Journal of Immunology Research The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Preferential Autoimmune Response in Prostate Cancer to Cyclin B1 in a Panel of Tumor-Associated Antigens Thu, 17 Apr 2014 16:49:42 +0000 Previous studies have demonstrated that sera from patients with prostate cancer (PCa) contain autoantibodies that react with tumor-associated antigens (TAAs). Autoantibodies to cyclin B1 and fourteen other TAAs were detected by enzyme-linked immunosorbent assay (ELISA) and Western blotting in 464 sera from patients with PCa, benign prostatic hyperplasia (BPH), and other controls. Autoantibodies to cyclin B1 were detected in 31.0% of sera from randomly selected patients with PCa versus 4.8% in sera with BPH. In the further analysis, 31.4% of sera from PCa patients at the early stage contained anti-cyclin B1 autoantibody, and even 29.4% of patients who had normal prostate-specific antigen (PSA) levels in their serum samples were observed anti-cyclin B1 positive. The cumulative positive rate of autoantibodies against seven selected TAAs (cyclin B1, survivin, p53, DFS70/LEDGFp75, RalA, MDM2, and NPM1) in PCa reached 80.5%, significantly higher than that in normal control sera. In summary, autoantibody to cyclin B1 might be a potential biomarker for the immunodiagnosis of early stage PCa, especially useful in patients with normal PSA level. This study further supports the hypothesis that a customized TAA array can be used for enhancing anti-TAA autoantibody detection, and it may constitute a promising and powerful tool for immunodiagnosis of PCa. Liping Dai, Jitian Li, Rosalia Ortega, Wei Qian, Carlos A. Casiano, and Jian-Ying Zhang Copyright © 2014 Liping Dai et al. All rights reserved. Antilymphocyte Antibodies in Systemic Lupus Erythematosus: Association with Disease Activity and Lymphopenia Thu, 17 Apr 2014 16:48:25 +0000 Purpose. We analyzed the prevalence, clinical correlation, and the functional significance of ALA in patients with systemic lupus erythematosus (SLE). Methods. ALA IgG was detected by indirect immunofluorescence in the serum of 130 SLE patients, 75 patients with various rheumatic diseases, and 45 healthy controls (HC). Results. The sensitivity and specificity of ALA IgG in SLE were 42.3% and 96.7%, respectively. ALA was observed in 55.6% (50/90) of patients with lymphopenia, which was significantly higher than in patients with normal lymphocytes (5/40, 12.5%; ). Patients with active SLE showed higher ALA positivity (60.9%) than those with inactive disease (24.2%; = 17.925; ). ALA correlated significantly with hypocomplementemia, anti-dsDNA antibodies, and higher SLEDAI scores. The incidences of ALA in SLE patients who were seronegative for anti-dsDNA, anti-Sm, or both antibodies were 32.9% (26/79), 41.0% (43/105), and 32.4% (22/68), respectively. The ALA-positive group also had higher incidences of neuropsychiatric SLE (NPSLE) and lupus nephritis (LN). In multivariate analyses, ALA was independently associated with lymphopenia, higher SLEDAI scores, and increased risk for LN. ALA titers significantly decreased as clinical disease was ameliorated following treatment. Conclusions. ALA occurred more frequently in patients with active SLE and was independently associated with lymphopenia, disease activity, and LN. Chun Li, Rong Mu, Xiao-yan Lu, Jing He, Ru-lin Jia, and Zhan-guo Li Copyright © 2014 Chun Li et al. All rights reserved. Serum SALL4 Is a Novel Prognosis Biomarker with Tumor Recurrence and Poor Survival of Patients in Hepatocellular Carcinoma Thu, 17 Apr 2014 12:29:10 +0000 Aim. Sal-like protein 4 (SALL4), is reexpressed in tissues of a subgroup of HCC associated with poor prognosis. Reports of SALL4 serological levels linked to HCC patients are meager and unclear in the prognosis of this malignancy. Methods. Immunohistochemistry and optical microscopy protocols were used to examine the presence of SALL4 in liver tissues from the following patients: 38 HCC, 11 chronic hepatitis B virus (HBV), 13 liver cirrhosis, and 12 healthy controls. Additionally, enzyme-linked immunosorbent assay (ELISA) was used to measure the SALL4 levels in serum samples isolated from patients as follows: 127 with HCC, 27 with HBV, 24 with liver cirrhosis, and 23 normal controls. Results. Analysis of liver tissues sections from HCC patients (18 out 38; 47.4%) showed positive staining for SALL4 and its expression did no correlate with any of the clinicopathologic characteristics. HCC patients displayed higher levels (50.4%) of SALL4 protein in serum, compared with the three control groups. Moreover, SALL4 concentration reached the maximum level after one week after treatment and dropped quickly after one month. These HCC patients showing high SALL4 serum levels had poor prognosis, evidenced by both tumor recurrence and overall survival rate. Conclusions. High SALL4 serum levels are a novel biomarker in the prognosis of HCC patients. Su-xia Han, Jun-lan Wang, Xi-jing Guo, Chen-chen He, Xia Ying, Jin-lu Ma, Yuan-yuan Zhang, Qian Zhao, and Qing Zhu Copyright © 2014 Su-xia Han et al. All rights reserved. Disruption of the Suprachiasmatic Nucleus Blunts a Time of Day-Dependent Variation in Systemic Anaphylactic Reaction in Mice Thu, 17 Apr 2014 08:49:02 +0000 Anaphylaxis is a severe systemic allergic reaction which is rapid in onset and potentially fatal, caused by excessive release of mediators including histamine and cytokines/chemokines from mast cells and basophils upon allergen/IgE stimulation. Increased prevalence of anaphylaxis in industrialized countries requires urgent needs for better understanding of anaphylaxis. However, the pathophysiology of the disease is not fully understood. Here we report that the circadian clock may be an important regulator of anaphylaxis. In mammals, the central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus synchronizes and entrains peripheral circadian clock present in virtually all cell types via neural and endocrine pathways, thereby driving the daily rhythms in behavior and physiology. We found that mechanical disruption of the SCN resulted in the absence of a time of day-dependent variation in passive systemic anaphylactic (PSA) reaction in mice, associated with loss of daily variations in serum histamine, MCP-1 (CCL2), and IL-6 levels. These results suggest that the central SCN clock controls the time of day-dependent variation in IgE-mediated systemic anaphylactic reaction, which may provide a novel insight into the pathophysiology of anaphylaxis. Yuki Nakamura, Kayoko Ishimaru, Yu Tahara, Shigenobu Shibata, and Atsuhito Nakao Copyright © 2014 Yuki Nakamura et al. All rights reserved. Differential Transcript Profiles of MHC Class Ib(Qa-1, Qa-2, and Qa-10) and Aire Genes during the Ontogeny of Thymus and Other Tissues Wed, 16 Apr 2014 12:30:26 +0000 Qa-2 and Qa-1 are murine nonclassical MHC class I molecules involved in the modulation of immune responses by interacting with T CD8+ and NK cell inhibitory receptors. During thymic education, the Aire gene imposes the expression of thousands of tissue-related antigens in the thymic medulla, permitting the negative selection events. Aiming to characterize the transcriptional profiles of nonclassical MHC class I genes in spatial-temporal association with the Aire expression, we evaluated the gene expression of H2-Q7(Qa-2), H2-T23(Qa-1), H2-Q10(Qa-10), and Aire during fetal and postnatal development of thymus and other tissues. In the thymus, H2-Q7(Qa-2) transcripts were detected at high levels throughout development and were positively correlated with Aire expression during fetal ages. H2-Q7(Qa-2) and H2-T23(Qa-1) showed distinct expression patterns with gradual increasing levels according to age in most tissues analyzed. H2-Q10(Qa-10) was preferentially expressed by the liver. The Aire transcriptional profile showed increased levels during the fetal period and was detectable in postnatal ages in the thymus. Overall, nonclassical MHC class I genes started to be expressed early during the ontogeny. Their levels varied according to age, tissue, and mouse strain analyzed. This differential expression may contribute to the distinct patterns of mouse susceptibility/resistance to infectious and noninfectious disorders. Breno Luiz Melo-Lima, Adriane Feijó Evangelista, Danielle Aparecida Rosa de Magalhães, Geraldo Aleixo Passos, Philippe Moreau, and Eduardo Antonio Donadi Copyright © 2014 Breno Luiz Melo-Lima et al. All rights reserved. Multifunctional Roles of Reticular Fibroblastic Cells: More Than Meets the Eye? Wed, 16 Apr 2014 09:08:49 +0000 Fibroblastic reticular cells (FRCs) are stromal cells found in secondary lymphoid organ. Despite its structural function in the lymph nodes being well established, recent studies indicate that the FRCs also play a key role in immunological processes, associated with cell transit, immune response, and cells activation quality, and contribute to peripheral tolerance. To this end, we focus this review on lymph nodes FRC characterization and discuss functional aspects such as production of cytokines and chemokines and their involvement in the immune response, seeking to establish whether certain subsets have a more functional specialization. H. G. Alvarenga and L. Marti Copyright © 2014 H. G. Alvarenga and L. Marti. All rights reserved. Immunomodulatory Properties of HLA-G in Infectious Diseases Tue, 15 Apr 2014 08:09:49 +0000 HLA-G is a nonclassical major histocompatibility complex molecule first described at the maternal-fetal interface, on extravillous cytotrophoblasts. Its expression is restricted to some tissues in normal conditions but increases strongly in pathological conditions. The expression of this molecule has been studied in detail in cancers and is now also beginning to be described in infectious diseases. The relevance of studies on HLA-G expression lies in the well known inhibitory effect of this molecule on all cell types involved in innate and adaptive immunity, favoring escape from immune control. In this review, we summarize the features of HLA-G expression by type of infections (i.e, bacterial, viral, or parasitic) detailing the state of knowledge for each pathogenic agent. The polymorphism, the interference of viral proteins with HLA-G intracellular trafficking, and various cytokines have been described to modulate HLA-G expression during infections. We also discuss the cellular source of HLA-G, according to the type of infection and the potential role of HLA-G. New therapeutic approaches based on synthetic HLA-G-derived proteins or antibodies are emerging in mouse models of cancer or transplantation, and these new therapeutic tools may eventually prove useful for the treatment of infectious diseases. Laurence Amiot, Nicolas Vu, and Michel Samson Copyright © 2014 Laurence Amiot et al. All rights reserved. Immunological Aspect on Late Allograft Dysfunction Mon, 14 Apr 2014 12:37:32 +0000 Qiquan Sun, Akinlolu O. Ojo, and Xian C. Li Copyright © 2014 Qiquan Sun et al. All rights reserved. Potential Involvement of IL-17F in Asthma Mon, 14 Apr 2014 09:52:28 +0000 The expression of IL-17F is seen in the airway of asthmatics and its level is correlated with disease severity. Several studies have demonstrated that IL-17F plays a pivotal role in allergic airway inflammation and induces several asthma-related molecules such as CCL20. IL-17F-induced CCL20 may attract Th17 cells into the airway resulting in the recruitment of additional Th17 cells to enhance allergic airway inflammation. We have recently identified, for the first time, that bronchial epithelial cells are its novel cell source in response to IL-33 via ST2-ERK1/2-MSK1 signaling pathway. The receptor for IL-17F is the heterodimeric complex of IL-17RA and IL-17RC, and IL-17F activates many signaling pathways. In a case-control study of 867 unrelated Japanese subjects, a His161 to Arg161 (H161R) substitution in the third exon of the IL-17F gene was associated with asthma. In atopic patients with asthma, prebronchodilator baseline FEV1/FVC values showed a significant association with the H161R variant. Moreover, this variant is a natural antagonist for the wild-type IL-17F. Moreover, IL-17F is involved in airway remodeling and steroid resistance. Hence, IL-17F may play an orchestrating role in the pathogenesis of asthma and may provide a valuable therapeutic target for development of novel strategies. Kyoko Ota, Mio Kawaguchi, Satoshi Matsukura, Masatsugu Kurokawa, Fumio Kokubu, Junichi Fujita, Yuko Morishima, Shau-Ku Huang, Yukio Ishii, Hiroaki Satoh, and Nobuyuki Hizawa Copyright © 2014 Kyoko Ota et al. All rights reserved. Evaluation of Diagnostic Value in Using a Panel of Multiple Tumor-Associated Antigens for Immunodiagnosis of Cancer Sun, 13 Apr 2014 00:00:00 +0000 To determine whether a panel of multiple tumor-associated antigens (TAAs) would enhance antibody detection, the diagnostic value of autoantibodies to a panel of multiple TAAs in cancer has been evaluated. The TAAs used in this study was composed of eight TAAs including Imp1, p62, Koc, p53, C-myc, Cyclin B1, Survivin, and p16 full-length recombinant proteins. Enzyme-linked immunosorbent assay and immunoblotting were used to detect antibodies in 304 cancer sera and also 58 sera from normal individuals. The antibody frequency to any individual TAA in cancer was variable but rarely exceeded 20%. With the successive addition of TAAs to a final combination of total of eight antigens, there was a stepwise increase of positive antibody reactions reaching a sensitivity of 63.5% and a specificity of 86.2% in the combined cancer group. In different types of cancer, the ranges of positive and negative likelihood ratio were 4.07–4.76 and 0.39–0.51, respectively, and the ranges of positive and negative predictive values were 74.2–88.7% and 58.8–75.8%, respectively. Agreement rate and Kappa value were 67.1% and 0.51, respectively. These results further support our previous hypothesis that detection of anti-TAAs autoantibodies for diagnosis of certain type of cancer can be enhanced by using a miniarray of several TAAs. Peng Wang, Chunhua Song, Weihong Xie, Hua Ye, Kaijuan Wang, Liping Dai, Yi Zhang, and Jianying Zhang Copyright © 2014 Peng Wang et al. All rights reserved. Serum Level of Antibody against Benzo[a]pyrene-7,8-diol-9,10-epoxide-DNA Adducts in People Dermally Exposed to PAHs Sun, 13 Apr 2014 00:00:00 +0000 Some specific antibodies indicate the presence of antigenic structures on DNA (DNA adducts) that can play an important role in the process of mutagenesis and/or carcinogenesis. They indicate the presence of increased genotoxic potential (hazard) prior to the formation of disease (primary prevention). The present study was focused on the serum level of benzo[a]pyrene 7,8-diol-9,10-epoxide-DNA adducts antibodies (anti-BPDE-DNA) in psoriatic patients dermally exposed to different levels of polycyclic aromatic hydrocarbons (PAHs). The general goal of the study was to contribute to better understanding of the value of the assumed biomarker (anti-BPDE-DNA) for evaluation of the organism's answer to genotoxic exposure to PAHs. Elevated level of exposure to PAHs resulted in the increased level of anti-BPDE-DNA. However, almost all levels of anti-BPDE-DNA ranged within the field of low values. Both variants of GT (CCT-3% and CCT-5%) induced higher expression of anti-BPDE-DNA in the group of nonsmokers. Significant relations between the level of anti-BPDE-DNA and PASI score, total duration of the therapy, or time of UVR exposure were not found. Further studies are needed to reduce interpretation uncertainty of this promising bioindicator. Lenka Borska, Ctirad Andrys, Jan Krejsek, Vladimir Palicka, Marcela Chmelarova, Kvetoslava Hamakova, Jan Kremlacek, Pavel Borsky, and Zdenek Fiala Copyright © 2014 Lenka Borska et al. All rights reserved. Targeted Inhibition of mTOR Signaling Improves Sensitivity of Esophageal Squamous Cell Carcinoma Cells to Cisplatin Thu, 10 Apr 2014 11:37:49 +0000 mTOR is an evolutionarily conserved serine-threonine kinase with a central role in cell growth, invasion, and metastasis of tumors, and is activated in many cancers. The aims of this study were to investigate the expression of mTOR in ESCC tissues and its relationship with progression of ESCC and measure the changes of sensitivity of ESCC cells to cisplatin after cells were treated with mTOR siRNA by WST-8 assays, TUNEL, RT-PCR, and western blots in vitro and in vivo. The results showed that the expression of mTOR was higher in ESCC specimens than that in normal esophageal tissues and its expression was closely correlated with the TNM stage of ESCC. mTOR siRNA significantly increased the sensitivity of the EC9706 cells to cisplatin at proliferation in vitro and in vivo. The growth of ESCC xenografts was significantly inhibited by mTOR siRNA or cisplatin, and the cell number of apoptosis was obviously increased after xenografts were treated with mTOR siRNA or cisplatin alone, especially when mTOR siRNA combined with cisplatin. The present study demonstrates that the expression of mTOR has important clinical significance and inhibition of mTOR pathway by mTOR siRNA can improve the sensitivity of ESCC cells to cisplatin. Guiqin Hou, Shuai Yang, Yuanyuan Zhou, Cong Wang, Wen Zhao, and Zhaoming Lu Copyright © 2014 Guiqin Hou et al. All rights reserved. The Role of PAM4 in the Management of Pancreatic Cancer: Diagnosis, Radioimmunodetection, and Radioimmunotherapy Thu, 10 Apr 2014 09:09:45 +0000 PAM4, a new monoclonal antibody (MAb) known as clivatuzumab, is highly reactive with pancreatic cancer and precursor lesions. It is absent from the normal tissues and has limited reactivity with nonpancreatic cancer. The detailed characteristic of the PAM4 epitope is unknown but recent studies have shown that it is dependent on MUC1 glycosylation status. The limited PAM4 expression pattern makes it an attractive candidate for management of pancreatic adenocarcinoma. In addition, PAM4 is a serum biomarker for diagnosis of pancreatic cancer. Several different radiolabeled immunodiagnostic and immunotherapeutic agents of PAM4 have been developed and some are being evaluated in preclinical and/or clinical studies. The review will focus on PAM4 and its potential utility for the diagnosis, radioimmunodetection, and radioimmunotherapy of pancreatic cancer. Suxia Han, Guihua Jin, Lijuan Wang, Meng Li, Chenchen He, Xijing Guo, and Qing Zhu Copyright © 2014 Suxia Han et al. All rights reserved. Renal Transplantation Dramatically Reduces IgA Anti-beta-2-glycoprotein I Antibodies in Patients with Endstage Renal Disease Thu, 10 Apr 2014 08:18:25 +0000 IgA anti-beta-2-glycoprotein I (aB2GPI) antibodies have been related to vascular pathology in the general population and mainly in hemodialyzed patients (prevalence 33%) in whom an elevated incidence of thrombosis and mortality is found. In this paper we have studied the presence of IgA aB2GPI antibodies at pretransplant and their evolution after transplantation with a cross-sectional-based follow-up study of a cohort of 288 endstage renal disease (ESRD) patients treated with kidney transplantation. Pretransplant IgA aB2GPI levels were elevated  U/mL without differences in age or type of dialysis. Patients with different etiologies of ESRD showed higher levels of IgA aB2GPI than blood donors, except the groups of non-IgA glomerular disease and systemic erythematosus lupus, whose nonsignificant differences were observed. IgA aB2GPI antibodies dropped immediately after transplantation ( U/mL, ), coinciding with a high degree of immunosuppression, and remained significantly lower than that observed in pretransplant status. Prevalence of patients with elevated antibodies was also less in transplanted patients (8.9% versus 30.4%, ). Among, positivity for IgA aB2GPI was higher than in patients who had received their first transplant that those were retransplanted. This finding could have important clinical implications and can suggest new therapeutic strategies in patients with IgA aB2GPI antibodies. Manuel Serrano, Jose Angel Martínez-Flores, Maria José Castro, Florencio García, David Lora, Dolores Pérez, Esther Gonzalez, Estela Paz-Artal, Jose M. Morales, and Antonio Serrano Copyright © 2014 Manuel Serrano et al. All rights reserved. Some Basic Aspects of HLA-G Biology Wed, 09 Apr 2014 12:17:44 +0000 Human leukocyte antigen-G (HLA-G) is a low polymorphic nonclassical HLA-I molecule restrictively expressed and with suppressive functions. HLA-G gene products are quite complex, with seven HLA-G isoforms, four membrane bound, and other three soluble isoforms that can suffer different posttranslational modifications or even complex formations. In addition, HLA-G has been described included in exosomes. In this review we will focus on HLA-G biochemistry with special emphasis to the mechanisms that regulate its expression and how the protein modifications affect the quantification in biological fluids. Estibaliz Alegre, Roberta Rizzo, Daria Bortolotti, Sara Fernandez-Landázuri, Enrico Fainardi, and Alvaro González Copyright © 2014 Estibaliz Alegre et al. All rights reserved. Antiphospholipase A2 Receptor Autoantibodies: A Comparison of Three Different Immunoassays for the Diagnosis of Idiopathic Membranous Nephropathy Wed, 09 Apr 2014 08:08:07 +0000 Background. The recent identification of circulating autoantibodies directed towards the M-type phospholipase A2 receptor (PLA2R) has been a major advancement in the serological diagnosis of idiopathic membranous nephropathy (IMN), a common cause of nephrotic syndrome in adults. The goal of this study was to compare the performance characteristics of two commercial assays as well as the first addressable laser bead immunoassay (ALBIA) developed for the detection of anti-PLA2R antibodies. Methods. Serum samples of 157 IMN patients and 142 controls were studied. Samples were tested by a cell based immunofluorescence assay (CBA-IFA, Euroimmun, Germany), by ELISA (Euroimmun), and by a novel ALBIA employing an in vivo expressed recombinant human PLA2R. Results. Overall, the three assays showed significant qualitative and quantitative correlation. As revealed by receiver operating characteristic analysis, the ALBIA correlated better with the CBA-IFA than the ELISA (). The clinical sensitivities/specificities for IMN were 60.0% (51.0–68.5%)/98.6% (95.0–99.8%) and 56.2% (47.2–64.8%)/100.0% (97.4–100.0%) for ALBIA and CBA-IFA, respectively. Conclusion. The ALBIA represents a promising assay for the detection of anti-PLA2R antibodies showing similar performance to the CBA-IFA and the advantage of ease of use and suitability for high throughput, rapid turnaround times, and multiplexing. Astrid Behnert, Mario Schiffer, Janina Müller-Deile, Laurence H. Beck Jr., Michael Mahler, and Marvin J. Fritzler Copyright © 2014 Astrid Behnert et al. All rights reserved. Anti-Cyclic Citrullinated Peptide (Anti-CCP) and Anti-Mutated Citrullinated Vimentin (Anti-MCV) Relation with Extra-Articular Manifestations in Rheumatoid Arthritis Mon, 07 Apr 2014 09:57:33 +0000 We evaluated the association between anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-mutated citrullinated vimentin antibodies (anti-MCV) with the presence of extra-articular (ExRA) manifestations in 225 patients with rheumatoid arthritis (RA). Ninety-five patients had ExRA and 130 had no ExRA. There was no association of anti-CCP and anti-MCV levels with the presence of ExRA as total group ( and , resp.). Making an analysis of individual manifestations, rheumatoid nodules were associated with positivity for rheumatoid factor (RF); (), anti-CCP (), and anti-MCV (). Instead, RF, anti-CCP, or anti-MCV were not associated with SS, chronic anemia, or peripheral neuropathy. Levels of anti-CCP correlated with the score of the Health Assessment Questionnaire-Disability Index (HAQ-Di) (, ), erythrocyte sedimentation rate (ESR); (, ), and RF (, ), whereas anti-MCV titres only correlated with RF (, ). On adjusted analysis, ExRA was associated with longer age (), longer disease duration (), higher DAS-28 score (), and higher HAQ-DI score (), but serum levels of anti-CCP and anti-MCV were not associated. These findings show the need to strengthen the evaluation of the pathogenic mechanisms implied in each specific ExRA manifestation. Laura Gonzalez-Lopez, Alberto Daniel Rocha-Muñoz, Manuel Ponce-Guarneros, Alejandra Flores-Chavez, Mario Salazar-Paramo, Arnulfo Nava, Ernesto German Cardona-Muñoz, Nicte Selene Fajardo-Robledo, Soraya Amali Zavaleta-Muñiz, Teresa Garcia-Cobian, and Jorge Ivan Gamez-Nava Copyright © 2014 Laura Gonzalez-Lopez et al. All rights reserved. Temporal Regulation of Cytokines by the Circadian Clock Sun, 06 Apr 2014 12:14:23 +0000 Several parameters of the immune system exhibit oscillations with a period of approximately 24 hours that refers to “circadian rhythms.” Such daily variations in host immune system status might evolve to maximize immune reactions at times when encounters with pathogens are most likely to occur. However, the mechanisms behind circadian immunity have not been fully understood. Recent studies reveal that the internal time keeping system “circadian clock” plays a key role in driving the daily rhythms evident in the immune system. Importantly, several studies unveil molecular mechanisms of how certain clock proteins (e.g., BMAL1 and CLOCK) temporally regulate expression of cytokines. Since cytokines are crucial mediators for shaping immune responses, this review mainly summarizes the new knowledge that highlights an emerging role of the circadian clock as a novel regulator of cytokines. A greater understanding of circadian regulation of cytokines will be important to exploit new strategies to protect host against infection by efficient cytokine induction or to treat autoimmunity and allergy by ameliorating excessive activity of cytokines. Atsuhito Nakao Copyright © 2014 Atsuhito Nakao. All rights reserved. The Impact of Two Different Transfusion Strategies on Patient Immune Response during Major Abdominal Surgery: A Preliminary Report Thu, 03 Apr 2014 16:07:04 +0000 Blood transfusion is associated with well-known risks. We investigated the difference between a restrictive versus a liberal transfusion strategy on the immune response, as expressed by the production of inflammatory mediators, in patients subjected to major abdominal surgery procedures. Fifty-eight patients undergoing major abdominal surgery were randomized preoperatively to either a restrictive transfusion protocol or a liberal transfusion protocol (with transfusion if hemoglobin dropped below 7.7 g dL−1 or 9.9 g dL−1, respectively). In a subgroup of 20 patients randomly selected from the original allocation groups, blood was sampled for measurement of IL-6, IL-10, and TNFα. Postoperative levels of IL-10 were higher in the liberal transfusion group on the first postoperative day ( vs.  pg mL−1, ). Peak postoperative IL-10 levels correlated with the units of blood transfused as well as the mean duration of storage and the storage time of the oldest unit transfused (, , , , and , , respectively). IL-10 levels were elevated in patients with a more liberal red blood cell transfusion strategy. The strength of the association between anti-inflammatory IL-10 and transfusion variables indicates that IL-10 may be an important factor in transfusion-associated immunomodulation. This trial is registered under Identifier: NCT02020525. Kassiani Theodoraki, Maria Markatou, Demetrios Rizos, and Argyro Fassoulaki Copyright © 2014 Kassiani Theodoraki et al. All rights reserved. The Spectrum of Anti-Chromatin/Nucleosome Autoantibodies: Independent and Interdependent Biomarkers of Disease Thu, 03 Apr 2014 15:44:14 +0000 Autoantibodies directed to chromatin components date back to the discovery of the LE cell and the LE cell phenomenon circa 1950, and subsequent evidence that major components of that reaction were chromatin components and histones in particular. Over time, immunoassays ranging from ELISA and line immunoassays to more modern bead-based assays incorporated histone and DNA mixtures, purified histones, and purified nucleosomes leading to a more thorough understanding of the genesis and pathogenetic relationships of antibodies to chromatin components in systemic lupus erythematosus and other autoimmune conditions. More recently, interest has focussed on other components of chromatin such as high mobility group (HMG) proteins both as targets of B cell responses and pro-inflammatory mediators. This review will focus on immunoassays that utilize chromatin components, their clinical relationships, and newer evidence implicating HMG proteins and DNA neutrophil extracellular traps (NETs) as important players in systemic autoimmune rheumatic diseases. Sonal Mehra and Marvin J. Fritzler Copyright © 2014 Sonal Mehra and Marvin J. Fritzler. All rights reserved. Current Vaccine Trials in Glioblastoma: A Review Thu, 03 Apr 2014 06:32:17 +0000 Glioblastoma (GBM) is the most common primary brain tumor, and despite aggressive therapy with surgery, radiation, and chemotherapy, average survival remains at about 1.5 years. The highly infiltrative and invasive nature of GBM requires that alternative treatments for this disease be widespread and targeted to tumor cells. Immunotherapy in the form of tumor vaccines has the potential to meet this need. Vaccines against GBM hold the promise of triggering specific and systemic antitumor immune responses that may be the key to eradicating this unrelenting cancer. In this review, we will discuss past and present clinical trials of various GBM vaccines and their potential impact on the future care of GBM patients. There have been many promising phase I and phase II GBM vaccine studies that have led to ongoing and upcoming phase III trials. If the results of these randomized trials show a survival benefit, immunotherapy will become a standard part of the treatment of this devastating disease. Linda W. Xu, Kevin K. H. Chow, Michael Lim, and Gordon Li Copyright © 2014 Linda W. Xu et al. All rights reserved. Fusion-Expressed CTB Improves Both Systemic and Mucosal T-Cell Responses Elicited by an Intranasal DNA Priming/Intramuscular Recombinant Vaccinia Boosting Regimen Tue, 01 Apr 2014 11:34:55 +0000 Previous study showed that CTB (Cholera toxin subunit B) can be used as a genetic adjuvant to enhance the systemic immune responses. To further investigate whether it can also be used as a genetic adjuvant to improve mucosal immune responses, we constructed DNA and recombinant Tiantan vaccinia (rTTV) vaccines expressing OVA-CTB fusion antigen. Female C57BL/6 mice were immunized with an intranasal DNA priming/intramuscular rTTV boosting regimen. OVA specific T-cell responses were measured by IFN-γ ELISPOT and specific antibody responses were determined by ELISA. Compared to the nonadjuvant group (pSV-OVA intranasal priming/rTTV-OVA intramuscular boosting), pSV-OVA-CTB intranasal priming/rTTV-OVA-CTB intramuscular boosting group significantly improved the magnitudes of T-cell responses at spleen ( SFCs/106 splenocytes versus SFCs/106 splenocytes, ), mesenteric LN ( SFCs/106 lymphocytes versus SFCs/106 lymphocytes, ), draining LNs of respiratory tract ( SFCs/106 lymphocytes versus SFCs/106 lymphocytes, ) and female genital tract ( SFCs/106 lymphocytes versus SFCs/106 lymphocytes, ). These results collectively demonstrated that fusion-expressed CTB could act as a potent adjuvant to improve both systemic and mucosal T-cell responses. Sugan Qiu, Xiaonan Ren, Yinyin Ben, Yanqin Ren, Jing Wang, Xiaoyan Zhang, Yanmin Wan, and Jianqing Xu Copyright © 2014 Sugan Qiu et al. All rights reserved. Tumor-Activated T Cells from Gastric Cancer Patients Induce the Antitumor Immune Response of T Cells via Their Antigen-Presenting Cell-Like Effects Mon, 31 Mar 2014 16:36:44 +0000 Human γδ T cells display the principal characteristics of professional antigen-presenting cells (APCs), in addition to playing a vital role in immunity through cytokine secretion and their cytotoxic activity. However, it is not clear whether γδ T cells perform APC-like functions under pathological conditions. In this study, we showed that, in contrast to peripheral-derived γδ T cells directly isolated from PBMCs of gastric cancer patients, tumor-activated γδ T cells not only killed tumor cells efficiently but also strongly induced primary CD4+ and CD8+  αβ T cells proliferation and differentiation. More importantly, they abrogated the immunosuppression induced by CD4+CD25+ Treg cells and induced the cytotoxic function of CD8+  αβ T cells from patients with gastric cancer. In conclusion, tumor-activated γδ T cells can induce adaptive immune responses through their APC-like functions, and these cells may be a potentially useful tool in the development of tumor vaccines and immunotherapy. Chaoming Mao, Xiao Mou, Yuepeng Zhou, Guoyue Yuan, Chengcheng Xu, Hongli Liu, Tingting Zheng, Jia Tong, Shengjun Wang, and Deyu Chen Copyright © 2014 Chaoming Mao et al. All rights reserved. Protective Effects of Baicalin on Decidua Cells of LPS-Induced Mice Abortion Mon, 31 Mar 2014 13:46:44 +0000 The study was carried out to investigate the protective effects of Baicalin on decidual cells of LPS-induced abortion mice. In the in vitro experiment, the decidual cells were cultured by uterus tissue mass cultivation sampled at day 6 of pregnancy, and gradient concentrations of LPS were used to determine the optimal LPS concentration of the injured decidual cells model. The injured decidual cells were treated with Baicalin (4 μg/mL) to determine the protective role of Baicalin. In the in vivo experiment, lipopolysaccharide (LPS) was injected intravenously via the tail vein to induce abortion at day 6 of pregnancy, and the mice were given different concentrations of Baicalin by oral gavage consecutively at days 7 to 8 of pregnancy. On day 9 of gestation, the mice were sacrificed. The TNF and progesterone contents in the serum were assayed by ELISA. The results clearly revealed that Baicalin can prevent the injury to decidual cells from LPS dose dependently, TNF was decreased significantly compared to LPS group, and there was no effect on the progesterone. These findings suggest that Baicalin has protective effects on the injured decidual cells in the pregnant mice. Xiaodan Wang, Yantao Zhao, and Xiuhui Zhong Copyright © 2014 Xiaodan Wang et al. All rights reserved. Idiopathic Non Cirrhotic Portal Hypertension and Spleno-Portal Axis Abnormalities in Patients with Severe Primary Antibody Deficiencies Mon, 31 Mar 2014 12:09:02 +0000 Background and Aim. Portal hypertension has been reported in association with acquired and primary immune deficiencies without a comprehensive description of associated spleno-portal axis abnormalities. Pathological mechanisms are poorly defined. Methods. Observational, single centre study with the aim of assessing the prevalence of spleno-portal axis abnormalities in an unselected cohort of 123 patients with primary antibody deficiencies and without known causes of liver diseases regularly followed up for a mean time of 18 ± 14 years. A cumulative period of 1867 patients-year was analysed. Clinical and immunological data, abdominal ultrasounds, CT scans, and endoscopy features were included in the analysis. Results. Twenty-five percent of patients with primary antibody deficiencies had signs of portal vein enlargement but only 4% of them had portal hypertension, with portal systemic collaterals. Liver biopsies showed liver sinusoids congestive dilatation, endothelization, and micronodularity fulfilling the criteria for noncirrhotic portal hypertension. Patients with portal vein enlargement had severe clinical and immunological phenotypes. Conclusions. In primary antibody deficient patients, infections, inflammations, splenomegaly, increased blood venous flow, and lymphocyte abnormalities contribute to establishment of liver damage possibly leading to noncirrhotic portal hypertension. Patients with primary antibody deficiency should be considered a good model to give insight into the pathological mechanisms underlying noncirrhotic portal hypertension. Federica Pulvirenti, Ilaria Pentassuglio, Cinzia Milito, Michele Valente, Adriano De Santis, Valentina Conti, Giulia d’Amati, Oliviero Riggio, and Isabella Quinti Copyright © 2014 Federica Pulvirenti et al. All rights reserved. Gαs Protein Expression Is an Independent Predictor of Recurrence in Prostate Cancer Mon, 31 Mar 2014 11:57:46 +0000 Background. T393C polymorphism in the gene GNAS1, which encodes the G-protein alpha s subunit (Gαs) of heterotrimeric G protein, is significantly associated with the clinical outcome of patients suffering from several cancers. However, studies on the role and protein expression of Gαs subunit in prostate cancer were still unavailable. Methods. The immunohistochemical staining was used to assess Gαs expression through tissue microarray procedure of 56 metastatic PCas, 291 localized PCas, and 67 benign hyperplasia (BPH). Gαs expression was semiquantitatively scored and evaluated the correlation with pathologic parameters and biochemical recurrence of prostate-specific antigen (PSA). Results. Gαs expression was localized in nuclear and cytoplasm in prostate cancer cells and downregulated in metastatic PCa compared to localized PCa and BPH . Gαs was inversely associated with PSA level and Gleason scores; patients with low expression of Gαs had adverse clincopathological features. In multivariable Cox regression analysis, high Gαs expression and Gleason scores were independent predictors of both PSA progression-free and overall survival. Conclusions. Gαs down-expression is associated with adverse pathologic features and clinical PSA biochemical recurrence of prostate cancer. Gαs is an independent predictor to help determine the risk of PSA progression and death. Lijuan Wang, Guihua Jin, Chenchen He, Xijing Guo, Xia Zhou, Meng Li, Xia Ying, Le Wang, Huili Wu, and Qing Zhu Copyright © 2014 Lijuan Wang et al. All rights reserved. Rapamycin Regulates iTreg Function through CD39 and Runx1 Pathways Mon, 31 Mar 2014 11:35:05 +0000 It has been shown that rapamycin is able to significantly increase the expression of FoxP3 and suppress activity in induced Treg (iTreg) cells in vivo and in vitro. CD39 is a newly determined Treg marker that relates to cell suppression. Runx1, a regulator of FoxP3, controls the expression of adenosine deaminase (ADA) gene, which is found recently in the downstream of CD39 pathway in trophoblast cells. Whether rapamycin would influence CD39 pathway and regulate the expression of Runx1 remains to be determined. The addition of rapamycin to human CD4+ naïve cells in the presence of IL-2, TGF-β promotes the expression of FoxP3. In this paper, we found that CD39 positively correlated with the FoxP3 expression in iTreg cells. Rapamycin induced iTreg cells showed a stronger CD39/Runx1 expression with the enhanced suppressive function. These data suggested that CD39 expression was involved in iTreg generation and the enhanced suppressive ability of rapamycin induced Treg was partly due to Runx1 pathway. We conclude that rapamycin favors CD39/Runx1 expression in human iTreg and provides a novel insight into the mechanisms of iTreg generation enhanced by rapamycin. Yunjie Lu, Jirong Wang, Jian Gu, Hao Lu, Xiangcheng Li, Xiaofeng Qian, Xiaoshan Liu, Xuehao Wang, Feng Zhang, and Ling Lu Copyright © 2014 Yunjie Lu et al. All rights reserved. The Dual Role of HLA-G in Cancer Mon, 31 Mar 2014 00:00:00 +0000 We here review the current data on the role of HLA-G in cancer based on recent findings of an unexpected antitumor activity of HLA-G in hematological malignancies. For the past decade, HLA-G has been described as a tumor-escape mechanism favoring cancer progression, and blocking strategies have been proposed to counteract it. Aside from these numerous studies on solid tumors, recent data showed that HLA-G inhibits the proliferation of malignant B cells due to the interaction between HLA-G and its receptor ILT2, which mediates negative signaling on B cell proliferation. These results led to the conjecture that, according to the malignant cell type, HLA-G should be blocked or conversely induced to counteract tumor progression. In this context, we will here present (i) the dual role of HLA-G in solid and liquid tumors with special emphasis on (ii) the HLA-G active structures and their related ILT2 and ILT4 receptors and (iii) the current knowledge on regulatory mechanisms of HLA-G expression in tumors. Nathalie Rouas-Freiss, Philippe Moreau, Joel LeMaoult, and Edgardo D. Carosella Copyright © 2014 Nathalie Rouas-Freiss et al. All rights reserved. HLA-G Dimers in the Prolongation of Kidney Allograft Survival Sun, 30 Mar 2014 07:58:50 +0000 Human leukocyte antigen-G (HLA-G) contributes to acceptance of allografts in solid organ/tissue transplantation. Most studies have determined that soluble HLA-G isoforms are systematically detected in serum/plasma of transplanted patients with significantly fewer episodes of acute and/or chronic rejection of allogeneic tissue/organ. Current models of the interactions of HLA-G and its specific receptors explain it as functioning in a monomeric form. However, in recent years, new data has revealed the ability of HLA-G to form disulfide-linked dimeric complexes with high preferential binding and functional activities. Limited data are available on the role of soluble HLA-G dimers in clinical pathological conditions. We describe here the presence of soluble HLA-G dimers in kidney transplant patients. Our study showed that a high level of HLA-G dimers in plasma and increased expression of the membrane-bound form of HLA-G on monocytes are associated with prolongation of kidney allograft survival. We also determined that the presence of soluble HLA-G dimers links to the lower levels of proinflammatory cytokines, suggesting a potential role of HLA-G dimers in controlling the accompanying inflammatory state. Maureen Ezeakile, Vera Portik-Dobos, Juan Wu, Daniel D. Horuzsko, Rajan Kapoor, Muralidharan Jagadeesan, Laura L. Mulloy, and Anatolij Horuzsko Copyright © 2014 Maureen Ezeakile et al. All rights reserved. Oxidative Stress Is Differentially Present in Multiple Sclerosis Courses, Early Evident, and Unrelated to Treatment Wed, 26 Mar 2014 08:45:29 +0000 Background. Oxidative stress is well documented in multiple sclerosis (MS) lesions, but its correspondence at peripheral level is still controversial. Objective. To evaluate peripheral oxidative stress markers in MS patients. Methods. We studied total blood levels of Coenzyme Q10 (CoQ10), oxidized and reduced forms of glutathione, malondialdehyde, reactive oxygen species (ROS), anti-oxidized-low-density lipoproteins (anti-oxLDL) antibodies, and antioxidant power (PAO) in 87 patients with different MS clinical phenotypes and in 77 controls. Results. CoQ10 was lower whereas anti-oxLDL antibodies titer was higher in MS patients than in controls. The benign variant of MS displayed both higher CoQ10 and higher anti-oxLDL than other MS clinical variants. Female patients had lower CoQ10 and PAO and higher ROS than male patients. Differences were greater in younger patients with shorter disease duration. Surprisingly, there was no difference for these markers between treated and untreated patients. Conclusion. We found lower antioxidant agents and higher anti-oxLDL antibodies in MS, and the highest antibody titers occurred in the benign form. We suggest that natural anti-oxLDL antibodies can be protective against MS, saving blood brain barrier integrity. Our findings also suggest that milder MS is associated with a distinct oxidative stress pattern, which may provide a useful biomarker of disease prognosis. Maira Gironi, Bruno Borgiani, Enrica Mariani, Cristina Cursano, Laura Mendozzi, Rossella Cavarretta, Marina Saresella, Mario Clerici, Giancarlo Comi, Marco Rovaris, and Roberto Furlan Copyright © 2014 Maira Gironi et al. All rights reserved.