Journal of Immunology Research The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Immunization with Bivalent Flagellin Protects Mice against Fatal Pseudomonas aeruginosa Pneumonia Thu, 19 Oct 2017 02:02:26 +0000 Pseudomonas aeruginosa lung infections present a major challenge to healthcare systems worldwide because they are commonly associated with high morbidity and mortality. Here, we demonstrate the protective efficacy of type a and b flagellins (bivalent flagellin) against acute fatal pneumonia in mice. Mice immunized intranasally with a bivalent flagellin vaccine were challenged by different flagellated strains of P. aeruginosa in an acute pneumonia model. Besides the protective effect of the vaccine, we further measured the host innate and cellular immunity responses. The immunized mice in our study were protected against both strains. Remarkably, active immunization with type a or b flagellin significantly improved survival of mice against heterologous strain compared to flagellin a or b antisera. We also showed that after an intranasal challenge by P. aeruginosa strain, neutrophils are recruited to the airways of vaccinated mice, and that the bivalent flagellin vaccine was proved to be protective by the generated CD4+IL-17+ Th17 cells. In conclusion, bivalent flagellin vaccine can confer protection against different strains of P. aeruginosa in an acute pneumonia mouse model by eliciting effective cellular and humoral immune responses, including increased IL-17 production and improved opsonophagocytic killing. Bahador Behrouz, Farhad B. Hashemi, Mohammad Javad Fatemi, Sara Naghavi, Gholamreza Irajian, Raheleh Halabian, and Abbas Ali Imani Fooladi Copyright © 2017 Bahador Behrouz et al. All rights reserved. Regulation of Leukocyte Recruitment to the Spleen and Peritoneal Cavity during Pristane-Induced Inflammation Thu, 19 Oct 2017 00:00:00 +0000 Chronic inflammation is associated with an increased number of leukocytes in the spleen, which are then redirected to the site of inflammation. However, it remains unknown how leukocyte recruitment is regulated. Herein, chronic inflammation was induced by intraperitoneal injection of pristane into mice. Leukocytes in the spleen or in the peritoneal cavity were quantified by flow cytometry. We found that the loss of IL-6 decreased macrophage recruitment to the spleen and the peritoneal cavity during pristane-induced inflammation. The loss of TNFα delayed the recruitment of neutrophils and macrophages to the spleen and inhibited the recruitment of neutrophils, macrophages, B cells, and T cells. The recruitment of neutrophils and macrophages into the spleen or peritoneal cavity was largely inhibited in the absence of LTα. The loss of TNFα receptor 1/2 resulted in reduced recruitment of neutrophils, macrophages, and dendritic cells into the spleen, but only neutrophil recruitment was inhibited in the peritoneal cavity. Similarly, a lack of B cells significantly impeded the recruitment of neutrophils, macrophages, and dendritic cells to the spleen. However, only macrophage recruitment was inhibited in the absence of T cells in the spleen. These data provide insight into the development of chronic inflammation induced by noninfectious substances. Yu Li, Junping Wu, Long Xu, Qi Wu, Zhen Wan, Li Li, Hongzhi Yu, Xue Li, Kuan Li, Qiuyang Zhang, Zhili Hou, Xin Sun, and Huaiyong Chen Copyright © 2017 Yu Li et al. All rights reserved. CD80 Expressed by CD8+ T Cells Contributes to PD-L1-Induced Apoptosis of Activated CD8+ T Cells Wed, 18 Oct 2017 00:00:00 +0000 Tumor cells are capable of limiting antitumor CD8+ T cell responses through their cell surface expression of PD-L1. In addition to PD-1 expressed by CD8+ T cells, PD-L1 also binds to CD80 expressed by CD8+ T cells. The influence of the PD-L1/CD80 interaction on CD8+ T cell function has not been fully characterized, so we sought to investigate the impact of the PD-L1/CD80 interaction on PD-L1-induced apoptosis of activated CD8+ T cells. We found that CD8+ T cells that lacked CD80 expression got activated to the same extent as wild-type CD8+ T cells, but when cultured with anti-CD3 and PD-L1/Fc protein, activated CD8+ T cells that lacked CD80 expression survived better than activated wild-type CD8+ T cells. These findings indicate that PD-L1 induces apoptosis in activated CD8+ T cells in part by signaling through CD80. Thus, in the design and implementation of checkpoint blockade therapies that target PD-L1, it is essential that both binding partners for PD-L1, PD-1, and CD80 are considered. Meagan R. Rollins and Rachel M. Gibbons Johnson Copyright © 2017 Meagan R. Rollins and Rachel M. Gibbons Johnson. All rights reserved. Toll-Like Receptor Ligand-Induced Liver Injury in D-Galactosamine-Sensitized Mice: Differences between TLR7/8 and TLR9 Ligands, Cytokine Patterns, and Cross-Tolerance Induction by TLR2 Ligand Pretreatment Tue, 17 Oct 2017 00:00:00 +0000 Administration of Toll-like receptor ligands (TLRLs) is known to cause liver injury in D-galN-sensitized mice. In the present study, we aimed to complement preceding reports on the TLRL/D-galN system by analyzing comparisons among TLRLs, mouse strain dependence, effects on serum levels of cytokines, and effects of sequential administrations of different TLRLs. In a preliminary set of analyses, we first confirmed that liver failure can be induced by diverse TLRLs, including LTA and R848 in combination with D-galN. Analysis using TLR4-deficient mice excluded potential confounding effects of endogenous TLR4Ls that include those referred to as DAMPs in CpG DNA/D-galN hepatotoxicity. Subsequently, we showed that LTA pretreatment could prevent mortality in both CpG DNA/D-galN- and R848/D-galN-treated mice compared to without pretreatment. Incidentally, we observed that without the LTA pretreatment, CpG DNA/D-galN showed relatively higher liver-specific toxicity whereas R848/D-galN showed more symptoms of multiple organ failure. These findings suggest that, in D-galN-sensitized mice, different TLRLs not only show similarity in the ability to induce hepatic injury but also exhibit distinctive abilities in inducing systemic inflammation and multiple organ failure. These findings also suggest the potential usefulness of cross-tolerance induction using LTA in the prevention of organ failure in TLRL-mediated acute inflammation. Reiko Seki Copyright © 2017 Reiko Seki. All rights reserved. Endothelial STAT3 Modulates Protective Mechanisms in a Mouse Ischemia-Reperfusion Model of Acute Kidney Injury Tue, 17 Oct 2017 00:00:00 +0000 STAT3 is a transcriptional regulator that plays an important role in coordinating inflammation and immunity. In addition, there is a growing appreciation of the role STAT3 signaling plays in response to organ injury following diverse insults. Acute kidney injury (AKI) from ischemia-reperfusion injury is a common clinical entity with devastating consequences, and the recognition that endothelial alterations contribute to kidney dysfunction in this setting is of growing interest. Consequently, we used a mouse with a genetic deletion of Stat3 restricted to the endothelium to examine the role of STAT3 signaling in the pathophysiology of ischemic AKI. In a mouse model of ischemic AKI, the loss of endothelial STAT3 signaling significantly exacerbated kidney dysfunction, morphologic injury, and proximal tubular oxidative stress. The increased severity of ischemic AKI was associated with more robust endothelial-leukocyte adhesion and increased tissue accumulation of F4/80+ macrophages. Moreover, important proximal tubular adaptive mechanisms to injury were diminished in association with decreased tissue mRNA levels of the epithelial cell survival cytokine IL-22. In aggregate, these findings suggest that the endothelial STAT3 signaling plays an important role in limiting kidney dysfunction in ischemic AKI and that selective pharmacologic activation of endothelial STAT3 signaling could serve as a potential therapeutic target. Shataakshi Dube, Tejasvi Matam, Jessica Yen, Henry E. Mang, Pierre C. Dagher, Takashi Hato, and Timothy A. Sutton Copyright © 2017 Shataakshi Dube et al. All rights reserved. Decitabine-Induced Changes in Human Myelodysplastic Syndrome Cell Line SKM-1 Are Mediated by FOXO3A Activation Mon, 16 Oct 2017 06:53:05 +0000 The epigenetic silencing of tumor suppressor genes in myelodysplastic syndromes (MDS) can potentially confer a growth advantage to individual cellular clones. Currently, the recommended treatment for patients with high-risk MDS is the methylation agent decitabine (DAC), a drug that can induce the reexpression of silenced tumor suppressor genes. We investigated the effects of DAC treatment on the myeloid MDS cell line SKM-1 and investigated the role of FOXO3A, a potentially tumor-suppressive transcription factor, by silencing its expression prior to DAC treatment. We found that FOXO3A exists in an inactive, hyperphosphorylated form in SKM-1 cells, but that DAC both induces FOXO3A expression and reactivates the protein by reducing its phosphorylation level. Furthermore, we show that this FOXO3A activation is responsible for the DAC-induced differentiation of SKM-1 cells into monocytes, as well as for SKM-1 cell cycle arrest, apoptosis, and autophagy. Collectively, these results suggest that FOXO3A reactivation may contribute to the therapeutic effects of DAC in MDS. Wen Zeng, Hanjun Dai, Ming Yan, Xiaojun Cai, Hong Luo, Min Ke, and Zeming Liu Copyright © 2017 Wen Zeng et al. All rights reserved. The Application of Dextran Sedimentation as an Initial Step in Neutrophil Purification Promotes Their Stimulation, due to the Presence of Monocytes Sun, 15 Oct 2017 00:00:00 +0000 The purification of human neutrophils for in vitro studies is challenging as they are easily activated through ex vivo manipulations. The technique of erythrocyte sedimentation combined with density gradient centrifugation remains widely practiced and was the subject of this study. Since in the sedimentation step the leukocytes are incubated with dextran, we have raised the likelihood that cellular activation would occur with mediator release leading to neutrophil activation. By comparing the activity of neutrophils purified from whole blood by the classical 2-step method of dextran sedimentation followed by low-density Ficoll-Hypaque (1.077 g/mL) medium, and the 1-step high-density Ficoll-Hypaque (1.114 g/mL) gradient centrifugation, we found that neutrophils from the 2-step method had a significant increase in cell surface CD11b expression and CD62L shedding and a marked increase in adhesion. Decreased random migration and chemotaxis and raised baseline oxidative burst activity were also observed. The effect was not specific to dextran, as using Ficoll for erythrocyte sedimentation replicated the elevated neutrophil adherence. Through the depletion of monocytes, lymphocytes, and platelets prior to sedimentation, we deduced that monocytes were responsible for the neutrophil activation. Our findings suggest that care needs to be exercised in choosing the method of neutrophil purification for functional studies. Alex Quach and Antonio Ferrante Copyright © 2017 Alex Quach and Antonio Ferrante. All rights reserved. New Insights into the Mechanisms of Chinese Herbal Products on Diabetes: A Focus on the “Bacteria-Mucosal Immunity-Inflammation-Diabetes” Axis Sun, 15 Oct 2017 00:00:00 +0000 Diabetes, especially type 2, has been rapidly increasing all over the world. Although many drugs have been developed and used to treat diabetes, side effects and long-term efficacy are of great challenge. Therefore, natural health product and dietary supplements have been of increasing interest alternatively. In this regard, Chinese herbs and herbal products have been considered a rich resource of product development. Although increasing evidence has been produced from various scientific studies, the mechanisms of action are lacking. Here, we have proposed that many herbal monomers and formulae improve glucose homeostasis and diabetes through the BMID axis; B represents gut microbiota, M means mucosal immunity, I represents inflammation, and D represents diabetes. Chinese herbs have been traditionally used to treat diabetes, with minimal side and toxic effects. Here, we reviewed monomers such as berberine, ginsenoside, M. charantia extract, and curcumin and herbal formulae such as Gegen Qinlian Decoction, Danggui Liuhuang Decoction, and Huanglian Wendan Decoction. This review was intended to provide new perspectives and strategies for future diabetes research and product. Zezheng Gao, Qingwei Li, Xuemin Wu, Xuemin Zhao, Linhua Zhao, and Xiaolin Tong Copyright © 2017 Zezheng Gao et al. All rights reserved. Protective Effects of Ophiocordyceps lanpingensis on Glycerol-Induced Acute Renal Failure in Mice Thu, 12 Oct 2017 00:00:00 +0000 Objective. Oxidative stress and immune response are associated with acute renal failure (ARF). Ophiocordyceps lanpingensis (OL) might be an antioxidant and immunopotentiator. In this study, we explored the protective effects of OL on glycerol-induced ARF. Methods. Male mice were randomly divided into four groups, specifically, glycerol-induced ARF model group, low-dose OL-treated group (1.0 g/kg/d), high-dose OL-treated group (2.0 g/kg/d), and control group. Renal conditions were evaluated using kidney index, serum creatinine (Cr), blood urea nitrogen (BUN), and histological analysis. Rhabdomyolysis was monitored using creatine kinase (CK) level. Oxidative stress was determined using kidney tissue glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) levels. Immune status was evaluated using immune organ indices and immunoglobulin G (IgG) level. Results. OL could relieve renal pathological injury and decrease the abnormal levels of kidney index, serum Cr, CK, BUN, and MDA, as well as increase the immune organ indices and the levels of IgG, GSH, and SOD. Treatment with a high dose of OL had more positive therapeutic effects on ARF than using a low dose of OL. Conclusion. OL could ameliorate renal dysfunction in glycerol-induced ARF in mice by inhibiting oxidative stress and enhancing immune response. Yanyan Zhang, Yaxi Du, Hong Yu, Yongchun Zhou, and Feng Ge Copyright © 2017 Yanyan Zhang et al. All rights reserved. The Role of Costimulation Blockade in Solid Organ and Islet Xenotransplantation Wed, 11 Oct 2017 00:00:00 +0000 Pig-to-human xenotransplantation offers a potential bridge to the growing disparity between patients with end-stage organ failure and graft availability. Early studies attempting to overcome cross-species barriers demonstrated robust humoral immune responses to discordant xenoantigens. Recent advances have led to highly efficient and targeted genomic editing, drastically altering the playing field towards rapid production of less immunogenic porcine tissues and even the discussion of human xenotransplantation trials. However, as these humoral immune barriers to cross-species transplantation are overcome with advanced transgenics, cellular immunity to these novel xenografts remains an outstanding issue. Therefore, understanding and optimizing immunomodulation will be paramount for successful clinical xenotransplantation. Costimulation blockade agents have been introduced in xenotransplantation research in 2000 with anti-CD154mAb. Most recently, prolonged survival has been achieved in solid organ (kidney xenograft survival > 400 days with anti-CD154mAb, heart xenograft survival > 900 days, and liver xenograft survival 29 days with anti-CD40mAb) and islet xenotransplantation (>600 days with anti-CD154mAb) with the use of these potent experimental agents. As the development of novel genetic modifications and costimulation blocking agents converges, we review their impact thus far on preclinical xenotransplantation and the potential for future application. Kannan P. Samy, James R. Butler, Ping Li, David K. C. Cooper, and Burcin Ekser Copyright © 2017 Kannan P. Samy et al. All rights reserved. An Exploration of the Impact of Anticentromere Antibody on Early-Stage Embryo Wed, 04 Oct 2017 00:00:00 +0000 Background. Previously, we found women with positive anticentromere antibody showed impaired potential of oocyte maturation and embryo cleavage; the possible mechanism behind this phenomenon was still unknown. Objective. Thus, the present study aimed to preliminarily explore whether ACA could penetrate into the living embryos and impair their developmental potential via in vitro coculture with mouse embryos. Methods. Mouse embryos were collected and used for in vitro culture with polyclonal anticentromere protein A (CENP-A) antibody; then, immunofluorescence assay was performed to determine the penetration of antibody into embryos, and embryo development potential was observed. Results. All embryos cultured with anti-CENP-A antibody exhibited immunofluorescence on the nucleus, while none of the embryos from the control groups showed immunofluorescence. Additionally, embryos cultured with anti-CENP-A antibody experienced significant growth impairment compared with controls. Conclusion. Mouse embryos may be a direct target for ACA in vitro prior to implantation. However, the precise mechanism needs further clarification. Ying Ying, Xi Guo, Yiping Zhong, and Canquan Zhou Copyright © 2017 Ying Ying et al. All rights reserved. Cytokine Profile of Patients with Allergic Rhinitis Caused by Pollen, Mite, and Microbial Allergen Sensitization Wed, 04 Oct 2017 00:00:00 +0000 Allergic rhinitis (AR) is especially prevalent among the population of large cities. Immunologically, the airway epithelium is a region where the population of allergen-presenting cells concentrates. These cells actively express a group of receptors of the innate immune system. A specific cytokine profile is its representation. The study was aimed at evaluating the cytokine profile in patients with seasonal and perennial allergic rhinitis. The cytokine profile of nasal secretion and blood serum of 44 patients with AR was studied. 24 of them had seasonal allergic rhinitis (SAR), and 20 patients suffered from perennial allergic rhinitis (PAR). The patients’ age ranged from 4 to 60 years. It was determined in our study that the activation of the GM-CSF production retained in patients with PAR sensitized to mite allergen components (Dermatophagoides pteronyssinus). There was a higher production profile of TNF-α and TSLP in nasal secretion in the patients with perennial allergic rhinitis and additional high sensitization to SEs. Sensitization to mold fungal allergen components significantly increases in patients with seasonal allergic rhinitis. They demonstrated high level of sensitization to the Aspergillus fumigatus component m3. Thus, along with other clinical trials, the study performed would clarify some aspects of molecular pathogenesis of human allergic rhinitis. Yury A. Tyurin, Svetlana A. Lissovskaya, Rustem S. Fassahov, Ilshat G. Mustafin, Anton F. Shamsutdinov, Marina A. Shilova, and Albert A. Rizvanov Copyright © 2017 Yury A. Tyurin et al. All rights reserved. Immunotherapy as a Promising Treatment for Prostate Cancer: A Systematic Review Tue, 03 Oct 2017 00:00:00 +0000 Prostate cancer treatment is currently based on surgical removal, radiotherapy, and hormone therapy. In recent years, another therapeutic method has emerged—immunological treatment. Immunotherapy modulates and strengthens one’s immune responses against cancer. Neoplastic cells naturally escape from the control of the immune system, and the main goal of immune therapy is to bring the control back. Satisfying outcomes after treatment of advanced melanoma and lung cancer suggest a great potential of immunotherapy as an approach for other tumors’ treatment, especially in patients primarily introduced to palliative care. After initial clinical trials, immunotherapy seems to have different side effects than chemotherapy. Prostate cancer was the first neoplasm in which a specific vaccine significantly improved survival. There is a tremendous potential for synergistic combinations of immunotherapy with conventional cancer treatments. A combination of several drugs or methods can be a key in radical treatment of metastatic prostate cancer as demonstrated by preliminary studies. Marlena Janiczek, Łukasz Szylberg, Anna Kasperska, Adam Kowalewski, Martyna Parol, Paulina Antosik, Barbara Radecka, and Andrzej Marszałek Copyright © 2017 Marlena Janiczek et al. All rights reserved. Computer-Aided Design of an Epitope-Based Vaccine against Epstein-Barr Virus Thu, 28 Sep 2017 07:16:14 +0000 Epstein-Barr virus is a very common human virus that infects 90% of human adults. EBV replicates in epithelial and B cells and causes infectious mononucleosis. EBV infection is also linked to various cancers, including Burkitt’s lymphoma and nasopharyngeal carcinomas, and autoimmune diseases such as multiple sclerosis. Currently, there are no effective drugs or vaccines to treat or prevent EBV infection. Herein, we applied a computer-aided strategy to design a prophylactic epitope vaccine ensemble from experimentally defined T and B cell epitopes. Such strategy relies on identifying conserved epitopes in conjunction with predictions of HLA presentation for T cell epitope selection and calculations of accessibility and flexibility for B cell epitope selection. The T cell component includes 14 CD8 T cell epitopes from early antigens and 4 CD4 T cell epitopes, targeted during the course of a natural infection and providing a population protection coverage of over 95% and 81.8%, respectively. The B cell component consists of 3 experimentally defined B cell epitopes from gp350 plus 4 predicted B cell epitopes from other EBV envelope glycoproteins, all mapping in flexible and solvent accessible regions. We discuss the rationale for the formulation and possible deployment of this epitope vaccine ensemble. Julio Alonso-Padilla, Esther M. Lafuente, and Pedro A. Reche Copyright © 2017 Julio Alonso-Padilla et al. All rights reserved. Maternal and Perinatal Outcome in Women with Systemic Lupus Erythematosus: A Retrospective Bicenter Cohort Study Thu, 28 Sep 2017 06:42:56 +0000 Objective. To investigate disease activity around and during pregnancy and pregnancy outcome in women with systemic lupus erythematosus (SLE) considering antiphospholipid antibody status. Moreover, differences between first and consecutive pregnancies were examined. Methods. Pregnancies > 16 weeks gestation of SLE patients receiving joint care from rheumatologists and gynecologists in two tertiary centers in the Netherlands between 2000 and 2015 were included. Disease activity, flare rate, and pregnancy outcomes and complications were assessed. Results. Ninety-six women (84% Caucasian) with 144 pregnancies were included. The median SLE(P)DAI score was 2 before, during, and after pregnancy. Flare rates were 6.3%, 20.1%, and 15.3%, respectively. Severe hypertensive disorder of pregnancy, intrauterine fetal death, preterm birth, and small-for-gestational age infants occurred in 18.1%, 4.1%, 32.7%, and 14.8%, respectively. Complication rates were similar in the first and consecutive pregnancies. Half of the women did not experience any pregnancy complication whereas 42.7% developed a complication during all pregnancies. Mean number of pregnancies was 2.4 and live births 1.7. Conclusion. In this SLE population with low disease activity, pregnancy complications were present irrespective of antiphospholipid antibody status. Furthermore, there were no differences in complication rates between the first and consecutive pregnancies as seen in healthy mothers. This information is useful for patient counseling. Sylvia J. Kroese, Carolien N. H. Abheiden, Birgit S. Blomjous, Jacob M. van Laar, Ronald W. H. M. Derksen, Irene E. M. Bultink, Alexandre E. Voskuyl, A. Titia Lely, Marjon A. de Boer, Johanna I. P. de Vries, and Ruth D. E. Fritsch-Stork Copyright © 2017 Sylvia J. Kroese et al. All rights reserved. A Novel System for the Quantification of the ADCC Activity of Therapeutic Antibodies Wed, 27 Sep 2017 00:00:00 +0000 Novel ADCC effector cells expressing the V-variant or F-variant of FcγRIIIa (CD16a) and firefly luciferase under the control of a chimeric promoter incorporating recognition sequences for the principal transcription factors involved in FcγRIIIa signal transduction, together with novel target cells overexpressing a constant high level of the specific antigen recognized by rituximab, trastuzumab, cetuximab, infliximab, adalimumab, or etanercept, confer improved sensitivity, specificity, and dynamic range in an ADCC assay relative to effector cells expressing a NFAT-regulated reporter gene and wild-type target cells. The effector cells also contain a normalization gene rendering ADCC assays independent of cell number or serum matrix effects. The novel effector and target cells in a frozen thaw-and-use format exhibit low vial-to-vial and lot-to-lot variation in their performance characteristics reflected by CVs of 10% or less. Homologous control target cells in which the specific target gene has been invalidated by genome editing providing an ideal control and a means of correcting for nonspecific effects were observed with certain samples of human serum. The novel effector cells and target cells expressing noncleavable membrane-bound TNFα have been used to quantify ADCC activity in serum from patients with Crohn’s disease treated with infliximab and to relate ADCC activity to drug levels. Christophe Lallemand, Feifei Liang, Flore Staub, Maud Simansour, Benoit Vallette, Lue Huang, Rosa Ferrando-Miguel, and Michael G. Tovey Copyright © 2017 Christophe Lallemand et al. All rights reserved. The Hydroalcoholic Extract Obtained from Mentha piperita L. Leaves Attenuates Oxidative Stress and Improves Survival in Lipopolysaccharide-Treated Macrophages Wed, 20 Sep 2017 05:56:25 +0000 Mentha piperita L. (peppermint) possesses antimicrobial properties, but little is known of its ability to modulate macrophages. Macrophages are essential in bacterial infection control due to their antimicrobial functions and ability to link the innate and adaptive immune responses. We evaluated the effects of the peppermint leaf hydroalcoholic extract (LHAE) on cultured murine peritoneal macrophages stimulated or not with lipopolysaccharide (LPS) in vitro. Vehicle-treated cells were used as controls. The constituents of the extract were also identified. Epicatechin was the major compound detected in the LHAE. LPS-induced macrophage death was reversed by incubation with LHAE (1–30 μg/ml). Higher concentrations of the extract (≥100 μg/ml) decreased macrophage viability (49–57%) in the absence of LPS. LHAE (1–300 μg/ml) attenuated H2O2 (34.6–53.4%) but not nitric oxide production by these cells. At similar concentrations, the extract increased the activity of superoxide dismutase (15.3–63.5-fold) and glutathione peroxidase (34.4–73.6-fold) in LPS-treated macrophages. Only LPS-unstimulated macrophages presented enhanced phagocytosis (3.6–6.6-fold increase) when incubated with LHAE (3–30 μg/ml). Overall, the LHAE obtained from peppermint modulates macrophage-mediated inflammatory responses, by stimulating the antioxidant pathway in these cells. These effects may be beneficial when the excessive activation of macrophages contributes to tissue damage during infectious disease. Mariana Oliveira Arruda, Saulo José Figueiredo Mendes, Simone Aparecida Teixeira, Ludmilla Santos Silva de Mesquita, Maria Nilce de Sousa Ribeiro, Stanley de Sousa Lima Galvão, Marcelo Nicolás Muscará, Elizabeth Soares Fernandes, and Valério Monteiro-Neto Copyright © 2017 Mariana Oliveira Arruda et al. All rights reserved. Dendritic Cells in Sepsis: Pathological Alterations and Therapeutic Implications Mon, 18 Sep 2017 00:00:00 +0000 Sepsis is the leading cause of death for critically ill patients in recent years. Dendritic cells (DCs) are important antigen-presenting cells and play a key role in immune response by regulating the innate and adaptive immunity. The number of DCs, the differentiation of monocytes into DCs, and the levels of surface molecules associated with the function of DCs are changed in the development of sepsis. There are many mechanisms involved in the alterations of DCs during sepsis, including the induction of apoptosis, reactive oxygen species generation, activation of the Wnt signaling pathway, epigenetic regulation, and variation in Toll-like receptor-dependent signaling. In this review, we present the classifications of DC subsets and mechanisms involved in the alterations of DCs in sepsis, as well as further discuss the therapeutic strategies targeting DCs in sepsis to improve the aberrant immune response and prolong the life during sepsis progression. Dong-Dong Wu, Tao Li, and Xin-Ying Ji Copyright © 2017 Dong-Dong Wu et al. All rights reserved. Enavatuzumab, a Humanized Anti-TWEAK Receptor Monoclonal Antibody, Exerts Antitumor Activity through Attracting and Activating Innate Immune Effector Cells Sun, 17 Sep 2017 00:00:00 +0000 Enavatuzumab is a humanized IgG1 anti-TWEAK receptor monoclonal antibody that was evaluated in a phase I clinical study for the treatment of solid malignancies. The current study was to determine whether and how myeloid effector cells were involved in postulated mechanisms for its potent antitumor activity in xenograft models. The initial evidence for a role of effector cells was obtained in a subset of tumor xenograft mouse models whose response to enavatuzumab relied on the binding of Fc of the antibody to Fcγ receptor. The involvement of effector cells was further confirmed by immunohistochemistry, which revealed strong infiltration of CD45+ effector cells into tumor xenografts in responding models, but minimal infiltration in nonresponders. Consistent with the xenograft studies, human effector cells preferentially migrated toward in vivo-responsive tumor cells treated by enavatuzumab in vitro, with the majority of migratory cells being monocytes. Conditioned media from enavatuzumab-treated tumor cells contained elevated levels of chemokines, which might be responsible for enavatuzumab-triggered effector cell migration. These preclinical studies demonstrate that enavatuzumab can exert its potent antitumor activity by actively recruiting and activating myeloid effectors to kill tumor cells. Enavatuzumab-induced chemokines warrant further evaluation in clinical studies as potential biomarkers for such activity. Shiming Ye, Melvin I. Fox, Nicole A. Belmar, Mien Sho, Debra T. Chao, Donghee Choi, Yuni Fang, Vivian Zhao, Stephen F. Keller, Gary C. Starling, and Patricia A. Culp Copyright © 2017 Shiming Ye et al. All rights reserved. Propyl Gallate Exerts an Antimigration Effect on Temozolomide-Treated Malignant Glioma Cells through Inhibition of ROS and the NF-κB Pathway Thu, 14 Sep 2017 00:00:00 +0000 In this study, we demonstrated that temozolomide (TMZ) and propyl gallate (PG) combination enhanced the inhibition of migration in human U87MG glioma cells. PG inhibited the TMZ-induced reactive oxygen species (ROS) generation. The mitochondrial complex III and NADPH oxidase are two critical sites that can be considered to regulate antimigration in TMZ-treated U87MG cells. PG can enhance the antimigration effect of TMZ through suppression of metalloproteinase-2 and metalloproteinase-9 activities, ROS generation, and the NF-κB pathway and possibly provide a novel prospective strategy for treating malignant glioma. Jen-Tsung Yang, I-Neng Lee, Fung-Jou Lu, Chiu-Yen Chung, Ming-Hsueh Lee, Yu-Ching Cheng, Kuo-Tai Chen, and Ching-Hsein Chen Copyright © 2017 Jen-Tsung Yang et al. All rights reserved. MicroRNAs Regulate Thymic Epithelium in Age-Related Thymic Involution via Down- or Upregulation of Transcription Factors Sun, 10 Sep 2017 00:00:00 +0000 Age-related thymic involution is primarily induced by defects in nonhematopoietic thymic epithelial cells (TECs). It is characterized by dysfunction of multiple transcription factors (TFs), such as p63 and FoxN1, and also involves other TEC-associated regulators, such as Aire. These TFs and regulators are controlled by complicated regulatory networks, in which microRNAs (miRNAs) act as a key player. miRNAs can either directly target the 3-UTRs (untranslated regions) of the TFs to suppress TF expression or target TF inhibitors to reduce or increase TF inhibitor expression and thereby indirectly enhance or inhibit TF expression. Here, we review the current understanding and recent studies about how miRNAs are involved in age-related thymic involution via regulation of TEC-autonomous TFs. We also discuss potential strategies for targeting miRNAs to rejuvenate age-related declined thymic function. Minwen Xu, Xiaoli Zhang, Ruiyun Hong, Dong-Ming Su, and Liefeng Wang Copyright © 2017 Minwen Xu et al. All rights reserved. Vaccinomics Approach for Designing Potential Peptide Vaccine by Targeting Shigella spp. Serine Protease Autotransporter Subfamily Protein SigA Thu, 07 Sep 2017 09:16:44 +0000 Shigellosis, a bacillary dysentery, is closely associated with diarrhoea in human and causes infection of 165 million people worldwide per year. Casein-degrading serine protease autotransporter of enterobacteriaceae (SPATE) subfamily protein SigA, an outer membrane protein, exerts both cytopathic and enterotoxic effects especially cytopathic to human epithelial cell type-2 (HEp-2) and is shown to be highly immunogenic. In the present study, we have tried to impose the vaccinomics approach for designing a common peptide vaccine candidate against the immunogenic SigA of Shigella spp. At first, 44 SigA proteins from different variants of S. flexneri, S. dysenteriae, S. boydii, and S. sonnei were assessed to find the most antigenic protein. We retrieved 12 peptides based on the highest score for human leukocyte antigen (HLA) supertypes analysed by NetCTL. Initially, these peptides were assessed for the affinity with MHC class I and class II alleles, and four potential core epitopes VTARAGLGY, FHTVTVNTL, HTTWTLTGY, and IELAGTLTL were selected. From these, FHTVTVNTL and IELAGTLTL peptides were shown to have 100% conservancy. Finally, IELAGTLTL was shown to have the highest population coverage (83.86%) among the whole world population. In vivo study of the proposed epitope might contribute to the development of functional and unique widespread vaccine, which might be an operative alleyway to thwart dysentery from the world. Arafat Rahman Oany, Tahmina Pervin, Mamun Mia, Motaher Hossain, Mohammad Shahnaij, Shahin Mahmud, and K. M. Kaderi Kibria Copyright © 2017 Arafat Rahman Oany et al. All rights reserved. Traditional Chinese Medicine Protects against Cytokine Production as the Potential Immunosuppressive Agents in Atherosclerosis Wed, 06 Sep 2017 00:00:00 +0000 Atherosclerosis is a chronic inflammatory disease caused by dyslipidemia and mediated by both innate and adaptive immune responses. Inflammation is a critical factor at all stages of atherosclerosis progression. Proinflammatory cytokines accelerate atherosclerosis progression, while anti-inflammatory cytokines ameliorate the disease. Accordingly, strategies to inhibit immune activation and impede immune responses towards anti-inflammatory activity are an alternative therapeutic strategy to conventional chemotherapy on cardiocerebrovascular outcomes. Since a number of Chinese medicinal plants have been used traditionally to prevent and treat atherosclerosis, it is reasonable to assume that the plants used for such disease may suppress the immune responses and the resultant inflammation. This review focuses on plants that have immunomodulatory effects on the production of inflammatory cytokine burst and are used in Chinese traditional medicine for the prevention and therapy of atherosclerosis. Yan Ren, Wei Qiao, Dongliang Fu, Zhiwei Han, Wei Liu, Weijie Ye, and Zunjing Liu Copyright © 2017 Yan Ren et al. All rights reserved. Intestinal Dysbiosis and Rheumatoid Arthritis: A Link between Gut Microbiota and the Pathogenesis of Rheumatoid Arthritis Wed, 30 Aug 2017 04:17:23 +0000 Characterization and understanding of gut microbiota has recently increased representing a wide research field, especially in autoimmune diseases. Gut microbiota is the major source of microbes which might exert beneficial as well as pathogenic effects on human health. Intestinal microbiome’s role as mediator of inflammation has only recently emerged. Microbiota has been observed to differ in subjects with early rheumatoid arthritis compared to controls, and this finding has commanded this study as a possible autoimmune process. Studies with intestinal microbiota have shown that rheumatoid arthritis is characterized by an expansion and/or decrease of bacterial groups as compared to controls. In this review, we present evidence linking intestinal dysbiosis with the autoimmune mechanisms involved in the development of rheumatoid arthritis. Gabriel Horta-Baas, María del Socorro Romero-Figueroa, Alvaro José Montiel-Jarquín, María Luisa Pizano-Zárate, Jaime García-Mena, and Ninfa Ramírez-Durán Copyright © 2017 Gabriel Horta-Baas et al. All rights reserved. In Vitro Immunomodulatory Activity of a Transition-State Analog Inhibitor of Human Purine Nucleoside Phosphorylase in Cutaneous Leishmaniasis Sun, 27 Aug 2017 00:00:00 +0000 Cutaneous leishmaniasis (CL) is the most common clinical form of American tegumentary leishmaniasis caused by Leishmania (Viannia) braziliensis. CL is associated with a strong Th1 immune response. This exacerbated inflammatory response is correlated with severity of disease and delays the healing time of the ulcer. The fourth-generation immucillin derivative (DI4G), a potent inhibitor of purine nucleoside phosphorylase, has been proposed as a promising agent in the treatment of diseases associated with T cell activation. Herein, we evaluated the in vitro immunomodulatory activity of DI4G in cells of patients presenting with CL. Peripheral blood mononuclear cells (PBMC) from CL patients were stimulated with soluble leishmania antigen (SLA), in the presence or absence of DI4G, and IFN-γ, TNF, CXCL9, and CXCL10 levels were determined by ELISA. Lymphocyte proliferation in the presence or absence of DI4G was also evaluated, using flow cytometry. DI4G was able to decrease () IFN-γ production but did not change the TNF, CXCL9, and CXCL10 levels. DI4G decreased () the lymphoproliferative response mediated by CD8+ T cells, but not that by CD4+ T cells. DI4G is able to attenuate the exaggerated immune response in CL, exhibiting immunomodulatory activity in IFN-γ production and in CD8+ T cell proliferation. Natália Barbosa Carvalho, Fernanda Ventin de Oliveira Prates, Rafael de Castro da Silva, Mayra Elizabeth Ferreira Dourado, Camila Farias Amorim, Paulo Roberto Lima Machado, Fernanda Grendene Pacheco, Temis Weber Furlanetto Corte, Pablo Machado, Diógenes Santiago Santos, and Edgar Marcelino de Carvalho Copyright © 2017 Natália Barbosa Carvalho et al. All rights reserved. The Differential Contribution of the Innate Immune System to a Good Pathological Response in the Breast and Axillary Lymph Nodes Induced by Neoadjuvant Chemotherapy in Women with Large and Locally Advanced Breast Cancers Wed, 23 Aug 2017 00:00:00 +0000 The tumour microenvironment consists of malignant cells, stroma, and immune cells. The role of adaptive immunity in inducing a pathological complete response (pCR) in breast cancer with neoadjuvant chemotherapy (NAC) is well studied. The contribution of innate immunity, however, is poorly documented. Breast tumours and axillary lymph nodes (ALNs) from 33 women with large and locally advanced breast cancers (LLABCs) undergoing NAC were immunohistochemically assessed for tumour-infiltrating macrophages (TIMs: M1 and M2), neutrophils (TINs), and dendritic cells (TIDCs) using labelled antibodies and semiquantitative methods. Patients’ blood neutrophils (), DCs (mDC1 and pDC), and their costimulatory molecules () were also studied. Pathological results were classified as pCR, good (GPR) or poor (PRR). In breast and metastatic ALNs, high levels of CD163+ TIMs were significantly associated with a pCR. In blood, high levels of neutrophils were significantly associated with pCR in metastatic ALNs, whilst the % of mDC1 and pDC and expression of HLA-DR, mDC1 CD40, and CD83 were significantly reduced. NAC significantly reduced tumour DCs but increased blood DCs. PPRs to NAC had significantly reduced HLA-DR, CD40, and CD86 expression. Our study demonstrated novel findings documenting the differential but important contributions of innate immunity to pCRs in patients with LLABCs undergoing NAC. Viriya Kaewkangsadan, Chandan Verma, Jennifer M. Eremin, Gerard Cowley, Mohammad Ilyas, Sukchai Satthaporn, and Oleg Eremin Copyright © 2017 Viriya Kaewkangsadan et al. All rights reserved. Efficacy of Tumor-Infiltrating Lymphocytes Combined with IFN-α in Chinese Resected Stage III Malignant Melanoma Sun, 20 Aug 2017 00:00:00 +0000 Background. This study aims to explore the efficacy of tumor-infiltrating lymphocytes (TIL) along with interferon-α (IFN-α) to treat stage III malignant melanoma (MM) patients in China. Methods. Between May 2010 and October 2014, 77 patients of stage III MM who underwent surgery were collected in this study. These patients were divided into two groups: patients who received TIL + IFN-α ± RetroNectin-activated cytokine-induced killer cells (R-CIK) in Arm 1 () and IFN-α ± R-CIK in Arm 2 () as adjuvant therapy. The primary endpoints were disease-free survival (DFS) time and DFS rates measured at time points of 1, 2, and 3 years. The secondary endpoints were overall survival (OS) rates measured at time points of 1, 2, 3, and 5 years as well as OS as evaluated by Kaplan-Meier. Results. Our results indicated that the median DFS and OS in Arm 1 were significantly better than those in Arm 2. The data also demonstrated that DFS rate and OS rates in Arm 1 were significantly better than those in Arm 2 at all measured time points. Conclusion. Patients who undergo surgical excision of stage III MM appear to enjoy prolonged DFS and OS when treated with TIL + IFN-α compared to IFN-α alone. Wei Li, Linping Xu, Yaomei Wang, Lingdi Zhao, Daniel B. Kellner, and Quanli Gao Copyright © 2017 Wei Li et al. All rights reserved. Erratum to “Low Baseline Interleukin-17A Levels Are Associated with Better Treatment Response at 12 Weeks to Tocilizumab Therapy in Rheumatoid Arthritis Patients” Sun, 20 Aug 2017 00:00:00 +0000 Sang Jin Lee, Won Park, Sung Hwan Park, Seung-Cheol Shim, Han Joo Baek, Dae-Hyun Yoo, Hyun Ah Kim, Soo Kon Lee, Yun Jong Lee, Young Eun Park, Hoon-Suk Cha, Jin Kyun Park, Eun Young Lee, Eun Bong Lee, and Yeong Wook Song Copyright © 2017 Sang Jin Lee et al. All rights reserved. Chinese Herbal Formula, Modified Danggui Buxue Tang, Attenuates Apoptosis of Hematopoietic Stem Cells in Immune-Mediated Aplastic Anemia Mouse Model Wed, 16 Aug 2017 00:00:00 +0000 A derivative formula, DGBX, which is composed of three herbs (Radix astragali, Radix Angelicae sinensis, and Coptis chinensis Franch), is derived from a famous Chinese herbal formula, Danggui Buxue Tang (DBT) (Radix astragali and Radix Angelicae sinensis). We aimed to investigate the effects of DGBX on the regulation of the balance between proliferation and apoptosis of hematopoietic stem cells (HSCs) due to the aberrant immune response in a mouse model of aplastic anemia (AA). Cyclosporine (CsA), an immunosuppressor, was used as the positive control. Our results indicated that DGBX could downregulate the production of IFNγ in bone marrow cells by interfering with the binding between SLAM and SAP and the expressions of Fyn and T-bet. This herbal formula can also inhibit the activation of Fas-mediated apoptosis, interferon regulatory factor-1-induced JAK/Stat, and eukaryotic initiation factor 2 signaling pathways and thereby induce proliferation and attenuate apoptosis of HSCs. In conclusion, DGBX can relieve the immune-mediated destruction of HSCs, repair hematopoietic failure, and recover the hematopoietic function of HSCs in hematogenesis. Therefore, DGBX can be used in traditional medicine against AA as a complementary and alternative immunosuppressive therapeutic formula. Jingwei Zhou, Xue Li, Peiying Deng, Yi Wei, Juan Liu, Meng Chen, Yamei Xu, Dongmei Zhang, Lingqun Zhu, Lixia Lou, Bin Dong, Qiushuo Jin, and Limin Chai Copyright © 2017 Jingwei Zhou et al. All rights reserved. SIAE Rare Variants in Juvenile Idiopathic Arthritis and Primary Antibody Deficiencies Wed, 16 Aug 2017 00:00:00 +0000 Sialic acid acetylesterase (SIAE) deficiency was suggested to lower the levels of ligands for sialic acid-binding immunoglobulin-like receptors, decreasing the threshold for B-cell activation. In humans, studies of rare heterozygous loss-of-function mutations in SIAE gene in common autoimmune diseases, including juvenile idiopathic arthritis (JIA), yielded inconsistent results. Considering the distinct pathogenesis of the two main subtypes of JIA, autoinflammatory systemic (sJIA) and autoimmune oligo/polyarticular (aJIA), and a predisposition to autoimmunity displayed by patients and families with primary antibody deficiencies (PADs), the aim of our study was to analyze whether SIAE rare variants are associated with both the phenotype of JIA and the autoimmunity risk in families with PADs. A cohort of 69 patients with JIA, 117 healthy children, 54 patients, and family members with PADs were enrolled in the study. Three novel SIAE variants (p.Q343P, p.Y495X, and c.1320+33T>C) were found only in patients with aJIA but interestingly also in their healthy relatives without autoimmunity, while none of PAD patients or their relatives carried SIAE defects. Our results show that SIAE rare variants are not causative of autoimmunity as single defects. Eirini Sevdali, Elena Tsitsami, Maria Tsinti, Evangelia Farmaki, Efimia Papadopoulou-Alataki, Anastasios E. Germenis, and Matthaios Speletas Copyright © 2017 Eirini Sevdali et al. All rights reserved.