A novel comprehensive paradigm for the etiopathogenesis of multiple sclerosis: therapeutic approaches and future perspectives on its treatment
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It is well recognized that variation in the geographical distribution of prevalence of multiple sclerosis (MS) exists: increasing the latitude its prevalence increases as well, but the underlying causes of such dissimilarity still remained elusive as of today. Currently, the most accredited hypothesis is that the closer to the equator the more pronounced is the amount of sunlight which, in turn, increases the production of vitamin D. Cholecalciferol is indeed deficient in MS patients, but this factor does not explain by itself the etiopathogenesis of the disease. In the present study, to search for a pattern and provide a model of the disease’s etiology consistent with this regional factor, as well with its changing ethnic, sex-ratio, lifestyle variations and the other unexplained aspects of MS, an extensive analysis of peer-reviewed literature and data was conducted. The arisen hypothesis was that, increasing the latitude, the factor that varies and can have the stronger effect on the human organism, is the continuous and ever-increasing diversity of the natural light–dark cycle. The consequent effort of the suprachiasmatic nucleus to entrain the organism’s circadian rhythm affects the hypothalamic–pituitary–adrenal axis resulting in desynchronizing the central and peripheral circadian clocks and pathologizing the immunitary system. To verify such hypothesis, a theoretical framework of the etiopathogenesis, coherent with the gathered literature, was conceived and a demonstration to corroborate it was eventually devised and performed. The results underscored that people living in countries subjected to a further circadian disruptive factor, as daylight saving time, have a 6.35 times higher prevalence of MS than States placed on their same latitude that do not observe it, thus strongly supporting the hypothesis. As further reinforcement of the conclusions, it is worth mentioning that the levels of polyamines rise abruptly in autoimmune diseases. Moreover, among their numerous roles, these polycations participate to the regulation of the circadian clock so their sudden variation might disrupt it. Following these interesting findings, new perspectives in therapies are, therefore, proposed.
KeywordsEpidemiology Etiology Multiple sclerosis Autoimmunity Circadian rhythm Suprachiasmatic nucleus Therapies Desynchronization Peripheral clocks Oligodendrocytes Remyelination Polyamine
- HPA axis
Daylight saving time
Summer winter solstice
Gender identity disorders
Central nervous system
Multiple sclerosis is an autoimmune disease that alters the central nervous system, causing the appearance of focal areas of inflammation and demyelination (Mohammed 2016). According to the Atlas of MS (2013), in the world, there are about 2.3 million people affected by MS. The etiopathogenesis of MS in spite of the several attempts to predict the risk of acquiring the illness did not yet lead to a paradigm that encompassed all the observations (Wu and Alvarez 2011). MS geoepidemiology follows a latitudinal gradient (Milo and Kahana 2010; Kurtzke 2000). Therefore, a study was carried out to identify the etiological gap involving population from 71 countries with homogenous geographical characteristics. Following the numerous investigations, the distribution of MS is not uniform. It is in fact more widespread in areas with a temperate climate far from the equator and has a progressive reduction as we proceed towards it (Ascherio and Munger 2007). Studies configured a multifactorial etiology to MS, including ethnical and environmental factors related to the disorders’ susceptibility, however, its geographical distribution and the changes in its risk with migration suggest that latitude is the key. Moreover, the incidence of MS seems to decrease with migration in early life, from high to low latitude areas and vice versa (Beretich and Beretich 2009; Dean and Kurtzke 1971). What is more, migration from one geographic area to another one seems to alter a person’s risk of developing the disease (Wallin et al. 2012). For these subjects the factor that defines the risk of contracting the disease is the place of arrival and not the starting ones and it particularly results evident when migration starts from lower to higher latitudes (Field 1977). As concerns this geographic discrepancy, various hypotheses have been made regarding the variable factors that could change on earth that affect its inhabitants, when they move towards the equator or away from it. The presence of more hours of sunlight in the day was considered an accredited answer and, consequently, exposure to sunlight and increase of vitamin D, appears to be an important factor for MS susceptibility (Cantorna 2008; Ebers et al. 2004). The secretion of large amounts of vitamin D in the blood flux, as a matter of fact, leads to a decrease of the cell number of the immunological system, which are associated with the inflammatory process responsible for MS (Sotirchos et al. 2015). It was reported that each increase in Vitamin D induces in Caucasians a 41% reduction in the risk of developing MS and even more a significant result emerged considering the subjects under the age of 20 years (Munger et al. 2006; Salzer et al. 2012). Among the demonstrated immunomodulatory effects, there is the inhibition of secretion and a consequent production of autoantibodies by B lymphocytes (Lemire et al. 1995; Simpson et al. 2010). Vitamin D appears capable of inducing both a reduction in the production of pro-inflammatory cytokines and of the differentiation of T cells towards a subtype TH1 and TH17. In addition, B cells would be influenced with a consequent reduction of antibody production and plasma cell maturation (Hart et al. 2011; Zahoor and Haq 2017). Nevertheless, although the scarcity of this vitamin in MS patients exists, a direct cause–effect relationship with the etiology of the disease was not yet identified. Hence, the geoepidemiological gap was still unfilled.
The new etiopathogenesis paradigm
Following the above investigation, a study reported that several neurodegenerative diseases, specifically Alzheimer’s, Parkinson’s and Huntington’s diseases, share the common feature of abnormal circadian rhythms, such as those in behavior (e.g., disrupted sleep/wake cycles), in physiological processes (e.g., diminished hormone release) and in biochemical activities (e.g., antioxidant production). Circadian disturbances are among the earliest symptoms of these diseases (Hood and Amir 2017; Wulff et al. 2010) and “chronic misalignment” between our lifestyle and the rhythm dictated by our endogenous circadian clock may be associated with increased risk for various disorders including cancer, neurodegenerative diseases and metabolic disorder and inflammations (Ibáñez 2017). In addition, there are indications that low amplitude light–dark cycles contribute to create this condition (Roenneberg and Merrow 2016), while other findings support the novel hypothesis that circadian rhythm disorder is an environmental risk factor for developing PD (Lauretti et al. 2016). Experimental data obtained on mice provided mechanistic insights into how time-of-day and clock disruption in myeloid cells impact on autoimmunity (Sutton et al. 2017). In an interesting review with an evocative title, chrono-immunology, the authors reported the following sentence: it will, therefore, be of great interest to perform immunological studies on individuals in an environment that only allows for sleep during the natural active phase or exposure of subjects to light during the inactive, and darkness in the active phase (Geiger et al. 2015). Furthermore, vitamin D is produced during the day, melatonin at night and cortisol is synthesized more in the morning, to avoid conflicts with the melatonin formation, and it is secreted unscheduled in case of perceived danger. All the other hormones under the control of hypothalamus are synthesized in balanced quantities, a process governed by the suprachiasmatic nucleus (SCN). The circadian system of humans is composed of a hierarchy of oscillators that function at the cellular, tissue and systems levels. A common molecular mechanism underlies the cell autonomous circadian oscillator throughout the body, yet this clock system is adapted to different physiological functional contexts, such as, liver, thymus, and peritoneal macrophages. In normal conditions, the SCN acts as a master pacemaker for the organism and it relays temporal information to peripheral oscillators through autonomic innervation, body temperature, rest, activity cycles, humoral signals, such as glucocorticoids, and feeding-related cues. Local signaling pathways can also affect peripheral oscillators independently from the SCN (Mohawk et al. 2012; Schibler et al. 2015). The environmental determination of such normal conditions, for the present study purposes, was deduced from the human circadian rhythm itself. Since the human circadian rhythm lasts about 24 h, and half of its endogenous activities are meant to take place at night while the other half in daylight, it was legitimate to assume that the perfect environment it was meant to be conducted in, was one with an LD cycle of 12 h of light and 12 h of darkness. Considering that the only place on the earth with constant 12 h of light and 12 h of darkness is the equator, also believed to be the area where man evolution started and, therefore, the place where the circadian rhythm was originally entrained, our latter assumption received some support (White et al. 2003). For these reasons, our hypothesis is that at the equator the internal clock does not need to continuously re-entrain, thus it never gets disrupted altering the immune system equilibrium and, therefore, triggering autoimmunity. In view of the above, the hereinafter becomes evident: a factor that can affect the immune systems of the human population and that varies on earth as the distance from the equator increases, is the ever-increasing diversity of the duration of the day and night. This continuous variation, however, could not by itself explain some differences in the prevalence among countries resting upon the same latitude, but this uneven pattern sheds a light on the pathway towards a possible demonstration to support our hypothesis.
The uneven pattern
Corroborating the new model
Statistical analysis was performed for the graphical presentations. It is important to notify that the statistical data of the Atlas of MS (2013), used for the analysis in the demonstration, were collected in a large international study from October 2012 to June 2013. Only the Australian values were taken from another study with homogeneous characteristics with the Atlas (Palmer et al. 2013). Since the distribution of most of the data was skewed, due to the reasons addressed as of today in the present study, in the Atlas the median was used to depict the central tendency of the various variables. Consequently, we have used the median prevalence in this report as well so that comparisons could be made with the data from the Atlas. The data were analyzed using MS Excel as in the Atlas. The raw Atlas data can be accessed at (www.msif.org).
A novel outlook on MS
The SWS variations. Here is an indicative table of this index at the main latitudes
Prev. X 100 k
The feeble success of most current therapies is evidently due to the incorrect target addressed (Loma and Heyman 2011; Monzani et al. 1999; Goodin et al. 2008). To treat successfully the disease, we must begin by acting on the causes, i.e., to restore the potential circadian rhythm in the patient. Thus, to do so, re-establishing an healthy homeostasis, a correct functioning of the immune system and eventually re-starting remyelination on a given MS patient, the following approach might be feasible: at first, measure out the amounts of the SCN-driven hormones averagely produced at the equator by the organism of an healthy subjects cohort homogeneous with the subject; subsequently, repeat the said measurement on our patient at the latitude at which she or he lives with the full-aggregated LD cycle; eventually, after an analysis of the collected data, administer to the subject the integrative doses accordingly. Moreover, considering that timing of meals play a role in synchronizing peripheral circadian rhythms in man, it might have particular relevance for patients with circadian rhythm disorders, as shift workers and transmeridian travelers, to provide them a rhythmically constant feeding cycle to help their re-entrainment (Wehrens et al. 2017; Patel et al. 2016). Following the conditions above reported, the normal functioning of the circadian rhythm and of the immunogenic system should be restored and consequently the remyelination process by the oligodendrocytes reactivated. To relocate the patient to the equator areas, or to artificially provide all the zeitgebers of it, although possible, is indeed complicated and, therefore, a partly pharmaceutical intervention deserves to be considered. In the treatment, BMAL1 antibody could be administered. The transcription factor BMAL1 (ARNTL) is a core component of the molecular clock, regulating the circadian rhythms in both behavior and physiology. It was observed that the absence of BMAL1 from myeloid cells results in a hyper-inflammatory environment leading to enhanced Th1 and Th17 responses (Sutton et al. 2017). Although focusing on the genetic mechanism, a recent study hypothesized that the influence of latitude on MS prevalence might be partially associated with its effects on the genetic variability of key circadian rhythm regulators, namely ARNTL and CLOCK genes, which in turn might contribute to the risk for MS consequently pointing out the ethnical factor of the disease. Such study also solicited further research on populations with different genetic background to validate the association given the potential limitation of the sample that was investigated on, that is a population of Slave origin of 1924 units (Lavtar et al. 2018). In addition, autoreactive effector CD4 T cells have been associated with the pathogenesis of autoimmune disorders (Damsker et al. 2010), while it was administrated a casein kinase 1 δ-based drug because CK1 δ regulates the pace of the mammalian circadian clock (Etchegaray et al. 2009). Moreover, due to the fact that polyamines modulate the interaction between the core clock proteins PER2 and CRY1, that lengthening of the circadian period with age can be reversed by these polycations (Zwighaft et al. 2015). Therefore, a balanced dietary polyamine supplementation, well planned, could be provided to stabilize the SCN clock. In Norway, for example, an uneven distribution of MS was detected, with the highest prevalence in the inland areas and the lowest along the coast. Such differences might be caused by the diet with a high intake of fish which offers protection against MS (Grytten et al. 2015). It is worth mentioning that the content of polyamines is high in the Norwegian fish diet reaching the highest values of putrescine, spermidine and spermine in Cod Roe, a Norwegian caviar (Ali et al. 2011). Other studies highlight that, in particular, spermidine addition in meals protects from autoimmune-directed demyelination of neurons in a mouse model for multiple sclerosis, attenuates disease progression, improves visual functions and indirectly suppresses autoimmune-reactive T cells (Madeo et al. 2018). Furthermore, given the neurodegenerative nature of MS, polyamines, in particular spermine, may function as neuromodulators in the brain (Masuko et al. 2003), while spermidine can protect neurons from dying after various types of neurotrauma. It was also demonstrated that a series of novel polyamine-based structures have therapeutic potential as neuroprotective agents (Gilad and Gilad 1999). It might be interesting in this context to point out the effects of agmatine in CNS and its potential action as new pharmacological treatment for several neurological and neurodegenerative diseases (Moretti 2014). In fact, studies have revealed that exogenously administered agmatine has neuroprotective effects (Chen et al. 2007) and that polyamines can modulate synaptic plasticity by regulating a variety of ion channels (Zhu et al. 2008). Lastly, to gather fresh data for future research, it will be useful to integrate the MS patients’ screening questionnaires with new questions regarding lifestyle, so to obtain circadian rhythm-sensitive habit data that was not considered relevant as of today. Thanks to new mobile technologies, for example, it will be possible to analyze circadian rhythms on large scale from the accelerometer data of such devices to try to prevent MS.
Conclusions and open questions
Increasing the latitude, the continuous and constantly growing diversity of the natural light–dark cycle, desynchronizes the central and peripheral circadian clocks which in turn, as described in the present study, may eventually pathologize the organism’s immunogenic system, triggering autoimmunity. DST, light at night and other lifestyle factors dramatically intensify the effects. To substantiate the circadian influence on MS, we have underlined the disease prevalence in countries located on the same latitude with an added homogeneous circadian disruptive factor, identified as DST, that approximately show 6.35 times higher MS prevalence. Our hypothesis, i.e., the circadian rhythm disruption is what underlies the etiology of MS, is thus strongly supported by these results. It is also worth mentioning that the MS prevalence has not only risen from 2008 to 2013. Even though long-term comprehensive global studies are not available at this point in time, in the last 50 years, significant traces of a growth pattern may be locally identified, pointing out the need to spread the investigation. In Norway, for instance, from 1961 to 2014, the reported prevalence of MS increased from 20 to 203 per 100,000 inhabitants (Grytten et al. 2015; Alla et al. 2014). This 10 times increase is too evident to be only due to the diagnostic capabilities that have improved during the years. Instead, this phenomenon could be explained with the proposed paradigm principles because in the 1960s, the time in which the increase occurs, artificial lighting has tended to use increasingly higher intensity discharge lamps. These lamps mainly consist of blue wavelengths that affect the circadian system to a greater extent than any other (Bonmati-Carrion et al. 2014), leading, therefore, to the circadian rhythm disruption which can set off autoimmunity. Given the significant implications of the exposure to circadian rhythm disruption on MS risk, understanding the effect of different aspects of lifestyle, both habitudes and work deserve further investigation. Identifying populations and individuals with a high risk of developing the disease opens the possibility of a window of opportunity to reverse its early processes before it clinically becomes evident providing a possibility to develop strategies aimed at preventing it. For example, immigrants from south countries of the world need to be warned to avoid rising their risk of developing MS, especially if they migrate at a young age (Detels et al. 1978; Hammond 2000). But how intense must the circadian disruption be to determine the phase shifting from homeostasis to disease and how can we measure such intensity? May other autoimmune diseases then share the same etiology? A candidate for such similarity, to give an instance, might be autoimmune diabetes (type one). Such disorder, in fact, as MS has generally greater incidence rates at higher latitudes that then approach zero in equator areas (Mohr et al. 2008), reduces the risk of being developed by vitamin D supplementation (Hyppönen et al. 2001), some lifestyle aspects producing a circadian misalignment are associated with the disorder (Larcher et al. 2016) and, ultimately, that circadian genes are involved in its onset (Lebailly et al. 2015). And if so, when and why is the type of autoimmunity chosen? Lastly, to entertain speculation, given the fact that multivalent cations, such as natural polyamines, are excellent promoters of DNA/RNA condensation to nanoparticles, is it possible that they might become spontaneous gene delivery vehicles, significantly altering gene expression patterns of specific circadian genes accordingly disrupting the internal clock (Vijayanathan et al. 2013)? Although these unanswered questions need to be properly addressed, the model proposed gives a novel perspective of MS and opens new pathways for the treatment of the disorder. In conclusion, given that countries without DST have the MS prevalence 6.35 times lower, taking for example the case of Italy, in which the health care and social cost of multiple sclerosis reaches 4.1 billions (2015 euros) (Battaglia and Bezzini 2016) and the overall DST savings in 2017 were limited to 110 million (Terna SPA 2017), the data produced in the present study may also have relevant economical implications for healthcare.
The authors thank Anna Petrova for the helpful and fruitful suggestions and discussion as well as for the daily insights provided and Arch. Roberto Mezzaroma for having continuously encouraged the writing out of the manuscript and the drawing up of the project. Our gratitude is also due to the “International Polyamines Foundation—ONLUS” for the availability to look up in the Polyamines documentation.
FG and EA conceived this investigation and coordinated the collaboration among the authors. All the authors wrote the manuscript and all the authors have read and approved the final manuscript.
This study was also supported by resources provided by SAPIENZA University of Rome, Italy (EA).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
Research involving human participants and/or animals
The present review does not contain any studies with human participants or animals performed by any of the authors.
Patient consent for publication
For this type of study, informed consent is not required.
Availability of data
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
- Anglmayer I (2017) EU summer-time arrangements under Directive 2000/84/EC. Ex-post impact assessment. (Ex-Post Evaluation unit of the directorate for impact assessment and European added value, secretariat of the European parliament. http://www.europarl.europa.eu/thinktank https://doi.org/10.2861/380995. Accessed 14 Apr 2018
- Atlas of MS (2013) Mapping multiple sclerosis around the world. London: Multiple sclerosis international federation 2013. Available at: http://www.msif.org/about-ms/ publications-and-resources/. Accessed October 10, 2013
- Atlas: multiple sclerosis resources in the world (2008) Geneva, Switzerland: World Health Organisation; 2008. Available at: http://www.msif.org/about-ms/publications-and-esources/. Accessed 4 Feb 2018
- Cree BA, Khan O, Bourdette D, Goodin DS, Cohen JA, Marrie RA, Hauser SL (2004) Clinical characteristics of African Americans vs Caucasian Americans with multiple sclerosis. Neurology 63(11):2039–2045. https://doi.org/10.1212/01.wnl.0000145762.60562.5d Google Scholar
- Czeisler Charles A, Duffy Jeanne F, Shanahan Theresa L, Brown Emery N, Mitchell Jude F, Rimmer David W, Ronda Joseph M, Silva Edward J, Allan James S, Emens Jonathan S, Derk-Jan Dijk, Kronauer Richard E (1999) Stability, precision, and near-24-h period of the human circadian pacemaker. Science 284(5423):2177–2181. https://doi.org/10.1126/science.284.5423.2177 Google Scholar
- Detels R, Visscher BR, Haile RW, Malmgren RM, Dudley JP, Coulson AH (1978) Multiple sclerosis and age at migration. Am J Epidemiol 108(5):386–393. https://doi.org/10.1093/oxfordjournals.aje.a112636 Google Scholar
- Edholm OG, Gunderson EKE (1973) Polar human biology. Butterworth-Heinemann, Oxford, p 313Google Scholar
- Gilad GM, Gilad VH (1999) Novel polyamine derivatives as neuroprotective agents. J Pharmacol Exp Ther. 291(1):39–43. http://jpet.aspetjournals.org/content/jpet/291/1/39.full.pdf. Accessed 31 May 2018
- Goodin DS, Cohen BA, O’connor P, Kappos L, Stevens JC (2008) Assessment: the use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review): report of the therapeutics and technology assessment subcommittee of the american academy of neurology. Neurology 71(10):766–773. https://doi.org/10.1212/01.wnl.0000320512.21919.d2 Google Scholar
- Ibáñez (2017) Scientific background discoveries of molecular mechanisms controlling the circadian rhythm. The Nobel Assembly at Karolinska institute, Stockholm. https://www.nobelprize.org/uploads/2018/06/advanced-medicineprize2017.pdf. Accessed 24 Feb 2018
- Kurtzke JF (2000). Multiple sclerosis in time and space - Geographic clues to cause. J Neurovirol. 6(Suppl 2):S134–40. https://pdfs.semanticscholar.org/d522/df170c2f692afa82c79794e82c18399dad2a.pdf
- Madeo F, Eisenberg T, Pietrocola F, Kroemer G. (2018) Spermidine in health and disease. Science. 359–410(6374):eaan 2788. https://doi.org/10.1126/science.aan2788
- Masuko T, Kusama-Eguchi K, Sakata K, Kusama T, Chaki S, Okuyama S, Igarashi K (2003) Polyamine transport, accumulation, and release in brain. J Neurochem 84(3):610–617. https://doi.org/10.1046/j.1471-4159.2003.01558.x-> Google Scholar
- Materljan E, Sepčić J, Materljan B (2001). Sclerosi multipla e ambiente—multiple sclerosis and environment. Conference paper: ambiente e salute—environment and health, At San Marino, AIEP editore, pp 155–171Google Scholar
- Mohawk JA, Green CB, Takahashi JS (2012) Central and peripheral circadian clocks in mammals. Annu Rev Neurosci 35(1):445–462. https://doi.org/10.1146/annurev-neuro-060909-153128 Google Scholar
- Monzani F, Caraccio N, Meucci G, Lombardo F, Moscato G, Casolaro A, Ferdeghini M, Murri M, Ferrannini E (1999) Effect of 1-year treatment with interferon-beta1b on thyroid function and autoimmunity in patients with multiple sclerosis. Eur J Endocrinol 141(4):325–331. https://doi.org/10.1530/eje.0.1410325 Google Scholar
- Papantoniou K, Pozo OJ, Espinosa A, Marcos J, Castano-Vinyals G, Basagana X, Ribas FC, Mirabent J, Martφn J, Carenys G, Martφn CR, Middleton B, Skene DJ, Kogevinas M (2014) Circadian variation of melatonin, light exposure, and diurnal preference in day and night shift workers of both sexes. Cancer Epidemiol Biomark Prev 23(7):1176–1186. https://doi.org/10.1158/1055-9965.epi-13-1271 Google Scholar
- Reifman A, Biernat M, Lang EL (1991) Stress, social support, and health in married professional women with small children. Psychol Women Q 15(3):431–445. https://doi.org/10.1111/j.1471-6402.1991.tb00419.x Google Scholar
- Reinberg AE, Touitou Y, Soudant É, Bernard D, Bazin R, Mechkouri M (1996) Oral contraceptives alter circadian rhythm parameters of cortisol, melatonin, blood pressure, heart rate, skin blood flow, transepidermal water loss, and skin amino acids of healthy young women. Chronobiol Int 13(3):199–211. https://doi.org/10.3109/07420529609012653 Google Scholar
- Terna SPA (2017) N 7 Mesi di ora legale minori consumi elettrici per 567 milioni di kilowattora http://download.terna.it/terna/0000/0994/35.PDF. Accessed 27 Feb 2018
- United Nations (2015) Department of economic and social affairs, population division. Trends in Contraceptive Use Worldwide 2015 (ST/ESA/SER.A/349). http://www.un.org/en/development/desa/population/publications/pdf/family/trendsContraceptiveUse2015Report.pdf. Accessed 3 Mar 2018
- Zahoor I, Haq E (2017) Vitamin D and multiple sclerosis: an update. In: Zagon IS, McLaughlin PJ (eds) Multiple sclerosis: perspectives in treatment and pathogenesis. Codon Publications, Brisbane. https://doi.org/10.15586/codon.multiplesclerosis.2017.ch5 Google Scholar
- Zwighaft Z, Aviram R, Shalev M, Rousso-Noori L, Kraut-Cohen J, Golik M, Brandis A, Reinke H, Aharoni A, Kahana C, Asher G (2015) Circadian clock control by polyamine levels through a mechanism that declines with age. Cell Metab 22(5):874–885. https://doi.org/10.1016/j.cmet.2015.09.011 Google Scholar