AUTREV-01810; No of Pages 6 Autoimmunity Reviews xxx (2016) xxx–xxx
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Article history: Received 4 January 2016 Accepted 20 January 2016 Available online xxxx
Neonatal Intensive Care Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), Siena, Italy Child Neuropsychiatry Unit, University Hospital, Siena, Italy Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy d Department of Medical Biotechnologies, University of Siena, Siena, Italy e Laboratory of Peptide and Protein Chemistry and Biology—PeptLab (www.peptlab.eu), Italy f Section of Pharmaceutical and Nutraceutical Sciences, Department NeuroFarBa, University of Florence, Sesto Fiorentino, Italy g Department of Chemistry “Ugo Schiff”, University of Florence, Sesto Fiorentino, Italy h Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS/UM/ENSCM, Montpellier, France i PeptLab@UCP and Laboratory of Chemical Biology EA4505, University of Cergy-Pontoise, 5 Mail Gay-Lussac, 95031 Cergy-Pontoise, France b
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Rett syndrome (RTT) is a devastating neurodevelopmental disease, previously included into the autistic spectrum disorders, affecting almost exclusively females (frequency 1:10,000). RTT leads to intellective deficit, purposeful hands use loss and late major motor impairment besides featuring breathing disorders, epilepsy and increased risk of sudden death. The condition is caused in up to 95% of the cases by mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. Our group has shown a number of previously unrecognized features, such as systemic redox imbalance, chronic inflammatory status, respiratory bronchiolitis-associated interstitial lung disease-like lung disease, and erythrocyte morphology changes. While evidence on an intimate involvement of MeCP2 in the immune response is cumulating, we have recently shown a cytokine dysregulation in RTT. Increasing evidence on the relationship between MeCP2 and an immune dysfunction is reported, with, apparently, a link between MeCP2 gene polymorphisms and autoimmune diseases, including primary Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis. Antineuronal (i.e., brain proteins) antibodies have been shown in RTT. Recently, high levels of anti-N-glucosylation (N-Glc) IgM serum autoantibodies [i.e., anti-CSF114(N-Glc) IgMs] have been detected by our group in a statistically significant number of RTT patients. In the current review, the Authors explore the current evidence, either in favor or against, the presence of an autoimmune component in RTT. © 2016 Published by Elsevier B.V.
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Claudio De Felice a,⁎, Silvia Leoncini b,c, Cinzia Signorini c, Alessio Cortelazzo b,d, Paolo Rovero e,f, Thierry Durand h, Lucia Ciccoli c, Anna Maria Papini e,g,i, Joussef Hayek b
Keywords: MECP2 Inflammation Aberrant N-glucosylation Synthetic antigenic peptides Autoimmunity
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Rett syndrome: An autoimmune disease?
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Contents
1. Rett syndrome: clinical and genetic background . . . . . . . . . . . . . . . . . . . . . . 2. Rett syndrome: not just a neurological disease . . . . . . . . . . . . . . . . . . . . . . 3. Rett syndrome and oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Rett syndrome, inflammatory response and immunity . . . . . . . . . . . . . . . . . . . 5. Rett syndrome and omega-3 polyunsaturated fatty acids . . . . . . . . . . . . . . . . . . 6. Rett syndrome and autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Specific igms to n-glucosylated peptide antigens: the first example of molecular mimicry in RTT 8. Rett syndrome and altered brain N-glycosylation . . . . . . . . . . . . . . . . . . . . . 9. Conclusive remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uncited reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Correspondence author at: Neonatal Intensive Care Unit, University Hospital AOUS, Policlinico “S. M. alle Scotte, Viale M. Bracci 1, Siena 53100, Italy. Tel.: +39 0577 586542/586550 (Secretary), +39 347 3309885 (mobile). E-mail address: [email protected] (C.D. Felice).
http://dx.doi.org/10.1016/j.autrev.2016.01.011 1568-9972/© 2016 Published by Elsevier B.V.
Please cite this article as: Felice CD, et al, Rett syndrome: An autoimmune disease?, Autoimmun Rev (2016), http://dx.doi.org/10.1016/ j.autrev.2016.01.011
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1. Rett syndrome: clinical and genetic background
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Rett syndrome (RTT; OMIM #312750) [1 and references herein], with a frequency of ∼ 1:10,000 to 1:15,000 females, is a devastating neurodevelopmental disorder, representing the second most common cause of severe intellectual disability retardation in the female gender. The disease was recently removed from the list of syndromes classified as autism spectrum disorders (DSM-5). RTT is mainly caused (∼90–95% of cases) by loss-of-function mutations in the X-linked methyl-CpGbinding protein 2 (MECP2) gene [1 and references herein], although mutations in other genes can be found (i.e., cyclin-dependent kinase-like 5, CDKL5, mutations in the infantile seizure onset variant and forkhead box protein G1, FOXG1, mutations in the congenital variant). The protein encoded by the MECP2 gene, — i.e., MeCP2, is a multifunctional protein with involvement in chromatin architecture, regulation of RNA splicing, and a role both as transcriptional repressor or activator. Over 200 mutations have been identified so far, although nine most frequent “hotspots” comprise more than 3/4 (i.e., 78%) of all the reported pathogenic mutations [1 and references herein]. Although knowing the gene mutation is sufficient to make a diagnosis, this information is not sufficient to understand the mechanisms by which, the MECP2 gene mutation drives the clinical manifestations. Despite almost two decades of research into the functions and roles of MeCP2, surprisingly little is known about the mechanisms leading from MeCP2 deficiency to disease expression, with many questions still unsolved regarding, in particular, the role of MeCP2 in the brain and, more generally, development and physiopathology [2]. At least 4 major different clinical presentations are known to date: typical, preserved speech, early seizure onset variant, and congenital variant. In its classic clinical picture, following an apparently normal development for 6–18 months, RTT girls lose their acquired cognitive, social, and motor skills in a typical four-stage neurological regression and develop autistic behavior accompanied by stereotypic hand movements. Further deterioration leads to severe mental retardation and motor impairment, including ataxia, apraxia, and tremors. Seizures, hyperventilation, and apnea are common features of the disease [1 and references herein]. In clinical terms RTT appears as a multi-systemic disorder [Table 1] (Personal data from Dr. JH, based on N = 205 consecutive RTT admissions to the Child Neuropsychiatric Unit). Although the key concept of a potential reversibility in RTT is known since 2007 [2 and references therein], to date, no treatment able to reverse or even arrest the neurologic regression in patients is currently available. One of the main reasons for lack of an effective therapy in RTT may reside in an incomplete understanding of the disease pathogenesis.
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2. Rett syndrome: not just a neurological disease
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Cumulating evidence indicates that RTT is indeed a multisystemic disease, as it can affect several organs and systems [3 and also Table 1], including the autonomic nervous system [4], microvascular/endothelial system [4], bone [5], heart [6], lungs [7 and references therein, 8], skin fibroblasts [9], red blood cells [10 and references therein], the gastrointestinal tract [1 and references therein], and the immune system (see below sections). Mouse models assessing the potential role of non-neuronal cell types have confirmed both roles in disease and potential therapeutic targets [3]. However, whether the known neuronal tissues are a secondary or a primary target of the disease it remains to be ascertained. A careful clinical observation of RTT patients indicates also the presence of some associated-phenotypical traits that could suggest the coexistence of immune/autoimmune dysfunction [Table 1]. Although the occurrence of Raynaud's phenomenon (RP) can be secondary to several conditions, it also associates to a relevant number of classical autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), systemic sclerosis (SSc), Sjögren's syndrome, dermatomyositis, polymyositis, mixed connective tissue disease, and cold agglutinin disease. Therefore, a possible autoimmune
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Breathing abnormalities Stereotyped hand movements Autistic-like traits (usually transient)⁎⁎ Seizures Scoliosis Osteopenia⁎⁎⁎
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Lost nonverbal communication Gastrointestinal dysmotility Biliary tract disorders Swallowing difficulties (any degree) Raynaud's phenomenon (RP) Wheat allergy§ Proven celiac disease (CD) Serum anti-ENA positivity
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100 75.1 36.6 90.2 95.6 32.7 81.5 (88.8 in typical RTT) 100 75.1 100 90.7 75.1 75.1 96 5.8 91.7 4.9 86.8 80 24.8 3.4 3.4
Legends: RP, Raynaud's phenomenon; NCGS, non-celiac gluten sensitivity; CD, celiac disease; ENA, extractable nuclear antigen. ⁎ When ambulation is present. ⁎⁎ Loss of social interaction. ⁎⁎⁎ Bone density b −2 z scores for gender and age at the quantitative ultrasound (QUS) of the distal end of the first phalanx diaphysis of the last four fingers of the hand (courtesy of Drs. S. Gonnelli and C. Caffarelli, Dept. Medicine, Surgery and Neuroscience, University of Siena). § Positive IgE against wheat antigens.
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Phenotypical trait
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component could at least be suggested. RP is a quite common clinical finding in RTT albeit of uncertain significance. RP is usually included among the autonomic nervous system abnormalities traditionally observed in RTT. In contrast, the frequency of serum anti-ENA positivity in the RTT population does not appear to be significantly different from those observed in a general mixed adult healthy population (1.5 to 1.9%) [11]. As it concerns the prevalence of CD and non-celiac gluten sensitivity in RTT, further explorations is needed although the prevalence of CD does not appear to be significantly different from that observed in a general control population (~ 1%) [12]. The positivity of IgE against wheat antigens is a quite common finding (24.8%) although of uncertain clinical significance.
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3. Rett syndrome and oxidative stress
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Cumulating evidence indicates that a series of biochemical processes precede and coexist with the clinical expression of the disease, and can be rescued by specific gene reactivation in the brain. The occurrence of a systemic redox imbalance in RTT has been reported both in patients [7 and references therein, 12 and references therein] [Table 2] and in an experimental mouse model [14]. A clear evidence of oxidative damage in the brain, the key organ in this neurodevelopmental disease, was lacking until the demonstration of a cause–effect relationship between oxidative stress (OS) and RTT in several murine models of the disease [15]. The underlying possible source(s) for OS in RTT is a current matter of debate and a hot focus of research. According to some researchers, mitochondrial dysfunction could be the main source for an excessive free radical production in RTT [13 and references therein]. The hypothesis of RTT as a mitochondrial disease has been based on supportive evidence on mitochondrial morphology alterations and reduction of specific enzyme activities [13 and references therein]. The mitochondrial hypothesis is a quite plausible explanation, also given the specific role for the mitochondrial electron transport chain in reactive oxygen species production. Nonetheless, the MeCP2 control on cellular signaling
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Table 1 Clinical features in Rett syndrome (RTT) (N = 205).
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Please cite this article as: Felice CD, et al, Rett syndrome: An autoimmune disease?, Autoimmun Rev (2016), http://dx.doi.org/10.1016/ j.autrev.2016.01.011
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Table 2 Links of MeCP2 with immunity and inflammatory response: evidence from the literature.
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Inflammation
MECP2-related RTT
Observation
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Systemic oxidative stress is present in typical RTT
[7] and refs therein, [13] [7] and refs therein, [13] [7] and refs therein, [13] [7] and refs therein, [13] [18],[24] [8] [20]
Respiratory bronchiolitis-associated interstitial lung disease-like (RB-ILD) lesions in typical RTT (50% of population, age N 10 yrs) Plasma F4-neuroprostanes (markers of gray matter oxidation) mediate neurological severity in RTT
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Plasma F2-dihomo-isoprostanes (markers of white matter oxidation) as early biomarkers in RTT
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A subclinical chronic inflammatory status is present in typical RTT Inflammatory lung disease in MECP2-related RTT MeCP2 plays a critical role for the activation of STAT3 in naïve CD4+ T cells with consequent generation of Th17 cells MeCP2 is a critical safeguard that confers T-reg cells with resilience against inflammation A major cytokine dysregulation is present in RTT MeCP2 deficiency increases expression of TNF-α and other inflammatory cytokines by enhancing NF-κB signaling ▪ Reduced CD8+ suppressor-cytotoxic cells and CD57+ cytotoxic natural killer cells in RTT (75% of the cases) ▪ Increased CD4+/CD8+ ratio in RTT ▪ Increased levels of IL-2 soluble receptor in RTT Increased levels of urinary neopterin in young RTT
Immunity
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Increased serum IgA against gluten, gliadin, and casein proteins in RTT MeCP2 regulates T-bet expression (Th1 differentiation) by modulating T-box 21 Transplantation of wild-type bone marrow into lethally irradiated Mecp2-null (Mecp2tm1.1Jae/y) mice prevents neurological decline (microglia) Loss of MeCP2 in mouse T cells leads to impaired Th1 cell differentiation and TH1-mediated responses Wild-type microglia do not reverse pathology in mouse models of RTT MeCP2-overexpressing mice are defective in mounting efficient Th1 cell responses (impaired release of IFN-γ and reduced Th1 cell type immunity) against Leishmania major
[21] [23] [22] [25]
[22] and refs therein [26] [19] [3] and refs therein [20] [27] [3] and refs therein
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Legends: RTT, Rett syndrome; MeCP2, methyl-CpG binding protein 2; STAT3, signal transducer and activator of transcription 3; Th1, T helper 1 cell; T-reg, T-regulatory cell. T-bet, T-box transcription factor.
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pathways must also be taken into account. In particular, molecules exist that are implicated in the general regulation of the redox homeostasis, such as the Nrf2/Keap1, MAPKs, NF-κB, PKC, STAT3 and PPARγ. Interestingly, at least for some of these signaling molecules, an epigenetic modulation by MeCP2 has been demonstrated [13 and references therein]. Although MeCP2 has been extensively studied in the central nervous system, MeCP2 is a ubiquitous nuclear protein [2 and references therein]. Moreover, OS in RTT is a systemic phenomenon, detectable in several tissues and the circulating bloodstream. It is therefore unlikely that the pathophysiological mechanisms behind RTT could be confined to the central nervous system. This reasoning has led us to explore more carefully the possible involvement of more organs and systems in RTT.
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4. Rett syndrome, inflammatory response and immunity
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Cytokine signaling is a key component of the inflammatory response [16] while inflammation is a key component of autoimmune diseases [17]. Several observations indicate the presence of a previously unrecognized subclinical inflammatory status in typical RTT [8,18] in the absence of obvious correlates. Intriguingly, MeCP2 seems to be a key player in regulating Th1 cell differentiation, Th1-mediated responses [19,20], and regulatory T cells' resilience to inflammation [21]. Moreover, emerging evidence indicates that MeCP2 deficiency could lead to cytokine dysregulation, including macrophage-related cytokines, in Mecp2-null mice [3 and references therein, 22] and RTT girls [23] [Fig. 1]. Several clues, suggesting a possible relationship between MeCP2 and immune/
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Fig. 1. Cytokine dysregulation in RTT: combined evidence from observed data [33] and literature [12 and references therein, 30–32]. The modulatory effects ofMeCP2 are referred to in [12] and references therein, [30–32]. Legends: Th1, T helper 1 cell; Th2, T helper 2 cell; Th17, T helper 17 cell; T-reg, T-regulatory cell. The symbol ↓, ↑, or = indicates a significant decrease, increase, or unchanged value of the examined cytokine versus examined healthy subject values.
Please cite this article as: Felice CD, et al, Rett syndrome: An autoimmune disease?, Autoimmun Rev (2016), http://dx.doi.org/10.1016/ j.autrev.2016.01.011
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Since: 1) some macrophage related cytokines (i.e., TNF-α, IL-6, IL-12p70, IL-10, TGF-β1, IL-8, and RANTES) appear to be dysregulated in RTT [3 and references therein, 23]; 2) MeCP2 influences the expression of Foxp3, a known transcription factor needed for the generation of T regulatory (T-reg) cells [21]; 3) increased secretion of IL-17 A is detectable in RTT [21]; and that 4) the Th17/T-reg balance plays a major role in the development and the disease outcomes of animal model and human autoimmune/inflammatory diseases [21], we
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Table 3 MeCP2 and autoimmunity: clues from the literature.
Presence of antineuronal (brain proteins) antibodies in RTT patients Increased serum levels of autoantibodies to nerve growth factor (NGF) in serum from RTT patients High levels of MeCP2 may contribute to the repression of MHC I expression in mature neuronal cells Presence of folate receptor autoantibodies in serum from RTT patients (24% of population) Association between MECP2 gene polymorphisms systemic lupus erythematosus (SLE) Association between MECP2 gene polymorphisms and primary Sjögren's syndrome Association of an activity-enhancing variant of IRAK1 and an MECP2-IRAK1 haplotype with increased susceptibility to rheumatoid arthritis (RA) MeCP2 is associated with the most severe subtype of systemic sclerosis (SSc)
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Ref [30] [31] [33] [32] [23] and refs therein [23] and refs therein [23] and refs therein [34]
Legends: RTT, Rett syndrome; MeCP2, methyl-CpG binding protein 2; IRAK1, interleukin-1 receptor-associated kinase 1.
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7. Specific igms to n-glucosylated peptide antigens: the first example 235 of molecular mimicry in RTT 236
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Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have multiple health benefits mediated at least in part by their anti-inflammatory actions. In particular, ω-3 PUFAs are known to partly inhibit several aspects of inflammation, including leukocyte chemotaxis, adhesion molecule expression, production of eicosanoids, production of inflammatory cytokines, and T-helper 1 lymphocyte reactivity [23 and references therein]. The results of one of our major lines of research in RTT indicate beneficial effects of ω-3 PUFAs, (i.e., of a mixture of eicosapentaenoic and docosahexaenoic acids) supplementation on several aspects of the disease. In particular, ω-3 PUFAs improve clinical severity [7 and references therein, 10 and references therein, 13,23], redox homeostasis [7 and references therein, 10 and references therein, 13, 23–24], ω-6/ω-3 ratio [24], serum plasma lipid profile [24], fatty acid composition of erythrocyte membranes [24] and erythrocyte morphology [10 and references therein], as well as the pro-inflammatory status in RTT [18,23–24]. Moreover, ω-3 PUFAs appear to significantly lower the risk of sudden death associated with the disease [28]. These findings support and corroborate the relevance of inflammatory and immune components behind the pathophysiology of RTT.
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The easiest way to identify autoantibodies in autoimmune diseases is based on enzyme-linked immunosorbent assays (ELISA) on sera. To date, however, very few specific antibodies have been characterized in serum. A ground-breaking concept resides in the hypothesis that post-translational modifications can occur in vivo, with the aberrantly modified proteins representing neoantigens able to trigger an immune response leading to autoimmunity [36]. As compared to recombinant proteins, synthetic antigenic peptides (SAPs) have the key advantage to be easily and specifically modified during the synthetic process with the aberrant post-translational modifications in order to mimic and selectively detect specific autoantibodies as disease biomarkers. The PeptLab group led by A.M. Papini and P. Rovero has previously proposed an innovative “Chemical Reverse Approach” that successfully leads to develop the N-glucosylated peptide CSF114(Glc) as a mimetic antigen, selected and optimized from a library of differently glycosylated peptide secondary structures. This glycopeptide is characterized by a β-turn structure bearing as minimal, but fundamental epitope a β-Dglucopyranosyl moiety linked to an Asn residue in the turn structure, possibly reproducing an aberrant N-glucosylation of native proteins. Moreover, some SAPs have been successfully used to fish out autoantibodies leading to the identification of protein autoantigens, a proof-ofconcept of the “Chemical Reverse Approach” in which peptide structures manipulation can lead to the discovery of cryptic autoantigens by increasing epitope specific antibody recognition. In particular, CSF114(Glc) is a very good example of SAP applied to autoimmune neurological disorders. Specifically, CSF114(Glc) has proven to be able to identify with high specificity and affinity autoantibodies linked to disease activity in MS [37]. More recently our group has measured serum immunoglobulins (IgG and IgM) in RTT patients (N = 53; mean age 12.8 ± 10.7 years, N = 41 with classical clinical presentation and proven MECP2 gene mutation and N = 12 with atypical presentation (of whom N = 9, N = 2, and N = 1 linked to CDKL5, FOXG1, and MeCP2 mutations, respectively) [38]. By comparison, the same assay was tested in agematched children affected by non-RTT pervasive developmental disorders (non-RTT PDD) (N = 82) and healthy age-matched controls (N = 29). Immunoglobulins were determined by the use of both a conventional agglutination assay and the novel ELISA based on antibody recognition by CSF114(Glc). Both assays provided evidence for an increase in IgM titer, but very few IgG, in RTT patients relative to both healthy controls and non-RTT PDD patients. The significant difference in IgM titers between RTT patients and healthy subjects by the CSF114(Glc)-based ELISA (p = 0.001) suggests that this procedure specifically detects a fraction of IgM antibodies likely to be relevant for the RTT disease. Of interest, a large serum IgM increase is also reported in a subset of MS patients, as well as meningitis and encephalitis [37]. IgM changes, noted in these central nervous system (CNS) pathologies, may reflect a common underlying mechanism, likely a pervasive neuroinflammation. We suggest that the association between neuroinflammation and the observed serum IgM rise might be causal to the RTT disease initiation and/or progression. A question arises whether the neuronal derangement elicits the immune response, or conversely, the
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explored the hypothesis that an autoimmune component may coexist in RTT. Published evidence suggests that more than one link exists between MeCP2 and autoimmunity [Table 3] [23 and references therein, 30–34]. In particular, in RTT, the following autoimmune clues have been reported: 1) antineuronal (brain proteins) antibodies [30], 2) autoantibodies to nerve growth factor [31], and 3) folate receptor autoantibodies [32] [Table 3]. On the other hand, other authors were unable to detect antineuronal and antiganglioside antibodies, antinuclear, antistriated muscle and antismooth muscle antibodies [22] as well as antithyroglobulin autoantibodies, antithyroid peroxidase, and anti-TSHr autoantibodies [35].
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inflammatory response, are shown in Table 2 [3 and references therein, 7 and references therein, 8, 13 and references therein, 18–27]. Of particular relevance is the observation that MeCP2 plays a critical role for the activation of STAT3 in naïve CD4+ T cells [20]. Moreover, MeCP2 appears to be a critical safeguard that confers regulatory T cells with resilience against inflammation [21]. Interestingly, a finely tuned MeCP2 dosage appears to be of paramount importance for a balanced immune response [20 and references therein].
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Please cite this article as: Felice CD, et al, Rett syndrome: An autoimmune disease?, Autoimmun Rev (2016), http://dx.doi.org/10.1016/ j.autrev.2016.01.011
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Take home messages
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• MeCP2 is a multifunctional protein, with involvement in chromatin architecture, regulation of RNA splicing, and a role both as transcriptional repressor or activator. • The MeCP2 protein plays a critical role in the complex pathways linking innate and adaptive immune systems. • MECP2 loss-of-function mutations elicit an inflammatory– autoinflammatory response in Rett syndrome patients.
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[29]
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This review has shown an unexpected connection between RTT and MeCP2 to immune dysfunction and autoimmunity. From the current available knowledge, it is clear that MECP2 gene loss-of-function mutations can lead to oxidative damage, cytokine dysregulation, acute phase protein response, as well as the occurrence of anti-neuronal antibodies and specific IgMs to N-glucosylated peptide antigens. On the other hand, several major autoimmune diseases, such as RA, SLE, SSc, and primary Sjögren syndrome, show an association with MECP2 gene polymorphisms. Although “no classical autoimmunity” has been to date evidenced in RTT patients, several clues suggest the coexistence of an autoimmune component in the disease. These concepts and observations could be of help in clarifying pathophysiological mechanisms and pave the way for novel therapeutic strategies for the disease.
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[1] Christodoulou J, Ho G. MECP2-Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015Available from: http://www.ncbi.nlm.nih.gov/books/NBK1497/. [2] Guy J, Cheval H, Selfridge J, Bird A. The role of MeCP2 in the brain. Annu Rev Cell Dev Biol 2011;27:631–652. [3] Cronk JC, Derecki NC, Litvak V, Kipnis J. Unexpected cellular players in Rett syndrome pathology. Neurobiol Dis 2015. http://dx.doi.org/10.1016/j.nbd.2015.05.005. [4] Julu PO, Kerr AM, Apartopoulos F et al. Characterisation of breathing and associated central autonomic dysfunction in the Rett disorder. Arch Dis Child 2001:85:29–37. [5] Gonnelli S, Caffarelli C, Hayek J, et al. Bone ultrasonography at phalanxes in patients with Rett syndrome: a 3-year longitudinal study. Bone 2008;42:737–742. [6] De Felice C, Maffei S, Signorini C, et al. Subclinical myocardial dysfunction in Rett syndrome. Eur Heart J Cardiovasc Imaging 2012;13:339–45. [7] De Felice C, Signorini C, Leoncini S, et al. J. The role of oxidative stress in Rett syndrome: an overview. Ann N Y Acad Sci 2012;1259:121–135. [8] De Felice C, Rossi M, Leoncini S, et al. Inflammatory lung disease in Rett syndrome. Mediators Inflamm 2014;2014:560120. [9] Signorini C, Leoncini S, De Felice C, et al. Redox imbalance and morphological changes in skin fibroblasts in typical Rett syndrome. Oxid Med Cell Longev 2014;2014:195935. [10] Ciccoli L, De Felice C, Leoncini S, et al. Red blood cells in Rett syndrome: oxidative stress, morphological changes and altered membrane organization. Biol Chem 2015;396:1233–1240. [11] Selmi C, Ceribelli A, Generali E, et al. Serum antinuclear and extractable nuclear antigen antibody prevalence and associated morbidity and mortality in the general population over 15 years. Autoimmun Rev 2015. http://dx.doi.org/10.1016/j.autrev. 2015.10.007. [12] Lebwohl B, Ludvigsson JF, Green PH. Celiac disease and non-celiac gluten sensitivity. BMJ 2015;351:h4347. [13] De Felice C, Signorini C, Leoncini S, et al. Oxidative stress: a hallmark of Rett syndrome. Future Neurol 2015;10:179–182. [14] Grosser E, Hirt U, Janc OA, et al. Oxidative burden and mitochondrial dysfunction in a mouse model of Rett syndrome. Neurobiol Dis 2012;48:102–114. [15] De Felice C, Della Ragione F, Signorini C, et al. Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome. Neurobiol Dis 2014;68:66–77. [16] Cantarini L, Lopalco G, Cattalini M, Vitale A, Galeazzi M, Rigante D. Interleukin-1: Ariadne's thread in autoinflammatory and autoimmune disorders. IMAJ 2015;17: 93–97.
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The finding of autoantibodies against anti-N-glucosylated targets in RTT prompted us to explore brain N-glycosylation patterns in murine models of the disease. An increasing number of glycosylation-related diseases are being discovered, including cognitive and neurodegenerative disorders [40 and references therein]. Membrane glycoproteins of neural cells play crucial roles in axon guidance, synaptogenesis and neuronal transmission. Among the heavily N-glycosylated membrane glycoproteins in the brain, nucleotide pyrophosphatase-5 (NPP-5), highly expressed in the mouse brain, presumably plays a role in neuronal cell communication [40 and references therein]. Interestingly, this glycoprotein belongs to the nucleotide pyrophosphatases/phosphodiesterases family that includes seven members with multiple roles in extracellular nucleotide metabolism and in the regulation of nucleotide-based intercellular signaling [40 and references therein]. Recently, our group has applied glycoprotein detection strategies (i.e., lectin-blotting) in order to identify target glycosylation changes in the whole brain of Mecp2 mutant murine models of the disease [40 and references therein]. Remarkable glycosylation pattern changes for a peculiar 50 kDa protein, i.e., the N-linked brain nucleotide pyrophosphatase-5 have been evidenced, with decreased N-glycosylation in the presymptomatic and symptomatic mutant mice. Remarkably, glycosylation changes were rescued by selected brain Mecp2 reactivation. These findings indicate a causal link between the amount of Mecp2 and the N-glycosylation of NPP-5. These observations confirm the relevance of altered N-glycosylation and in particular possibly Nglucosylation in the pathogenesis of the disease.
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Our sincere thanks go to the Administrative Direction of the Azienda Ospedaliera Universitaria Senese for their continued support; to Roberto Faleri from the Medical Central Library for online bibliographic research assistance; to the Medical Genetics Unit of the Siena University (Head: Pr. Alessandra Renieri) for MECP2 gene mutation analysis; and to professional singer Matteo Setti (http://www.matteosetti.com/) for many charity concerts and continued interest in the scientific aspects of our research in Rett syndrome. This work was supported by the Regione Toscana (Bando Salute 2009; “Antioxidants (Ω-3 polyunsaturated Fatty Acids, lipoic acid) supplementation in Rett syndrome: A novel approach to therapy,” RT no. 142; Principal Investigator JH) and by the “Chaire d'Excellence” of the Agence Nationale de la Recherche to AMP at the PeptLab@UCP&LCB/EA4505 of the University of Cergy-Pontoise (Project Pepkit: Development of peptide-based-diagnostic kits for autoimmune diseases, ANR-09-CEXC-013-01) and in part by the Fondazione Ente Cassa di Risparmio di Firenze (Italy) to PeptLab of the University of Florence.
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immune dysfunction might trigger the neuroinflammation. Indications exist that IgM overexpression represents primarily a line of defense against noxious stimuli. In contrast to IgM fraction, small changes in the serum IgG of RTT patients were observed when assayed with the agglutination assay, while the CSF114(Glc) assay detected IgG antibodies in a limited number of patients [38]. Further considerations concern epigenetics, which reportedly appears to be involved in autoimmune diseases. These are generally considered to be caused by a combination of epigenetic modification, deregulated immunomodulation, and environmental factors. Recent reports on experimental models in mice have placed microglia at the center stage of the RTT progression, as the Mecp2-deficient mice reproduce most of the human RTT phenotype features [3 and references therein]. Since microglia exerts a prominent immune surveillance role in the CNS, it is likely that the large serum IgM increase mirrors and signals a severe disturbance of immune regulation in brain [39].
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[29] Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 2014;13:668–677. [30] Hayek J, Bianchi E, Milano C, Cardinali G, Guarna M. Antineuronal autoantibodies in Rett syndrome patients. World Congress on Rett syndrome, Gothenburg, Sweden, August 30 to September 1, 1996. Eur Child Adolesc Psychiatry 1997;6(Suppl. 1):85. [31] Gratchev VV, Bashina VM, Klushnik TP, Ulas VU, Gorbachevskaya NL, Vorsanova SG. Clinical, neurophysiological and immunological correlations in classical Rett syndrome. Brain Dev 2001;23(Suppl. 1):S108–S112. [32] Ramaekers VT, Sequeira JM, Artuch R, et al. Folate receptor autoantibodies and spinal fluid 5-methyltetrahydrofolate deficiency in Rett syndrome. Neuropediatrics 2007; 38:179–183. [33] Miralvès J, Magdeleine E, Kaddoum L, Brun H, Peries S, Joly E. High levels of MeCP2 depress MHC class I expression in neuronal cells. PLoS One 2007;2, e1354. [34] Carmona FD, Cénit MC, Diaz-Gallo LM, et al. New insight on the Xq28 association with systemic sclerosis. Ann Rheum Dis 2013;72:2032–2038. [35] Stagi S, Cavalli L, Congiu L, et al. Thyroid function in Rett syndrome. Horm Res Paediatr 2015;83:118–125. [36] Papini AM. The use of post-translationally modified peptides for detection of biomarkers of immune-mediated diseases. J Pept Sci 2009;15:621–628. [37] Lolli F, Mulinacci B, Carotenuto A, et al. An N-glucosylated peptide detecting diseasespecific autoantibodies, biomarkers of multiple sclerosis. Proc Natl Acad Sci U S A 2005;102:10273–10278. [38] Papini AM, Nuti F, Real-Fernandez F, et al. Immune dysfunction in Rett syndrome patients revealed by high levels of serum anti-N(Glc) IgM antibody fraction. J Immunol Res 2014;2014:260973. [39] Aguzzi A, Barres BA, Bennett ML. Microglia: scapegoat, saboteur, or something else? Science 2013;339:156–161. [40] Cortelazzo A, De Felice C, Guerranti R, et al. Abnormal N-glycosylation pattern for brain nucleotide pyrophosphatase-5 (NPP-5) in Mecp2-mutant murine models of Rett syndrome. Neurosci Res 2015. http://dx.doi.org/10.1016/j.neures.2015.10.002.
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[17] Grant CR, Liberal R, Mieli-Vergani G, Vergani D, Longhi MS. Regulatory T-cells in autoimmune diseases: challenges, controversies and–yet–unanswered questions. Autoimmun Rev 2015;14:105–116. [18] Cortelazzo A, De Felice C, Guerranti R, et al. Subclinical inflammatory status in Rett syndrome. Mediators Inflamm 2014;2014:480980. [19] Derecki NC, Privman E, Kipnis J. Rett syndrome and other autism spectrum disorders–brain diseases of immune malfunction? Mol Psychiatry 2010;15: 355–363. [20] Jiang S, Li C, McRae G, et al. MeCP2 reinforces STAT3 signaling and the generation of effector CD4+ T cells by promoting miR-124-mediated suppression of SOCS5. Sci Signal 2014;7 [ra25]. [21] Li C, Jiang S, Liu SQ, et al. MeCP2 enforces Foxp3 expression to promote regulatory T cells' resilience to inflammation. Proc Natl Acad Sci U S A 2014;111:E2807–16. [22] O'Driscoll CM, Lima MP, Kaufmann WE, Bressler JP. Methyl CpG binding protein 2 deficiency enhances expression of inflammatory cytokines by sustaining NF-κB signaling in myeloid derived cells. J Neuroimmunol 2015;283:23–29. [23] Leoncini S, De Felice C, Signorini C, et al. Cytokine dysregulation in MECP2- and CDKL5-related Rett syndrome: relationships with aberrant redox homeostasis, inflammation, and Ω-3 PUFAs. Oxid Med Cell Longev 2015;2015:421624. [24] Signorini C, De Felice C, Leoncini S, et al. Altered erythrocyte membrane fatty acid profile in typical Rett syndrome: effects of omega-3 polyunsaturated fatty acid supplementation. Prostaglandins Leukot Essent Fatty Acids 2014;91:183–193. [25] Fiumara A, Sciotto A, Barone R, et al. Peripheral lymphocyte subsets and other immune aspects in Rett syndrome. Pediatr Neurol 1999;21:619–621. [26] Reichelt KL, Skjeldal O. IgA antibodies in Rett syndrome. Autism 2006;10:189–197. [27] Wang J, Wegener JE, Huang TW, et al. Wild-type microglia do not reverse pathology in mouse models of Rett syndrome. Nature 2015;521:E1–4. [28] Hayek J, Signorini C, Leoncini S, et al. Unexplained sudden death in Rett syndrome: protective effect of Ω-3 PUFAs. Fourth European Congress on Rett Syndrome; 2015 [Rome 30 Oct −1 Nov Abstract].
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Article history: Received 4 January 2016 Accepted 20 January 2016 Available online xxxx
Neonatal Intensive Care Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), Siena, Italy Child Neuropsychiatry Unit, University Hospital, Siena, Italy Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy d Department of Medical Biotechnologies, University of Siena, Siena, Italy e Laboratory of Peptide and Protein Chemistry and Biology—PeptLab (www.peptlab.eu), Italy f Section of Pharmaceutical and Nutraceutical Sciences, Department NeuroFarBa, University of Florence, Sesto Fiorentino, Italy g Department of Chemistry “Ugo Schiff”, University of Florence, Sesto Fiorentino, Italy h Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS/UM/ENSCM, Montpellier, France i PeptLab@UCP and Laboratory of Chemical Biology EA4505, University of Cergy-Pontoise, 5 Mail Gay-Lussac, 95031 Cergy-Pontoise, France b
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Rett syndrome (RTT) is a devastating neurodevelopmental disease, previously included into the autistic spectrum disorders, affecting almost exclusively females (frequency 1:10,000). RTT leads to intellective deficit, purposeful hands use loss and late major motor impairment besides featuring breathing disorders, epilepsy and increased risk of sudden death. The condition is caused in up to 95% of the cases by mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. Our group has shown a number of previously unrecognized features, such as systemic redox imbalance, chronic inflammatory status, respiratory bronchiolitis-associated interstitial lung disease-like lung disease, and erythrocyte morphology changes. While evidence on an intimate involvement of MeCP2 in the immune response is cumulating, we have recently shown a cytokine dysregulation in RTT. Increasing evidence on the relationship between MeCP2 and an immune dysfunction is reported, with, apparently, a link between MeCP2 gene polymorphisms and autoimmune diseases, including primary Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis. Antineuronal (i.e., brain proteins) antibodies have been shown in RTT. Recently, high levels of anti-N-glucosylation (N-Glc) IgM serum autoantibodies [i.e., anti-CSF114(N-Glc) IgMs] have been detected by our group in a statistically significant number of RTT patients. In the current review, the Authors explore the current evidence, either in favor or against, the presence of an autoimmune component in RTT. © 2016 Published by Elsevier B.V.
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Claudio De Felice a,⁎, Silvia Leoncini b,c, Cinzia Signorini c, Alessio Cortelazzo b,d, Paolo Rovero e,f, Thierry Durand h, Lucia Ciccoli c, Anna Maria Papini e,g,i, Joussef Hayek b
Keywords: MECP2 Inflammation Aberrant N-glucosylation Synthetic antigenic peptides Autoimmunity
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Contents
1. Rett syndrome: clinical and genetic background . . . . . . . . . . . . . . . . . . . . . . 2. Rett syndrome: not just a neurological disease . . . . . . . . . . . . . . . . . . . . . . 3. Rett syndrome and oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Rett syndrome, inflammatory response and immunity . . . . . . . . . . . . . . . . . . . 5. Rett syndrome and omega-3 polyunsaturated fatty acids . . . . . . . . . . . . . . . . . . 6. Rett syndrome and autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Specific igms to n-glucosylated peptide antigens: the first example of molecular mimicry in RTT 8. Rett syndrome and altered brain N-glycosylation . . . . . . . . . . . . . . . . . . . . . 9. Conclusive remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uncited reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Correspondence author at: Neonatal Intensive Care Unit, University Hospital AOUS, Policlinico “S. M. alle Scotte, Viale M. Bracci 1, Siena 53100, Italy. Tel.: +39 0577 586542/586550 (Secretary), +39 347 3309885 (mobile). E-mail address: [email protected] (C.D. Felice).
http://dx.doi.org/10.1016/j.autrev.2016.01.011 1568-9972/© 2016 Published by Elsevier B.V.
Please cite this article as: Felice CD, et al, Rett syndrome: An autoimmune disease?, Autoimmun Rev (2016), http://dx.doi.org/10.1016/ j.autrev.2016.01.011
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1. Rett syndrome: clinical and genetic background
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Rett syndrome (RTT; OMIM #312750) [1 and references herein], with a frequency of ∼ 1:10,000 to 1:15,000 females, is a devastating neurodevelopmental disorder, representing the second most common cause of severe intellectual disability retardation in the female gender. The disease was recently removed from the list of syndromes classified as autism spectrum disorders (DSM-5). RTT is mainly caused (∼90–95% of cases) by loss-of-function mutations in the X-linked methyl-CpGbinding protein 2 (MECP2) gene [1 and references herein], although mutations in other genes can be found (i.e., cyclin-dependent kinase-like 5, CDKL5, mutations in the infantile seizure onset variant and forkhead box protein G1, FOXG1, mutations in the congenital variant). The protein encoded by the MECP2 gene, — i.e., MeCP2, is a multifunctional protein with involvement in chromatin architecture, regulation of RNA splicing, and a role both as transcriptional repressor or activator. Over 200 mutations have been identified so far, although nine most frequent “hotspots” comprise more than 3/4 (i.e., 78%) of all the reported pathogenic mutations [1 and references herein]. Although knowing the gene mutation is sufficient to make a diagnosis, this information is not sufficient to understand the mechanisms by which, the MECP2 gene mutation drives the clinical manifestations. Despite almost two decades of research into the functions and roles of MeCP2, surprisingly little is known about the mechanisms leading from MeCP2 deficiency to disease expression, with many questions still unsolved regarding, in particular, the role of MeCP2 in the brain and, more generally, development and physiopathology [2]. At least 4 major different clinical presentations are known to date: typical, preserved speech, early seizure onset variant, and congenital variant. In its classic clinical picture, following an apparently normal development for 6–18 months, RTT girls lose their acquired cognitive, social, and motor skills in a typical four-stage neurological regression and develop autistic behavior accompanied by stereotypic hand movements. Further deterioration leads to severe mental retardation and motor impairment, including ataxia, apraxia, and tremors. Seizures, hyperventilation, and apnea are common features of the disease [1 and references herein]. In clinical terms RTT appears as a multi-systemic disorder [Table 1] (Personal data from Dr. JH, based on N = 205 consecutive RTT admissions to the Child Neuropsychiatric Unit). Although the key concept of a potential reversibility in RTT is known since 2007 [2 and references therein], to date, no treatment able to reverse or even arrest the neurologic regression in patients is currently available. One of the main reasons for lack of an effective therapy in RTT may reside in an incomplete understanding of the disease pathogenesis.
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Cumulating evidence indicates that RTT is indeed a multisystemic disease, as it can affect several organs and systems [3 and also Table 1], including the autonomic nervous system [4], microvascular/endothelial system [4], bone [5], heart [6], lungs [7 and references therein, 8], skin fibroblasts [9], red blood cells [10 and references therein], the gastrointestinal tract [1 and references therein], and the immune system (see below sections). Mouse models assessing the potential role of non-neuronal cell types have confirmed both roles in disease and potential therapeutic targets [3]. However, whether the known neuronal tissues are a secondary or a primary target of the disease it remains to be ascertained. A careful clinical observation of RTT patients indicates also the presence of some associated-phenotypical traits that could suggest the coexistence of immune/autoimmune dysfunction [Table 1]. Although the occurrence of Raynaud's phenomenon (RP) can be secondary to several conditions, it also associates to a relevant number of classical autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), systemic sclerosis (SSc), Sjögren's syndrome, dermatomyositis, polymyositis, mixed connective tissue disease, and cold agglutinin disease. Therefore, a possible autoimmune
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Breathing abnormalities Stereotyped hand movements Autistic-like traits (usually transient)⁎⁎ Seizures Scoliosis Osteopenia⁎⁎⁎
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Lost nonverbal communication Gastrointestinal dysmotility Biliary tract disorders Swallowing difficulties (any degree) Raynaud's phenomenon (RP) Wheat allergy§ Proven celiac disease (CD) Serum anti-ENA positivity
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100 75.1 36.6 90.2 95.6 32.7 81.5 (88.8 in typical RTT) 100 75.1 100 90.7 75.1 75.1 96 5.8 91.7 4.9 86.8 80 24.8 3.4 3.4
Legends: RP, Raynaud's phenomenon; NCGS, non-celiac gluten sensitivity; CD, celiac disease; ENA, extractable nuclear antigen. ⁎ When ambulation is present. ⁎⁎ Loss of social interaction. ⁎⁎⁎ Bone density b −2 z scores for gender and age at the quantitative ultrasound (QUS) of the distal end of the first phalanx diaphysis of the last four fingers of the hand (courtesy of Drs. S. Gonnelli and C. Caffarelli, Dept. Medicine, Surgery and Neuroscience, University of Siena). § Positive IgE against wheat antigens.
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Phenotypical trait
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component could at least be suggested. RP is a quite common clinical finding in RTT albeit of uncertain significance. RP is usually included among the autonomic nervous system abnormalities traditionally observed in RTT. In contrast, the frequency of serum anti-ENA positivity in the RTT population does not appear to be significantly different from those observed in a general mixed adult healthy population (1.5 to 1.9%) [11]. As it concerns the prevalence of CD and non-celiac gluten sensitivity in RTT, further explorations is needed although the prevalence of CD does not appear to be significantly different from that observed in a general control population (~ 1%) [12]. The positivity of IgE against wheat antigens is a quite common finding (24.8%) although of uncertain clinical significance.
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Cumulating evidence indicates that a series of biochemical processes precede and coexist with the clinical expression of the disease, and can be rescued by specific gene reactivation in the brain. The occurrence of a systemic redox imbalance in RTT has been reported both in patients [7 and references therein, 12 and references therein] [Table 2] and in an experimental mouse model [14]. A clear evidence of oxidative damage in the brain, the key organ in this neurodevelopmental disease, was lacking until the demonstration of a cause–effect relationship between oxidative stress (OS) and RTT in several murine models of the disease [15]. The underlying possible source(s) for OS in RTT is a current matter of debate and a hot focus of research. According to some researchers, mitochondrial dysfunction could be the main source for an excessive free radical production in RTT [13 and references therein]. The hypothesis of RTT as a mitochondrial disease has been based on supportive evidence on mitochondrial morphology alterations and reduction of specific enzyme activities [13 and references therein]. The mitochondrial hypothesis is a quite plausible explanation, also given the specific role for the mitochondrial electron transport chain in reactive oxygen species production. Nonetheless, the MeCP2 control on cellular signaling
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Table 1 Clinical features in Rett syndrome (RTT) (N = 205).
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Table 2 Links of MeCP2 with immunity and inflammatory response: evidence from the literature.
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MECP2-related RTT
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Systemic oxidative stress is present in typical RTT
[7] and refs therein, [13] [7] and refs therein, [13] [7] and refs therein, [13] [7] and refs therein, [13] [18],[24] [8] [20]
Respiratory bronchiolitis-associated interstitial lung disease-like (RB-ILD) lesions in typical RTT (50% of population, age N 10 yrs) Plasma F4-neuroprostanes (markers of gray matter oxidation) mediate neurological severity in RTT
t2:8
Plasma F2-dihomo-isoprostanes (markers of white matter oxidation) as early biomarkers in RTT
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A subclinical chronic inflammatory status is present in typical RTT Inflammatory lung disease in MECP2-related RTT MeCP2 plays a critical role for the activation of STAT3 in naïve CD4+ T cells with consequent generation of Th17 cells MeCP2 is a critical safeguard that confers T-reg cells with resilience against inflammation A major cytokine dysregulation is present in RTT MeCP2 deficiency increases expression of TNF-α and other inflammatory cytokines by enhancing NF-κB signaling ▪ Reduced CD8+ suppressor-cytotoxic cells and CD57+ cytotoxic natural killer cells in RTT (75% of the cases) ▪ Increased CD4+/CD8+ ratio in RTT ▪ Increased levels of IL-2 soluble receptor in RTT Increased levels of urinary neopterin in young RTT
Immunity
MECP2-related RTT
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Increased serum IgA against gluten, gliadin, and casein proteins in RTT MeCP2 regulates T-bet expression (Th1 differentiation) by modulating T-box 21 Transplantation of wild-type bone marrow into lethally irradiated Mecp2-null (Mecp2tm1.1Jae/y) mice prevents neurological decline (microglia) Loss of MeCP2 in mouse T cells leads to impaired Th1 cell differentiation and TH1-mediated responses Wild-type microglia do not reverse pathology in mouse models of RTT MeCP2-overexpressing mice are defective in mounting efficient Th1 cell responses (impaired release of IFN-γ and reduced Th1 cell type immunity) against Leishmania major
[21] [23] [22] [25]
[22] and refs therein [26] [19] [3] and refs therein [20] [27] [3] and refs therein
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Legends: RTT, Rett syndrome; MeCP2, methyl-CpG binding protein 2; STAT3, signal transducer and activator of transcription 3; Th1, T helper 1 cell; T-reg, T-regulatory cell. T-bet, T-box transcription factor.
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pathways must also be taken into account. In particular, molecules exist that are implicated in the general regulation of the redox homeostasis, such as the Nrf2/Keap1, MAPKs, NF-κB, PKC, STAT3 and PPARγ. Interestingly, at least for some of these signaling molecules, an epigenetic modulation by MeCP2 has been demonstrated [13 and references therein]. Although MeCP2 has been extensively studied in the central nervous system, MeCP2 is a ubiquitous nuclear protein [2 and references therein]. Moreover, OS in RTT is a systemic phenomenon, detectable in several tissues and the circulating bloodstream. It is therefore unlikely that the pathophysiological mechanisms behind RTT could be confined to the central nervous system. This reasoning has led us to explore more carefully the possible involvement of more organs and systems in RTT.
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Cytokine signaling is a key component of the inflammatory response [16] while inflammation is a key component of autoimmune diseases [17]. Several observations indicate the presence of a previously unrecognized subclinical inflammatory status in typical RTT [8,18] in the absence of obvious correlates. Intriguingly, MeCP2 seems to be a key player in regulating Th1 cell differentiation, Th1-mediated responses [19,20], and regulatory T cells' resilience to inflammation [21]. Moreover, emerging evidence indicates that MeCP2 deficiency could lead to cytokine dysregulation, including macrophage-related cytokines, in Mecp2-null mice [3 and references therein, 22] and RTT girls [23] [Fig. 1]. Several clues, suggesting a possible relationship between MeCP2 and immune/
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Fig. 1. Cytokine dysregulation in RTT: combined evidence from observed data [33] and literature [12 and references therein, 30–32]. The modulatory effects ofMeCP2 are referred to in [12] and references therein, [30–32]. Legends: Th1, T helper 1 cell; Th2, T helper 2 cell; Th17, T helper 17 cell; T-reg, T-regulatory cell. The symbol ↓, ↑, or = indicates a significant decrease, increase, or unchanged value of the examined cytokine versus examined healthy subject values.
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Since: 1) some macrophage related cytokines (i.e., TNF-α, IL-6, IL-12p70, IL-10, TGF-β1, IL-8, and RANTES) appear to be dysregulated in RTT [3 and references therein, 23]; 2) MeCP2 influences the expression of Foxp3, a known transcription factor needed for the generation of T regulatory (T-reg) cells [21]; 3) increased secretion of IL-17 A is detectable in RTT [21]; and that 4) the Th17/T-reg balance plays a major role in the development and the disease outcomes of animal model and human autoimmune/inflammatory diseases [21], we
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Table 3 MeCP2 and autoimmunity: clues from the literature.
Presence of antineuronal (brain proteins) antibodies in RTT patients Increased serum levels of autoantibodies to nerve growth factor (NGF) in serum from RTT patients High levels of MeCP2 may contribute to the repression of MHC I expression in mature neuronal cells Presence of folate receptor autoantibodies in serum from RTT patients (24% of population) Association between MECP2 gene polymorphisms systemic lupus erythematosus (SLE) Association between MECP2 gene polymorphisms and primary Sjögren's syndrome Association of an activity-enhancing variant of IRAK1 and an MECP2-IRAK1 haplotype with increased susceptibility to rheumatoid arthritis (RA) MeCP2 is associated with the most severe subtype of systemic sclerosis (SSc)
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Ref [30] [31] [33] [32] [23] and refs therein [23] and refs therein [23] and refs therein [34]
Legends: RTT, Rett syndrome; MeCP2, methyl-CpG binding protein 2; IRAK1, interleukin-1 receptor-associated kinase 1.
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7. Specific igms to n-glucosylated peptide antigens: the first example 235 of molecular mimicry in RTT 236
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Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have multiple health benefits mediated at least in part by their anti-inflammatory actions. In particular, ω-3 PUFAs are known to partly inhibit several aspects of inflammation, including leukocyte chemotaxis, adhesion molecule expression, production of eicosanoids, production of inflammatory cytokines, and T-helper 1 lymphocyte reactivity [23 and references therein]. The results of one of our major lines of research in RTT indicate beneficial effects of ω-3 PUFAs, (i.e., of a mixture of eicosapentaenoic and docosahexaenoic acids) supplementation on several aspects of the disease. In particular, ω-3 PUFAs improve clinical severity [7 and references therein, 10 and references therein, 13,23], redox homeostasis [7 and references therein, 10 and references therein, 13, 23–24], ω-6/ω-3 ratio [24], serum plasma lipid profile [24], fatty acid composition of erythrocyte membranes [24] and erythrocyte morphology [10 and references therein], as well as the pro-inflammatory status in RTT [18,23–24]. Moreover, ω-3 PUFAs appear to significantly lower the risk of sudden death associated with the disease [28]. These findings support and corroborate the relevance of inflammatory and immune components behind the pathophysiology of RTT.
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The easiest way to identify autoantibodies in autoimmune diseases is based on enzyme-linked immunosorbent assays (ELISA) on sera. To date, however, very few specific antibodies have been characterized in serum. A ground-breaking concept resides in the hypothesis that post-translational modifications can occur in vivo, with the aberrantly modified proteins representing neoantigens able to trigger an immune response leading to autoimmunity [36]. As compared to recombinant proteins, synthetic antigenic peptides (SAPs) have the key advantage to be easily and specifically modified during the synthetic process with the aberrant post-translational modifications in order to mimic and selectively detect specific autoantibodies as disease biomarkers. The PeptLab group led by A.M. Papini and P. Rovero has previously proposed an innovative “Chemical Reverse Approach” that successfully leads to develop the N-glucosylated peptide CSF114(Glc) as a mimetic antigen, selected and optimized from a library of differently glycosylated peptide secondary structures. This glycopeptide is characterized by a β-turn structure bearing as minimal, but fundamental epitope a β-Dglucopyranosyl moiety linked to an Asn residue in the turn structure, possibly reproducing an aberrant N-glucosylation of native proteins. Moreover, some SAPs have been successfully used to fish out autoantibodies leading to the identification of protein autoantigens, a proof-ofconcept of the “Chemical Reverse Approach” in which peptide structures manipulation can lead to the discovery of cryptic autoantigens by increasing epitope specific antibody recognition. In particular, CSF114(Glc) is a very good example of SAP applied to autoimmune neurological disorders. Specifically, CSF114(Glc) has proven to be able to identify with high specificity and affinity autoantibodies linked to disease activity in MS [37]. More recently our group has measured serum immunoglobulins (IgG and IgM) in RTT patients (N = 53; mean age 12.8 ± 10.7 years, N = 41 with classical clinical presentation and proven MECP2 gene mutation and N = 12 with atypical presentation (of whom N = 9, N = 2, and N = 1 linked to CDKL5, FOXG1, and MeCP2 mutations, respectively) [38]. By comparison, the same assay was tested in agematched children affected by non-RTT pervasive developmental disorders (non-RTT PDD) (N = 82) and healthy age-matched controls (N = 29). Immunoglobulins were determined by the use of both a conventional agglutination assay and the novel ELISA based on antibody recognition by CSF114(Glc). Both assays provided evidence for an increase in IgM titer, but very few IgG, in RTT patients relative to both healthy controls and non-RTT PDD patients. The significant difference in IgM titers between RTT patients and healthy subjects by the CSF114(Glc)-based ELISA (p = 0.001) suggests that this procedure specifically detects a fraction of IgM antibodies likely to be relevant for the RTT disease. Of interest, a large serum IgM increase is also reported in a subset of MS patients, as well as meningitis and encephalitis [37]. IgM changes, noted in these central nervous system (CNS) pathologies, may reflect a common underlying mechanism, likely a pervasive neuroinflammation. We suggest that the association between neuroinflammation and the observed serum IgM rise might be causal to the RTT disease initiation and/or progression. A question arises whether the neuronal derangement elicits the immune response, or conversely, the
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explored the hypothesis that an autoimmune component may coexist in RTT. Published evidence suggests that more than one link exists between MeCP2 and autoimmunity [Table 3] [23 and references therein, 30–34]. In particular, in RTT, the following autoimmune clues have been reported: 1) antineuronal (brain proteins) antibodies [30], 2) autoantibodies to nerve growth factor [31], and 3) folate receptor autoantibodies [32] [Table 3]. On the other hand, other authors were unable to detect antineuronal and antiganglioside antibodies, antinuclear, antistriated muscle and antismooth muscle antibodies [22] as well as antithyroglobulin autoantibodies, antithyroid peroxidase, and anti-TSHr autoantibodies [35].
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inflammatory response, are shown in Table 2 [3 and references therein, 7 and references therein, 8, 13 and references therein, 18–27]. Of particular relevance is the observation that MeCP2 plays a critical role for the activation of STAT3 in naïve CD4+ T cells [20]. Moreover, MeCP2 appears to be a critical safeguard that confers regulatory T cells with resilience against inflammation [21]. Interestingly, a finely tuned MeCP2 dosage appears to be of paramount importance for a balanced immune response [20 and references therein].
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Take home messages
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• MeCP2 is a multifunctional protein, with involvement in chromatin architecture, regulation of RNA splicing, and a role both as transcriptional repressor or activator. • The MeCP2 protein plays a critical role in the complex pathways linking innate and adaptive immune systems. • MECP2 loss-of-function mutations elicit an inflammatory– autoinflammatory response in Rett syndrome patients.
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This review has shown an unexpected connection between RTT and MeCP2 to immune dysfunction and autoimmunity. From the current available knowledge, it is clear that MECP2 gene loss-of-function mutations can lead to oxidative damage, cytokine dysregulation, acute phase protein response, as well as the occurrence of anti-neuronal antibodies and specific IgMs to N-glucosylated peptide antigens. On the other hand, several major autoimmune diseases, such as RA, SLE, SSc, and primary Sjögren syndrome, show an association with MECP2 gene polymorphisms. Although “no classical autoimmunity” has been to date evidenced in RTT patients, several clues suggest the coexistence of an autoimmune component in the disease. These concepts and observations could be of help in clarifying pathophysiological mechanisms and pave the way for novel therapeutic strategies for the disease.
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The finding of autoantibodies against anti-N-glucosylated targets in RTT prompted us to explore brain N-glycosylation patterns in murine models of the disease. An increasing number of glycosylation-related diseases are being discovered, including cognitive and neurodegenerative disorders [40 and references therein]. Membrane glycoproteins of neural cells play crucial roles in axon guidance, synaptogenesis and neuronal transmission. Among the heavily N-glycosylated membrane glycoproteins in the brain, nucleotide pyrophosphatase-5 (NPP-5), highly expressed in the mouse brain, presumably plays a role in neuronal cell communication [40 and references therein]. Interestingly, this glycoprotein belongs to the nucleotide pyrophosphatases/phosphodiesterases family that includes seven members with multiple roles in extracellular nucleotide metabolism and in the regulation of nucleotide-based intercellular signaling [40 and references therein]. Recently, our group has applied glycoprotein detection strategies (i.e., lectin-blotting) in order to identify target glycosylation changes in the whole brain of Mecp2 mutant murine models of the disease [40 and references therein]. Remarkable glycosylation pattern changes for a peculiar 50 kDa protein, i.e., the N-linked brain nucleotide pyrophosphatase-5 have been evidenced, with decreased N-glycosylation in the presymptomatic and symptomatic mutant mice. Remarkably, glycosylation changes were rescued by selected brain Mecp2 reactivation. These findings indicate a causal link between the amount of Mecp2 and the N-glycosylation of NPP-5. These observations confirm the relevance of altered N-glycosylation and in particular possibly Nglucosylation in the pathogenesis of the disease.
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Our sincere thanks go to the Administrative Direction of the Azienda Ospedaliera Universitaria Senese for their continued support; to Roberto Faleri from the Medical Central Library for online bibliographic research assistance; to the Medical Genetics Unit of the Siena University (Head: Pr. Alessandra Renieri) for MECP2 gene mutation analysis; and to professional singer Matteo Setti (http://www.matteosetti.com/) for many charity concerts and continued interest in the scientific aspects of our research in Rett syndrome. This work was supported by the Regione Toscana (Bando Salute 2009; “Antioxidants (Ω-3 polyunsaturated Fatty Acids, lipoic acid) supplementation in Rett syndrome: A novel approach to therapy,” RT no. 142; Principal Investigator JH) and by the “Chaire d'Excellence” of the Agence Nationale de la Recherche to AMP at the PeptLab@UCP&LCB/EA4505 of the University of Cergy-Pontoise (Project Pepkit: Development of peptide-based-diagnostic kits for autoimmune diseases, ANR-09-CEXC-013-01) and in part by the Fondazione Ente Cassa di Risparmio di Firenze (Italy) to PeptLab of the University of Florence.
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immune dysfunction might trigger the neuroinflammation. Indications exist that IgM overexpression represents primarily a line of defense against noxious stimuli. In contrast to IgM fraction, small changes in the serum IgG of RTT patients were observed when assayed with the agglutination assay, while the CSF114(Glc) assay detected IgG antibodies in a limited number of patients [38]. Further considerations concern epigenetics, which reportedly appears to be involved in autoimmune diseases. These are generally considered to be caused by a combination of epigenetic modification, deregulated immunomodulation, and environmental factors. Recent reports on experimental models in mice have placed microglia at the center stage of the RTT progression, as the Mecp2-deficient mice reproduce most of the human RTT phenotype features [3 and references therein]. Since microglia exerts a prominent immune surveillance role in the CNS, it is likely that the large serum IgM increase mirrors and signals a severe disturbance of immune regulation in brain [39].
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[29] Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 2014;13:668–677. [30] Hayek J, Bianchi E, Milano C, Cardinali G, Guarna M. Antineuronal autoantibodies in Rett syndrome patients. World Congress on Rett syndrome, Gothenburg, Sweden, August 30 to September 1, 1996. Eur Child Adolesc Psychiatry 1997;6(Suppl. 1):85. [31] Gratchev VV, Bashina VM, Klushnik TP, Ulas VU, Gorbachevskaya NL, Vorsanova SG. Clinical, neurophysiological and immunological correlations in classical Rett syndrome. Brain Dev 2001;23(Suppl. 1):S108–S112. [32] Ramaekers VT, Sequeira JM, Artuch R, et al. Folate receptor autoantibodies and spinal fluid 5-methyltetrahydrofolate deficiency in Rett syndrome. Neuropediatrics 2007; 38:179–183. [33] Miralvès J, Magdeleine E, Kaddoum L, Brun H, Peries S, Joly E. High levels of MeCP2 depress MHC class I expression in neuronal cells. PLoS One 2007;2, e1354. [34] Carmona FD, Cénit MC, Diaz-Gallo LM, et al. New insight on the Xq28 association with systemic sclerosis. Ann Rheum Dis 2013;72:2032–2038. [35] Stagi S, Cavalli L, Congiu L, et al. Thyroid function in Rett syndrome. Horm Res Paediatr 2015;83:118–125. [36] Papini AM. The use of post-translationally modified peptides for detection of biomarkers of immune-mediated diseases. J Pept Sci 2009;15:621–628. [37] Lolli F, Mulinacci B, Carotenuto A, et al. An N-glucosylated peptide detecting diseasespecific autoantibodies, biomarkers of multiple sclerosis. Proc Natl Acad Sci U S A 2005;102:10273–10278. [38] Papini AM, Nuti F, Real-Fernandez F, et al. Immune dysfunction in Rett syndrome patients revealed by high levels of serum anti-N(Glc) IgM antibody fraction. J Immunol Res 2014;2014:260973. [39] Aguzzi A, Barres BA, Bennett ML. Microglia: scapegoat, saboteur, or something else? Science 2013;339:156–161. [40] Cortelazzo A, De Felice C, Guerranti R, et al. Abnormal N-glycosylation pattern for brain nucleotide pyrophosphatase-5 (NPP-5) in Mecp2-mutant murine models of Rett syndrome. Neurosci Res 2015. http://dx.doi.org/10.1016/j.neures.2015.10.002.
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