title: Cytokine Dysregulation in MECP2- and CDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, and ω-3 PUFAs.
abstract: An involvement of the immune system has been suggested in Rett syndrome (RTT), a devastating neurodevelopmental disorder related to oxidative stress, and caused by a mutation in the methyl-CpG binding protein 2 gene (MECP2) or, more rarely, cyclin-dependent kinase-like 5 (CDKL5). To date, it is unclear whether both mutations may have an impact on the circulating cytokine patterns. In the present study, cytokines involved in the Th1-, Th2-, and T regulatory (T-reg) response, as well as chemokines, were investigated in MECP2- (MECP2-RTT) (n = 16) and CDKL5-Rett syndrome (CDKL5-RTT) (n = 8), before and after ω-3 polyunsaturated fatty acids (PUFAs) supplementation. A major cytokine dysregulation was evidenced in untreated RTT patients. In MECP2-RTT, a Th2-shifted balance was evidenced, whereas in CDKL5-RTT both Th1- and Th2-related cytokines (except for IL-4) were upregulated. In MECP2-RTT, decreased levels of IL-22 were observed, whereas increased IL-22 and T-reg cytokine levels were evidenced in CDKL5-RTT. Chemokines were unchanged. The cytokine dysregulation was proportional to clinical severity, inflammatory status, and redox imbalance. Omega-3 PUFAs partially counterbalanced cytokine changes, as well as aberrant redox homeostasis and the inflammatory status. RTT is associated with a subclinical immune dysregulation as the likely consequence of a defective inflammation regulatory signaling system.
authors.affiliation: Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), Policlinico "S. M. alle Scotte", 53100 Siena, Italy ; Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Leoncini
authors.affiliation: Neonatal Intensive Care Unit, University Hospital, AOUS, Policlinico "S. M. alle Scotte", 53100 Siena, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: De Felice
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Signorini
authors.affiliation: Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), Policlinico "S. M. alle Scotte", 53100 Siena, Italy ; Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Zollo
authors.affiliation: Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), Policlinico "S. M. alle Scotte", 53100 Siena, Italy ; Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Cortelazzo
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS/UM/ENSCM, BP 14491, 34093 Montpellier Cedex 5, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Durand
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS/UM/ENSCM, BP 14491, 34093 Montpellier Cedex 5, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Galano
authors.affiliation: Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Guerranti
authors.affiliation: Respiratory Pathophysiology and Rehabilitation Unit, University Hospital, AOUS, Policlinico "S. M. alle Scotte", 53100 Siena, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ciccoli
authors.affiliation: Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), Policlinico "S. M. alle Scotte", 53100 Siena, Italy.
authors.forename: Joussef
authors.initials: J
authors.lastname: Hayek
mesh_terms: D000293:Adolescent; D000328:Adult; D001799:Blood Sedimentation / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000032:analysis* / Q000097:blood; D019587:Dietary Supplements; D004797:Enzyme-Linked Immunosorbent Assay; D004912:Erythrocytes / Q000166:cytology; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007249:Inflammation; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015518:Rett Syndrome / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055815:Young Adult
chemical_list: D016207:Cytokines; D015525:Fatty Acids, Omega-3; D051783:Methyl-CpG-Binding Protein 2; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human