Journal of Immunology Research The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. The Role of γδ T Cells in Systemic Lupus Erythematosus Thu, 11 Feb 2016 16:27:40 +0000 Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by the overproduction of autoantibodies against an array of nuclear and cytoplasmic antigens and affects multiple organs, such as the skin, joints, kidneys, and neuronal tissues. T cells have been recognized as important players in the development of SLE due to their functions in cytokine secretion, antigen presentation, and supporting B cells for antibody production. T cells are a minor population of T cells that play important roles in infection and tumor-associated disease. In recent years, the role of T cells in autoimmune diseases has been investigated. In this review, we discussed the role of T cells in the pathogenesis of SLE. Meng Wu, Jinhua Yang, Xiaofeng Li, and Junwei Chen Copyright © 2016 Meng Wu et al. All rights reserved. Molecular Mechanisms of Induction of Tolerant and Tolerogenic Intestinal Dendritic Cells in Mice Thu, 11 Feb 2016 12:09:07 +0000 How does the host manage to tolerate its own intestinal microbiota? A simple question leading to complicated answers. In order to maintain balanced immune responses in the intestine, the host immune system must tolerate commensal bacteria in the gut while it has to simultaneously keep the ability to fight pathogens and to clear infections. If this tender equilibrium is disturbed, severe chronic inflammatory reactions can result. Tolerogenic intestinal dendritic cells fulfil a crucial role in balancing immune responses and therefore creating homeostatic conditions and preventing from uncontrolled inflammation. Although several dendritic cell subsets have already been characterized to play a pivotal role in this process, less is known about definite molecular mechanisms of how intestinal dendritic cells are converted into tolerogenic ones. Here we review how gut commensal bacteria interact with intestinal dendritic cells and why this bacteria-host cell interaction is crucial for induction of dendritic cell tolerance in the intestine. Hereby, different commensal bacteria can have distinct effects on the phenotype of intestinal dendritic cells and these effects are mainly mediated by impacting toll-like receptor signalling in dendritic cells. Alex Steimle and Julia-Stefanie Frick Copyright © 2016 Alex Steimle and Julia-Stefanie Frick. All rights reserved. Systematic and Cell Type-Specific Telomere Length Changes in Subsets of Lymphocytes Wed, 10 Feb 2016 14:20:22 +0000 Telomeres, the protective DNA-protein complexes at the ends of linear chromosomes, are important for genome stability. Leukocyte or peripheral blood mononuclear cell (PBMC) telomere length is a potential biomarker for human aging that integrates genetic, environmental, and lifestyle factors and is associated with mortality and risks for major diseases. However, only a limited number of studies have examined longitudinal changes of telomere length and few have reported data on sorted circulating immune cells. We examined the average telomere length (TL) in CD4+, CD8+CD28+, and CD8+CD28− T cells, B cells, and PBMCs, cross-sectionally and longitudinally, in a cohort of premenopausal women. We report that TL changes over 18 months were correlated among these three T cell types within the same participant. Additionally, PBMC TL change was also correlated with those of all three T cell types, and B cells. The rate of shortening for B cells was significantly greater than for the three T cell types. CD8+CD28− cells, despite having the shortest TL, showed significantly more rapid attrition when compared to CD8+CD28+ T cells. These results suggest systematically coordinated, yet cell type-specific responses to factors and pathways contribute to telomere length regulation. Jue Lin, Joshua Cheon, Rashida Brown, Michael Coccia, Eli Puterman, Kirstin Aschbacher, Elizabeth Sinclair, Elissa Epel, and Elizabeth H. Blackburn Copyright © 2016 Jue Lin et al. All rights reserved. Dendritic Cells under Hypoxia: How Oxygen Shortage Affects the Linkage between Innate and Adaptive Immunity Thu, 04 Feb 2016 13:20:07 +0000 Dendritic cells (DCs) are considered as one of the main regulators of immune responses. They collect antigens, process them, and present typical antigenic structures to lymphocytes, thereby inducing an adaptive immune response. All these processes take place under conditions of oxygen shortage (hypoxia) which is often not considered in experimental settings. This review highlights how deeply hypoxia modulates human as well as mouse immature and mature dendritic cell functions. It tries to link in vitro results to actual in vivo studies and outlines how hypoxia-mediated shaping of dendritic cells affects the activation of (innate) immunity. Sandra Winning and Joachim Fandrey Copyright © 2016 Sandra Winning and Joachim Fandrey. All rights reserved. Development of Immunocapture-LC/MS Assay for Simultaneous ADA Isotyping and Semiquantitation Thu, 28 Jan 2016 08:31:23 +0000 Therapeutic proteins and peptides have potential to elicit immune responses resulting in anti-drug antibodies that can pose problems for both patient safety and product efficacy. During drug development immunogenicity is usually examined by risk-based approach along with specific strategies for developing “fit-for-purpose” bioanalytical approaches. Enzyme-linked immunosorbent assays and electrochemiluminescence immunoassays are the most widely used platform for ADA detection due to their high sensitivity and throughput. During the past decade, LC/MS has emerged as a promising technology for quantitation of biotherapeutics and protein biomarkers in biological matrices, mainly owing to its high specificity, selectivity, multiplexing, and wide dynamic range. In fully taking these advantages, we describe here an immunocapture-LC/MS methodology for simultaneous isotyping and semiquantitation of ADA in human plasma. Briefly, ADA and/or drug-ADA complex is captured by biotinylated drug or anti-drug Ab, immobilized on streptavidin magnetic beads, and separated from human plasma by a magnet. ADA is then released from the beads and subjected to trypsin digestion followed by LC/MS detection of specific universal peptides for each ADA isotype. The LC/MS data are analyzed using cut-point and calibration curve. The proof-of-concept of this methodology is demonstrated by detecting preexisting ADA in human plasma. Lin-Zhi Chen, David Roos, and Elsy Philip Copyright © 2016 Lin-Zhi Chen et al. All rights reserved. Involvement of HMGB1 in Resistance to Tumor Vessel-Targeted, Monoclonal Antibody-Based Immunotherapy Wed, 27 Jan 2016 07:22:51 +0000 High mobility group box 1 (HMGB1) is a member of the “danger associated molecular patterns” (DAMPs) than can localize in various compartments of the cell (from the nucleus to the cell surface) and subserve different functions accordingly. HMGB1 is implicated in maintenance of genomic stability, autophagy, immune regulation, and tumor growth. HMGB1-induced autophagy promotes tumor resistance to chemotherapy, as shown in different models of malignancy, for example, osteosarcoma, leukemia, and gastric cancer. To the best of our knowledge, there is virtually no information on the relationships between HMGB1 and resistance to immunotherapy. A recent study from our group has shed new light on this latter issue. We have demonstrated that targeting of tumor-derived endothelial cells with an anti-human CD31 monoclonal antibody in a human neuroblastoma model was unsuccessful due to a complex chain of events involving the participation of HMGB1. These results are discussed in detail since they provide the first evidence for a role of HMGB1 in resistance of tumor cells to monoclonal antibody-based immunotherapy. Vito Pistoia and Annalisa Pezzolo Copyright © 2016 Vito Pistoia and Annalisa Pezzolo. All rights reserved. Genetic Factors of Autoimmune Diseases Tue, 26 Jan 2016 09:06:10 +0000 Fulvia Ceccarelli, Nancy Agmon-Levin, and Carlo Perricone Copyright © 2016 Fulvia Ceccarelli et al. All rights reserved. Retracted: Cure of Chronic Viral Infection and Virus-Induced Type 1 Diabetes by Neutralizing Antibodies Sun, 24 Jan 2016 06:53:31 +0000 Journal of Immunology Research Copyright © 2016 Journal of Immunology Research. All rights reserved. Preparation and Biological Activity of the Monoclonal Antibody against the Second Extracellular Loop of the Angiotensin II Type 1 Receptor Wed, 20 Jan 2016 13:12:02 +0000 The current study was to prepare a mouse-derived antibody against the angiotensin II type 1 receptor (AT1-mAb) based on monoclonal antibody technology, to provide a foundation for research on AT1-AA-positive diseases. Balb/C mice were actively immunized with the second extracellular loop of the angiotensin II type 1 receptor (AT1R-ECII). Then, mouse spleen lymphocytes were fused with myeloma cells and monoclonal hybridomas that secreted AT1-mAb were generated and cultured, after which those in logarithmic-phase were injected into the abdominal cavity of mice to retrieve the ascites. Highly purified AT1-mAb was isolated from mouse ascites after injection with 1 × 107 hybridomas. A greater amount of AT1-mAb was purified from mouse ascites compared to the cell supernatant of hybridomas. AT1-mAb purified from mouse ascites constricted the thoracic aorta of mice and increased the beat frequency of neonatal rat myocardial cells via the AT1R, identical to the effects of AT1-AA extracted from patients’ sera. Murine blood pressure increased after intravenous injection of AT1-mAb via the tail vein. High purity and good biological activity of AT1-mAb can be obtained from mouse ascites after intraperitoneal injection of monoclonal hybridomas that secrete AT1-mAb. These data provide a simple tool for studying AT1-AA-positive diseases. Mingming Wei, Chengrui Zhao, Suli Zhang, Li Wang, Huirong Liu, and Xinliang Ma Copyright © 2016 Mingming Wei et al. All rights reserved. Hib Vaccines: Past, Present, and Future Perspectives Wed, 20 Jan 2016 11:09:45 +0000 Haemophilus influenzae type b (Hib) causes many severe diseases, including epiglottitis, pneumonia, sepsis, and meningitis. In developed countries, the annual incidence of meningitis caused by bacteria is approximately 5–10 cases per population of 100,000. The Hib conjugate vaccine is considered protective and safe. Adjuvants, molecules that can enhance and/or regulate the fundamental immunogenicity of an antigen, comprise a wide range of diverse compounds. While earlier developments of adjuvants created effective products, there is still a need to create new generations, rationally designed based on recent discoveries in immunology, mainly in innate immunity. Many factors may play a role in the immunogenicity of Hib conjugate vaccines, such as the polysaccharides and proteins carrier used in vaccine construction, as well as the method of conjugation. A Hib conjugate vaccine has been constructed via chemical synthesis of a Hib saccharide antigen. Two models of carbohydrate-protein conjugate have been established, the single ended model (terminal amination-single method) and cross-linked lattice matrix (dual amination method). Increased knowledge in the fields of immunology, molecular biology, glycobiology, glycoimmunology, and the biology of infectious microorganisms has led to a dramatic increase in vaccine efficacy. Adi Essam Zarei, Hussein A. Almehdar, and Elrashdy M. Redwan Copyright © 2016 Adi Essam Zarei et al. All rights reserved. Sirtuins Link Inflammation and Metabolism Wed, 20 Jan 2016 09:38:38 +0000 Sirtuins (SIRT), first discovered in yeast as NAD+ dependent epigenetic and metabolic regulators, have comparable activities in human physiology and disease. Mounting evidence supports that the seven-member mammalian sirtuin family (SIRT1–7) guard homeostasis by sensing bioenergy needs and responding by making alterations in the cell nutrients. Sirtuins play a critical role in restoring homeostasis during stress responses. Inflammation is designed to “defend and mend” against the invading organisms. Emerging evidence supports that metabolism and bioenergy reprogramming direct the sequential course of inflammation; failure of homeostasis retrieval results in many chronic and acute inflammatory diseases. Anabolic glycolysis quickly induced (compared to oxidative phosphorylation) for ROS and ATP generation is needed for immune activation to “defend” against invading microorganisms. Lipolysis/fatty acid oxidation, essential for cellular protection/hibernation and cell survival in order to “mend,” leads to immune repression. Acute/chronic inflammations are linked to altered glycolysis and fatty acid oxidation, at least in part, by NAD+ dependent function of sirtuins. Therapeutically targeting sirtuins may provide a new class of inflammation and immune regulators. This review discusses how sirtuins integrate metabolism, bioenergetics, and immunity during inflammation and how sirtuin-directed treatment improves outcome in chronic inflammatory diseases and in the extreme stress response of sepsis. Vidula T. Vachharajani, Tiefu Liu, Xianfeng Wang, Jason J. Hoth, Barbara K. Yoza, and Charles E. McCall Copyright © 2016 Vidula T. Vachharajani et al. All rights reserved. Neutrophil-Mediated Regulation of Innate and Adaptive Immunity: The Role of Myeloperoxidase Wed, 20 Jan 2016 07:55:06 +0000 Neutrophils are no longer seen as leukocytes with a sole function of being the essential first responders in the removal of pathogens at sites of infection. Being armed with numerous pro- and anti-inflammatory mediators, these phagocytes can also contribute to the development of various autoimmune diseases and can positively or negatively regulate the generation of adaptive immune responses. In this review, we will discuss how myeloperoxidase, the most abundant neutrophil granule protein, plays a key role in the various functions of neutrophils in innate and adaptive immunity. Dragana Odobasic, A. Richard Kitching, and Stephen R. Holdsworth Copyright © 2016 Dragana Odobasic et al. All rights reserved. Association of Sicca Syndrome with Proviral Load and Proinflammatory Cytokines in HTLV-1 Infection Tue, 19 Jan 2016 18:28:27 +0000 The Sjögren syndrome has been diagnosed in patients with HTLV-1 associated myelopathy and dry mouth and dry eyes are documented in HTLV-1 carriers. However the diagnosis of Sjögren syndrome in these subjects has been contested. In this cross-sectional study, we evaluated the role of immunological factors and proviral load, in sicca syndrome associated with HTLV-1 in patients without myelopathy. Subjects were recruited in the HTLV-1 Clinic, from 2009 to 2011. The proviral load and cytokine levels (IFN-γ, TNF-α, IL-5, and IL-10) were obtained from a database containing the values presented by the subjects at admission in the clinic. Of the 272 participants, 59 (21.7%) had sicca syndrome and in all of them anti-Sjögren syndrome related antigen A (SSA) and antigen B (SSB) were negatives. The production of TNF-α and IFN-γ was higher in the group with sicca syndrome () than in HTLV-1 infected subjects without sicca syndrome. Our data indicates that patients with sicca syndrome associated with HTLV-1 do not have Sjögren syndrome. However the increased production of TNF-α and IFN-γ in this group of patients may contribute to the pathogenesis of sicca syndrome associated with HTLV-1. Clara Mônica Lima, Silvane Santos, Adriana Dourado, Natália B. Carvalho, Valéria Bittencourt, Marcus Miranda Lessa, Isadora Siqueira, and Edgar M. Carvalho Copyright © 2016 Clara Mônica Lima et al. All rights reserved. Dendritic Cells and Leishmania Infection: Adding Layers of Complexity to a Complex Disease Tue, 19 Jan 2016 12:37:15 +0000 Leishmaniasis is a group of neglected diseases whose clinical manifestations depend on factors from the host and the pathogen. It is an important public health problem worldwide caused by the protozoan parasite from the Leishmania genus. Cutaneous Leishmaniasis (CL) is the most frequent form of this disease transmitted by the bite of an infected sandfly into the host skin. The parasites can be uptook and/or recognized by macrophages, neutrophils, and/or dendritic cells (DCs). Initially, DCs were described to play a protective role in activating the immune response against Leishmania parasites. However, several reports showed a dichotomic role of DCs in modulating the host immune response to susceptibility or resistance in CL. In this review, we discuss (1) the interactions between DCs and parasites from different species of Leishmania and (2) the crosstalk of DCs and other cells during CL infection. The complexity of these interactions profoundly affects the adaptive immune response and, consequently, the disease outcome, especially from Leishmania species of the New World. Daniel Feijó, Rafael Tibúrcio, Mariana Ampuero, Cláudia Brodskyn, and Natalia Tavares Copyright © 2016 Daniel Feijó et al. All rights reserved. Monocyte Activation in Immunopathology: Cellular Test for Development of Diagnostics and Therapy Mon, 18 Jan 2016 06:45:10 +0000 Several highly prevalent human diseases are associated with immunopathology. Alterations in the immune system are found in such life-threatening disorders as cancer and atherosclerosis. Monocyte activation followed by macrophage polarization is an important step in normal immune response to pathogens and other relevant stimuli. Depending on the nature of the activation signal, macrophages can acquire pro- or anti-inflammatory phenotypes that are characterized by the expression of distinct patterns of secreted cytokines and surface antigens. This process is disturbed in immunopathologies resulting in abnormal monocyte activation and/or bias of macrophage polarization towards one or the other phenotype. Such alterations could be used as important diagnostic markers and also as possible targets for the development of immunomodulating therapy. Recently developed cellular tests are designed to analyze the phenotype and activity of living cells circulating in patient’s bloodstream. Monocyte/macrophage activation test is a successful example of cellular test relevant for atherosclerosis and oncopathology. This test demonstrated changes in macrophage activation in subclinical atherosclerosis and breast cancer and could also be used for screening a panel of natural agents with immunomodulatory activity. Further development of cellular tests will allow broadening the scope of their clinical implication. Such tests may become useful tools for drug research and therapy optimization. Ekaterina A. Ivanova and Alexander N. Orekhov Copyright © 2016 Ekaterina A. Ivanova and Alexander N. Orekhov. All rights reserved. Gq-Coupled Receptors in Autoimmunity Sun, 17 Jan 2016 09:08:19 +0000 Heterotrimeric G proteins can be divided into Gi, Gs, Gq/11, and G12/13 subfamilies according to their α subunits. The main function of G proteins is transducing signals from G protein coupled receptors (GPCRs), a family of seven transmembrane receptors. In recent years, studies have demonstrated that GPCRs interact with Gq, a member of the Gq/11 subfamily of G proteins. This interaction facilitates the vital role of this family of proteins in immune regulation and autoimmunity, particularly for Gαq, which is considered the functional α subunit of Gq protein. Therefore, understanding the mechanisms through which Gq-coupled receptors control autoreactive lymphocytes is critical and may provide insights into the treatment of autoimmune disorders. In this review, we summarize recent advances in studies of the role of Gq-coupled receptors in autoimmunity, with a focus on their pathologic role and downstream signaling. Lu Zhang and Guixiu Shi Copyright © 2016 Lu Zhang and Guixiu Shi. All rights reserved. Differential Use of Human Neutrophil Fcγ Receptors for Inducing Neutrophil Extracellular Trap Formation Thu, 14 Jan 2016 14:06:51 +0000 Neutrophils (PMN) are the most abundant leukocytes in the blood. PMN migrate from the circulation to sites of infection, where they are responsible for antimicrobial functions. PMN use phagocytosis, degranulation, and formation of neutrophil extracellular traps (NETs) to kill microbes. NETs are fibers composed of chromatin and neutrophil-granule proteins. Several pathogens, including bacteria, fungi, and parasites, and also some pharmacological stimuli such as phorbol 12-myristate 13-acetate (PMA) are efficient inducers of NETs. Antigen-antibody complexes are also capable of inducing NET formation. However the particular Fcγ receptor involved in triggering this function is a matter of controversy. In order to provide some insight into what Fcγ receptor is responsible for NET formation, each of the two human Fcγ receptors was stimulated individually by specific monoclonal antibodies and NET formation was evaluated. FcγRIIa cross-linking did not promote NET formation. Cross-linking other receptors such as integrins also did not promote NET formation. In contrast FcγRIIIb cross-linking induced NET formation similarly to PMA stimulation. NET formation was dependent on NADPH-oxidase, PKC, and ERK activation. These data show that cross-linking FcγRIIIb is responsible for NET formation by the human neutrophil. Omar Rafael Alemán, Nancy Mora, Ricarda Cortes-Vieyra, Eileen Uribe-Querol, and Carlos Rosales Copyright © 2016 Omar Rafael Alemán et al. All rights reserved. Annexin A1 and the Resolution of Inflammation: Modulation of Neutrophil Recruitment, Apoptosis, and Clearance Wed, 13 Jan 2016 07:06:22 +0000 Neutrophils (also named polymorphonuclear leukocytes or PMN) are essential components of the immune system, rapidly recruited to sites of inflammation, providing the first line of defense against invading pathogens. Since neutrophils can also cause tissue damage, their fine-tuned regulation at the inflammatory site is required for proper resolution of inflammation. Annexin A1 (AnxA1), also known as lipocortin-1, is an endogenous glucocorticoid-regulated protein, which is able to counterregulate the inflammatory events restoring homeostasis. AnxA1 and its mimetic peptides inhibit neutrophil tissue accumulation by reducing leukocyte infiltration and activating neutrophil apoptosis. AnxA1 also promotes monocyte recruitment and clearance of apoptotic leukocytes by macrophages. More recently, some evidence has suggested the ability of AnxA1 to induce macrophage reprogramming toward a resolving phenotype, resulting in reduced production of proinflammatory cytokines and increased release of immunosuppressive and proresolving molecules. The combination of these mechanisms results in an effective resolution of inflammation, pointing to AnxA1 as a promising tool for the development of new therapeutic strategies to treat inflammatory diseases. Michelle Amantéa Sugimoto, Juliana Priscila Vago, Mauro Martins Teixeira, and Lirlândia Pires Sousa Copyright © 2016 Michelle Amantéa Sugimoto et al. All rights reserved. Luciferase mRNA Transfection of Antigen Presenting Cells Permits Sensitive Nonradioactive Measurement of Cellular and Humoral Cytotoxicity Tue, 05 Jan 2016 09:44:27 +0000 Immunotherapy is rapidly evolving as an effective treatment option for many cancers. With the emerging fields of cancer vaccines and adoptive cell transfer therapies, there is an increasing demand for high-throughput in vitro cytotoxicity assays that efficiently analyze immune effector functions. The gold standard 51Cr-release assay is very accurate but has the major disadvantage of being radioactive. We reveal the development of a versatile and nonradioactive firefly luciferase in vitro transcribed (IVT) RNA-based assay. Demonstrating high efficiency, consistency, and excellent target cell viability, our optimized luciferase IVT RNA is used to transfect dividing and nondividing primary antigen presenting cells. Together with the long-lasting expression and minimal background, the direct measurement of intracellular luciferase activity of living cells allows for the monitoring of killing kinetics and displays paramount sensitivity. The ability to cotransfect the IVT RNA of the luciferase reporter and the antigen of interest into the antigen presenting cells and its simple read-out procedure render the assay high-throughput in nature. Results generated were comparable to the 51Cr release and further confirmed the assay’s ability to measure antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. The assay’s combined simplicity, practicality, and efficiency tailor it for the analysis of antigen-specific cellular and humoral effector functions during the development of novel immunotherapies. Tana A. Omokoko, Uli Luxemburger, Shaheer Bardissi, Petra Simon, Magdalena Utsch, Andrea Breitkreuz, Özlem Türeci, and Ugur Sahin Copyright © 2016 Tana A. Omokoko et al. All rights reserved. A Preliminary Comparative Assessment of the Role of CD8+ T Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis Mon, 04 Jan 2016 14:01:11 +0000 Background. CD8+ T cells have putative roles in the regulation of adaptive immune responses during infection. The purpose of this paper is to compare the status of CD8+ T cells in Multiple Sclerosis (MS) and Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). Methods. This preliminary investigation comprised 23 CFS/ME patients, 11 untreated MS patients, and 30 nonfatigued controls. Whole blood samples were collected from participants, stained with monoclonal antibodies, and analysed on the flow cytometer. Using the following CD markers, CD27 and CD45RA (CD45 exon isoform 4), CD8+ T cells were divided into naïve, central memory (CM), effector memory CD45RA− (EM), and effector memory CD45RA+ (EMRA) cells. Results. Surface expressions of BTLA, CD127, and CD49/CD29 were increased on subsets of CD8+ T cells from MS patients. In the CFS/ME patients CD127 was significantly decreased on all subsets of CD8+ T cells in comparison to the nonfatigued controls. PSGL-1 was significantly reduced in the CFS/ME patients in comparison to the nonfatigued controls. Conclusions. The results suggest significant deficits in the expression of receptors and adhesion molecules on subsets of CD8+ T cells in both MS and CFS/ME patients. These deficits reported may contribute to the pathogenesis of these diseases. However, larger sample size is warranted to confirm and support these encouraging preliminary findings. Ekua W. Brenu, Simon Broadley, Thao Nguyen, Samantha Johnston, Sandra Ramos, Don Staines, and Sonya Marshall-Gradisnik Copyright © 2016 Ekua W. Brenu et al. All rights reserved. Immune Checkpoint Modulators: An Emerging Antiglioma Armamentarium Mon, 04 Jan 2016 08:59:58 +0000 Immune checkpoints have come to the forefront of cancer therapies as a powerful and promising strategy to stimulate antitumor T cell activity. Results from recent preclinical and clinical studies demonstrate how checkpoint inhibition can be utilized to prevent tumor immune evasion and both local and systemic immune suppression. This review encompasses the key immune checkpoints that have been found to play a role in tumorigenesis and, more specifically, gliomagenesis. The review will provide an overview of the existing preclinical and clinical data, antitumor efficacy, and clinical applications for each checkpoint with respect to GBM, as well as a summary of combination therapies with chemotherapy and radiation. Eileen S. Kim, Jennifer E. Kim, Mira A. Patel, Antonella Mangraviti, Jacob Ruzevick, and Michael Lim Copyright © 2016 Eileen S. Kim et al. All rights reserved. Secretion of S100A8, S100A9, and S100A12 by Neutrophils Involves Reactive Oxygen Species and Potassium Efflux Thu, 31 Dec 2015 06:24:07 +0000 S100A8/A9 (calprotectin) and S100A12 proinflammatory mediators are found at inflammatory sites and in the serum of patients with inflammatory or autoimmune diseases. These cytoplasmic proteins are secreted by neutrophils at sites of inflammation via alternative secretion pathways of which little is known. This study examined the nature of the stimuli leading to S100A8/A9 and S100A12 secretion as well as the mechanism involved in this alternative secretion pathway. Chemotactic agents, cytokines, and particulate molecules were used to stimulate human neutrophils. MSU crystals, PMA, and H2O2 induced the release of S100A8, S100A9, and S100A12 homodimers, as well as S100A8/A9 heterodimer. High concentrations of S100A8/A9 and S100A12 were secreted in response to nanoparticles like MSU, silica, TiO2, fullerene, and single-wall carbon nanotubes as well as in response to microbe-derived molecules, such as zymosan or HKCA. However, neutrophils exposed to the chemotactic factors fMLP failed to secrete S100A8/A9 or S100A12. Secretion of S100A8/A9 was dependent on the production of reactive oxygen species and required K+ exchanges through the ATP-sensitive K+ channel. Altogether, these findings suggest that S100A12 and S100A8/A9 are secreted independently either via distinct mechanisms of secretion or following the activation of different signal transduction pathways. Mélanie R. Tardif, Julie Andrea Chapeton-Montes, Alma Posvandzic, Nathalie Pagé, Caroline Gilbert, and Philippe A. Tessier Copyright © 2015 Mélanie R. Tardif et al. All rights reserved. Mutanome Engineered RNA Immunotherapy: Towards Patient-Centered Tumor Vaccination Wed, 30 Dec 2015 13:19:56 +0000 Advances in nucleic acid sequencing technologies have revolutionized the field of genomics, allowing the efficient targeting of mutated neoantigens for personalized cancer vaccination. Due to their absence during negative selection of T cells and their lack of expression in healthy tissue, tumor mutations are considered as optimal targets for cancer immunotherapy. Preclinical and early clinical data suggest that synthetic mRNA can serve as potent drug format allowing the cost efficient production of highly efficient vaccines in a timely manner. In this review, we describe a process, which integrates next generation sequencing based cancer mutanome mapping, in silico target selection and prioritization approaches, and mRNA vaccine manufacturing and delivery into a process we refer to as MERIT (mutanome engineered RNA immunotherapy). Mathias Vormehr, Barbara Schrörs, Sebastian Boegel, Martin Löwer, Özlem Türeci, and Ugur Sahin Copyright © 2015 Mathias Vormehr et al. All rights reserved. Advances in Computational Immunology Wed, 30 Dec 2015 12:47:13 +0000 Francesco Pappalardo, Vladimir Brusic, Marzio Pennisi, and Guanglan Zhang Copyright © 2015 Francesco Pappalardo et al. All rights reserved. MGL Receptor and Immunity: When the Ligand Can Make the Difference Tue, 29 Dec 2015 07:46:20 +0000 C-type lectin receptors (CLRs) on antigen-presenting cells (APCs) facilitate uptake of carbohydrate antigens for antigen presentation, modulating the immune response in infection, homeostasis, autoimmunity, allergy, and cancer. In this review, we focus on the role of the macrophage galactose type C-type lectin (MGL) in the immune response against self-antigens, pathogens, and tumor associated antigens (TAA). MGL is a CLR exclusively expressed by dendritic cells (DCs) and activated macrophages (MØs), able to recognize terminal GalNAc residues, including the sialylated and nonsialylated Tn antigens. We discuss the effects on DC function induced throughout the engagement of MGL, highlighting the importance of the antigen structure in the modulation of immune response. Indeed modifying Tn-density, the length, and steric structure of the Tn-antigens can result in generating immunogens that can efficiently bind to MGL, strongly activate DCs, mimic the effects of a danger signal, and achieve an efficient presentation in HLA classes I and II compartments. Ilaria Grazia Zizzari, Chiara Napoletano, Federico Battisti, Hassan Rahimi, Salvatore Caponnetto, Luca Pierelli, Marianna Nuti, and Aurelia Rughetti Copyright © 2015 Ilaria Grazia Zizzari et al. All rights reserved. Corrigendum to “GK-1 Improves the Immune Response Induced by Bone Marrow Dendritic Cells Loaded with MAGE-AX in Mice with Melanoma” Mon, 28 Dec 2015 09:07:03 +0000 Gabriela Piñón-Zárate, Miguel Ángel Herrera-Enríquez, Beatriz Hernández-Téllez, Katia Jarquín-Yáñez, and Andrés Eliú Castell-Rodríguez Copyright © 2015 Gabriela Piñón-Zárate et al. All rights reserved. Electroporated Antigen-Encoding mRNA Is Not a Danger Signal to Human Mature Monocyte-Derived Dendritic Cells Mon, 28 Dec 2015 08:49:19 +0000 For therapeutic cancer vaccination, the adoptive transfer of mRNA-electroporated dendritic cells (DCs) is frequently performed, usually with monocyte-derived, cytokine-matured DCs (moDCs). However, DCs are rich in danger-sensing receptors which could recognize the exogenously delivered mRNA and induce DC activation, hence influencing the DCs’ immunogenicity. Therefore, we examined whether electroporation of mRNA with a proper cap and a poly-A tail of at least 64 adenosines had any influence on cocktail-matured moDCs. We used 16 different RNAs, encoding tumor antigens (MelanA, NRAS, BRAF, GNAQ, GNA11, and WT1), and variants thereof. None of those RNAs induced changes in the expression of CD25, CD40, CD83, CD86, and CD70 or the secretion of the cytokines IL-8, IL-6, and TNFα of more than 1.5-fold compared to the control condition, while an mRNA encoding an NF-B-activation protein as positive control induced massive secretion of the cytokines. To determine whether mRNA electroporation had any effect on the whole transcriptome of the DCs, we performed microarray analyses of DCs of 6 different donors. None of 60,000 probes was significantly different between mock-electroporated DCs and MelanA-transfected DCs. Hence, we conclude that no transcriptional programs were induced within cocktail-matured DCs by electroporation of single tumor-antigen-encoding mRNAs. Stefanie Hoyer, Kerstin F. Gerer, Isabell A. Pfeiffer, Sabrina Prommersberger, Sandra Höfflin, Tanushree Jaitly, Luca Beltrame, Duccio Cavalieri, Gerold Schuler, Julio Vera, Niels Schaft, and Jan Dörrie Copyright © 2015 Stefanie Hoyer et al. All rights reserved. Heparin Interaction with the Primed Polymorphonuclear Leukocyte CD11b Induces Apoptosis and Prevents Cell Activation Sun, 27 Dec 2015 12:45:21 +0000 Heparin is known to have anti-inflammatory effects, yet the mechanisms are not completely understood. In this study, we tested the hypothesis that heparin has a direct effect on activated polymorphonuclear leukocytes (PMNLs), changing their activation state, and can explain its anti-inflammatory effect. To test our hypothesis, we designed both in vitro and ex vivo studies to elucidate the mechanism by which heparin modulates PMNL functions and therefore the inflammatory response. We specifically tested the hypothesis that priming of PMNLs renders them more susceptible to heparin. Amplified levels of CD11b and increased rate of superoxide release manifested PMNL priming. Increase in cell priming resulted in a dose-dependent increase in heparin binding to PMNLs followed by augmented apoptosis. Blocking antibodies to CD11b inhibited heparin binding and abolished the apoptotic response. Moreover, heparin caused a significant dose-dependent decrease in the rate of superoxide release from PMNLs, which was blunted by blocking antibodies to CD11b. Altogether, this study shows that the interaction of heparin with the PMNL CD11b results in cell apoptosis and explains heparin’s anti-inflammatory effects. Meital Cohen-Mazor, Rafi Mazor, Batya Kristal, Erik B. Kistler, Inbal Ziv, Judith Chezar, and Shifra Sela Copyright © 2015 Meital Cohen-Mazor et al. All rights reserved. Towards Targeted Delivery Systems: Ligand Conjugation Strategies for mRNA Nanoparticle Tumor Vaccines Thu, 24 Dec 2015 16:03:19 +0000 The use of nanoparticles encapsulating messenger RNA (mRNA) as a vaccine has recently attracted much attention because of encouraging results achieved in many nonviral genetic antitumor vaccination studies. Notably, in all of these studies, mRNA nanoparticles are passively targeted to dendritic cells (DCs) through careful selection of vaccination sites. Hence, DC-targeted mRNA nanoparticle vaccines may be an imminent next step forward. In this brief report, we will discuss established conjugation strategies that have been successfully applied to both polymeric and liposomal gene delivery systems. We will also briefly describe promising DC surface receptors amenable for targeting mRNA nanoparticles. Practicable conjugation strategies and receptors reviewed in this paper will provide a convenient reference to facilitate future development of targeted mRNA nanoparticle vaccine. Kyle K. L. Phua Copyright © 2015 Kyle K. L. Phua. All rights reserved. Immunoregulation of NKT Cells in Systemic Lupus Erythematosus Thu, 24 Dec 2015 15:08:35 +0000 Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with different variety of clinical manifestations. Natural killer T (NKT) cells are innate lymphocytes that play a regulatory role during broad range of immune responses. A number of studies demonstrated that the quantity and quality of invariant NKT (iNKT) cells showed marked defects in SLE patients in comparison to healthy controls. This finding suggests that iNKT cells may play a regulatory role in the occurrence and development of this disease. In this review, we mainly summarized the most recent findings about the behavior of NKT cells in SLE patients and mouse models, as well as how NKT cells affect the proportion of T helper cells and the production of autoreactive antibodies in the progress of SLE. This will help people better understand the role of NKT cells in the development of SLE and improve the therapy strategy. Junwei Chen, Meng Wu, Jing Wang, and Xiaofeng Li Copyright © 2015 Junwei Chen et al. All rights reserved.