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The role of puberty and adolescence in the pathobiology of pediatric multiple sclerosis

The role of puberty and adolescence in the pathobiology of pediatric multiple sclerosis Multiple sclerosis (MS) is increasingly recognized in the paediatric age. In a smaller, but well-established, proportion of paediatric MS patients [20% of total paediatric MS cases: 0.2% to 0.7% of the total MS patients] the onset of disease is before 10 years of age [pre-pubescent (childhood) MS]; in the majority [80%] of paediatric MS patients, however [1.7% to 5.6% of the total MS population], the onset of disease is between 10 and 18 years [post-pubertal (juvenile) MS]. Notably, while pre-pubertal MS occurs almost equally in both genders (female/male ratio = 0.9:1; reverting to 0.4–0.6/1 in pre-school MS children) the female/male ratio rises to 2.2/3:1 in the post-pubertal age. Interestingly, precocious puberty has been associated to: (a) a higher risk of developing MS; and (b)a more severe disease course. In addition to that, males are more susceptible to MS (and manifest more neurodegeneration) than females the latter being however more inflammatory than males; pregnancy however reduces MS relapses. All the above findings led to the suggestion of an underlying female sex hormonal involvement in the pathophysiology of MS vs. a protective role of male sex hormones. Epigenetic perspectives indicate that the interplay between genetic background, environmental triggers and neuroendocrine changes, typically occurring around the time of adolescence, could all play a combined role in initiating and/or promoting MS with onset in the paediatric age including many of the most frequent disease-associated risk factors (e.g., overweight/obesity, low vitamin D levels, reduced sunlight exposure, Epstein-Barr virus infection). According to this proposed complex multifactorial model,susceptibility to MS may be thus acquired during pre-pubertal age and children have probably to wait until the adolescence to manifest their first clinical signs/symptoms. Keywords: Paediatric multiple sclerosis, Childhood multiple sclerosis, Early-onset multiple sclerosis, Puberty, Hormones, Pathophysiology, Leptin,PI3K, Demyelination Background pubescent MS: 0.2% to 0.7% of total MS cases) [7, 18] The World Health Organisation (WHO)- Multiple including children with onset of disease in pre-school Sclerosis International Federation reported that the years [17] and (exceptionally) during early infancy (i.e., < interquartile range for signs/symptom onset in MS is be- age 2 years) [17, 19]. The mean annual incidence rates tween 25.3 and 31.8 years, placing the average age of MS for childhood/paediatric MS is at 0.1/100,000–0.9/ onset at 29.2 years [1]. However, late-onset cases have 100,000 [3–16] whilst annual incidence figures for pre- been well documented [2] and the occurrence of MS at pubescent onset MS are at 0.09/100,000] [7, 17–19]. the other end of the spectrum of life (i.e., < age 18 years: While pre-pubescent MS occurs almost equally in both childhood MS) is now well established (1.7% to 10% of genders (female/male ratio = 0.9:1; reverting to 0.4/0.6/1 total MS patients) [3–19]. A small, but well-established in pre-school MS children, as it occurs in acute disse- subgroup of paediatric MS cases is younger than (or had minated encephalomyelitis - ADEM) [20] the female/ the onset of symptoms before) 10 years of age (pre- male ratio rises to 2.2/3:1 in the post-pubertal age (“ju- venile MS”: i.e., MS with onset between age 10–18 years) * Correspondence: m.ruggieri@unict.it [7, 12, 17–19, 21, 22]. Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, AOU “Policlinico-Vittorio Emanuele”, Via S. Sofia, 78, 95124 Catania, Italy Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Salpietro et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:2 Page 2 of 10 In the present review, we summarize the gender effects defences of the immune system). Another important on inflammatory and neurodegenerative processes in MS signal is given by NOD receptors (nucleotide-binding and the relationship between pubertal hormonal and/or oligomerization domain: i.e., a cytoplasmic pattern rec- neuroendocrine changes and the risk of paediatric MS. ognition receptor, which regulates the innate system and cooperates with TLRs) activated also by potassium Pathophysiology of MS and the rationale for efflux-inducing agents such as ATP and TLR stimula- disease-modifying therapies tion. Additional signalling is provided by PAMS/PAMP The hallmark of MS is the demyelinated “MS plaque” (pathogen-associated molecule patterns), toxins, danger that is unique and different from that seen in other in- or stress, whose triggering induce the inflammasome flammatory diseases and consists of a well-demarcated (i.e., a cytoplasmic multiprotein oligomer) via NLRP hypocellular area characterised by the loss of myelin, the (NOD-like receptor protein) that form a complex with formation of astrocytic scars, and the presence of inflam- ASC (apoptosis-associated speck-like protein containing a matory mononuclear cell infiltrates, typically concentrated CARD: caspase recruitment domain) and caspase-1 (i.e., in perivascular, particularly perivenular, cuffs [23–25]. the interleukin-1 converting enzyme, which converts the These infiltrates, which are mainly composed of a mixture IL precursors into mature active IL proteins), activating of innate (CNS-resident) and adaptive (CNS-infiltrating) IL-1b, a major factor inducing inflammation, autophagy components of the immune system [24], include [among and cell death, particularly necrosis [23]. the innate effectors] monocytes/macrophages, dendritic All the above pro-inflammatory soluble factors activate cells, reactive microglial cells, astrocytes, and mast cells, microglia and endothelial cells [i.e., innate effectors], up- and [among the adaptive effectors] autoreactive lympho- regulating expression of adhesion molecules (e.g., E- cyte T cells, B lymphocytes, and plasma cells plus minor selectin), facilitating the migration of T cells into the additional components (e.g., ependymal cells), which after CNS. Matrix metalloproteinases (MMP) degrades BBB their migration into the central nervous system (CNS), in- enhancing further migration of autoreactive T cells and cite a pro-inflammatory reaction, resulting in local tissue macrophages via chemokines (CX3CL-1). The Th1 re- injury, which consists in blood brain barrier (BBB:an- sponse evocated via IL-12 and IFN-γ further activates other innate immune component) leakage, destruction of macrophages that in turn do so to T cells CD8+. Th2 re- myelin sheaths, oligodendrocytes damage, and cell death, sponse via IL-6 mainly stimulates maturation of B cells as well as axonal damage and loss, leading in turn to the and production of autoantibodies. Cytotoxic damage to glial scar (i.e., to the “MS plaque”, as seen at imaging and the oligodendrocyte mediates myelin loss and exposure histopathology) [23]. of the axon to reactive oxygen species, slowing or block- Thus, the migration and/or activation of (innate and ing action potentials and the production of neurological adaptive) pro-inflammatory cells into the CNS represent a manifestations. key stage in the natural history of MS (but what initiates There are intents to remyelinate these lesions via this event still remains unclear) [23]. From a pathophysio- OPCs (oligodendrocyte precursor cells), but neuronal logic viewpoint MS appears to be caused by a contact in factors such as LINGO-1 (Leucine rich repeat and early childhood with a pathogen coupled with other indi- immunoglobulin-like domain-containing protein 1: a vidual susceptibility factors (e.g., genetic, racial and demo- protein important for protein-protein interactions, graphic background), which can elicit their reactivation, which regulates/modulates neuronal differentiation and triggering innate mechanisms of defence as toll-like recep- growth, regulation of axon guidance and regeneration tors (TLRs: membrane-spanning, non-catalytic receptors processes) or TLR2 inhibit their migration [23–25]. expressed on sentinel cells - e.g., macrophages or dendritic Based on these premises, over the last two decades a cells - recognizing structurally conserved molecules de- dozen different preparations of immunomodulatory/im- rived from microbes), that signalizes downstream through munosuppressive agents, targeting the above CNS auto- its adapter protein MyD88 (myeloid differentiation pri- immune mechanisms, have been developed, showing mary response 88), and the phosphorylated/degraded beneficial effects in patients with MS and have been ap- protein IKB which permits translocation of NF-KB (nu- proved as first- or second-line disease-modifying therap- clear factor kappa-light-chain enhancer of activated B ies (DMTs), including [24, 26]: (a)[first-line DMTs] cells: a protein complex, which controls DNA transcrip- interferon-β (IFN-β1a and 1b), glatiramer acetate (GA), tion, cytokine production and cell survival) and the tran- dimethyl fumarate (DMF), and teriflunomide; and (b) scription of pro-inflammatory cytokines such as IL-6, [second-line DMTs] mitoxantrone, fingolimod (a small TNF, IL-1, IL-12, E-selectin, MCP-1, and IL-8. TLR molecule antagonist against SIP and SIP-receptors inhi- through IRF7 (Interferon regulatory factor 7) gives the sig- biting immune cell trafficking), natalizumab (an alpha-4 nal to the transcription of IFN α/β (i.e., the cytokines used integrin blocker of immune cell trafficking/migration), for communication between cells to trigger the protective alemtuzumab (an anti-CD52 cell-depleting monoclonal Salpietro et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:2 Page 3 of 10 antibody), daclizumab (a blocker of the interleukin 2Rα pubertal period irrespective to gender [Tanner stages chain), and ocrelizumab (an anti-CD20 cell-depleting (i.e., Breast, Genitalia, Pubic hair) I vs. I or II: Tanner monoclonal antibody) [23, 26]. stage I represents the true pre-pubertal stage]. By lower- Although these therapies are able to modulate the im- ing the cut-off period down to 10 years one could be mune adaptive response, they do not inhibit innate im- surer: (a) to exclude early pubertal children in analysis mune cells (e.g., microglial cells, macrophages, and of paediatric MS cases, thus avoiding inclusion of MS dendritic cells) that participate in the progression of MS. patients already targeted by the postulated effects of pu- In addition to that, some of these strategies, with their bertal sex hormones on predisposed tissues [e.g., bone indiscriminate targeting of both pathogenic and protect- marrow, thymus, central nervous system]; and (b)to ive immune cells, might have side effects. Several new limit multiple viral exposures as by age 10 years most drugs are imminently emerging including strategies tar- children (e.g., in Italy) have usually completed their vac- geting the innate immune system [e.g., inhibition of cination schedule of mandatory and recommended vac- tyrosine kinase, inhibition of NFkB, scavengers for active cines [17, 19]. oxygen species and nitric oxide, or pharmacological Pre-pubescent onset MS is characterised by peculiar interference with their production], or targeting the clinical, laboratory and imaging features and outcome inflammasome [23]. [17, 19, 28], including inversion of sex ratios, low to null family history for MS, preponderance of atypical mani- Disease-modifying therapies in pediatric MS festations at onset (e.g., hemiparesis, seizures, lethargy, No medication currently approved for adults with (re- brainstem signs/symptoms or cerebellar ataxia), polyfo- lapsing-remitting) MS has completed testing for pe- cal presentation, highest relapse number/year and fastest diatric MS in randomized placebo-controlled trials, recovery time, more severe neurological deficits at re- although several pediatric MS trials have recently been lapses with more completely or near-completely recov- launched [27]. Use of DMTs in pediatric MS remains ery, ADEM/leukodystrophy-like MRI patterns at onset off-label in many countries, especially in patients youn- vs. typical MS MRI patterns attained years after the first ger than 12 years; nevertheless, these medications are attacks, a worse outcome in the earliest onsets (i.e., < widely used. At present, IFN-b and GA continue to be 2 years of age) vs. a better outcome (as compared to the standard first-line treatments for pediatric patients post-pubertal MS) in onsets at toddler ages. with MS, as supported by observational studies and ex- perts’ consensus guidelines [26, 27]. Trials are on-going Age- and gender-related peculiarities of pediatric evaluating the clinical outcome of pediatric patients with MS vs. similar disorders MS treated with fingolimod, dimethyl fumarate, and teri- A peculiar female responsiveness to environmental trig- flunomide [27]. gers is noted across many disease models and is usually attributed to the need, in the female gender, to make re- Ages at presentation of MS in childhood and the peated, rapid and consistent physiologic accommoda- “true” pre-pubertal threshold tions to pregnancy. In female adolescents with MS, a Currently, MS in the paediatric age group is divided into number of genetic, non-genetic and lifestyle factors have two main groups according to the age at presentation of possibly sexually dimorphic effects on MS disease pre- first signs/symptoms [3–19]: disposition and on its clinical course [29, 30]. Similarly to what occurs in MS, the so-called pseudotu- (1)Childhood MS (when the first acute demyelinating mour cerebri syndrome (PTCS) is a neurological disorder, event occurs prior to age 12 years); which, within childhood, mostly affects post-pubertal (2)Juvenile MS (when onset of disease ranges from 12 females, who often are overweight. PTCS is a condition of to 18 years); unclear aetiology, characterised by increased intracranial pressure (ICP) without any radiographic evidence of brain A separate group defines (3) adult MS, when disease tissue abnormalities, and with normal chemical and cyto- onset is after age of 18 years [1, 2]. logical cerebrospinal fluid (CSF) composition [31–33]. The cut-off period up to 12 years to define childhood Multiple causes have been taken into consideration in the MS was chosen by most Authors in their studies because pathophysiology and aetiology of PTCS [32, 33] including this period was (and still is) considered as the pre- or obesity, endocrine abnormalities (e.g., hyperaldosteronism, early pubertal period [Tanner stages (i.e., Breast, Geni- Cushing syndrome, hyperandrogenism, Addison disease), talia, Pubic hair) I or II]. A restricted number of Authors kidney disease (e.g., nephrotic syndrome), systemic disease have proposed, in their studies, a lower cut-off for defin- (e.g., systemic lupus erythematous, Guillain-Barrè syn- ing “true” childhood MS at 10 years of age [12, 17, 19]; drome, antiphospholipid antibody syndrome, polycystic this (lowered) period better reflects the biological pre- ovary syndrome - PCOS, Behcet disease, familial Salpietro et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:2 Page 4 of 10 Mediterranean fever), medications (e.g., recombinant possible trigger(s) underlying both diseases could be rep- growth hormone therapy, tetracycline, steroids, mycophe- resented by the putative involvement of Leptin,which nolate mofetil, vitamins A and D, cytarabine, and cyclo- seem to be centrally involved either in PTCS and in MS sporine A), viral infections (e.g., chickenpox, measles, pathophysiology [7, 32] (Fig. 1). reactivation of varicella infection) and changes in CSF vol- ume and in cerebral CSF hemodynamic (increased cere- bral blood volume, increased cerebrospinal fluid The role of gender factors in paediatric MS production, decreased cerebrospinal fluid resorption or The sex discrepancy (with a female preponderance) in venous flow abnormalities); PTCS has been also observed MS is evident only in individuals who manifest disease in members of the same family presenting in either an symptoms after puberty [1, 7, 17, 19], implicating a likely autosomal dominant or recessive manner. A recently pro- role of female sex hormones in initiating and/or promot- posed unifying (neuroendocrine) hypothesis inferred that ing the disease [7] and of post-pubertal male (high) [32] multiple neuroendocrine interactions (e.g., cortisol, levels of testosterone in protecting from the disease [40]. aldosterone, progesteron) could influence the activation of The above notion is supported by a number of clinical the mineralocorticoid receptor (MR) in the choroid plexus and laboratory evidences: (a) men with MS present at an epithelial cells, which in turn stimulates (via a nuclear older age, concurrent with the start of the age-related + + pathway) the ATPase/Na /K pump leading to raised decline in testosterone levels; (b) a decrease of androgen intracranial CSF production [25]. Even though it typically levels in MS adult males is associated with a more severe affects both genders and all age groups, the post-pubertal disease course and a faster progression to disability; and PTCS typically occurs in overweight girls/women during (c) testosterone administration may ameliorate the clin- their reproductive age [34]. Notably, the overall incidence ical course of MS in males [41, 42]. of PTCS is estimated to be 0,9/100,000 rising to 19/ Oestrogens (17β-estradiol-E2- and estriol-E3), proges- 100,000 in overweight women [34, 35]. terone and testosterone may provide anti-inflammatory Paediatric PTCS is known to occur in association with and neuroprotective effects on induction and effector a broad variety of conditions, especially obesity and phases of experimental allergic encephalomyelitis (EAE) endocrine derangements (e.g., cortisol deficiency or ex- [29, 30]. Anti-inflammatory effects appear mainly medi- cess, hyperandrogenism, hyperaldosteronism) [32, 36]. ated by oestrogen nuclear receptors alpha (ERα) and Although pre-pubertal PTCS can occur in both genders beta (ERβ) expressed by regulatory CD4 + CD25+ T cells and ages, post-pubertal PTCS is usually recorded in (Treg), regulatory B (Breg) cells and dendritic cells and women during their reproductive age [34, 35]: in this re- may be abrogated in the absence of B cells and the co- spect, it has been previously proposed that the prone- inhibitory receptor, Programmed Death-1 (PD-1) on ness of some women to develop PTCS could be linked CD4+ Foxp3+ Treg cells. E2 protective effects on EAE to an estrogenic gynecoid (pear-shaped) fat distribution seem to be mediated by binding to the membrane G- [34]. Adipose tissue contains aromatase, which may be a protein-coupled receptor 30(GPR30). Testosterone may link between obesity and PTCS. Aromatase, which catal- work through androgen receptors or after its conversion yses the production of oestrogens from plasma andro- to oestrogen through ERs, or GPR30. Androgens may stenedione, is more prevalent in the fat of the buttock induce remyelination in cuprizone-induced CNS demye- regions (reflecting the typical female fat distribution) vs. lination by acting on neural androgen receptors. Experi- the abdominal (visceral) regions [34–36]. Of note, the mental studies also showed that androgens exert a reports of the onset of PTCS in postmenopausal women protective role against the development of EAE, the ani- following the initiation of hormone replacement therapy mal model of MS [30]. Additionally, therapeutic trials with further support the notion of an oestrogen involvement dihydrotestosterone (DHT) in castrated animals amelior- in the pathophysiology of this condition [31–33, 37, 38]. ate both symptoms and inflammation [29, 30, 40]. The PTCS neuroendocrine pathophysiology [32] Some neuroprotective effects of oestrogens in EAE are cannotbeappliedtoMS, as themechanism under- mediated by ERα expressed on astrocytes: ERβ ligands lying the rise of CSF pressure cannot be compared to can prevent demyelination and stimulate remyelination the process of demyelination and unlikely involves an and ERβ treatment can affect microglia with protective autoimmune aetiology [39]. Nonetheless, higher values effects in CNS inflammation. Progesterone appears to of ICP have been recently documented in the paediat- affect axonal protection and remyelination, and testos- ric MS population [31, 32], thus reflecting the fact terone can restore synaptic transmission deficits in the that both these conditions (PTCS and MS) could hippocampus. share similar precipitating factors (e.g., obesity, female Sex hormones play a pivotal role in the human immune sex hormones) on a background of alike clinical and an- system, regulating antigen presentation, cytokine gene thropometric features. A tenable hypothesis of common expression, lymphocyte activation and autoimmune Salpietro et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:2 Page 5 of 10 Fig. 1 Mechanisms of Leptin signalling in immune and neuroendocrine cells. Leptin binds to one of its receptors, LEPRb, activating JAK2 by auto- phosphorylation or cross-phosphorylation, and phosphorylates tyrosine residues in the receptor’s cytoplasmic domain. Four of the phosphorylated residues [974, 985, 1077, 1138] function as docking sites for cytoplasmic adaptors for STAT factors, particularly STAT3, which dimerizes translocating into the nucleus, where it induces expression of SOCS3, FOS and JUN genes. SOCS3 participates in a feedback loop that inhibits Leptin signalling by binding to phosphorylated tyrosines. SHP-2 is recruited to Tyr985 and Tyr974 and activates ERK1/2 and p38 MAPK pathways through the adaptor protein GRB2, ultimately inducing FOS and JUN gene expression [FOS and JUN encode for fos and jun proto-oncogene proteins, which form heterodimers (C-fos:c-jun) resulting in the formation of AP-1 (Activator Protein-1) complex, which binds DNA at AP-1 specific sites at the promoter and enhancer regions of target genes and converts extracellular signals into changes of gene expression]. PTP-1B is localized on the surface of the endoplasmic reticulum, and is involved in negative regulation of LEPRb signalling through dephosphorylation of JAK2 after internalization of the LEPRb complex; the endoplasmic reticulum is also the site of action (via Ca++) of the IP3-PIP2-mediated pathway of the Kissprotein1, which in turn modulates GnRH secretion and ultimately LH and FSH secretion [neuroendocrine cells are hereby represented as if they were inside the membrane for practical purposes: in the real pathways the Kiss1 protein binds to the Kiss1 receptor (R), which is expressed on the membrane surface of both immune and neuroendocrine cells: the latter cells promote secretion of GnRH, which in turn stimulate secretion of LH and FSH]. JAK2 can also induce phosphorylation of the IRS1 and 2 proteins, which are responsible for PI3K/AKT and mTOR pathway activation processes [30, 41]. Also, immune central tolerance at There are gender-related differences in immune re- the thymus level is strictly dependent on the hormo- sponse and women have higher levels of immunoglobu- nal status [29, 30, 42]. Elevation of sex steroids dur- lin and more vigorous T-cell activation when compared ing puberty has been, de facto, linked to the typical to males [44]. Oestrogens appear to have a controversial decline of the thymus, which starts around adoles- role on inflammation in EAE. At lower levels, oestrogens cence; the thymus rejuvenation after ablation of sex - such as estradiol - may promote inflammation; but at steroids further supports this notion [29, 30, 43]. It is higher levels, oestrogens - such as the pregnancy hor- unsure whether puberty and its related hormonal mone estriol - may induce a shift in the immune re- changes affect the susceptibility to environmental fac- sponse from a T helper 1 (TH1) response to a T helper tors such as infections. 2(TH2) response, muting inflammation [45]. This Salpietro et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:2 Page 6 of 10 would explain the reason for which disease activity usu- However, the question whether younger age at puberty ally decreases during late pregnancy, which is typically is a real trigger for the disease or a mere trigger factor characterized by high levels of estriol and also the on a background of multiple genetic and environmental beneficial effects of estriol administration to non- determinants remains unsolved. Additionally, it has also pregnant MS females in improving the disease manifes- been speculated that earlier menarche is a surrogate for tations [46–48]. the effect of an MS disease causative factor that influ- Studies in EAE also show that low dose oestrogen ences the risk of MS independently by oestrogens, whilst therapy may have also profound effects in inhibiting affecting the age of menarche as a by-product [53]. the development of autoimmunity, likely influencing Of note, puberty onset requires specific changes in the the immune reaction towards a protective anti- secretion of the pituitary gonadotropins, luteinizing hor- inflammatory cytokine response [29, 30]. However, in mone (LH) and follicle-stimulating hormone (FSH), one of these studies, oestrogen treatment at the onset which are dependent on the release of Gonadotropin [LH/ of active EAE failed to reduce disease severity, a result FSH] releasing hormone (GnRH) from the hypothalamus that is consistent with the hypothesis that naive cells (Fig. 1); thus, timing of puberty is strictly dependent on a aremoresensitive to sexhormonesthandifferentiated specific genetic susceptibility and on environmental condi- effector cells [49]. tions that can influence physiological and pathological Of note, post-pubertal EAE female mice develop in- processes acting on the hypothalamic-pituitary axis, in- creased myelin reactive T-cell responses compared to age- cluding nutrition, adiposity, bone mass, emotional and matched mice that had been prevented from entering psychological factors, light-darkness cycles/melatonin and puberty via pre-pubertal ovariectomy surgery [49, 50]. To- endocrine disrupting compounds [55]. gether, these studies suggest that puberty in females en- Interestingly, also low vitamin D levels are usually hances central nervous system (CNS)autoimmune associated with an earlier age of pubertal onset in the mechanisms, further explaining the female preponderance paediatric population [56]. In this context, it is still un- of MS, at the post-pubertal ages. clear whether environmental exposures affecting pu- Lastly, the role of the female chromosome X on im- berty timing also affect the risk of developing MS in an munity and MS should be also regarded as crucial. This independent manner. Thus, the correlation between could involve hormones-independent mechanisms, in- precocious timing of puberty and menarche and the cluding microRNAs and cytokine genes present on risk of onset and/or worsening of MS and the higher chromosome X [51]. prevalence of obesity within the paediatric MS popula- tion are overall factors, which reflect a possible under- lying endocrinology/metabolic involvement in the Precocious puberty and the risk of MS pathophysiology of MS. Recent MS studies, further deepened, the (causal) rela- Some important MS-associated risk factors (i.e., low tionship between puberty and the disease: initially, only vitamin D level, obesity) are also known to be causes of the peri-pubertal period was regarded as typically associ- early puberty per se, further supporting the possibility ated to a dramatic, female-specific, rise in disease inci- that earlier puberty is a surrogate for the effect of an MS dence; later studies, however, demonstrated that an disease causative factor that influences both the risk of earlier occurrence of puberty and menarche was also as- MS and an earlier menarche. sociated to higher risks of disease onset and a more severe clinical course. One study demonstrated that the Obesity and Leptin: Correlations between age at first symptoms increased by 1.16 years as the age metabolism and paediatric MS of menarche increased by one year [52]. A further MS Pediatric obesity has been demonstrated in one study to collaborative Canadian study showed that females with be a risk factor for later development of adult-onset MS MS were younger at menarche (i.e., 12.4/12 years vs. in women whilst obesity occurring in adulthood carried 12.6/12 years) compared to controls [53]. An association out a null risk of developing MS [57]. Another study between earlier age at menarche in females and a more found that paediatric obesity was independently associ- severe disease course has been also recorded [54]. ated with an increased risk of paediatric onset MS in A potential effect of age of puberty and menarche on girls but not in boys: the association between body mass MS, further strengthens the putative involvement of fe- index (BMI) and paediatric MS was strikingly pro- male sex hormones in disease pathophysiology, due to nounced in extremely obese adolescent girls [7]. oestrogen-related changes in CNS and immune system Despite these findings, still there are many underex- (as outlined above). Thus, an earlier menarche may pos- plored and/or not yet fully understood aspects on these sibly upset a delicate oestrogen balance, making some relationships. The relative percentages of body fat during susceptible girls prone to develop MS. the paediatric age are known to be associated with Salpietro et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:2 Page 7 of 10 accelerated sexual maturation and precocious puberty: it syndromes [known as PIK3-related overgrowth syn- is unclear if overweight and obesity may predispose in- dromes,or PROS] [64, 65], which are also characterized dependently to both earlier puberty and MS, or if it hap- by diffuse white matter abnormalities and increased sig- pens in a consecutive manner [58, 59]. Obesity is nal on T2-weighted images on MRI [66, 67]. Studies that characterized by a low-grade inflammation state and it is investigate potential interactions between Leptin and the known to be associated with a T helper 17 (Th17) bias PI3K signalling in MS patients are needed. predisposing to autoimmune reactions [60]. Additionally, One of the principal observations, which indicate that interactions between obesity and vitamin D status re- Leptin could represent a key mediator in the pathogen- mains unexplored [47]. esis of MS, is due to its female-specific rise during the Adipose tissue is not an inert tissue implied only in en- peri-pubertal age. In fact, numerous studies showed that ergy storage, but can be regarded as a part of an endo- during pubertal age Leptin levels continue to increase in crine organ, which releases many mediators that in turn girls but not in boys due to the testosterone-related in- may predispose to both puberty and MS; additionally, hibition on Leptin secretion [63]. Besides its interaction some of these mediators and/or adipokines released by with the PIK/AKT pathway, possibly implicated in early adipocytes are involved in several inflammatory pro- cytodegenerative processes of myelin, the actions of Lep- cesses, including tumor necrosis factor alpha (TNF-a), tin include a strong influence in both the innate and the interleukin 6 (IL-6) and Leptin. The adipokine hormone adaptive immune system. In the innate system, Leptin Leptin is an amino-acid cytokine-like protein, which is stimulate the activation of the monocyte-macrophage known to play a crucial role in regulating puberty, espe- lineage and the secretion of pro-inflammatory cytokines; cially in females. At central (hypothalamic) level, Leptin in the adaptive immune system Leptin induces pro- facilitates puberty onset likely stimulating the Kisspep- inflammatory Th1 responses [61, 62]. Interestingly, the tin1 (Kiss1) pathways, the upstream regulators of GnRH Leptin deficient mice are resistant to the induction of neurons [55] (Fig. 1). EAE, and administration of Leptin in this animal model Besides its metabolic role in promoting puberty shifts the Th2-type response, characteristic of this animal onset, Leptin has many additional central and/or per- model, to a Th1-type response [68]. ipheral actions, including regulation of both innate and Moreover, it has been observed that Leptin is able to adaptive immunity. In fact Leptin stimulates the secre- maintain environmental conditions that promote loss of tion of pro-inflammatory cytokines (e.g., Il-6, IL-18) immune self-tolerance [69, 70]; in particular, both in and at the adaptive immune system level, Leptin pro- vitro and in vivo, leptin can affect the generation, prolif- motes switch towards pro-inflammatory Th1 immuno- eration and responsiveness of t cells, a key type of t reG logical responses [61]. cells that is involved in the control of immunological tol- Leptin mediates its effects by binding to Leptin recep- erance [71]. tors (LepRs) expressed in the brain and a in wide array of Thus, the crucial involvement of leptin in initiating peripheral tissues. Various alternatively spliced isoforms of and promoting puberty, the observation that it continues LepRs have been described, but the long isoform of Leptin to rise in female but not in male adolescents, the in- receptor (LepRb) is primarily responsible for Leptin sig- creased levels of leptin in the pediatric obese population, nalling (Fig. 1). The binding of Leptin to LepRb activates a the central role of this hormone in regulating inflam- number of signalling pathways, including AK2/STAT 3 matory and autoimmune processes, the demonstration and STAT5, SHP2/MAPK and PI3K/AKT/mTOR [59–61]. of its necessary role for the induction of the animal Notably, the activation of the phosphatidylinositol-3 kinase model of MS (i.e., EAE), are all convincing evidences of (PI3K) pathway by Leptin is one of the most studied the involvement of leptin in pathogenesis of MS, espe- effects of Leptin signalling in the brain and it has been cially in the post-pubertal pediatric age group. demonstrated to play crucial roles in several metabolic and energetic processes [61]. A number of studies have demon- Conclusions and future directions strated the relevance of PI3K as an underlying mechanism In conclusion, within the post-pubertal MS group both of Leptin actions in vivo [52]. In rats, peripheral Leptin the disease prevalence and the female-male ratio are administration was found to activate PI3K in the brain and much higher if compared to the pre-pubertal MS group. pre-treatment with inhibitors of PI3K abolished the anor- Furthermore, a more precocious onset of puberty has ectic response induced by Leptin [61–63]. been associated to both a higher risk of developing MS Interestingly, the balance of PI3K/AKT pathway is and an even more severe disease course. Additional sup- essential for oligodendrocytes survival and axon myeli- port linking puberty with the pathogenesis of MS may nation and gain of functions mutations of genes enclosed be driven from the observations of remarkable similar- in this pathway (especially mutations in PIK3CA gene) ities between the neuroendocrine mechanisms under- have been linked to various types of overgrowth lying the onset of puberty and those associated with the Salpietro et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:2 Page 8 of 10 postpartum period [72]. In fact, the hypogonadotrophic AP drafted the final version. AP along with MR designed and drew Fig. 1. All authors read and approved the final manuscript. state of the postpartum phase resembles the pre- pubertal (hypogonadotrophic) state [73, 74]. Ethics approval and consent to participate Interestingly, the postpartum recovery of gonadotropin This was submitted to and approved by the Ethical Committee (Catania 1) based at the AOU “Policlinico-Vittorio Emanuele”, Catania. release follows a predictable sequence of a preferential rise of FSH followed by LH secretion, a pattern identical Consent for publication to that of the peri-pubertal state [72]. For these reasons, All Authors were informed and gave their consent to publication in MSDD. the neuroendocrine changes in the postpartum period Competing interests have been also known as “puberty in miniature” and The authors declare that they have no competing interests. have been frequently associated to the significantly in- creased risk of onset and relapse of MS after partum. Publisher’sNote Thus, it is possible that the biological mechanisms, Springer Nature remains neutral with regard to jurisdictional claims in which are responsible for the development of the clinical published maps and institutional affiliations. manifestations of MS in the pubertal or post-pubertal Author details periods, are also involved in the onset or the reactivation Department of Molecular Neuroscience, University College of London, of the disease in the post-partum period. London, UK. National Centre for Rare Diseases, Istituto Superiore di Sanità, Thus, recent researches in the field suggest that the Rome, Italy. Institute of Neurological Sciences, National Research Council, Catania, Italy. Unit of Rare Diseases of the Nervous System in Childhood, neuroendocrine changes, typically occurring around the Department of Clinical and Experimental Medicine, Section of Pediatrics and time of puberty, could play a role in initiating and/or Child Neuropsychiatry, University of Catania, AOU “Policlinico-Vittorio promoting pediatric MS associated with additional gen- Emanuele”, Via S. Sofia, 78, 95124 Catania, Italy. etic/non-genetic (e.g., environmental) factors. Received: 2 March 2017 Accepted: 10 November 2017 According to this multifactorial model, susceptibility to MS may be thus acquired during a wide window of risk through childhood and most pre-pubertal children References 1. Compston A, Coles A. Multiple sclerosis. 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The role of puberty and adolescence in the pathobiology of pediatric multiple sclerosis

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Abstract

Multiple sclerosis (MS) is increasingly recognized in the paediatric age. In a smaller, but well-established, proportion of paediatric MS patients [20% of total paediatric MS cases: 0.2% to 0.7% of the total MS patients] the onset of disease is before 10 years of age [pre-pubescent (childhood) MS]; in the majority [80%] of paediatric MS patients, however [1.7% to 5.6% of the total MS population], the onset of disease is between 10 and 18 years [post-pubertal (juvenile) MS]. Notably, while pre-pubertal MS occurs almost equally in both genders (female/male ratio = 0.9:1; reverting to 0.4–0.6/1 in pre-school MS children) the female/male ratio rises to 2.2/3:1 in the post-pubertal age. Interestingly, precocious puberty has been associated to: (a) a higher risk of developing MS; and (b)a more severe disease course. In addition to that, males are more susceptible to MS (and manifest more neurodegeneration) than females the latter being however more inflammatory than males; pregnancy however reduces MS relapses. All the above findings led to the suggestion of an underlying female sex hormonal involvement in the pathophysiology of MS vs. a protective role of male sex hormones. Epigenetic perspectives indicate that the interplay between genetic background, environmental triggers and neuroendocrine changes, typically occurring around the time of adolescence, could all play a combined role in initiating and/or promoting MS with onset in the paediatric age including many of the most frequent disease-associated risk factors (e.g., overweight/obesity, low vitamin D levels, reduced sunlight exposure, Epstein-Barr virus infection). According to this proposed complex multifactorial model,susceptibility to MS may be thus acquired during pre-pubertal age and children have probably to wait until the adolescence to manifest their first clinical signs/symptoms. Keywords: Paediatric multiple sclerosis, Childhood multiple sclerosis, Early-onset multiple sclerosis, Puberty, Hormones, Pathophysiology, Leptin,PI3K, Demyelination Background pubescent MS: 0.2% to 0.7% of total MS cases) [7, 18] The World Health Organisation (WHO)- Multiple including children with onset of disease in pre-school Sclerosis International Federation reported that the years [17] and (exceptionally) during early infancy (i.e., < interquartile range for signs/symptom onset in MS is be- age 2 years) [17, 19]. The mean annual incidence rates tween 25.3 and 31.8 years, placing the average age of MS for childhood/paediatric MS is at 0.1/100,000–0.9/ onset at 29.2 years [1]. However, late-onset cases have 100,000 [3–16] whilst annual incidence figures for pre- been well documented [2] and the occurrence of MS at pubescent onset MS are at 0.09/100,000] [7, 17–19]. the other end of the spectrum of life (i.e., < age 18 years: While pre-pubescent MS occurs almost equally in both childhood MS) is now well established (1.7% to 10% of genders (female/male ratio = 0.9:1; reverting to 0.4/0.6/1 total MS patients) [3–19]. A small, but well-established in pre-school MS children, as it occurs in acute disse- subgroup of paediatric MS cases is younger than (or had minated encephalomyelitis - ADEM) [20] the female/ the onset of symptoms before) 10 years of age (pre- male ratio rises to 2.2/3:1 in the post-pubertal age (“ju- venile MS”: i.e., MS with onset between age 10–18 years) * Correspondence: m.ruggieri@unict.it [7, 12, 17–19, 21, 22]. Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, AOU “Policlinico-Vittorio Emanuele”, Via S. Sofia, 78, 95124 Catania, Italy Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Salpietro et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:2 Page 2 of 10 In the present review, we summarize the gender effects defences of the immune system). Another important on inflammatory and neurodegenerative processes in MS signal is given by NOD receptors (nucleotide-binding and the relationship between pubertal hormonal and/or oligomerization domain: i.e., a cytoplasmic pattern rec- neuroendocrine changes and the risk of paediatric MS. ognition receptor, which regulates the innate system and cooperates with TLRs) activated also by potassium Pathophysiology of MS and the rationale for efflux-inducing agents such as ATP and TLR stimula- disease-modifying therapies tion. Additional signalling is provided by PAMS/PAMP The hallmark of MS is the demyelinated “MS plaque” (pathogen-associated molecule patterns), toxins, danger that is unique and different from that seen in other in- or stress, whose triggering induce the inflammasome flammatory diseases and consists of a well-demarcated (i.e., a cytoplasmic multiprotein oligomer) via NLRP hypocellular area characterised by the loss of myelin, the (NOD-like receptor protein) that form a complex with formation of astrocytic scars, and the presence of inflam- ASC (apoptosis-associated speck-like protein containing a matory mononuclear cell infiltrates, typically concentrated CARD: caspase recruitment domain) and caspase-1 (i.e., in perivascular, particularly perivenular, cuffs [23–25]. the interleukin-1 converting enzyme, which converts the These infiltrates, which are mainly composed of a mixture IL precursors into mature active IL proteins), activating of innate (CNS-resident) and adaptive (CNS-infiltrating) IL-1b, a major factor inducing inflammation, autophagy components of the immune system [24], include [among and cell death, particularly necrosis [23]. the innate effectors] monocytes/macrophages, dendritic All the above pro-inflammatory soluble factors activate cells, reactive microglial cells, astrocytes, and mast cells, microglia and endothelial cells [i.e., innate effectors], up- and [among the adaptive effectors] autoreactive lympho- regulating expression of adhesion molecules (e.g., E- cyte T cells, B lymphocytes, and plasma cells plus minor selectin), facilitating the migration of T cells into the additional components (e.g., ependymal cells), which after CNS. Matrix metalloproteinases (MMP) degrades BBB their migration into the central nervous system (CNS), in- enhancing further migration of autoreactive T cells and cite a pro-inflammatory reaction, resulting in local tissue macrophages via chemokines (CX3CL-1). The Th1 re- injury, which consists in blood brain barrier (BBB:an- sponse evocated via IL-12 and IFN-γ further activates other innate immune component) leakage, destruction of macrophages that in turn do so to T cells CD8+. Th2 re- myelin sheaths, oligodendrocytes damage, and cell death, sponse via IL-6 mainly stimulates maturation of B cells as well as axonal damage and loss, leading in turn to the and production of autoantibodies. Cytotoxic damage to glial scar (i.e., to the “MS plaque”, as seen at imaging and the oligodendrocyte mediates myelin loss and exposure histopathology) [23]. of the axon to reactive oxygen species, slowing or block- Thus, the migration and/or activation of (innate and ing action potentials and the production of neurological adaptive) pro-inflammatory cells into the CNS represent a manifestations. key stage in the natural history of MS (but what initiates There are intents to remyelinate these lesions via this event still remains unclear) [23]. From a pathophysio- OPCs (oligodendrocyte precursor cells), but neuronal logic viewpoint MS appears to be caused by a contact in factors such as LINGO-1 (Leucine rich repeat and early childhood with a pathogen coupled with other indi- immunoglobulin-like domain-containing protein 1: a vidual susceptibility factors (e.g., genetic, racial and demo- protein important for protein-protein interactions, graphic background), which can elicit their reactivation, which regulates/modulates neuronal differentiation and triggering innate mechanisms of defence as toll-like recep- growth, regulation of axon guidance and regeneration tors (TLRs: membrane-spanning, non-catalytic receptors processes) or TLR2 inhibit their migration [23–25]. expressed on sentinel cells - e.g., macrophages or dendritic Based on these premises, over the last two decades a cells - recognizing structurally conserved molecules de- dozen different preparations of immunomodulatory/im- rived from microbes), that signalizes downstream through munosuppressive agents, targeting the above CNS auto- its adapter protein MyD88 (myeloid differentiation pri- immune mechanisms, have been developed, showing mary response 88), and the phosphorylated/degraded beneficial effects in patients with MS and have been ap- protein IKB which permits translocation of NF-KB (nu- proved as first- or second-line disease-modifying therap- clear factor kappa-light-chain enhancer of activated B ies (DMTs), including [24, 26]: (a)[first-line DMTs] cells: a protein complex, which controls DNA transcrip- interferon-β (IFN-β1a and 1b), glatiramer acetate (GA), tion, cytokine production and cell survival) and the tran- dimethyl fumarate (DMF), and teriflunomide; and (b) scription of pro-inflammatory cytokines such as IL-6, [second-line DMTs] mitoxantrone, fingolimod (a small TNF, IL-1, IL-12, E-selectin, MCP-1, and IL-8. TLR molecule antagonist against SIP and SIP-receptors inhi- through IRF7 (Interferon regulatory factor 7) gives the sig- biting immune cell trafficking), natalizumab (an alpha-4 nal to the transcription of IFN α/β (i.e., the cytokines used integrin blocker of immune cell trafficking/migration), for communication between cells to trigger the protective alemtuzumab (an anti-CD52 cell-depleting monoclonal Salpietro et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:2 Page 3 of 10 antibody), daclizumab (a blocker of the interleukin 2Rα pubertal period irrespective to gender [Tanner stages chain), and ocrelizumab (an anti-CD20 cell-depleting (i.e., Breast, Genitalia, Pubic hair) I vs. I or II: Tanner monoclonal antibody) [23, 26]. stage I represents the true pre-pubertal stage]. By lower- Although these therapies are able to modulate the im- ing the cut-off period down to 10 years one could be mune adaptive response, they do not inhibit innate im- surer: (a) to exclude early pubertal children in analysis mune cells (e.g., microglial cells, macrophages, and of paediatric MS cases, thus avoiding inclusion of MS dendritic cells) that participate in the progression of MS. patients already targeted by the postulated effects of pu- In addition to that, some of these strategies, with their bertal sex hormones on predisposed tissues [e.g., bone indiscriminate targeting of both pathogenic and protect- marrow, thymus, central nervous system]; and (b)to ive immune cells, might have side effects. Several new limit multiple viral exposures as by age 10 years most drugs are imminently emerging including strategies tar- children (e.g., in Italy) have usually completed their vac- geting the innate immune system [e.g., inhibition of cination schedule of mandatory and recommended vac- tyrosine kinase, inhibition of NFkB, scavengers for active cines [17, 19]. oxygen species and nitric oxide, or pharmacological Pre-pubescent onset MS is characterised by peculiar interference with their production], or targeting the clinical, laboratory and imaging features and outcome inflammasome [23]. [17, 19, 28], including inversion of sex ratios, low to null family history for MS, preponderance of atypical mani- Disease-modifying therapies in pediatric MS festations at onset (e.g., hemiparesis, seizures, lethargy, No medication currently approved for adults with (re- brainstem signs/symptoms or cerebellar ataxia), polyfo- lapsing-remitting) MS has completed testing for pe- cal presentation, highest relapse number/year and fastest diatric MS in randomized placebo-controlled trials, recovery time, more severe neurological deficits at re- although several pediatric MS trials have recently been lapses with more completely or near-completely recov- launched [27]. Use of DMTs in pediatric MS remains ery, ADEM/leukodystrophy-like MRI patterns at onset off-label in many countries, especially in patients youn- vs. typical MS MRI patterns attained years after the first ger than 12 years; nevertheless, these medications are attacks, a worse outcome in the earliest onsets (i.e., < widely used. At present, IFN-b and GA continue to be 2 years of age) vs. a better outcome (as compared to the standard first-line treatments for pediatric patients post-pubertal MS) in onsets at toddler ages. with MS, as supported by observational studies and ex- perts’ consensus guidelines [26, 27]. Trials are on-going Age- and gender-related peculiarities of pediatric evaluating the clinical outcome of pediatric patients with MS vs. similar disorders MS treated with fingolimod, dimethyl fumarate, and teri- A peculiar female responsiveness to environmental trig- flunomide [27]. gers is noted across many disease models and is usually attributed to the need, in the female gender, to make re- Ages at presentation of MS in childhood and the peated, rapid and consistent physiologic accommoda- “true” pre-pubertal threshold tions to pregnancy. In female adolescents with MS, a Currently, MS in the paediatric age group is divided into number of genetic, non-genetic and lifestyle factors have two main groups according to the age at presentation of possibly sexually dimorphic effects on MS disease pre- first signs/symptoms [3–19]: disposition and on its clinical course [29, 30]. Similarly to what occurs in MS, the so-called pseudotu- (1)Childhood MS (when the first acute demyelinating mour cerebri syndrome (PTCS) is a neurological disorder, event occurs prior to age 12 years); which, within childhood, mostly affects post-pubertal (2)Juvenile MS (when onset of disease ranges from 12 females, who often are overweight. PTCS is a condition of to 18 years); unclear aetiology, characterised by increased intracranial pressure (ICP) without any radiographic evidence of brain A separate group defines (3) adult MS, when disease tissue abnormalities, and with normal chemical and cyto- onset is after age of 18 years [1, 2]. logical cerebrospinal fluid (CSF) composition [31–33]. The cut-off period up to 12 years to define childhood Multiple causes have been taken into consideration in the MS was chosen by most Authors in their studies because pathophysiology and aetiology of PTCS [32, 33] including this period was (and still is) considered as the pre- or obesity, endocrine abnormalities (e.g., hyperaldosteronism, early pubertal period [Tanner stages (i.e., Breast, Geni- Cushing syndrome, hyperandrogenism, Addison disease), talia, Pubic hair) I or II]. A restricted number of Authors kidney disease (e.g., nephrotic syndrome), systemic disease have proposed, in their studies, a lower cut-off for defin- (e.g., systemic lupus erythematous, Guillain-Barrè syn- ing “true” childhood MS at 10 years of age [12, 17, 19]; drome, antiphospholipid antibody syndrome, polycystic this (lowered) period better reflects the biological pre- ovary syndrome - PCOS, Behcet disease, familial Salpietro et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:2 Page 4 of 10 Mediterranean fever), medications (e.g., recombinant possible trigger(s) underlying both diseases could be rep- growth hormone therapy, tetracycline, steroids, mycophe- resented by the putative involvement of Leptin,which nolate mofetil, vitamins A and D, cytarabine, and cyclo- seem to be centrally involved either in PTCS and in MS sporine A), viral infections (e.g., chickenpox, measles, pathophysiology [7, 32] (Fig. 1). reactivation of varicella infection) and changes in CSF vol- ume and in cerebral CSF hemodynamic (increased cere- bral blood volume, increased cerebrospinal fluid The role of gender factors in paediatric MS production, decreased cerebrospinal fluid resorption or The sex discrepancy (with a female preponderance) in venous flow abnormalities); PTCS has been also observed MS is evident only in individuals who manifest disease in members of the same family presenting in either an symptoms after puberty [1, 7, 17, 19], implicating a likely autosomal dominant or recessive manner. A recently pro- role of female sex hormones in initiating and/or promot- posed unifying (neuroendocrine) hypothesis inferred that ing the disease [7] and of post-pubertal male (high) [32] multiple neuroendocrine interactions (e.g., cortisol, levels of testosterone in protecting from the disease [40]. aldosterone, progesteron) could influence the activation of The above notion is supported by a number of clinical the mineralocorticoid receptor (MR) in the choroid plexus and laboratory evidences: (a) men with MS present at an epithelial cells, which in turn stimulates (via a nuclear older age, concurrent with the start of the age-related + + pathway) the ATPase/Na /K pump leading to raised decline in testosterone levels; (b) a decrease of androgen intracranial CSF production [25]. Even though it typically levels in MS adult males is associated with a more severe affects both genders and all age groups, the post-pubertal disease course and a faster progression to disability; and PTCS typically occurs in overweight girls/women during (c) testosterone administration may ameliorate the clin- their reproductive age [34]. Notably, the overall incidence ical course of MS in males [41, 42]. of PTCS is estimated to be 0,9/100,000 rising to 19/ Oestrogens (17β-estradiol-E2- and estriol-E3), proges- 100,000 in overweight women [34, 35]. terone and testosterone may provide anti-inflammatory Paediatric PTCS is known to occur in association with and neuroprotective effects on induction and effector a broad variety of conditions, especially obesity and phases of experimental allergic encephalomyelitis (EAE) endocrine derangements (e.g., cortisol deficiency or ex- [29, 30]. Anti-inflammatory effects appear mainly medi- cess, hyperandrogenism, hyperaldosteronism) [32, 36]. ated by oestrogen nuclear receptors alpha (ERα) and Although pre-pubertal PTCS can occur in both genders beta (ERβ) expressed by regulatory CD4 + CD25+ T cells and ages, post-pubertal PTCS is usually recorded in (Treg), regulatory B (Breg) cells and dendritic cells and women during their reproductive age [34, 35]: in this re- may be abrogated in the absence of B cells and the co- spect, it has been previously proposed that the prone- inhibitory receptor, Programmed Death-1 (PD-1) on ness of some women to develop PTCS could be linked CD4+ Foxp3+ Treg cells. E2 protective effects on EAE to an estrogenic gynecoid (pear-shaped) fat distribution seem to be mediated by binding to the membrane G- [34]. Adipose tissue contains aromatase, which may be a protein-coupled receptor 30(GPR30). Testosterone may link between obesity and PTCS. Aromatase, which catal- work through androgen receptors or after its conversion yses the production of oestrogens from plasma andro- to oestrogen through ERs, or GPR30. Androgens may stenedione, is more prevalent in the fat of the buttock induce remyelination in cuprizone-induced CNS demye- regions (reflecting the typical female fat distribution) vs. lination by acting on neural androgen receptors. Experi- the abdominal (visceral) regions [34–36]. Of note, the mental studies also showed that androgens exert a reports of the onset of PTCS in postmenopausal women protective role against the development of EAE, the ani- following the initiation of hormone replacement therapy mal model of MS [30]. Additionally, therapeutic trials with further support the notion of an oestrogen involvement dihydrotestosterone (DHT) in castrated animals amelior- in the pathophysiology of this condition [31–33, 37, 38]. ate both symptoms and inflammation [29, 30, 40]. The PTCS neuroendocrine pathophysiology [32] Some neuroprotective effects of oestrogens in EAE are cannotbeappliedtoMS, as themechanism under- mediated by ERα expressed on astrocytes: ERβ ligands lying the rise of CSF pressure cannot be compared to can prevent demyelination and stimulate remyelination the process of demyelination and unlikely involves an and ERβ treatment can affect microglia with protective autoimmune aetiology [39]. Nonetheless, higher values effects in CNS inflammation. Progesterone appears to of ICP have been recently documented in the paediat- affect axonal protection and remyelination, and testos- ric MS population [31, 32], thus reflecting the fact terone can restore synaptic transmission deficits in the that both these conditions (PTCS and MS) could hippocampus. share similar precipitating factors (e.g., obesity, female Sex hormones play a pivotal role in the human immune sex hormones) on a background of alike clinical and an- system, regulating antigen presentation, cytokine gene thropometric features. A tenable hypothesis of common expression, lymphocyte activation and autoimmune Salpietro et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:2 Page 5 of 10 Fig. 1 Mechanisms of Leptin signalling in immune and neuroendocrine cells. Leptin binds to one of its receptors, LEPRb, activating JAK2 by auto- phosphorylation or cross-phosphorylation, and phosphorylates tyrosine residues in the receptor’s cytoplasmic domain. Four of the phosphorylated residues [974, 985, 1077, 1138] function as docking sites for cytoplasmic adaptors for STAT factors, particularly STAT3, which dimerizes translocating into the nucleus, where it induces expression of SOCS3, FOS and JUN genes. SOCS3 participates in a feedback loop that inhibits Leptin signalling by binding to phosphorylated tyrosines. SHP-2 is recruited to Tyr985 and Tyr974 and activates ERK1/2 and p38 MAPK pathways through the adaptor protein GRB2, ultimately inducing FOS and JUN gene expression [FOS and JUN encode for fos and jun proto-oncogene proteins, which form heterodimers (C-fos:c-jun) resulting in the formation of AP-1 (Activator Protein-1) complex, which binds DNA at AP-1 specific sites at the promoter and enhancer regions of target genes and converts extracellular signals into changes of gene expression]. PTP-1B is localized on the surface of the endoplasmic reticulum, and is involved in negative regulation of LEPRb signalling through dephosphorylation of JAK2 after internalization of the LEPRb complex; the endoplasmic reticulum is also the site of action (via Ca++) of the IP3-PIP2-mediated pathway of the Kissprotein1, which in turn modulates GnRH secretion and ultimately LH and FSH secretion [neuroendocrine cells are hereby represented as if they were inside the membrane for practical purposes: in the real pathways the Kiss1 protein binds to the Kiss1 receptor (R), which is expressed on the membrane surface of both immune and neuroendocrine cells: the latter cells promote secretion of GnRH, which in turn stimulate secretion of LH and FSH]. JAK2 can also induce phosphorylation of the IRS1 and 2 proteins, which are responsible for PI3K/AKT and mTOR pathway activation processes [30, 41]. Also, immune central tolerance at There are gender-related differences in immune re- the thymus level is strictly dependent on the hormo- sponse and women have higher levels of immunoglobu- nal status [29, 30, 42]. Elevation of sex steroids dur- lin and more vigorous T-cell activation when compared ing puberty has been, de facto, linked to the typical to males [44]. Oestrogens appear to have a controversial decline of the thymus, which starts around adoles- role on inflammation in EAE. At lower levels, oestrogens cence; the thymus rejuvenation after ablation of sex - such as estradiol - may promote inflammation; but at steroids further supports this notion [29, 30, 43]. It is higher levels, oestrogens - such as the pregnancy hor- unsure whether puberty and its related hormonal mone estriol - may induce a shift in the immune re- changes affect the susceptibility to environmental fac- sponse from a T helper 1 (TH1) response to a T helper tors such as infections. 2(TH2) response, muting inflammation [45]. This Salpietro et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:2 Page 6 of 10 would explain the reason for which disease activity usu- However, the question whether younger age at puberty ally decreases during late pregnancy, which is typically is a real trigger for the disease or a mere trigger factor characterized by high levels of estriol and also the on a background of multiple genetic and environmental beneficial effects of estriol administration to non- determinants remains unsolved. Additionally, it has also pregnant MS females in improving the disease manifes- been speculated that earlier menarche is a surrogate for tations [46–48]. the effect of an MS disease causative factor that influ- Studies in EAE also show that low dose oestrogen ences the risk of MS independently by oestrogens, whilst therapy may have also profound effects in inhibiting affecting the age of menarche as a by-product [53]. the development of autoimmunity, likely influencing Of note, puberty onset requires specific changes in the the immune reaction towards a protective anti- secretion of the pituitary gonadotropins, luteinizing hor- inflammatory cytokine response [29, 30]. However, in mone (LH) and follicle-stimulating hormone (FSH), one of these studies, oestrogen treatment at the onset which are dependent on the release of Gonadotropin [LH/ of active EAE failed to reduce disease severity, a result FSH] releasing hormone (GnRH) from the hypothalamus that is consistent with the hypothesis that naive cells (Fig. 1); thus, timing of puberty is strictly dependent on a aremoresensitive to sexhormonesthandifferentiated specific genetic susceptibility and on environmental condi- effector cells [49]. tions that can influence physiological and pathological Of note, post-pubertal EAE female mice develop in- processes acting on the hypothalamic-pituitary axis, in- creased myelin reactive T-cell responses compared to age- cluding nutrition, adiposity, bone mass, emotional and matched mice that had been prevented from entering psychological factors, light-darkness cycles/melatonin and puberty via pre-pubertal ovariectomy surgery [49, 50]. To- endocrine disrupting compounds [55]. gether, these studies suggest that puberty in females en- Interestingly, also low vitamin D levels are usually hances central nervous system (CNS)autoimmune associated with an earlier age of pubertal onset in the mechanisms, further explaining the female preponderance paediatric population [56]. In this context, it is still un- of MS, at the post-pubertal ages. clear whether environmental exposures affecting pu- Lastly, the role of the female chromosome X on im- berty timing also affect the risk of developing MS in an munity and MS should be also regarded as crucial. This independent manner. Thus, the correlation between could involve hormones-independent mechanisms, in- precocious timing of puberty and menarche and the cluding microRNAs and cytokine genes present on risk of onset and/or worsening of MS and the higher chromosome X [51]. prevalence of obesity within the paediatric MS popula- tion are overall factors, which reflect a possible under- lying endocrinology/metabolic involvement in the Precocious puberty and the risk of MS pathophysiology of MS. Recent MS studies, further deepened, the (causal) rela- Some important MS-associated risk factors (i.e., low tionship between puberty and the disease: initially, only vitamin D level, obesity) are also known to be causes of the peri-pubertal period was regarded as typically associ- early puberty per se, further supporting the possibility ated to a dramatic, female-specific, rise in disease inci- that earlier puberty is a surrogate for the effect of an MS dence; later studies, however, demonstrated that an disease causative factor that influences both the risk of earlier occurrence of puberty and menarche was also as- MS and an earlier menarche. sociated to higher risks of disease onset and a more severe clinical course. One study demonstrated that the Obesity and Leptin: Correlations between age at first symptoms increased by 1.16 years as the age metabolism and paediatric MS of menarche increased by one year [52]. A further MS Pediatric obesity has been demonstrated in one study to collaborative Canadian study showed that females with be a risk factor for later development of adult-onset MS MS were younger at menarche (i.e., 12.4/12 years vs. in women whilst obesity occurring in adulthood carried 12.6/12 years) compared to controls [53]. An association out a null risk of developing MS [57]. Another study between earlier age at menarche in females and a more found that paediatric obesity was independently associ- severe disease course has been also recorded [54]. ated with an increased risk of paediatric onset MS in A potential effect of age of puberty and menarche on girls but not in boys: the association between body mass MS, further strengthens the putative involvement of fe- index (BMI) and paediatric MS was strikingly pro- male sex hormones in disease pathophysiology, due to nounced in extremely obese adolescent girls [7]. oestrogen-related changes in CNS and immune system Despite these findings, still there are many underex- (as outlined above). Thus, an earlier menarche may pos- plored and/or not yet fully understood aspects on these sibly upset a delicate oestrogen balance, making some relationships. The relative percentages of body fat during susceptible girls prone to develop MS. the paediatric age are known to be associated with Salpietro et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:2 Page 7 of 10 accelerated sexual maturation and precocious puberty: it syndromes [known as PIK3-related overgrowth syn- is unclear if overweight and obesity may predispose in- dromes,or PROS] [64, 65], which are also characterized dependently to both earlier puberty and MS, or if it hap- by diffuse white matter abnormalities and increased sig- pens in a consecutive manner [58, 59]. Obesity is nal on T2-weighted images on MRI [66, 67]. Studies that characterized by a low-grade inflammation state and it is investigate potential interactions between Leptin and the known to be associated with a T helper 17 (Th17) bias PI3K signalling in MS patients are needed. predisposing to autoimmune reactions [60]. Additionally, One of the principal observations, which indicate that interactions between obesity and vitamin D status re- Leptin could represent a key mediator in the pathogen- mains unexplored [47]. esis of MS, is due to its female-specific rise during the Adipose tissue is not an inert tissue implied only in en- peri-pubertal age. In fact, numerous studies showed that ergy storage, but can be regarded as a part of an endo- during pubertal age Leptin levels continue to increase in crine organ, which releases many mediators that in turn girls but not in boys due to the testosterone-related in- may predispose to both puberty and MS; additionally, hibition on Leptin secretion [63]. Besides its interaction some of these mediators and/or adipokines released by with the PIK/AKT pathway, possibly implicated in early adipocytes are involved in several inflammatory pro- cytodegenerative processes of myelin, the actions of Lep- cesses, including tumor necrosis factor alpha (TNF-a), tin include a strong influence in both the innate and the interleukin 6 (IL-6) and Leptin. The adipokine hormone adaptive immune system. In the innate system, Leptin Leptin is an amino-acid cytokine-like protein, which is stimulate the activation of the monocyte-macrophage known to play a crucial role in regulating puberty, espe- lineage and the secretion of pro-inflammatory cytokines; cially in females. At central (hypothalamic) level, Leptin in the adaptive immune system Leptin induces pro- facilitates puberty onset likely stimulating the Kisspep- inflammatory Th1 responses [61, 62]. Interestingly, the tin1 (Kiss1) pathways, the upstream regulators of GnRH Leptin deficient mice are resistant to the induction of neurons [55] (Fig. 1). EAE, and administration of Leptin in this animal model Besides its metabolic role in promoting puberty shifts the Th2-type response, characteristic of this animal onset, Leptin has many additional central and/or per- model, to a Th1-type response [68]. ipheral actions, including regulation of both innate and Moreover, it has been observed that Leptin is able to adaptive immunity. In fact Leptin stimulates the secre- maintain environmental conditions that promote loss of tion of pro-inflammatory cytokines (e.g., Il-6, IL-18) immune self-tolerance [69, 70]; in particular, both in and at the adaptive immune system level, Leptin pro- vitro and in vivo, leptin can affect the generation, prolif- motes switch towards pro-inflammatory Th1 immuno- eration and responsiveness of t cells, a key type of t reG logical responses [61]. cells that is involved in the control of immunological tol- Leptin mediates its effects by binding to Leptin recep- erance [71]. tors (LepRs) expressed in the brain and a in wide array of Thus, the crucial involvement of leptin in initiating peripheral tissues. Various alternatively spliced isoforms of and promoting puberty, the observation that it continues LepRs have been described, but the long isoform of Leptin to rise in female but not in male adolescents, the in- receptor (LepRb) is primarily responsible for Leptin sig- creased levels of leptin in the pediatric obese population, nalling (Fig. 1). The binding of Leptin to LepRb activates a the central role of this hormone in regulating inflam- number of signalling pathways, including AK2/STAT 3 matory and autoimmune processes, the demonstration and STAT5, SHP2/MAPK and PI3K/AKT/mTOR [59–61]. of its necessary role for the induction of the animal Notably, the activation of the phosphatidylinositol-3 kinase model of MS (i.e., EAE), are all convincing evidences of (PI3K) pathway by Leptin is one of the most studied the involvement of leptin in pathogenesis of MS, espe- effects of Leptin signalling in the brain and it has been cially in the post-pubertal pediatric age group. demonstrated to play crucial roles in several metabolic and energetic processes [61]. A number of studies have demon- Conclusions and future directions strated the relevance of PI3K as an underlying mechanism In conclusion, within the post-pubertal MS group both of Leptin actions in vivo [52]. In rats, peripheral Leptin the disease prevalence and the female-male ratio are administration was found to activate PI3K in the brain and much higher if compared to the pre-pubertal MS group. pre-treatment with inhibitors of PI3K abolished the anor- Furthermore, a more precocious onset of puberty has ectic response induced by Leptin [61–63]. been associated to both a higher risk of developing MS Interestingly, the balance of PI3K/AKT pathway is and an even more severe disease course. Additional sup- essential for oligodendrocytes survival and axon myeli- port linking puberty with the pathogenesis of MS may nation and gain of functions mutations of genes enclosed be driven from the observations of remarkable similar- in this pathway (especially mutations in PIK3CA gene) ities between the neuroendocrine mechanisms under- have been linked to various types of overgrowth lying the onset of puberty and those associated with the Salpietro et al. Multiple Sclerosis and Demyelinating Disorders (2018) 3:2 Page 8 of 10 postpartum period [72]. In fact, the hypogonadotrophic AP drafted the final version. AP along with MR designed and drew Fig. 1. All authors read and approved the final manuscript. state of the postpartum phase resembles the pre- pubertal (hypogonadotrophic) state [73, 74]. Ethics approval and consent to participate Interestingly, the postpartum recovery of gonadotropin This was submitted to and approved by the Ethical Committee (Catania 1) based at the AOU “Policlinico-Vittorio Emanuele”, Catania. release follows a predictable sequence of a preferential rise of FSH followed by LH secretion, a pattern identical Consent for publication to that of the peri-pubertal state [72]. For these reasons, All Authors were informed and gave their consent to publication in MSDD. the neuroendocrine changes in the postpartum period Competing interests have been also known as “puberty in miniature” and The authors declare that they have no competing interests. have been frequently associated to the significantly in- creased risk of onset and relapse of MS after partum. Publisher’sNote Thus, it is possible that the biological mechanisms, Springer Nature remains neutral with regard to jurisdictional claims in which are responsible for the development of the clinical published maps and institutional affiliations. manifestations of MS in the pubertal or post-pubertal Author details periods, are also involved in the onset or the reactivation Department of Molecular Neuroscience, University College of London, of the disease in the post-partum period. London, UK. National Centre for Rare Diseases, Istituto Superiore di Sanità, Thus, recent researches in the field suggest that the Rome, Italy. Institute of Neurological Sciences, National Research Council, Catania, Italy. Unit of Rare Diseases of the Nervous System in Childhood, neuroendocrine changes, typically occurring around the Department of Clinical and Experimental Medicine, Section of Pediatrics and time of puberty, could play a role in initiating and/or Child Neuropsychiatry, University of Catania, AOU “Policlinico-Vittorio promoting pediatric MS associated with additional gen- Emanuele”, Via S. Sofia, 78, 95124 Catania, Italy. etic/non-genetic (e.g., environmental) factors. Received: 2 March 2017 Accepted: 10 November 2017 According to this multifactorial model, susceptibility to MS may be thus acquired during a wide window of risk through childhood and most pre-pubertal children References 1. Compston A, Coles A. Multiple sclerosis. 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J Endocrinol. 2014;223:T37–48. Submit your next manuscript to BioMed Central and we will help you at every step: • We accept pre-submission inquiries � Our selector tool helps you to find the most relevant journal � We provide round the clock customer support � Convenient online submission � Thorough peer review � Inclusion in PubMed and all major indexing services � Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit

Journal

Multiple Sclerosis and Demyelinating DisordersSpringer Journals

Published: Feb 22, 2018

References