title: Th17 cells correlate positively to the structural and functional integrity of the brain in bipolar depression and healthy controls.
abstract: Abnormalities of T cell-mediated immune activation, in the absence of active somatic immune diseases, have consistently been reported in mood disorders. Apart from being important players in the regulation of cells of the immune system, T cells are essential for normal brain development. We here report studies on the relationship between circulating levels of T helper cells and structural and functional brain imaging in depressed bipolar patients. Since the CCL20-CCR6 axis is an important entry to the brain we differentiated the various T helper cell subpopulations on the basis of their chemokine receptor expression.
  
  
  METHODS
  FACS staining was performed for Th1, Th2, Th17, Th22 and T regulatory cells on frozen leukocytes of 25 consecutively admitted inpatients affected by a major depressive episode, without psychotic features, in the course of Bipolar Disorder I and 21 healthy controls. The frequency of the T helper populations was associated with DTI and fMRI data acquired on a Philips 3.0 Tesla scanner. Tract based spatial statistic was used to obtain measures of white matter integrity (fractional anisotropy, axial, radial and mean diffusivity) from a standard DTI sequence with 35 directions. Patients were also studied for fMRI through a moral valence decision task were subjects had to decide whether morally tuned stimuli were positive or negative.
  
  
  RESULTS
  The percentage of circulating Th17 (CCR6+CXCR3negCCR4+CCR10neg) cells correlated positively with higher fractional anisotropy in fiber tracts contributing to the functional integrity of the brain both in patients and healthy controls, while the frequency of circulating T regulatory (CD4+CD25+FOXP3+) cells correlated positively with higher radial and mean diffusivity in patients. The frequency of circulating T regulatory cells also correlated to lower neuronal responses to negative versus positive morally tuned stimuli in the right dorsolateral prefrontal cortex of patients. Th1 cells correlated negatively with white matter integrity in several tracts (healthy controls), while the cells showed a positive correlation to the levels of pro-inflammatory cytokines (patients).
  
  
  CONCLUSIONS
  This study shows a new putative role for Th17 cells. Th17 cells are not only playing a role in inducing autoimmunity and auto-inflammation, but might also play a counter intuitive anabolic role in the maintenance of the functional and structural integrity of the brain.
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy. Electronic address: poletti.sara@hsr.it.
authors.forename: Sara
authors.initials: S
authors.lastname: Poletti
authors.affiliation: Department of Immunology, Erasmus University Medical Centre, Rotterdam, Netherlands.
authors.forename: Harm
authors.initials: H
authors.lastname: de Wit
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Mazza
authors.affiliation: Department of Immunology, Erasmus University Medical Centre, Rotterdam, Netherlands.
authors.forename: Annemarie J M
authors.initials: AJM
authors.lastname: Wijkhuijs
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Locatelli
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Aggio
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Colombo
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Benedetti
authors.affiliation: Department of Immunology, Erasmus University Medical Centre, Rotterdam, Netherlands.
authors.forename: Hemmo A
authors.initials: HA
authors.lastname: Drexhage
mesh_terms: D000328:Adult; D016880:Anisotropy; D001714:Bipolar Disorder / Q000000981:diagnostic imaging* / Q000276:immunology; D001921:Brain / Q000000981:diagnostic imaging* / Q000276:immunology; D056324:Diffusion Tensor Imaging; D005260:Female; D059907:Functional Neuroimaging; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*
keywords: Bipolar disorder; Neuro-inflammation; Neuroimaging; T cells