A positive correlation with serum levels of apolipoprotein A-I and white matter volume in right temporal ROI was observed within patients.

<p>Voxels with <i>p</i> < 0.005 (uncorrected, for visualization only; see corrected <i>p</i>-values in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125112#pone.0125112.t004" target="_blank">Table 4</a>) within the ROI are shown in hot colors on an SPM’s canonical single subject T1-image. Depicted are the sagittal, coronal, and axial views at <i>x</i> = 18, <i>y</i> = -42, <i>z</i> = 7. At the bottom right, a color plate shows the <i>t</i>-value. Left hemisphere is on the left.</p

A positive correlation with serum levels of apolipoprotein A-I and white matter volume in right temporal ROI was observed within patients.

<p>Voxels with <i>p</i> < 0.005 (uncorrected, for visualization only; see corrected <i>p</i>-values in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125112#pone.0125112.t004" target="_blank">Table 4</a>) within the ROI are shown in hot colors on an SPM’s canonical single subject T1-image. Depicted are the sagittal, coronal, and axial views at <i>x</i> = 18, <i>y</i> = -42, <i>z</i> = 7. At the bottom right, a color plate shows the <i>t</i>-value. Left hemisphere is on the left.</p

Differences between cases (<i>n</i> = 37) and controls (<i>n</i> = 19) in metabolic and inflammatory factors.

<p>^a If not indicated, we present medians for non-normally distributed continuous or ordinal variables; means as indicated by M and SD are presented for normally distributed variables. Abbreviations: Apo, apolipoprotein; CCL, chemokine (C-C motif) ligand; CXCL, Chemokine (C-X-C motif) ligand; EGF, epidermal growth factor; FGF, fibroblast growth factor; FLT-3L, Fms-related tyrosine kinase 3 ligand; G-CSF, Granulocyte-colony stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HDL-C, high density lipoprotein cholesterol; hs-CRP, high sensitivity C-reactive protein; IFN, interferon; IL, interleukin; LDL-C, Low Density Lipoprotein cholesterol; sCD40L, soluble CD40 Ligand; TGF, transforming growth factor; TNF, tumor necrosis factor.</p><p>Differences between cases (<i>n</i> = 37) and controls (<i>n</i> = 19) in metabolic and inflammatory factors.</p

Baseline sociodemographic and clinical characteristics of the sample including cases (<i>n</i> = 37) and controls (<i>n</i> = 19).

<p>^a Diagnosis Schizophrenia (<i>n</i> = 19), Schizophreniform disorder (<i>n</i> = 4), BD with psychotic features (<i>n</i> = 3), MDD with psychotic features (<i>n</i> = 1), Psychotic disorder NOS (<i>n</i> = 1), Schizoaffective disorder (<i>n</i> = 2), Substance-induced psychotic disorder (<i>n</i> = 1, Magnetic resonance images were not available from this participant), Delusional disorder (<i>n</i> = 1).</p><p>^b Substance use does not include alcohol, nicotine or caffeine.</p><p>Abbreviations: AUDIT, the alcohol use disorders identification test; BAI, Beck anxiety inventory; BDI, Beck depression inventory; BMI, body mass index; GAF, global assessment of functioning scale; MDQ, mood disorder questionnaire; OCI-R, obsessive-compulsive inventory revised; SOFAS, social and occupational functioning assessment scale.</p><p>Baseline sociodemographic and clinical characteristics of the sample including cases (<i>n</i> = 37) and controls (<i>n</i> = 19).</p

White matter volume and DTI measures within the patient group associating with inflammatory measures.

<p>^aIn the Measure column, left and right refer to the side of the region of interest. Analyses indicated as “whole” are corrected for family-wise error rate for the whole WM tract skeleton volume.</p><p>^bIn the case of white matter volume (WMV), extent refers to contiguous voxels with <i>p</i> < 0.005, uncorrected, while with the DTI measures, extent refers to clusters defined as in [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125112#pone.0125112.ref072" target="_blank">72</a>].</p><p>^cThe results are corrected for family-wise error rate for the whole brain for CCL22 and CXCL1, and for a sphere with a radius of 20 mm for CCL22 (cluster level with a primary threshold of <i>p</i> < 0.005) and ApoA-I (peak level). In the DTI analyses, the reported <i>p</i>-level is the minimum <i>p</i>-level within a cluster.</p><p>^dThe tracts and the sizes of overlap are based on the Johns Hopkins University ICBM-DTI-81 WM labels atlas [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125112#pone.0125112.ref073" target="_blank">73</a>] and are a combination of the clusters concerning particular marker and measure. Notice that the sizes of the overlap do not equal the summed extent due to unspecified areas in the atlas.</p><p>^eSee <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125112#pone.0125112.s003" target="_blank">S3 Results</a> for full listings of these tracts.</p><p>Abbreviations: ApoA-I, apolipoprotein A-I; CC, corpus callosum; CCL, chemokine (C-C motif) ligand; CR, corona radiata; CXCL, Chemokine (C-X-C motif) ligand; FA, fractional anisotropy; IC, internal capsule; MD, mean diffusivity; MNI, Montreal Neurological Institute; RD, radial diffusivity; WMV, white matter volume.</p><p>White matter volume and DTI measures within the patient group associating with inflammatory measures.</p

pDCs express cell-surface IL-6Rα and are not dependent on the presence of serum components for IL-6 signal transduction.

<p>Flowcytometric analysis of IL-6Rα expression on DC subsets was performed in whole blood samples from healthy volunteers. IL-6Rα is expressed on pDCs, although in lower levels than on CD1c+ mDCs (A). PBMCs were isolated from fresh peripheral blood samples from three healthy volunteers in independent experiments. Cells were incubated at 37°C in RPMI 1640 culture medium (supplemented with 2 mM L-glutamine) either with 1/3 vol. of autologous serum or without serum for one hour prior to stimulation with 50 ng/ml of recombinant IL-6 for 10 minutes (in the presence or absence of serum), followed by flowcytometric DC identification and pSTAT3 measurement using similar gating strategy as indicated in Fig. 1. Despite lower IL-6Rα expression on pDCs, IL-6-induced pSTAT3 response in pDCs is not impaired in the absence of autologous serum, whereas mDCs (serving as intrinsic controls) exhibit somewhat reduced responses when stimulated in serum-free conditions. Samples from each donor are indicated with different symbols (B).</p

Patient characteristics in DC enumeration, surface marker expression and STAT phosphorylation studies.

<p>Abbreviations: PD = perianal disease; AZA = azathioprine; IFX = infliximab; 5-ASA = 5-aminosalicylic acid; MTX = methotrexate; 6-MP = 6-mercaptopurine; ESR = erythrocyte sedimentation rate, mm/h; CPR = C-reactive protein, mg/L; CDAI = Crohn's disease activity index, generally interpreted as follows: <150 = inactive disease, ≥150 = active disease; SES-CD = Simple Endoscopic Score for Crohn's disease, generally interpreted as: ≤3 = inactive disease, 4–14 = mild to moderate disease, ≥15 = severe disease.</p

Expression of maturation markers on DCs.

<p>pDCs and CD1c+ mDCs were identified as shown in Fig. 1, and the expression of maturation markers was assessed by flow cytometry. The expression of CD123 or CD11c is shown to demonstrate the specificity of DC subtype identification. Light-colored histograms represent isotype controls. A representative example of a healthy control is shown (A). pDCs from CD patients exhibit lower expression of HLA-DR, whereas in CD1c+ mDCs no difference between the groups is observed. Low expression of CD40 is seen on both DC subtypes, the levels on CD1c+ mDCs being, however, higher in CD patients. Values represent median fluorescence intensity (MFI) after subtraction of isotype control fluorescence. Horizontal lines indicate medians for each group (B).</p

IL-6-treated pDCs promote Th2-type responses.

<p>pDCs were matured for two days with IL-3 and the indicated treatments (IL-6 and CpG). Allogeneic naive CD4+ T cells were primed for six days with the pDCs and then restimulated for 16 hours with anti-CD3 and anti-CD28 antibodies. The levels of mRNA transcripts were analyzed by RT-qPCR. Induction of IL-4 is significantly enhanced by the IL-6 treatment of pDCs in the presence of the TLR9 ligand CpG. In addition, the expression of IL-10 mRNA transcripts is higher (A). The concentrations of Th signature cytokines in culture supernatants were determined. IFN-γ to IL-4, i.e., Th1/Th2 ratio, is reduced by the IL-6 treatment of pDCs both in the presence and absence of CpG during the pDC maturation (B).</p

IL-6 modulates pDC maturation.

<p>Human pDCs from healthy volunteers were either treated with 50 ng/ml of IL-6 or cultured only in the presence of 10 ng/ml of IL-3 (to maintain pDC viability), with or without stimulation with CpG, for two days. IL-6 inhibits the phenotypic maturation induced by the culture with IL-3. In contrast, IL-6 further upregulates CD40 expression on pDCs when stimulated with CpG-rich hypomethylated oligodeoxynucleotides (mimicking fragments of microbial DNA). Freshly isolated pDCs at d0 consistently had high levels of HLA-DR expression and typically low levels of CD86 and CD40, whereas the staining intensities for CD80 and ICOS-L were at the isotype control level (data not shown). % expression values (in the bottom right part of the figure) were calculated for each experiment ((expression in the presence of IL-6/expression in the absence of IL-6) ×100) and presented as mean ± SD. Flow cytometry data from five independent experiments are presented. * <i>P</i><0.05; ** <i>P</i><0.01.</p