, early intervention in autism and developmental disabilities, and behavioral parent training. 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In this sense, it is academically subdivided into innate and adaptive immune responses. Innate immunity is the first defense line and includes the microbicidal activity of macrophages and polymorphonuclear cells. Host defense against microorganisms is dependent upon recognition of pathogen-associated molecular patterns, mainly by toll-like receptors (TLRs) present in these cells. Otherwise, adaptive immunity requires specific antigen recognition by B and T lymphocytes. Differently from B cells that can directly recognize the antigens, T cells require previous antigen processing and interaction of epitopes with major histocompatibility complex proteins that are then expressed at the surface of antigen-presenting cells (APCs) as, for example, dendritic cells (DCs). Due to their strong potential for proliferation and activation, B and T cell activity needs to be regulated. A special T-cell subpopulation called regulatory T (Treg) cell plays a major role in controlling inflammatory immune responses. To maintain its homeostasis, the immune system has to manage a balance between inflammatory and anti-inflammatory responses. The imbalance of these immune responses leads to the development of many diseases such as autoimmune pathologies. In this context, other T-cell subpopulations such as T helper type 1 (Th1) and type 17 (Th17) cells, which are inflammatory, and type 2 cells (Th2), which are predominantly anti-inflammatory, are also involved. Besides its ability to eliminate pathogens and restore the host homeostasis, the immune system has also a mechanism to hamper the development of an immune response against the body’s own tissues. This mechanism, called self-tolerance, can be disrupted by the combination of a variety of genetic, environmental, and immunological factors that lead to autoimmunity. The relevance of vitamin D (VitD) in multiple sclerosis (MS), which is an autoimmune disease involving the central nervous system (CNS), is discussed in this chapter.
\nThe history of VitD is strongly linked to rickets and its treatment with cod liver oil. In 1922, McCollum [1] coined the term vitamin D to refer to the antirachitic factor found in cod liver oil [2]. For this reason and for a long time, the most widely accepted physiological role of VitD was related to calcium and phosphorus metabolism and bone mineralization [3]. However, since the 1980s, many researches implicated VitD on the cardiovascular, endocrine, and central nervous system (CNS), as well as on the immune system physiology. The active form of VitD (1α,25-dihydroxyvitamin D3) determines pleiotropic effects in human body through binding to vitamin D receptor (VDR), which is a member of the steroid hormone receptor superfamily found in a variety of human cells. The biological effects of VitD can be elicited by non-genomic and genomic mechanisms depending on the cell location of VDR. The non-genomic (rapid) mechanisms consist in VitD direct effect on the cells through membrane VDR binding. These effects include, for example, the activation of protein kinase C in different organs [4]. The genomic mechanism is determined by intracellular VDR that heterodimerizes with retinoic X receptor after binding to active VitD. This heterodimer is then translocated to the nucleus leading to activation or inhibition of a vast diversity of genes [5].
\nSome of the most important aspects of VitD epidemiology have been established by the scientist Michael Holick and his collaborators. As many people do not have an adequate sunlight exposure due to skin cancer risk, sedentary lifestyle, darker skin, or during the winter in countries far from the equator, there is an increasing number of persons with VitD deficiency around the world [6]. In the past few years, VitD deficiency has been associated with the etiology of many chronic diseases, like Crohn’s disease, infections of the upper respiratory tract, cancer, myocardial infarction, Alzheimer’s disease, autoimmune diseases, and others [7]. According to current knowledge, VitD serum levels should be between 30 and 100 ng/mL in healthy humans. VitD insufficiency is related to levels between 21 and 29 ng/mL, whereas a pronounced VitD deficiency is considered in individuals whose VitD levels are below 20 ng/mL. On the other hand, serum levels over 150 ng/mL can determine intoxication VitD intoxication [8]. Excessive oral intake of VitD may cause a hypervitaminosis condition with toxic effects such as hypercalcemia and hypercalciuria. Theories concerning the mechanisms of VitD toxicity involve elevated plasma concentration of VitD itself or its metabolites that culminates in overexpression of a variety of genes [9]. Although solubility of vitamins (fat or water) has no direct effect on toxicity, the ability of fat-soluble vitamins such as VitD to accumulate in the adipose tissue determines their higher toxic potential than water-soluble vitamins. For example, subcutaneous fat necrosis releases tissue-accumulated VitD that leads to hypervitaminosis and its toxic effects [10].
\nThe highest amounts of VitD are synthesized by the skin exposed to sunlight. Ultraviolet radiation converts 7-dehydrocholesterol in pre-vitamin D3. Then pre-vitamin D3 suffers a spontaneous thermal isomerization into vitamin D3, named cholecalciferol [11]. Due to this essential role of sunlight, this vitamin has been called “sunshine vitamin” [12]. Smaller amounts of VitD can be obtained from intake of certain foods such as mushrooms, fish, milk, and eggs [13]. To become a metabolically active hormone, cholecalciferol needs to be hydroxylated twice. The first hydroxylation takes place in the liver and converts cholecalciferol into 25-dyhidroxyvitamin D (calcidiol) via the enzyme 25-hydroxilase [14]. Plasma calcidiol levels are usually used as a parameter of VitD status because it increases in proportion to VitD intake [15]. After that, calcidiol binds to a carrier molecule, known as the vitamin D-binding protein, to be systemically transported to tissues that express 1α-hydroxylase (CYP27B1) [16]. The second hydroxylation, which generates the bioactive metabolite 1,25-dihydroxyvitamin D3 (calcitriol), occurs at the renal proximal tubular cells that are rich in CYP27B1 [17]. This reaction involves the sequential reduction of flavoprotein, renal ferredoxin, and cytochrome P-450 [18]. A critical physiological role in skeletal homeostasis is mediated by calcitriol. Concisely, hypocalcemia stimulates parathyroid glands to release parathyroid hormone, which activates renal CYP27B1 enzyme function, resulting in calcitriol production. Besides, parathyroid hormone stimulates osteoclast maturation to release calcium and phosphate from the bones. Calcitriol also reduces renal calcium excretion and increases calcium absorption from foods in the intestine. When normal calcium levels are obtained, calcitriol exerts a feedback regulation in the parathyroid gland, downregulating CYP27B1 activity to avoid VitD intoxication [14]. Besides the kidneys, 1α-hydroxylase has been reported in many tissues including bone, placenta, prostate, and parathyroid gland. In addition, several cancer cells and immune cells, such as macrophages, T lymphocytes, and DCs, are also able to produce this enzyme [19,20].
\nFirst evidences of VitD role in the immune system regulation date from the 80s. Haq [21] demonstrated that active VitD, but not its non-active form, blocked the production of IL (interleukin)-2 and consequently inhibited T-cell proliferation. Based on this downmodulatory effect, the potential of VitD to increase organ survival in experimental allograft transplantation was also evaluated. First studies in this field were based on the
It is well known that VitD stimulates the innate immune system by enhancing the antimicrobial ability of monocytes and macrophages. This effect is mainly associated with TLRs activation and increased release of cathelicidin and IL-1β by these cells [26]. Clinical evidences suggested a strong correlation between a poor VitD status and an increased susceptibility to infections. VitD has also been linked to more severe infectious diseases [27–29]. Moreover, Nouari et al. [30] recently demonstrated that active VitD can enhance the microbicidal activity of human monocyte-derived macrophages against
Conversely, VitD has an inhibitory effect on the adaptive immune system. It directly targets APCs, which are a very important link between the innate and adaptive immunity. In this sense, conventional APCs as DCs are profoundly affected by VitD. The mechanisms underlying the effects of VitD on DC function were recently reviewed by Barragan et al. [31].
The direct effect of VitD on T cells was the first evidence of the immunomodulatory activity of this hormone. Active VitD suppresses Th1 inflammatory immune response through inhibition of IL-2 and IFN-γ production, which are the main cytokines produced by this Th cell subset. This subject was revised by Lemire et al. [37]. These authors described that VitD preferentially inhibited Th1 functions having little effects over Th2 cells. At that time, they already suggested that this vitamin could have a potential therapeutic application in Th1-mediated diseases as is the case of some autoimmune pathologies.
\nMany inflammatory responses are also related to the development of Th17 cells and its signature cytokine named IL-17. It is largely known that this T-cell subpopulation is involved in the pathogenesis of a variety of inflammatory and autoimmune disorders [38]. In this context, Th17 cell pathogenicity is frequently related to a Th17-Th1 functional plasticity that is regulated by the cytokine milieu [39]. The immunomodulatory effects of VitD on Th17 cells are not clear and depend upon the disease. Most of what is known concerning VitD effect on these cells is based on experimental studies. For example, oral treatment with active VitD prevented and partly reversed experimental autoimmune uveitis in mice. This effect was related to both decreased IL-17 production and impaired development of Th17 cells [40]. Moreover, Chang et al. [41] demonstrated that active VitD treatment protected mice from experimental autoimmune encephalomyelitis (EAE) by inhibiting the differentiation and further migration of Th17 cells to the central nervous system (CNS). Even though the effect of VitD on animal models is evident, human data are controversial and there is not a consensus in the literature yet.
\nData on the effects of VitD on the development of Th2 cells are also conflicting. This T-cell subset is able to suppress Th1 inflammatory immune response through the production of anti-inflammatory cytokines such as IL-4 and IL-5. A direct effect of active VitD on Th2 cells was demonstrated by Boonstra et al. [42]. Even in the absence of APCs, these authors observed an increased frequency of IL-4-, IL-5-, and IL-10-producing murine CD4+ T cells after
Other T-cell subsets such as CD8+ T cells and natural-killer T cells (NKT) are also targets of VitD. Chen et al. [44] demonstrated that active VitD signaling through VDR is essential to control pathogenic CD8+ T cells in inflammatory bowel diseases. The importance of VDR was also highlighted by Yu et al. [45] who demonstrated a critical role of VDR expression in the development of induced NKT cells from mice fed with synthetic diets containing active VitD. There are few studies concerning the impact of VitD on B cells.
VitD action on the immune and the central nervous systems. (A) Effect of active VitD on the innate and the adaptive immunity cells and (B) direct and indirect effects of active VitD on the central nervous system.
The immunomodulatory potential of VitD has been widely explored in the field of autoimmune diseases. Epidemiological studies demonstrated that low VitD is correlated with a higher incidence of autoimmune diseases. Besides, genetic factors as VDR polymorphisms are also linked to autoimmune disorder susceptibility. The association between VitD and systemic and organ-specific autoimmune diseases, including multiple sclerosis (MS), was carefully reviewed by Agmon-Levin et al. [49].
\nMS is an autoimmune disease characterized by the activation of self-reactive T cells specific for CNS antigens. This immune response triggers an initial inflammation in brain and spinal cord that is then followed by demyelination, axonal damage, and scar formation [50]. The pathogenic immune response observed in MS is mainly mediated by Th1 and Th17 [51]. About 85% of MS patients present with a biphasic disease characterized by alternating episodes of neurological disability and recovery, which is entitled as relapsing remitting MS (RRMS). Within 20–25 years, 60–70% of these patients progress to a secondary-progressive disease that is characterized by progressive neurological deterioration. Approximately 10% of the patients display a disease course classified as primary progressive MS, which is characterized by a continuous decline in neurological performance without any recovery episode [52]. Magnetic resonance imaging (MRI) is playing a prominent role in the diagnosis and also in the analysis of MS therapy efficacy [53]. As mentioned before, autoimmune diseases result from the interactions of environmental and genetic risk factors. Environmental risk factors considered essential for MS development include infections and non-infectious factors that comprise differences in diet and other behaviors, such as cigarette smoking and sunlight exposure [54,55]. The development of MS has been strongly associated with viral and bacterial infections [54,56]. More recently, a possible relationship between MS and Candida species was proposed [57–59]. Our research team recently demonstrated that previous infection with
Epidemiological data on MS incidence and prevalence drew attention to a possible link between the geographical distribution of the disease and exposure to the sun, UV radiation/intensity, and VitD levels. This sunshine hypothesis also known as latitude-gradient effect was initially proposed by Limburg [61] that suggested a correlation between higher MS occurrence and increasing distance from the equator. According to the World Health Organization [62], the highest prevalence of MS occurs in Europe (80 per 100,000 people) and the lowest prevalence in Africa (0.3 per 100,000). More recently it was reported that, until 2013, the number of MS was higher in northern hemisphere and lower in southern hemisphere, with the exception of Australia and New Zealand [63]. A latitudinal variation was also identified in the continents. For example, geospatial analysis carried out in North American regions showed an inverse correlation between MS and UV radiation, that is, higher MS rates have been associated with lower UV radiation due to a south-north latitudinal gradient [64]. Interestingly, a series of lifestyle changes that include sun evasion associated with skin protection and extra time indoors, or increased charter tourism to warmer countries during the winter, seems to abolish latitude effects on UV radiation exposure [65]. According to these authors, this association between sun exposure and MS can be determined by distinct effects: by the VitD generated by sun exposure, by direct sun effects, or by a combination of both. These possibilities are reinforced by data from experimental animals and also from dietary studies in human populations. Dermal application of VitD ointments and UV radiation in VDR knockout mice were both able to induce Treg cells [66]. Further study indicated that these UV-induced Treg cells were able to migrate to the CNS of mice with EAE where they downregulated the inflammatory activity [67].
\nA lower prevalence of MS in some northern countries, which in a general way are expected to have a higher number of patients with the disease, could be explained by VitD-related dietary factors. For example, VitD sufficiency could be achieved through a traditional diet that includes fatty fish and cod liver oil. This possibility has been suggested to explain the reduced risk of MS in Norway that is located at the north of the Arctic Circle [68]. The relevant role of dietary VitD intake in MS was examined in two large cohorts of women: the Nurses\' Health Study (NHS; 92,253 women followed between 1980 and 2000) and the Nurses\' Health Study II (NHS II; 95,310 women followed between 1991 and 2001). The authors concluded that intake of VitD from supplements had a protective effect on the risk of developing MS [69]. A recent study with 953 MS patients indicated an inverse association between MS risk and the dose of cod liver oil during adolescence, suggesting that this stage of life is an important susceptible period for adult-onset MS, reinforcing the importance of dietary VitD as a risk factor for MS [70]. Altogether these data supported the possibility that MS patients could have lower levels of VitD. Regarding this, the largest study to date compared VitD levels present in Iranian MS patients (
The recent identification of VitD as a risk factor for MS susceptibility, and more recently as a potential modifier of disease course, inspired several clinical trials in relapsing MS [77]. It has been proposed that VitD supplementation is a low-cost and a low-risk intervention that may potentiate the efficacy of certain treatments against MS, without the risk of provoking serious adverse events as occurs with other combination therapies [76]. In effect, many patients are being already supplemented with VitD. However, it is not known whether supplementation has a significant impact on MS progression. A clinical trial (NCTO1339676) employing oral supplementation with active VitD (20,000 IU/week, cholecalciferol, Dekristol) administered once a week during 12 months together with IFN-β-1b resulted in reduction of MRI lesions in the brain of MS patients [78]. In another clinical trial (NCT 00785473), this same dose (20,000 IU/week, cholecalciferol, Dekristol) was administered during 24 months in RRMS patients under treatment with IFN-β-1b, GA, or natalizumab. Even though the patients presented a significant increase in serum VitD levels, the markers of systemic inflammation were not modified. The authors suggested that the anti-inflammatory effects of VitD supplementation are limited to RRMS patients with VitD insufficiency or to earlier stages of the disease [79]. A higher dose of VitD3 (50,000 IU/week) administered by oral route during a short period (2 months) reduced disability in RRMS patients and surprisingly upregulated IL-6 and IL-17 gene expression in the peripheral blood mononuclear cells of these patients [80]. Similarly, the same VitD dose (50,000 IU) administered by oral route every five days for 3 months in 94 RRMS patients under treatment with IFN-β-1b reduced disability of these patients but also increased IL-17 serum levels in comparison to a placebo group [81]. Investigations in this area suggested that changes in IL-17 levels could be related to the adopted VitD doses. For example, Golan et al. [82] demonstrated that IL-17 serum levels were significantly increased in a lower dose group (800 IU/per day), whereas patients that were taking higher doses (4370 IU/per day) presented heterogeneous IL-17 responses: 40% of them had decreased serum IL-17 levels, whereas 45% had increased IL-17 levels after three months of supplementation. These authors suggested that IL-17 data must be interpreted with caution as serum IL-17 is not an established biomarker of MS disease activity. Furthermore, IL-17 serum levels before treatment with IFN-β could not be correlated to disease activity parameters [83]; IL-17 also showed a trend toward higher levels in MS patients with inactive disease compared to those with active disease [84]. More recently, 40 patients with RRMS were randomized to receive 10,400 IU or 800 IU of cholecalciferol daily for 6 months. Mean increase of VitD levels from baseline to the ones detected at final visit was larger in the high-dose group than in the low-dose one and adverse events were minor and did not differ between the two groups. Interestingly, in the high-dose group, but not in the low-dose one, there was a reduction in the proportion of IL-17+CD4+ T cells. The authors concluded that daily cholecalciferol supplementation with 10,400 IU is safe and well tolerated in patients with MS and determines
The researches done so far strongly suggest that VitD supplementation could be useful in MS treatment. However, the exact doses to be prescribed to patients presenting different clinical symptoms are still waiting to be determined [86]. Regarding the side effects of VitD that include hypercalcemia [87] and the imbalance in serum concentration of parathyroid hormone [88], monitoring serum VitD would also be extremely important. In spite of the findings that VitD directly regulates the nervous system development and function [89], there is no scientific evidence to support its use as a monotherapy for MS in clinical practice [90]. Recent human trials concerning VitD supplementation in MS patients suggest that higher VitD doses are more efficient to control the symptoms and disease inflammatory markers. Nonetheless, to fix the ideal dose, it is essential to measure VitD serum levels before supplementation and to follow up the patients by constantly monitoring side effects. It is important, however, to highlight that the ideal dose could vary from one patient to another. The possible use of VitD analogs devoid of side effects must be also evaluated. World Health Organization (WHO) and Multiple Sclerosis International Federation (MSIF) published in 2008 the first Atlas of MS [62], correlating the epidemiology, diagnosis, and therapy. To the best of our knowledge, WHO did not define a specific VitD dose to treat MS.
\nExperimental autoimmune encephalomyelitis (EAE) is an animal model universally employed to investigate mechanisms of inflammation in the CNS in the context of MS. EAE is mainly induced in rodents either by active immunization with CNS antigens associated with adjuvant or by passive transfer of CNS-specific T cells. Most of the therapeutic procedures adopted nowadays were initially tested in murine EAE [91]. In 1991, it was demonstrated that VitD administration every other day for 15 days, starting 3 days before EAE induction, significantly prevented disease development and prolonged the survival of SJL/J mice [92]. This was the first report concerning the therapeutic potential of VitD on EAE. To avoid undesirable hypercalcemia
Critical effects of VitD on CD4+ T cells have been reported, whereas it is not evident if this vitamin affects CD8+ T cells, which express the highest concentrations of VDR. The effect of VitD on CD8+ T cells in EAE was evaluated in one report. The authors demonstrated that VitD inhibits EAE development even in mice lacking functional CD8+ cells, suggesting that they were not essential for VitD-suppressive effect in murine EAE [101]. The conception that the CD4+ T-cell subset was the main VitD target during EAE therapy was then established. VitD treatment triggered a reduction in the total number of lymphocytes, while the amount of IL-4 and TGF-β-1 transcripts increased in the CNS of EAE mice [102]. Still regarding anti-inflammatory cytokines, VitD therapy was reported to be much less effective in preventing EAE symptoms in IL-4-deficient mice [103] and also failed to inhibit EAE in mice with a disrupted IL-10 or IL-10R gene [104]. A more recently described profile of CD4+ T cells termed Th17 plays a critical role in numerous inflammatory conditions and autoimmune diseases. In this context, researchers showed that VitD can inhibit the differentiation and migration of Th17 cells to the CNS, ameliorating EAE symptoms [41,105].
\nAfter the first demonstration that VitD leads to induction of CD4+CD25+Foxp3+ cells with suppressive activity
Emphasis has been given to specific therapies, that is, to procedures that target CNS antigen and that would be, therefore, more efficient and devoid of side effects. In this context, MOG administration by different routes as intravenous [113], oral [114] or nasal [115], was able to suppress EAE symptoms. Various formulations containing myelin antigens were tested to control EAE. MOG conjugated with nanoparticles [116], mannan, [117] or inserted into a plasmid DNA [118] reduced EAE symptoms through induction of Foxp3+ Treg cells and dowmodulation of Th17 and Th1 cells. Our research group has been working in this context. Considering that an antigen from the CNS can provide the required specificity and that VitD is endowed with a strong downmodulatory potential, we anticipated that VitD could work as a tolerogenic adjuvant. Differently from the conventional immunogenic adjuvants that reinforce the immune response, the denominated tolerogenic adjuvants have the ability to downmodulate or modify the specific immune response when associated with specific antigens. Confirming this hypothesis, we recently demonstrated that a combined therapy with MOG + VitD blocked EAE development. This elevated efficacy was correlated with reduced production of IL-6 and IL-17 by spleen and CNS cell cultures stimulated with MOG, reduced splenic DC maturation, and also a striking decline in CNS inflammation [119] (Figure 2).
MOG + active vitamin D3 association strategy for EAE prophylaxis and treatment. C57BL/6 mice were vaccinated or treated with this association and the effect on EAE was evaluated in the acute EAE phase. Both strategies decreased production of inflammatory cytokines by CNS mononuclear cells, frequency of CD4+CD25+Foxp3+ Treg cells, and inflammation in the CNS.
Prophylactic strategies in EAE, and also in other autoimmune pathologies, are based in the concept of "inverse vaccination.” This procedure refers to the use of an immunization protocol that, differently from classical vaccination, aims to achieve an antigen-specific tolerogenic state [120]. Even though the term “inverse vaccination” could also be used as a therapeutical strategy, in this text we applied it only in the context of prophylactic vaccination. The majority of the prophylactic strategies in EAE have been done by administration of a diversity of MOG formulations delivered by distinct routes. A few examples of these procedures and the main histological and immunological findings are illustrated in Table 1.
\nThe prophylactic potential of VitD (or analogs) alone or associated with other pharmaceuticals has been tested in EAE. The adopted experimental protocols are not standardized and therefore, different amounts of VitD are administered by distinct routes. Time periods chosen for VitD administration in relation to EAE induction are also variable and some procedures consist in prolonged administration periods, even reaching the disease clinical phase. However, a general consensus is that VitD is able to improve clinical disease manifestation and also to trigger evident effects on the CNS and the immune system. Some of the effects observed in mice with EAE that were previously injected with VitD are exemplified in Table 2.
\nPeptide formulation | \nAnimal model | \nEffects | \nReferences | \n
---|---|---|---|
Plasmid DNA vaccines encoding MOG35–55 | \nC57BL6/J mice | \n↓Microglia/macrophage activation, astrogliosis, and axonal damage ↑CD4+CD25+Foxp3+ Treg | \nFissolo et al. [118] | \n
MOG35–55 conjugated to mannan, intradermally | \nC57BL/6 and SJL/J mice | \n↓Demyelination ↓Inflammatory infiltrates | \nTseveleki et al. [117] | \n
Tolerogenic DC pulsed with MOG40–55 | \nC57BL/6 mice | \n↑IL-10 production by MOG-stimulated splenocytes ↑CD3+CD4+CD25+FoxP3+ cells | \nMansilla et al. [121] | \n
MOG35–55-PLGA + IL-10-PLGA, subcutaneously | \nC57Bl/6 mice | \n↓IL-17 and IFN-α production by splenocytes↓Demyelination score | \nCappellano et al. [122] | \n
MOG prophylactic procedures in EAE.
Route | \nAnimal model | \nEffects | \nReferences | \n
---|---|---|---|
Diet | \nCD8+ −/− mice | \nProtection independent of TCD8+ cells | \nMeehan and DeLuca [101] | \n
Intraperitoneally | \nC57BL/6 mice | \n↓MyD88, IRF-4, IRF-7 and NF-kB expression ↓Several TLRs | \nLi et al. [123] | \n
Oral, gavage | \nC57BL/6 mice | \nIntact blood–CNS barrier ↓Inflammatory infiltrates in the CNS | \nGrishkan et al. [124] | \n
Intraperitoneally | \nC57BL/6 mice | \n↓Demyelination ↑Beclin-1 expression in neurons | \nZhen et al. [111] | \n
Vitamin D3 prophylactic procedures in EAE.
The combination of VitD with other substances as calcitonin [125], IFN-β [126], bisphosphonate [127], rapamycin [128], and cyclosporine [129] has determined cooperative effects over EAE control. We recently tested the association of VitD with MOG as a prophylactic approach to control EAE development. Again, in this procedure, we explored the concept of VitD as a tolerogenic adjuvant. This concept and its potential application to trigger self-tolerance in autoimmune diseases were conceived by Kang et al. [130]. These authors validated this hypothesis by demonstrating that FK506 (tacrolimus) associated with MOG was prophylactic in encephalomyelitis [131]. In this context, we hypothesized that active VitD could also behave as a tolerogenic adjuvant if associated with a CNS-specific antigen. Vaccination with MOG associated with VitD, before EAE induction in C57BL/6 female mice, determined a significant clinical improvement characterized by absence of clinical score and no body weight loss. An impressive reduction in CNS inflammation, DC maturation and also cytokine production by CNS and spleen cell cultures was detected in these vaccinated animals [132]. As described in Section 6 of this chapter, this combination of MOG with VitD was also very efficient as a therapeutic procedure in the EAE model. This prophylactic and therapeutic potential of the MOG/VitD association in EAE is illustrated in Figure 2. The possible use of VitD as a tolerogenic adjuvant in association with other self-antigens, as a strategy to control autoimmune pathologies, warrants future investigation. In our opinion, the fact that VitD is already accepted for human supplementation will facilitate its adoption for MS treatments based on its association with neuronal self-antigens.
\nThe authors are thankful for the financial support from São Paulo State Foundation (FAPESP)—Grant #2013/26257-8, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)—Grant #302710/2013-2 and also Pró-Reitoria de Pesquisa—Universidade Estadual Paulista (PROPe—UNESP). Special thanks are given to Danilo Sanches Moreno for his substantial contribution to the art of drawing and figures.
\nSpecific learning disorder (SLD) is defined as a neurodevelopmental disorder that includes the difficulties in understanding or learning, problems in writing or written expression, and difficulties in the perception/calculation of the numbers. These problems make the academic performance of the child lower than expected. This disorder is originated from biology affecting the acquisition or perception capabilities of the brain for the verbal and nonverbal information processes. There is an abnormality of cognitive level associated with behavioral findings in its etiology [1]. Therefore, it is defined as a failure to meet approved grade-level standards in listening comprehension, reading comprehension, basic reading and reading fluency skills, written expression, mathematics calculation, and/or mathematics problem-solving, despite age-appropriate learning opportunities and instruction [2]. These deficits are persistent and significantly interfere with academic achievement, occupational performance, or activities of daily life [3].
SLD is a multifactorial disorder which has in its etiology a genetic predisposition and family load, developmental and cognitive factors, language spoken, and environmental factors including the level of education and socioeconomic situation. In many studies, gender, level of intelligence, higher family history of learning disabilities, low parental education, the exposure during pregnancy to the use of medicines, exposure to radiation, smoking, infections, hypoxia, complicated deliveries, hypoxia during labor, premature labor, low birth weight, low Apgar score, neonatal jaundice, convulsions, developmental delay, low-income families, and low socioeconomic status, leading to the occurrence of the SLD, are defined as predeterminants [4, 5, 6, 7, 8, 9, 10, 11]. In the clinical examination of SLD, children’s developmental, medical, educational, and family history are assessed. Test scores and teacher observations and response to academic interventions are also evaluated. For SLD, current academic skills must be well below the average range of expected scores given the person’s chronological age (e.g., at least 1.5 standard deviations (SD)) below the population mean for age and age-appropriate education in culturally and linguistically appropriate tests of reading, writing, and/or mathematics [2, 3, 12] with normal levels of intelligence functioning (considering an intellectual coefficient (IQ) score greater than 70) [1]. These problems cannot be explained with mental retardation, loss of sense (vision or hearing), other psychiatric or neurological disorder, psychosocial difficulties, insufficiency of the language to be used in the academic environment, or education problems. The types like reading disorder (dyslexia), written expression disorder (dysgraphia), and mathematics disorder (dyscalculia) can be seen together or separately.
SLD are usually apparent in the early years of school; some children can show great learning difficulties later on, enabling diagnosis to be made at any point after formal education starts and in adolescence and even adulthood [1]. If treatment approaches are not initiated at an early age, the lives of children and adolescents with SLD are adversely affected due to academic failure. In almost 40% of cases dropout of school. Due to low academic failure, lack of self-confidence, social and behavioral problems may cause emotional problems. This can lead to anxiety disorders, depressive symptoms, somatic complaints, adaptation problems, and difficulties in maintaining a permanent job in the future [1, 13, 14, 15, 16].
The number of the prevalence studies with diagnostic criteria or scales for SLD is low. On the other hand, SLD is accepted as relatively frequent and is not known sufficiently [17, 18, 19]. There have been many studies on SLD from the past to today, and different ratios have been announced on the prevalence. The frequency and prevalence of the SLD are stated in various reports with different rates depending on the size of the sample and the inclusion criteria. For example, Al-Yagon et al. reported different prevalence rates that included 1.2% from Greek epidemiologic study in 2004 and 20.0% from a study in Australia in 2000 [20]. A lifelong prevalence estimative of learning disability was found to be 9.7% in children from 3 to 17 years of age by the 2003 National Survey of Children’s Health (NSCH) in the USA [4]. The study in Finland in 2001 reported a prevalence of 21.2% in school-aged children referred to special education [15]. Del’Homme et al. reported this prevalence of 28.0% in 2004 [21]. In an epidemiological study with 2174 primary school children in Turkey by using checklists, the probable prevalence rates were found to be 13.6% [7]. An important problem that is making the performance of the epidemiological studies harder is the lack of generally accepted definitions or diagnostic criteria for SLD and evaluations based only on a scale or other assessments that measure the level of academic achievement. DSM-V located the diagnosis of SLD into the category of neurodevelopmental disorders and included severity ratings for its assessment. This means that SLD is conceptualized as a dimensional developmental disorder that occurred as a result of multiple risk factors interacting with each other. One of the important changes is the elimination of IQ-achievement discrepancy criterion in DSM-V despite the exclusion criterion of intellectual disability. IQ-discrepancy criterion was taken into consideration in DSM-IV criteria, so prevalence rates have found different in studies. For example, in one of the recent studies with 1633 German children in third and fourth grades, the SLD frequency was investigated according to DSM-V criteria, and three different findings were calculated according to the 1, 1.25, and 1.5 standard deviations. Accordingly, the reading disorder for children having 1 as the standard deviation was estimated at 6.49%, written expression disorder was 6.67%, and mathematics disorder was 4.84%; the reading disorder for children having 1.25 as the standard deviation was estimated to be 5.14%, written expression disorder was 6.86%, and mathematics disorder was 3.31%; the reading disorder for children having 1.5 as the standard deviation had an estimated value of 3.8%, written expression disorder was 5.02%, and mathematics disorder was 2.39% [3]. In another study with 1618 Brazilian children and adolescents from second to sixth grades, different prevalence rates were found of SLD by using DSM-IV and DSM-V criteria. These rates were 7.6% for SLD (global) impairment, 5.4% for writing, 6.0% for arithmetic, and 7.5% for reading impairment. The prevalence rates were found to be higher by using DSM-V criteria as they expected [22]. In DSM-V, the American Psychiatric Association reports that the SLD prevalence of children from different languages and cultures is 5–15%, the prevalence of reading disorder is 4–9%, and the prevalence of mathematics disorder is 3–7 [1].
When the reading, writing, and mathematics difficulties were separated, or when reading and mathematics difficulties were grouped together, in studies conducted in different countries, the difficulty rates were found to be different from each other. In previous studies, researchers have suggested that arithmetic and reading functions may depend on similar cognitive predictors [23, 24, 25]. It was found that the same phonological processing abilities that are considered to influence growth in reading also appear to contribute to growth in general computation skills [24]. And it was determined that there is a relationship between deficits in processing words and accessing arithmetic facts in long-term memory by Geary [23]. Arithmetical skill is a skill that is based on counting, which involves number words and the use of phonological skills. Because counting involves the activation of number words, the association in long-term memory between problem and answer could be represented, at least in part, in the same phonetic and semantic memory systems that support word recognition. Therefore, it was suggested that the co-occurrence of reading and arithmetic disabilities might reflect a more general deficit in the representation or retrieval of information from semantic memory [26]. The roles of family history and genetic load are considered in reading difficulties and mathematics difficulties, and it is suggested that phonologic problems stated in the etiology of the reading difficulties can create different rates of reading difficulties interculturally, depending on the spoken language. The difficulties in phonemic compliance led to phonologic problems leading to reading difficulties; so, it is suggested that reading difficulties are seen less in countries that have good phoneme-grapheme harmony, and there are higher rates in countries that have poor phoneme-grapheme harmony. Majority of the studies suggested that the prevalence of reading disorder was 5–17% [27]. In the study conducted with 1476 children in 1983, the mathematics disorder rate was 3.6%, and the reading disorder was 2.2% [28]; in the study conducted by Lewis et al. [29] in 1994 with 1056 children who were 9–10 years old, the mathematics disorder was found to be 1.3%, and the reading disorder was 3.9%. In the study conducted by Miles et al. [30] in 1998, the reading disorder prevalence was suggested to be 4.19%, and also in the study of Badian [31] in 1999 with 1075 children, the reading disorder was suggested to be 6%, and the mathematics disorder was suggested to be 3.9%. The studies of Badian [31] and Lewis et al. [29] were designed to obtain an estimation of the prevalence of combined reading and arithmetic, reading only, and arithmetic-only disabilities. Badian found that the prevalence rate in arithmetic and reading was 3.4%, for reading only 6.6%, and for arithmetic only 2.3%. And Lewis reported prevalence proportions as follows: 2.3% for combined reading and arithmetic, 3.9% for reading only, and 1.3% for arithmetic only. When different methods and materials are used in the prevalence studies, different results are obtained as in the studies of Badian and Lewis. While Badian evaluated comprehension in reading, Lewis evaluated word weakness. Although they are both reading processes, they in part require different cognitive skills. Therefore it leads to the identification of a different population of weak readers. Furthermore, another source of variable results across studies is the use of different cutoff scores for the identification of reading and arithmetic disabilities as in these studies. Similarly Dirks et al. [32] found a higher percentage of combined reading and arithmetic disabilities than the disability in reading or arithmetic alone by using different assessments as in studies of Badian and Lewis et al. And they emphasized that children with combined reading and arithmetic disabilities were different from those who had reading or arithmetic disability alone in terms of cognitive and neuropsychological differences [32].
In 2007, Von Aster et al. [33] performed a study with 337 children, and the reading disorder was found in 3.3%, writing disorder in 5.7%, and mathematics disorder in 1.8%. In the study conducted by Landerl and Moll [34] in 2010 with 2586 children, the reading disorder was found to be prevalent in 2.9%, written expression disorder was 4.1%, and mathematics disorder was 3.2%. A study in France detected prevalence rates of dyslexia between 5.0 and 10.0% in school-age children in the same year [35]. Dhanda and Jagawat [36] worked with 1156 children, and the reading disorder was 22%, written expression disorder was 22%, and mathematics disorder was 16%. After the findings with different results according to the different standard deviations in 2014 by Moll et al. [3], Cappa et al. [37] performed a study in 2015 that reading disorder was found to be 4.75%; Fortes et al., on the other hand, found the cases of prevalence of SLD to be 7.6%, with reading disorder at 7.5%, writing disorder at 5.4%, and mathematics disorder at 6.0% [22]; Gorker et al. determined 3.6% for reading, 6.9% for writing, and 6.5% for mathematics difficulties [7].
The roles of family history and genetic load are considered in reading difficulties and mathematics difficulties, and it is suggested that phonologic problems stated in the etiology of the reading difficulties can create different rates of reading difficulties interculturally, depending on the spoken language. The difficulties in phonemic compliance led to phonologic problems leading to reading difficulties; so, it is suggested that reading difficulties are seen less in countries that have good phoneme-grapheme harmony, and there are higher rates in countries that have poor phoneme-grapheme harmony [27]. For instance, according to the UK Parliamentary Office of Science and Technology, the prevalence of SLD reading disorder in the UK is higher due to differences in pronunciation of a letter in English than most languages and inconsistencies in writing and vocabulary [38].
There are no prevalence studies of mathematic disability that considered longitudinal data, except with 210 sample that were followed multiple times during a 4-year period that found 9.6% by Mazzocco and Myers (2003) [39]. Although large cohort studies do exist with a larger sample initially, a small subset of children is identified as potentially displaying mathematics difficulties, so these studies have not provided a detailed comparison of the cognitive and demographic characteristics of subtypes of learning difficulty. And also two studies investigated the prevalence of specific learning difficulties in arithmetic skills but did not assess their types (e.g., number sense, number facts, and mathematical reasoning) [3, 22]. Different levels of prevalence results of mathematics disability are attributed to some methodological differences of studies. One of them is the method that uses IQ-achievement discrepancy. In retrospective population-based study with 5718 children assessed prevalence rates based on different formules and found 5.9% to 13.8% and also significantly more frequent among boys than girls [40]. Barahmand studied 1171 children who are at grades 2–5 and found 3.76% [41]. Others defined mathematics disability by the severity of the mathematics impairment have used performance cutoffs on standardized tests. Some of these studies and their prevalence rates are as follows: 3.6 and 3.9% by Badian’s studies [28, 31], 1.3% by study of Lewis et al. [29], 6.6% by study of Hein et al. [42], 9.6% by studies of Mazzocco and Myers [39], 5.9–13.8% by study of Barbaresi et al. [40], 2.27–6.59% by study of Desoete et al. [43], 5.6–10.3% by study of Dirks et al. [32], and 5.4% by study of Geary [44]. The other researchers defined mathematics disability using a 2-year achievement delay as a diagnostic criterion. They found the prevalence rates to be 6.55 [45] and 5.54–5.98% [46]. Recently, Devine et al. compared mathematics and reading difficulties with 1004 primary school children and reported that there were no differences between boys and girls when a discrepancy criterion was applied [47]. The study in 2018 by Morsanyi et al. evaluated the prevalence rates of specific learning disorder in mathematics, gender differences, and comorbid conditions. The prevalence rate was 6%. They found persistent difficulties in reading (5.6%) and language difficulties in English (11.5%) and also found that they had other comorbid symptoms and disorders such as social, emotional, and behavioral difficulties, autism, or attention deficit hyperactivity disorder [8]. There is still no agreed definition of mathematics disability and are controversies between researchers based on cutoff decisions, specificity and gender differences. Prevalence rates are summarized in Table 1.
Specific learning disorder (%) | Reading disorder (%) | Written expression disorder (%) | Mathematic disorder (%) | Reading + mathematics disorder (%) | Methodology | |
---|---|---|---|---|---|---|
Badian [28] | 2.2 | 3.6 | Questionnaire | |||
Lewis et al. [29] | 3.9 | 1.3 | 2.3 | Standardized tests | ||
Gross-Tsur et al. [45] | 6.55 | Standardized tests | ||||
Miles et al. [30] | 4.19 | Questionnaire and standardized tests | ||||
Badian [31] | 6 | 3.9 | 3.4 | Standardized tests | ||
20 | Questionnaire | |||||
Hein et al. [42] | 6.6 | Standardized tests | ||||
Ramaa and Gowramma [46] | 5.54–5.98 | Standardized tests | ||||
Mazzocco and Myers [39] | 9.6 | Standardized tests | ||||
Desoete et al. [43] | 2.27–6.59 | Standardized tests | ||||
Barbaresi et al. [40] | 5.9–13.8 | Questionnaire and standardized tests | ||||
Altarac et al. [4] | 9.7 | Questionnaire | ||||
Von Aster et al. [33] | 3.3 | 5.7 | 1.8 | Standardized tests | ||
Barahmand [41] | 3.76 | Standardized tests | ||||
Lagae [27] | 5–17 | Standardized tests | ||||
Dirks et al. [32] | 19.9 | 10.3 | 7.6 | Standardized tests | ||
Landerl and Moll [34] | 2.9 | 4.1 | 3.2 | Questionnaire and standardized tests | ||
Geary [44] | 5.4 | Standardized tests | ||||
Taanila et al. [15] | 21.2 | Questionnaire | ||||
Dhanda and Jagawat [36] | 22 | 22 | 16 | Questionnaire | ||
Al-Yagon et al. [20] | 1.2 | Questionnaire | ||||
Moll et al. [3] | 6.49 | 6.67 | 4.84 | DSM-V criteria 1 standard deviation | ||
5.14 | 6.86 | 3.31 | DSM-V criteria 1.25 standard deviation | |||
3.8 | 5.02 | 2.39 | DSM-V criteria 1.5 standard deviation | |||
Cappa et al. [37] | 4.75 | Questionnaire | ||||
Fortes et al. [22] | 7.6 | 7.5 | 5.4 | 6 | DSM-V criteria checklists and questionnaire | |
Gorker et al. [7] | 13.6 | 3.6 | 6.9 | 6.5 | Checklists | |
Morsanyi et al. [8] | 5.6 | 6 | DSM-V criteria and standardized tests |
Overview of the prevalence rates of specific learning disorder, reading disorder, written expression disorder, mathematics disorder, and reading-mathematics disorder.
In the prevalence studies of specific learning disorders, ADHD, which receives the most comorbidity and is the most studied disorder, should be considered [1, 48]. Two American national studies by the same researchers found 4% prevalence of comorbidity [17, 49]. DuPaul et al. reported this comorbidity rate as 18–60% and found that the incidence of SLD in ADHD patients was 7 times higher than that of the population [50]. Some clinical studies have reported extremely high prevalence rates of SLD as 70% or ADHD as 82.5% in comorbid cases [51, 52]. Genetic studies support that these two disorders may be associated with similar hereditary factors [53, 54, 55]. The high comorbidity between SLD and ADHD, inadequate SLD definitions, and different methods used in studies may have different results in evaluating the prevalence of SLD. And also symptoms of children diagnosed with SLD are more persistent when they have behavioral problems in the first years of school than with SLDs without ADHD or any comorbidity [56]. Therefore, early diagnosis and treatment interventions can significantly change the incidence and prevalence rates of SLD.
DSM-5 is stated that SLD is two to three times more prevalent in boys than in girls [1]. In 4 different epidemiologic studies including 9799 children from England, Wales, and New Zealand, boy/girl rates of reading difficulties were 21.6%/7.9%, 20.6%/9.8%, 17.6%/13.0%, and 18.0%/13.0%. In this study, reading and spelling deficits were not analyzed separately, so that it remained unresolved [12]. Landerl and Moll reported balanced gender ratios for reading (fluency) deficits but a disproportionate number of boys for spelling deficits in German population [34]. In a study of Moll et al., more problems in boys than girls for combined reading and spelling problems were identified, and when isolated spelling disorder was evaluated, gender ratios were found balanced [3]. According to these studies, dyslexia was found to be higher in boys than girls. The most common reported in the literature is that of no gender difference of mathematics disability [8, 29, 39, 42, 43, 45, 47]. The other studies reported higher prevalence of mathematics difficulties in girls [3, 32, 34, 45] or boys [31, 40, 46, 57]. And also some studies reported inconsistency findings. For example, Devine et al. reported that although there was no gender difference in the prevalence of math learning difficulties between boys and girls, mathematics difficulties were much more common for girls than for boys [47].
SLD is a multifactorial disorder which has in its etiology a genetic predisposition and family load, developmental and cognitive factors, language spoken, and environmental factors including the level of education and socioeconomic situation. Comorbidity with other mental disorders reveals more severe symptoms of it. And also if clinical and educational interventions are not performed, behavioral and emotional symptoms may accompany this diagnosis. The use of diagnostic criteria and structured scales, whether the disorder is a uniform or mixed type of disorder, the characteristics of the spoken language, and the assessment of environmental factors will help to determine the prevalence rate results and treatment interventions more specific. An educational approach and early intervention treatment after the awareness of SLD findings will reduce the difficulties that may arise with this disorder in the preschool period.
The authors declare no conflict of interest.
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