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A novel comprehensive paradigm for the etiopathogenesis of multiple sclerosis: therapeutic approaches and future perspectives on its treatment

  • Francesco Gasperoni
  • Paola Turini
  • Enzo AgostinelliEmail author
Invited Review
  • 2.9k Downloads

Abstract

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.

Keywords

Epidemiology Etiology Multiple sclerosis Autoimmunity Circadian rhythm Suprachiasmatic nucleus Therapies Desynchronization Peripheral clocks Oligodendrocytes Remyelination Polyamine 

Abbreviations

MS

Multiple sclerosis

HPA axis

Hypothalamic–pituitary–adrenal axis

DST

Daylight saving time

LD

Light–dark

SCN

Suprachiasmatic nucleus

SWS

Summer winter solstice

PD

Parkinson’s disease

NKs

Natural killer

GID

Gender identity disorders

CNS

Central nervous system

ST

Standard time

Introduction

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

Big data samples facilitate the discovery of patterns that might not be apparent in smaller samples (Kosinski et al. 2016). Therefore, to give stronger credit to the etiopathogenesis model proposed, being available the worldwide data on MS prevalence, a demonstration carried out with such data was conceived. The MS prevalence of the human population, living at a given latitude, was compared with the MS prevalence of the population living in a different country, resting upon the same latitude but subjected to an additional circadian disruptive factor. If the model hypothesized was accurate, this factor added to the latitude would result in an increased MS prevalence in such area. A reliable database regarding the lifestyles of MS patients is not yet available at this point in time, therefore, another circadian disruptive factor had to be identified. Such factor had to be easily retrievable and homogenous enough to be compared with the population we just described, that could then be used as a control group. Later on, while analyzing the literature, our attention was drawn on a peculiar concept referring to the use of daylight saving time (DST) in Frankfurt: the 1 h DST advance in spring corresponds to traveling 15° westward and the reduction of amplitude corresponds to traveling 17° latitude southward. Thus, DST translocates the inhabitants of Central Germany to Morocco in spring and back in autumn, without changing time zone or climate (Kantermann et al. 2007). To investigate if these issues had already been considered for their possible health repercussions by policy makers, a document of the European Union was recovered that, while assessing benefits and of DST, mentioned its potential disruption effects on the human circadian rhythm as well (Anglmayer 2017). That is when the world map of DST in the document came to our attention (Fig. 1). The map recalled the world distribution of MS included in some epidemiological trends in multiple sclerosis in 1983 by Kurtzke, in which the distribution of the prevalence of the disease in Australia was quite distinctive (Fig. 2). In the comparison of the two maps, it was observed that Australia had the same unique distribution in both. It was thus identified in the DST, the additional circadian disruptive factor for our demonstration. In fact, the adaptation to DST takes a relevant period of time at each hour change (Kantermann et al. 2007). DST is enough homogenous because, save for a few exceptions, each country uses it or not on its entire territory (https://www.timeanddate.com/time/dst/). The DST worldwide data are easy and accurate enough to gather from the public domain TZ database (https://www.iana.org/time-zones), an international organization backed by the internet corporation for assigned names and numbers (ICANN). Despite the fact that in many countries it is the leading cause of nontraumatic neurologic disability in young adults, updated global information on the epidemiology of MS is scarce. Due to the lacking of homogenous recent data on MS prevalence then, the World Atlas of MS database of 2013 was used for the demonstration. The first Atlas of MS was published in 2008, while a new data from 104 countries was acquired in 2012–2013. The last ones also included 12 countries who submitted data for the first time. Taken together with the existing 2008 data, this represents 87% of the world’s population. One of the main finding of the Atlas from the second survey was that in 2013 the global median prevalence of MS had increased from 30%, in 2008, to 33% in 2013 (Browne 2014). Due to the fact that this growth of ~ 10% might have also reflected on the improvements in the diagnosis, in the reporting of MS, in the establishment of clinical registers and in the publication of new epidemiologic research, the 2013 Atlas data appeared to be more rigorous and reliable. For the experimental group, we, therefore, selected the 44 countries with DST, taking into account both the 2013 MS prevalence and DST. Therefore, considering that no country used DST, in the year 2013, below 15° parallel of latitude, for the control group 30 countries were selected from 15° to 66° parallel of latitude that did not use DST. Exclusively for Australia, we used different peer-reviewed data from the same year that was consistent with that of the Atlas because it had separated MS prevalence values from territories observing DST and standard time (Palmer et al. 2013).
Fig. 1

DST map of the world. The countries/territories applying DST at some period during 2017 are indicated in gray. The image was redrawn from the map of DST on the EU document EU summertime arrangements under directive 2000/84/EC. Such map was in turn taken from (https://www.timeanddate.com/time/dst/2017.html)

Fig. 2

The world distribution of MS map included in by Kurtzke (1983). High-frequency areas are indicated in black, dots represent medium frequency areas, diagonal lines show low frequency areas while open areas are regions where the frequency of MS is not expressed. This image was done by a soldier or an employee of the US Army, taken up or made as part of that person’s official duties. The image is of public domain since represents a work of the US federal government

Corroborating the new model

The careful observation of both the maps (Figs. 1, 2) allowed us to evaluate the latitude of the countries, involved or not, in the partial application of DST for a particular period of the year. The histograms, derived from this evaluation, show the MS prevalence of several countries, ordered according to the latitude. The mean latitude of each country was calculated measuring the two extreme latitudes of their territory. Since in the present demonstration the prevalence data from the 2013 Atlas were used, only the 2013 DST statistics were taken into account. The histograms, represented in the Figs. 3 and 4, show that in the countries without DST there is a lower prevalence of MS than that observed in the nations placed on the same latitude that use DST. The resulting correlation between the values of the median prevalence of MS and the latitude values of each country, albeit evident, reflects the inaccuracy inherent in the fact that the DST, although represents the most homogeneous parameter, is obviously not the only circadian disruptive factor involved in MS. In fact, other factors, as shown in Fig. 5, can play a role in the etiology of the disease, such as light during the night, that disrupts the natural LD Cycle, and other lifestyle factors as night shifts and jet-lag. These factors cannot be individually quantified once they get mixed up, and become part of a comprehensive aggregated LD cycle. Since we were looking for the central tendency, the data collected were analyzed using the median prevalence as a measure of it. The median was used because it was the same statistical value employed by the Atlas of MS for presenting its results. Interestingly, the findings showed a clear pattern more dependent on its overall validity instead that on the precision of the individual data. The median prevalence per 100,000 individuals in the countries that use standard time (ST) was of 14, while the median prevalence of those who observe DST was of 88.95, i.e., 6.35 times the prevalence of the control group (corresponding to 635% higher). Thus, these results strongly support our hypothesis (Fig. 6). It is important to point out that the median prevalence in both 2008 and 2013 was taken into account to calculate the ratio between the MS prevalence of standard time and DST countries. The ratio of the experimental and the control group of 2008 corresponds, as order of magnitude, to the ones of 2013. It has a ratio value of 8.8 (data not shown). The studies performed were not assembled to determine a standard deviation, because over the 5-year period both the lifestyles of the subjects and the environment in which they live have substantially changed. These changes are mainly due to the technological progress. For instance, the light during the night represents a phenomenon which inhibits the secretion of melatonin. It became a widespread circadian disrupting factor, when the human digital migration increased. Therefore, if the data of the 2 years were associated for a standard deviation calculation, the values would have been too relevant and would have not corresponded to reality anymore.
Fig. 3

Median prevalence of MS ordered by latitudes in countries that do not use DST. It represents the control group. Data values were taken directly from the 2013 Atlas, grouped into categories (the countries latitude in this case) and ordered based on the demonstration hypothesis. Raw data of histograms shown in Table 2 (supplemental material section)

Fig. 4

Median prevalence of MS ordered by latitudes in countries that use DST. It represents the experimental cohort. Data values were taken directly from the 2013 Atlas, was grouped into categories (the countries latitude in this case) and ordered based on the demonstration hypothesis. Raw data of histograms shown in Table 3 (supplemental material section)

Fig. 5

The etiopathogenesis paradigm proposed. On the top of the scheme both latitude and lifestyle are reported, the main external zeitgeber entrainment sources for the SCN. Grouped in the rectangle with the diagonal line pattern the “circadian feedbacks” are indicated that collectively, with different weight, contribute to the “aggregated light cycle” factor which represents the main feedback to the internal clock of the SCN. As the demonstration corroborated, together with latitude, DST is the most widespread disruptive factor for the circadian rhythm. The main circadian sensitive organs are indicated with a vertical line pattern in the figure. The principal circadian hormones are depicted in a horizontal line pattern. In the lower part of the model, in white, the physiological effects caused directly by the circadian activities are shown that may trigger autoimmunity. Note: if the SWS is equal to 1 there is no need for entrainment. If the SWS is not detectable as it is in latitudes higher than the polar circle (66.33°), the SCN clock, not having a regular daily feedback, is completely endogenous

Fig. 6

The median prevalence of MS in countries with constant standard time and in those who apply DST. The use of DST adds severe disruption to the circadian adaptation process. In the countries that apply DST the prevalence is 6.35 times higher

Statistical analysis

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 human average internal clock is of 24 h and 11 min and imparts to the SCN to perform a series of tasks synchronized with the environmental zeitgebers that it uses as a reference, i.e., as a feedback (Czeisler et al. 1999). To determine how much the increase in latitude corresponded to an inaccurate feedback for our SCN and consequently to a continuous variation of the LD cycle (Fig. 7), the summer winter solstices index (SWS) was proposed (Table 1). Since the shortest day falls in the winter solstice while the longest ones falls in the summer solstice, the ratio between the duration of the daylight between the two solstice days, at a determined latitude, will provide both a strong indicator of the intensity of adaptation effort to which the SCN is subjected (Fig. 8). At the equator, where the length of the day corresponds to the night, the ratio index will be one and, therefore, the SCN will not need to adapt (Fig. 9). Once crossed the polar circle, we are not able to determine the SWS index anymore because the environment no longer provides recognizable daily zeitgebers. That is why the ethnic groups living in this region, to regulate their organism activities, use primarily their endogenous circadian clock, which in turn they entrain with meal timings and other biological tasks (Lu et al. 2010; Lobban 1967; Edholm and Gunderson 1973). The SCN signals to the organism the time to synthesize hormones and other molecules, synchronizing itself with the aggregated LD cycle. It represents the sum of all the light based on its external feedbacks. When the LD cycle does not correspond to the internal clock, due to a delay of the zeitgebers, the consequence could be the presence of some leftovers. Instead, when the zeitgebers are anticipated, there will be a lack of physiological products. In addition, since the individual clock works anticipating the external zeitgebers, the real damage is determined when the external feedback anticipates the clock, altering the activities coordinated by SCN which will not be entirely performed (Foster and Roenneberg 2008; Archer et al. 2003; Hatori et al. 2014; Herzog et al. 2015). The continuous diversity of the duration of the LD cycle, due to the different geographical causes or induced by the stressful lifestyle experienced, exposes the SCN to an excessive entrainment effort that consequently induces its malfunction inactivating the natural production of the hormones vitamin D, melatonin and cortisol. Furthermore, it has been observed that in the case of DST, jet-lag and, therefore, also in latitudes with SWS ≠ 1, although the SCN can adapt quickly the organism to the different light cycle, the extra-SCN circadian clock in the liver and in the other organs can take more than a week to get in sync (Harrington 2010). This desynchronization also provides a wrong signal transmitted from the HPA to the thymus and, therefore, as the selection of the lymphocytes malfunctions is housed by such organ, the autoimmunity is triggered. Circadian desynchrony alters components of the innate immune system, like to affect their response to a challenge and cause the dysregulation of the immune system. Such alterations affect the number of circulating lymphocytes, NK cells, and Ab titers in humans, as well as increased inflammatory cytokines involved in MS (Castanon-Cervantes et al. 2010; Malekzadeh et al. 2015). People living at the equator do not need to adapt and people living at the arctic polar circle do not either but for a different reason: in the latter geographic areas there are not daily environmental zeitgebers and, therefore, the clock is mainly endogenous and readapts itself on eating and other necessity patterns. In fact, MS is almost unheard of in the Eskimo population living in polar regions (Goodin 2009; Ascherio and Munger 2007) and, in our opinion, it is due to the absence of daily zeitgebers in their circadian clock. MS is almost unheard of at the equator among the black population living there (Dean et al. 1994), but as those individuals migrate to higher latitudes, they acquire the same risk of getting the disease associated with the location (Smestad et al. 2007). However, due to the scarce attitude to adapt of their internal clock (Yamasaki et al. 1998; Eastman et al. 2012), the course of the affection is faster and more invalidating (Cree et al. 2004). Another cause of continuous readjustment of the circadian rhythm is stress, which can, therefore, be a factor in MS insurgency (Materljan et al. 2001). Interestingly, the geographical distribution of MS is consistent with it, because work is considered a major stressor and the areas where the greatest prevalence of MS has been observed happen to be those where work (and, therefore, stress) is more widespread, namely the areas with a temperate climate (Masters and McMillan 2001). Furthermore, the stress produces cortisol which inhibits the effectiveness of melatonin, causing a further negative effect on the circadian rhythm. Even situations of unbalanced regular LD cycle due to work or lifestyle reasons, that add disruptiveness to the aggregated LD cycle, and hormonal production are also altered thus it effects the immunologic system. This kind of stress is considered a fake zeitgeber that is a wrong feedback constantly active when people use mobile phones or they watch television during the night. These conditions delay the release of melatonin in the organism altering in the man the circadian rhythms (Gooley et al. 2011). Men are increasingly migrating to the digital circuits (Kosinski et al. 2016), an environment in which the photoperiod cycle, although self-induced, is extreme and the light of the device blocks melatonin secretion (Skeldon et al. 2017; Krishnan and Lyons 2015). Melatonin is fundamental in immunologic defense since it appears to inhibit the differentiation of Th17 cells through the regulatory T cells (Farez et al. 2015). The secretion of melatonin is inhibited by sunlight and activated during its absence. Melatonin provides information on the duration of the night by acting as a light transducer and allowing to our body to adapt to the environment and react to circadian zeitgebers. In the plasma at night, the concentration of melatonin is from three to ten times higher than the diurnal ones (Papantoniou et al. 2014). Melatonin appears to increase the oligodendrocytes differentiation and consequently the remyelination process (Ghareghani et al. 2016; Villapol et al. 2011; Olivier et al. 2009). The melatonin also increases the cytotoxic action of fundamental natural killer (NKs) in immunogenic defense, indicating that its presence is sufficient and necessary to maintain the proper conditions of the nerves’ myelin coating. It also has a sedative effect and the increase of its concentration in the blood is an information to the body that sleep is needed. Antagonist of the melatonin is the cortisol, a hormone secreted by stress. Another enemy of melatonin is alcohol, a lifestyle product. An additional issue that might be answered with the help of our model is the sexual discrepancy in MS patients. Some recent studies have suggested that the female-to-male ratio may be as high as three or four to one (Harbo et al. 2013). This may be caused by the fact that women have a circadian rhythm more complex than men and, therefore, it results to be more sensitive and easy to disrupt (Santhi et al. 2016). Furthermore, increased immune system function causes increased susceptibility to autoimmunity in women. The factors to play a role for such an imbalance are most notably sex chromosomes, sex hormones and gut microbiota differences between sexes (Selmi et al. 2018). Among the issues, also the social stress that women have to endure, as the role and discrimination at work, is greater to that of men (Reifman et al. 1991). Additionally, in the world 14% of women use hormone based contraceptives (United Nations 2015). The oral contraceptives usually alter biochemical and physiological parameters of circadian rhythm in healthy young women (Reinberg et al. 1996). The findings of gender identity disorders (GID) and multiple sclerosis risk further substantiate our claims, revealing that low testosterone levels and/or feminizing gonadal hormones might influence MS risk in men with an increasing in GID of 6.63 times, as results by the investigation (Pakpoor et al. 2016). In addition, it was observed that MS tend to be less invalidating during pregnancy because central circadian clock undergoes marked adaptations throughout gestation and maternal physiological adaptations are central to pregnancy success (Wharfe et al. 2016). The best evidence of the hormonal effects on autoimmunity in men comes from pregnancy, in which disease activity could decrease and then worsen after delivery (Invernizzi et al. 2009). Furthermore, some infections as the Epstein–Barr virus (Ascherio and Munger 2007) and the malaria’s Plasmodium falciparum (Sotgiu et al. 2008) appear to independently trigger MS. Nevertheless, given the courses of the tertian and quartan fevers in malaria, the circadian rhythm disruption appear to be involved, but we have not included them in the model since they represent an exception. Once unleashed, autoimmunity can develop in other areas of our organism. For these reasons, other autoimmune diseases seem to follow MS, but current studies support that it involved the same autoimmunity mechanism (Rojas-Villarraga et al. 2012). It is also worth mentioning that high levels of polyamines, such as putrescine, spermidine and spermine, have been detected in autoreactive B and T cells in autoimmune diseases, while interesting findings highlight their connections to autoimmunity (Hesterberg et al. 2018). Brooks, in his study, reports that polyamines can inappropriately stabilize autoantigens, activating enzymes involved in the immunogenic response and resulting in release of autoantigenic material and tissue damage (Brooks 2013). This aspect provides further support to our hypothesis because, among the other numerous roles, the polyamines also participate to the regulation of the circadian clock, at least in the periphery, and their sudden variation might consequently disrupt it (Galluzzi et al. 2015).
Fig. 7

Three LD cycles at different latitudes and conditions. a Represents the natural cycle at the equator. Its shape is constant and it is determined by 12 h of daylight and 12 h of darkness; b shows the natural cycle, highly variable, obtained at 50° of latitude with a value of SWS index of about 2; c is the LD cycle at 50° of latitude and includes the DST as additional circadian disrupting factor

Table 1

The SWS variations. Here is an indicative table of this index at the main latitudes

Lat

20/6 summer

21/12 winter

Index SWS

Country

Prev. X 100 k

12:07

12:07

1

Kenya

1

10°

11:33

12:43

1.10

Venezuela

6.9

20°

13:21

10:55

1.22

Mexico

15

30°

14:05

10:13

1.38

Morocco

20

40°

15:01

09:20

1.61

Italy

113

50°

16:22

08:04

2.03

Germany

149

60°

18:52

05:52

3.22

Norway

160

65° 44'

23:47

03:01

7.88

Sweden

189

66° 33'

Polar day

Polar night

Not defin.

  
Fig. 8

A representation of the LD cycle determined in a country at 50° of latitude, e.g., Germany, and a SWS index value of about 2. The index is the resulting ratio between the summer solstice on the right, during which daylight lasts about 16 h, and the winter solstice on the left during which the daylight lasts about 8 h. There is, therefore, a constantly different duration of the LD cycle and a consequent desynchronization daily of the circadian rhythm

Fig. 9

A representation of the LD cycle at the equator. It corresponds to the image of the circadian rhythm commonly used, which depicts a day and a night of 12 h. It does not correspond to the real LD cycle on most of the planet. This LD cycle has a SWS index equal to 1, because at the equator the duration of the daylight of the summer solstice is equal to that of the winter one. In such environment, the SCN never needs to re-entrain, other than for lifestyle reasons. Therefore, a constant production of hormones and circadian activities is daily performed and correctly synchronized with the LD cycle. On the images, the production of the two LD cycles and more sensitive hormones are indicated

Clinical perspectives

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.

Notes

Acknowledgements

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.

Author contributions

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.

Funding

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

Not applicable.

Informed consent

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.

Supplementary material

726_2019_2718_MOESM1_ESM.docx (27 kb)
Supplementary material 1 (DOCX 28 kb)

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Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  • Francesco Gasperoni
    • 1
    • 2
  • Paola Turini
    • 1
    • 2
  • Enzo Agostinelli
    • 1
    • 2
    Email author
  1. 1.Department of Biochemical Sciences “A. Rossi Fanelli”Sapienza University of RomeRomeItaly
  2. 2.International Polyamines Foundation—ONLUSRomeItaly

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