The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity.

T helper cells secreting interleukin (IL)-17 (Th17 cells) play a crucial role in autoimmune diseases like multiple sclerosis (MS). Th17 differentiation, which is induced by a combination of transforming growth factor (TGF)-beta/IL-6 or IL-21, requires expression of the transcription factor retinoic acid receptor-related orphan receptor gamma t (ROR gamma t). We identify the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) as a key negative regulator of human and mouse Th17 differentiation. PPAR gamma activation in CD4(+) T cells selectively suppressed Th17 differentiation, but not differentiation into Th1, Th2, or regulatory T cells. Control of Th17 differentiation by PPAR gamma involved inhibition of TGF-beta/IL-6-induced expression of ROR gamma t in T cells. Pharmacologic activation of PPAR gamma prevented removal of the silencing mediator for retinoid and thyroid hormone receptors corepressor from the ROR gamma t promoter in T cells, thus interfering with ROR gamma t transcription. Both T cell-specific PPAR gamma knockout and endogenous ligand activation revealed the physiological role of PPAR gamma for continuous T cell-intrinsic control of Th17 differentiation and development of autoimmunity. Importantly, human CD4(+) T cells from healthy controls and MS patients were strongly susceptible to PPAR gamma-mediated suppression of Th17 differentiation. In summary, we report a PPAR gamma-mediated T cell-intrinsic molecular mechanism that selectively controls Th17 differentiation in mice and in humans and that is amenable to pharmacologic modulation. We therefore propose that PPAR gamma represents a promising molecular target for specific immunointervention in Th17-mediated autoimmune diseases such as MS.

The hippocampus in families with schizophrenia in relation to obstetric complications.

BACKGROUND: Hippocampal volume reduction is a well replicated finding in schizophrenia. Evidence indicates a contribution of genetic and environmental factors, especially the influence of obstetric complications to this volume reduction. The aim of this study was to compare hippocampal volume of schizophrenic patients as well as and their relatives with control subjects and to quantify the additional contribution of obstetric complications. METHODS: T1 weighted MRI brain scans of 50 schizophrenic patients, 88 first-degree relatives and 53 healthy control subjects were used to perform volumetric measurements on the left and right hippocampus. A set of clinical measures including obstetric complications were recorded for all family members. RESULTS: Numerically our measurements revealed a hippocampal volume reduction in schizophrenic patients (left: -14%, right: -15%) and, although less pronounced, in their unaffected relatives (left: -6%, right: -10%). Noted differences in hippocampal volume between schizophrenic patients and controls were only significant for the left side. Hippocampal volumes of patients and their relatives with obstetric complications were reduced bilaterally. CONCLUSIONS: Hippocampal volume reduction is present in schizophrenic patients and their first-degree relatives, suggesting an influence of genetic factors. In addition, however, obstetric complications have also been shown to play a major role.

Brain endothelial PPARgamma controls inflammation-induced CD4+ T cell adhesion and transmigration in vitro.

An important step in the pathogenesis of multiple sclerosis is adhesion and transmigration of encephalitogenic T cells across brain endothelial cells (EC) which strongly relies on interaction with EC-expressed adhesion molecules. We provide molecular evidence that the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) is a negative regulator of brain EC inflammation. The PPARgamma agonist pioglitazone reduces transendothelial migration of encephalitogenic T cells across TNFalpha-stimulated brain EC. This effect is clearly PPARgamma mediated, as lentiviral PPARgamma overexpression in brain EC results in selective abrogation of inflammation-induced ICAM-1 and VCAM-1 upregulation and subsequent adhesion and transmigration of T cells. We therefore propose that PPARgamma in brain EC may be exploited to target detrimental EC-T cell interactions under inflammatory conditions.

Peroxisome proliferator-activated receptor gamma control of dendritic cell function contributes to development of CD4+ T cell anergy.

There is increasing evidence that dendritic cell (DC) immunogenicity is not only positively regulated by ligands of pattern recognition receptors, but also negatively by signals that prevent DC activation and full functional maturation. Depending on their activation status, DCs can induce either immunity or tolerance. In this study, we provide molecular evidence that the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) is a negative regulator of DC maturation and function. Sustained PPARgamma activation in murine DCs reduced maturation-induced expression of costimulatory molecules and IL-12, and profoundly inhibited their capacity to prime naive CD4(+) T cells in vitro. Using PPARgamma-deficient DCs, generated by Cre-mediated ablation of the PPARgamma gene, agonist-mediated suppression of maturation-induced functional changes were abrogated. Moreover, absence of PPARgamma increased DC immunogenicity, suggesting a constitutive regulatory function of PPARgamma in DCs. Adoptive transfer of PPARgamma-activated Ag-presenting DCs induced CD4(+) T cell anergy, characterized by impaired differentiation resulting in absent Th1 and Th2 cytokine production and failure of secondary clonal expansion upon restimulation. Collectively, our data support the notion that PPARgamma is an efficient regulator of DC immunogenicity that may be exploited to deliberately target CD4(+) T cell-mediated immune responses.

Disturbed frontal gyrification within families affected with schizophrenia.

OBJECTIVE: Recently, in a post-mortem and a subsequent structural MR study, a significantly increased gyrification index (GI) was demonstrated in the frontal lobe in individuals with schizophrenia. To examine whether frontal lobe hypergyria is region-specific and whether this might be a suitable endophenotype in the search for the genetic basis of schizophrenia, the frontal as well as parieto-occipital GI were determined in MRI scans of families affected with schizophrenia. METHOD: In the MRI scans of 48 subjects suffering from schizophrenia, in 82 of their first-degree relatives and in 41 control subjects, the GI was determined in three sections anterior to the genu of the corpus callosum and three sections posterior to the splenium, thus allowing for a selective determination of this measure in the frontal as well as the parietal lobe. Outer and inner contours constituting the GI was determined in each section by manual tracing. Statistical analysis was performed using MANOVA with factors diagnostic group and intervening factors from preliminary analyses. RESULTS: The frontal, but not parieto-occipital GI was significantly higher in schizophrenic patients as well as unaffected relatives compared with control subjects (right: 7%, F=13.24, df=3, 155, p<0.0005, left: 6%, F=8.92, df=3, 155, p<0.0005). There was no overall difference between affected and unaffected family members. On the left side however, there was a significant interaction between diagnostic group and genetic loading (F=4.68, df=2, 101, p=0.01): significantly higher GI was found in affected compared with unaffected family members only in uniaffected and not multiaffected families. CONCLUSIONS: These results support our primary finding of hypergyria in the frontal lobe in schizophrenic patients. Compared to the parietal lobe, hypergyria seems to affect the frontal lobe selectively and serves as a suitable neurodevelopmental, possibly even an endophenotypic marker.

Phosphatidylinositol 3'-kinase/AKT signaling is activated in medulloblastoma cell proliferation and is associated with reduced expression of PTEN.

PURPOSE: Medulloblastomas represent the most frequent malignant brain tumors of childhood. They are supposed to originate from cerebellar neural precursor cells. Recently, it has been shown that Sonic Hedgehog-induced formation of medulloblastoma in an animal model is significantly enhanced by activation of the phosphatidylinositol 3'-kinase (PI3K) signaling pathway. EXPERIMENTAL DESIGN: To examine a role for PI3K/AKT signaling in the molecular pathogenesis of human medulloblastoma, we did an immunohistochemical study of the expression of Ser473-phosphorylated (p)-AKT protein in 22 medulloblastoma samples: All samples displayed p-AKT expression. To investigate if an activated PI3K/AKT pathway is required for medulloblastoma cell growth, we treated five human medulloblastoma cell lines with increasing concentrations of the PI3K inhibitor LY294002 and analyzed cellular proliferation and apoptosis. The antiproliferative effect could be antagonized by overexpressing constitutively active AKT. As the activation of PI3K/AKT signaling may be associated with alterations of the PTEN gene located at 10q23.3, a chromosomal region subject to frequent allelic losses in medulloblastoma, we screened PTEN for mutations and mRNA expression. RESULTS: Proliferation of all of the medulloblastoma cell lines was dependent on PI3K/AKT signaling, whereas apoptosis was not prominently affected. Allelic loss was detected in 16% of the cases. One medulloblastoma cell line was found to carry a truncating mutation in the PTEN coding sequence. Even more important, PTEN mRNA and protein levels were found to be significantly lower in medulloblastomas compared with normal cerebellar tissue of different developmental stages. Reduction of PTEN expression was found to be associated with PTEN promoter hypermethylation in 50% of the tumor samples. CONCLUSIONS: We conclude that activation of the PI3K/AKT pathway constitutes an important step in the molecular pathogenesis of medulloblastoma and that dysregulation of PTEN may play a significant role in this context.

Relation between cerebrospinal fluid, gray matter and white matter changes in families with schizophrenia.

BACKGROUND: Gray matter reduction and ventricular enlargement belong to the best replicated findings in schizophrenia. Brain morphologic changes were also found in non-schizophrenic family members (FM). The intention of this study was to examine whether non-psychotic first-degree relatives reveal similar morphologic changes as schizophrenic patients and how state of genetic loading contribute to these abnormalities. METHODS: Forty-nine schizophrenic patients, 71 non-schizophrenic FM and 48 control subjects took part in this volumetric MRI study. All subjects were between 18 and 59 years old. Dependent variables were gray matter, white matter and total cerebrospinal fluid (CSF) volume, determined by SPM99 segmentation algorithm. As an important part of CSF lateral ventricle volume was determined manually by removing surrounding CSF areas. RESULTS: In schizophrenic patients compared to controls and non-schizophrenic FM total CSF volumes and lateral ventricles were increased. Gray and, to a lesser degree, white matter volumes were decreased as well. For CSF, gray and white matter there was no significant difference between uni- and multiple affected families. CSF correlated significantly negative with gray matter (r=-0.78) and, less intensive, with white matter (r=-0.40). There were negative correlations between gray and white matter volume as well (r=-0.26). These correlations were not significantly different between the diagnostic groups. CONCLUSION: CSF enlargement and gray matter reductions in schizophrenic patients compared to controls and non-affected FM seem to be interdependent findings. However, this correlation is independent of the factor diagnosis and is therefore not specific for schizophrenia.

Insulin-like growth factor II is involved in the proliferation control of medulloblastoma and its cerebellar precursor cells.

Medulloblastomas (MBs), the most frequent malignant brain tumors of childhood, presumably originate from cerebellar neural precursor cells. An essential fetal mitogen involved in the pathogenesis of different embryonal tumors is insulin-like growth factor II (IGF-II). We screened human MB biopsies of the classic (CMB) and desmoplastic (DMB) variants for IGF2 transcripts of the four IGF2 promoters. We found IGF2 transcription from the imprinted promoter P3 to be significantly increased in the desmoplastic variant compared to the classic subgroup. This was not a result of loss of imprinting of IGF2 in desmoplastic tumors. We next examined the interaction of IGF-II and Sonic hedgehog (Shh), which serves as a critical mitogen for cerebellar granule cell precursors (GCPs) in the external granule cell layer from which DMBs are believed to originate. Mutations of genes encoding components of the Shh-Patched signaling pathway occur in approximately 50% of DMBs. To analyze the effects of IGF-II on Hedgehog signaling, we cultured murine GCP and human MB cells in the presence of Shh and Igf-II. In GCPs, a synergistic effect of Shh and Igf-II on proliferation and gli1 and cyclin D1 mRNA expression was found. Igf-II, but not Shh, induced phosphorylation of Akt and its downstream target Gsk-3beta. In six of nine human MB cell lines IGF-II displayed a growth-promoting effect that was mediated mainly through the IGF-I receptor. Together, our data point to an important role of IGF-II for the proliferation control of both cerebellar neural precursors and MB cells.

Shape changes in prefrontal, but not parieto-occipital regions: brains of schizophrenic patients come closer to a circle in coronal and sagittal view.

There is some evidence for prefrontal (PF) lobe changes in schizophrenia while the parieto-occipital (PO) region seems to be unaffected. This magnetic resonance imaging (MRI) study was performed to examine shape differences as part of the spectrum of structural abnormalities in schizophrenia. The measurements were done on families affected with schizophrenia to identify the influence of genetic and environmental factors on these changes. The sample under study consisted of 164 subjects including 45 family members (FM) suffering from schizophrenia, 27 FM with other psychiatric disorders and 51 FM without psychiatric disorders based on ICD-10 criteria. In addition, 41 nonpsychiatric control subjects were included in the study. On defined planes at the corpus callosum boundary of the PF and the PO, brain width, height and length were measured on coronal slices. Ratios of these linear measurements were also calculated based on the idea that a plane can be approximated by a circle if the concerning ratio comes close to 1. It was hypothesized that these relative brain shape parameters, especially the PF ratio width/height, would show differences between schizophrenic patients and control subjects. For all members from families with schizophrenia compared with control subjects, there were significant differences in the PF, but not in the PO region. PF height was increased. PF ratios of width/height and height/(2 x length) were closer to 1 in affected families than in control subjects. The results can be interpreted as an indication for PF brain shape changes in subjects with a disposition for schizophrenia. On coronal and sagittal planes situated at the corpus callosum, their PF could be approximated by a circle better than in control subjects. As the frontal lobe takes shape late in brain development, underlying genetic mechanisms may be dysregulated in schizophrenic patients and subjects at risk to develop the disorder.

[Volumetric analysis of gray matter, white matter and cerebrospinal fluid space in schizophrenia]. / Volumetrijska analiza sive mase, bele mase i prostora cerebrospinalne tecnosti u shizofreniji.

Schizophrenia is characterized by diffuse brain abnormalities, some of them involving volumes of three intracranial compartments: gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF). Novel methods, such as Statistical Parametrical Mapping, provide an automated means of comparing structural features across high quality MRI scans and the measurement based on the principles of voxel based morphometry. For the purposes of the present study, we selected sex balanced group of young adults with recent onset illness to assess the effects of the illness on the volumes of compartments and also to minimize the effects of chronicity, medication, sex and aging. Sixty-four subjects were selected from a larger sample (inclusion criteria: age range 18-31). Thirty-one had DSM IV diagnosis of schizophrenia or schizoaffective disorder, 33 were controls. T1 weighted MRI images were acquired on two scanners (1.5T both): a) fast gradient echo sequence, FLASH, 40 msec repetition time, 5 ms echo time, 40 degree flip angle and b) turbo gradient echo, 12 msec repetition time, 4 msec echo time, 20 degree flip angle, 1 excitation). The resulting data set consisted of: a) 128 consecutive slices with 1.17 mm thickness and 256 x 256 pixels per slice and b) 160 consecutive slices of 1 mm thickness and 256 x 256 pixels per slice. All 64 images were processed by ANALZYE, and normalized and segmented by SPM99. Following the automatic segmentation of the images into the three intracranial compartments, volumetry was performed based on the principles of voxel analysis. Results were expressed relative to whole brain volume, and MANOVA analyses were performed to correct the confounding effects of MRI acquisition center differences and age difference between diagnostic groups. Young adults with recent onset schizophrenia had 6% reduction in GM volume and 14% increase in the volume of CSF, after all confounders were included into analyses (MANCOVA: p = 0.006 and 0.0002, respectively). No significant changes in WM volume were evident. In comparison to a few similar studies published recently, all results yielded similar scores regarding effects of recent onset illness and young adult population, thus confirming the reliability of the procedure. In conclusion, global neuropil reduction was discussed as a consequence of the cortical neurodevelopmental disgenesis. It was suggested that neuropil reduction i.e. synaptic and dendritic changes were to induce functional abnormalities and the expression of schizophrenia.