Peritraumatic Distress, Watching Television, and Posttraumatic Stress Symptoms among Rescue Workers after the Great East Japan Earthquake

BACKGROUND: The Great East Japan Earthquake of March 11, 2001 left around 20,000 dead or missing. Previous studies showed that rescue workers, as well as survivors, of disasters are at high risk for posttraumatic stress disorder (PTSD). This study examined the predictive usefulness of the Peritraumatic Distress Inventory (PDI) among rescue workers of Disaster Medical Assistance Teams (DMATs) deployed during the acute disaster phase of the Great East Japan Earthquake. METHODOLOGY/PRINCIPAL FINDINGS: In this prospective observational study, the DMAT members recruited were assessed 1 month after the earthquake on the PDI and 4 months after the earthquake on the Impact of Event Scale-Revised to determine PTSD symptoms. The predictive value of the PDI at initial assessment for PTSD symptoms at the follow-up assessment was examined by univariate and multiple linear regression analysis. Of the 254 rescue workers who participated in the initial assessment, 173 completed the follow-up assessment. Univariate regression analysis revealed that PDI total score and most individual item scores predicted PTSD symptoms. In particular, high predictive values were seen for peritraumatic emotional distress such as losing control of emotions and being ashamed of emotional reactions. In multiple linear regression analysis, PDI total score was an independent predictor for PTSD symptoms after adjusting for covariates. As for covariates specifically, watching earthquake television news reports for more than 4 hours per day predicted PTSD symptoms. CONCLUSIONS/SIGNIFICANCE: The PDI predicted PTSD symptoms in rescue workers after the Great East Japan Earthquake. Peritraumatic emotional distress appears to be an important factor to screen for individuals at risk for developing PTSD among medical rescue workers. In addition, watching television for extended period of time might require attention at a time of crisis

Adrenergic β2 receptor activation stimulates anti-inflammatory properties of dendritic cells in vitro

Vagal nerve efferent activation has been shown to ameliorate the course of many inflammatory disease states. This neuromodulatory effect has been suggested to rest on acetylcholine receptor (AChR) activation on tissue macrophages or dendritic cells (DCs). In more recent studies, vagal anti-inflammatory activity was shown involve adrenergic, splenic, pathways. Here we provide evidence that the adrenergic, rather than cholinergic, receptor activation on bone marrow derived DCs results in enhanced endocytosis uptake, enhanced IL-10 production but a decreased IL-6, IL-12p70 and IL-23 production. In antigen specific T cell stimulation assays, adrenergic β2 receptor activation on bone marrow DCs led to an enhanced potential to induce Foxp3 positive suppressive Treg cells. These effects were independent of IL10-R activation, TGFβ release, or retinoic acid (RA) secretion. Hence, adrenergic receptor β2 activation modulates DC function resulting in skewing towards anti-inflammatory T cell phenotypes

Innate Immune Activation in Intestinal Homeostasis

Loss of intestinal immune regulation leading to aberrant immune responses to the commensal microbiota are believed to precipitate the chronic inflammation observed in the gastrointestinal tract of patients with inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis. Innate immune receptors that recognize conserved components derived from the microbiota are widely expressed by both epithelial cells and leucocytes of the gastrointestinal tract and play a key role in host protection from infectious pathogens; yet precisely how pathogenic and commensal microbes are distinguished is not understood. Furthermore, aberrant innate immune activation may also drive intestinal pathology, as patients with IBD exhibit extensive infiltration of innate immune cells to the inflamed intestine, and polymorphisms in many innate immunity genes influence susceptibility to IBD. Thus, a balanced interaction between the microbiota and innate immune activation is required to maintain a healthy mutualistic relationship between the microbiota and the host, which when disturbed can result in intestinal inflammation

Src Kinases Are Required for a Balanced Production of IL-12/IL-23 in Human Dendritic Cells Activated by Toll-Like Receptor Agonists

BACKGROUND: Pathogen recognition by dendritic cells (DC) is crucial for the initiation of both innate and adaptive immune responses. Activation of Toll-like Receptors (TLRs) by microbial molecular patterns leads to the maturation of DC, which present the antigen and activate T cells in secondary lymphoid tissues. Cytokine production by DC is critical for shaping the adaptive immune response by regulating T helper cell differentiation. It was previously shown by our group that Src kinases play a key role in cytokines production during TLR4 activation in human DC. PRINCIPAL FINDINGS: In this work we investigated the role of Src kinases during different TLRs triggering in human monocyte-derived DC (MoDC). We found that Src family kinases are important for a balanced production of inflammatory cytokines by human MoDC upon stimulation of TLR3 and 8 with their respective agonists. Disruption of this equilibrium through pharmacological inhibition of Src kinases alters the DC maturation pattern. In particular, while expression of IL-12 and other inflammatory cytokines depend on Src kinases, the induction of IL-23 and co-stimulatory molecules do not. Accordingly, DC treated with Src inhibitors are not compromised in their ability to induce CD4 T cell proliferation and to promote the Th17 subset survival but are less efficient in inducing Th1 differentiation. CONCLUSIONS: We suggest that the pharmacological modulation of DC maturation has the potential to shape the quality of the adaptive immune response and could be exploited for the treatment of inflammation-related diseases

Effector CD4+ T Cell Expression Signatures and Immune-Mediated Disease Associated Genes

Genome-wide association studies (GWAS) in immune-mediated diseases have identified over 150 associated genomic loci. Many of these loci play a role in T cell responses, and regulation of T cell differentiation plays a critical role in immune-mediated diseases; however, the relationship between implicated disease loci and T cell differentiation is incompletely understood. To further address this relationship, we examined differential gene expression in naïve human CD4+ T cells, as well as in in vitro differentiated Th1, memory Th17-negative and Th17-enriched CD4+ T cells subsets using microarray and RNASeq. We observed a marked enrichment for increased expression in memory CD4+ compared to naïve CD4+ T cells of genes contained among immune–mediated disease loci. Within memory T cells, expression of disease-associated genes was typically increased in Th17-enriched compared to Th17-negative cells. Utilizing RNASeq and promoter methylation studies, we identified a differential regulation pattern for genes solely expressed in Th17 cells (IL17A and CCL20) compared to genes expressed in both Th17 and Th1 cells (IL23R and IL12RB2), where high levels of promoter methylation are correlated to near zero RNASeq levels for IL17A and CCL20. These findings have implications for human Th17 celI plasticity and for the regulation of Th17-Th1 expression signatures. Importantly, utilizing RNASeq we found an abundant isoform of IL23R terminating before the transmembrane domain that was enriched in Th17 cells. In addition to molecular resolution, we find that RNASeq provides significantly improved power to define differential gene expression and identify alternative gene variants relative to microarray analysis. The comprehensive integration of differential gene expression between cell subsets with disease-association signals, and functional pathways provides insight into disease pathogenesis

Evaluation of 22 genetic variants with Crohn's Disease risk in the Ashkenazi Jewish population: a case-control study

<p>Abstract</p> <p>Background</p> <p>Crohn's disease (CD) has the highest prevalence among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Caucasian populations (NJ). We evaluated a set of well-established CD-susceptibility variants to determine if they can explain the increased CD risk in the AJ population.</p> <p>Methods</p> <p>We recruited 369 AJ CD patients and 503 AJ controls, genotyped 22 single nucleotide polymorphisms (SNPs) at or near 10 CD-associated genes, <it>NOD2</it>, <it>IL23R</it>, <it>IRGM</it>, <it>ATG16L1</it>, <it>PTGER4</it>, <it>NKX2-3</it>, <it>IL12B</it>, <it>PTPN2</it>, <it>TNFSF15 </it>and <it>STAT3</it>, and assessed their association with CD status. We generated genetic scores based on the risk allele count alone and the risk allele count weighed by the effect size, and evaluated their predictive value.</p> <p>Results</p> <p>Three <it>NOD2 </it>SNPs, two <it>IL23R </it>SNPs, and one SNP each at <it>IRGM </it>and <it>PTGER4 </it>were independently associated with CD risk. Carriage of 7 or more copies of these risk alleles or the weighted genetic risk score of 7 or greater correctly classified 92% (allelic count score) and 83% (weighted score) of the controls; however, only 29% and 47% of the cases were identified as having the disease, respectively. This cutoff was associated with a >4-fold increased disease risk (p < 10e-16).</p> <p>Conclusions</p> <p>CD-associated genetic risks were similar to those reported in NJ population and are unlikely to explain the excess prevalence of the disease in AJ individuals. These results support the existence of novel, yet unidentified, genetic variants unique to this population. Understanding of ethnic and racial differences in disease susceptibility may help unravel the pathogenesis of CD leading to new personalized diagnostic and therapeutic approaches.</p

Th17-related cytokines: new players in the control of chronic intestinal inflammation

Crohn's disease (CD) and ulcerative colitis (UC), the main forms of inflammatory bowel diseases (IBD) in man, are thought to be caused by an excessive and poorly controlled immune response that is directed against components of the normal microflora. The exact sequence of events by which this pathological process is triggered and maintained is not fully understood, but studies in experimental models of IBD and data emerging from recent clinical trials indicate that T cell-derived cytokines are crucial mediators of the tissue damage. Although CD and UC have been traditionally considered two typical examples of T helper (Th)1 or Th2-associated disease respectively, it is now known that CD- and UC-related inflammation is also marked by enhanced production of cytokines made by a distinct subset of Th cells, termed Th17 cells. Th17 cytokines can have both tissue-protective and inflammatory effects in the gut and there is evidence that Th17 cells can alter their cytokine program according to the stimuli received and convert into Th1-producing cells. These novel findings have contributed to advancing our understanding of mechanisms of gut tissue damage and open new avenues for development of therapeutic strategies in IBD