Journal of Immunology Research The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Antitumor Effect of KML-B-Treated Dendritic Cells via Induction of Lymphocyte Activation Mon, 29 May 2017 09:52:14 +0000 Lectins are carbohydrate-binding proteins with various biological activities, such as antitumor and immunomodulatory effects. Although lectins have various biological activities, they are still limited by cytotoxicity in normal cells. To overcome this problem, we used the noncytotoxic part of Korean mistletoe lectin B-chain (KML-B) to induce maturation of dendritic cells (DCs). A previous study reported that KML-B induces DC maturation by triggering TLR-4, including expression of costimulatory molecules (CD40, CD80, and CD86), MHC II, and secretion of cytokines in DCs. Additionally, matured DCs by KML-B induced T helper (Th) cell activation and differentiation toward Th1 cells. However, the interaction of KML-B-treated DCs with CD8+ T cells is still poorly understood. In this study, we confirmed the ability of matured DCs by KML-B to stimulate cytotoxic T cells using OT-1 mouse-derived CD8+ T cells. KML-B induced MHC I expression in DCs, stimulation of CD8+ T cell activation and proliferation, and IFN-γ secretion. Moreover, tumor sizes were reduced by KML-B treatment during vaccination of OVA257−264-pulsed DCs. Here, we confirmed induction of CD8+ T cell activation and the antitumor effect of KML-B treatment in DCs. Jong-Jin Kim, Yun-Ho Hwang, Kyung-Yun Kang, Sung-Ju Lee, Jong-Bae Kim, Jina Choi, and Sung-Tae Yee Copyright © 2017 Jong-Jin Kim et al. All rights reserved. The Immune Epitope Database: How Data Are Entered and Retrieved Mon, 29 May 2017 03:37:41 +0000 Easy access to a vast collection of experimental data on immune epitopes can greatly facilitate the development of therapeutics and vaccines. The Immune Epitope Database and Analysis Resource (IEDB) was developed to provide such a resource as a free service to the biomedical research community. The IEDB contains epitope and assay information related to infectious diseases, autoimmune diseases, allergic diseases, and transplant/alloantigens for humans, nonhuman primates, mice, and any other species studied. It contains T cell, B cell, MHC binding, and MHC ligand elution experiments. Its data are curated primarily from the published literature and also include direct submissions from researchers involved in epitope discovery. This article describes the process of capturing data from these sources and how the information is organized in the IEDB data. Different approaches for querying the data are then presented, using the home page search interface and the various specialized search interfaces. Specific examples covering diverse applications of interest are given to highlight the power and functionality of the IEDB. Ward Fleri, Kerrie Vaughan, Nima Salimi, Randi Vita, Bjoern Peters, and Alessandro Sette Copyright © 2017 Ward Fleri et al. All rights reserved. Examination of the Microbial Spectrum in the Etiology of Erythema Nodosum: A Retrospective Descriptive Study Sun, 28 May 2017 00:00:00 +0000 Even though infections are the most common cause of erythema nodosum (EN), only certain microorganisms take the great interest such as streptococci in knowledge. Our aim was to examine the frequency and type of infections in EN, to determine the characteristics of patients with an infectious etiology, and to discuss the role of these microbes in EN pathology in the context of their interactions with humans. Charts of 81 patients with EN who were seen between 2003 and 2017 were retrospectively reviewed. Identified etiological factors were classified into three groups: infectious, noninfectious, and idiopathic. While there were no significant demographic and clinical differences between the infectious and idiopathic groups, systemic symptoms () and the number of EN lesions () were significantly lower; the mean erythrocyte sedimentation rate was significantly higher (), but the mean aspartate aminotransferase value was significantly lower in the infectious group compared to the noninfectious group (). Besides streptococci, many other microbes, including the ones living on and inside us, were identified in the etiology of EN. There is a need for large-scale prospective studies involving control groups for a better understanding of the microbial immunopathology of EN. Ozlem Ozbagcivan, Sevgi Akarsu, Ceylan Avci, Burcu Bahar Inci, and Emel Fetil Copyright © 2017 Ozlem Ozbagcivan et al. All rights reserved. HLA Class Ia and Ib Polyreactive Anti-HLA-E IgG2a Monoclonal Antibodies (TFL-006 and TFL-007) Suppress Anti-HLA IgG Production by CD19+ B Cells and Proliferation of CD4+ T Cells While Upregulating Tregs Sun, 28 May 2017 00:00:00 +0000 The anti-HLA-E IgG2a mAbs, TFL-006 and TFL-007, reacted with all HLA-I antigens, similar to the therapeutic preparations of IVIg. Indeed, IVIg lost its HLA reactivity, when its HLA-E reactivity was adsorbed out. US-FDA approved IVIg to reduce antibodies in autoimmune diseases. But the mechanism underlying IVIg-mediated antibody reduction could not be ascertained due to the presence of other polyclonal antibodies. In spite of it, the cost prohibitive high or low IVIg is administered to patients waiting for donor organ and for allograft recipients for lowering antiallograft antibodies. A mAb that could mimic IVIg in lowering Abs, with defined mechanism of action, would be highly beneficial for patients. Demonstrably, the anti-HLA-E mAbs mimicked several functions of IVIg relevant to suppressing the antiallograft Abs. The mAbs suppressed activated T cells and anti-HLA antibody production by activated B cells, which were dose-wise superior to IVIg. The anti-HLA-E mAb expanded CD4+, CD25+, and Foxp3+ Tregs, which are known to suppress T and B cells involved in antibody production. These defined functions of the anti-HLA-E IgG2a mAbs at a level superior to IVIg encourage developing their humanized version to lower antibodies in allograft recipients, to promote graft survival, and to control autoimmune diseases. Mepur H. Ravindranath Copyright © 2017 Mepur H. Ravindranath. All rights reserved. Adenosine Triphosphate Promotes Allergen-Induced Airway Inflammation and Th17 Cell Polarization in Neutrophilic Asthma Thu, 25 May 2017 00:00:00 +0000 Adenosine triphosphate (ATP) is a key mediator to alert the immune dysfunction by acting on P2 receptors. Here, we found that allergen challenge caused an increase of ATP secretion in a murine model of neutrophilic asthma, which correlated well with neutrophil counts and interleukin-17 production. When ATP signaling was blocked by intratracheal administration of the ATP receptor antagonist suramin before challenge, neutrophilic airway inflammation, airway hyperresponsiveness, and Th17-type responses were reduced significantly. Also, neutrophilic inflammation was abrogated when airway ATP levels were locally neutralized using apyrase. Furthermore, ATP promoted the Th17 polarization of splenic CD4+ T cells from DO11.10 mice in vitro. In addition, ovalbumin (OVA) challenge induced neutrophilic inflammation and Th17 polarization in DO11.10 mice, whereas administration of suramin before challenge alleviated these parameters. Thus, ATP may serve as a marker of neutrophilic asthma, and local blockade of ATP signaling might provide an alternative method to prevent Th17-mediated airway inflammation in neutrophilic asthma. Fang Zhang, Xin Su, Gang Huang, Xiao-Feng Xin, E-Hong Cao, Yi Shi, and Yong Song Copyright © 2017 Fang Zhang et al. All rights reserved. HLA Epitopes: The Targets of Monoclonal and Alloantibodies Defined Wed, 24 May 2017 00:00:00 +0000 Sensitization to human leukocyte antigens (HLA) in organ transplant patients causes graft rejection, according to the humoral theory of transplantation. Sensitization is almost ubiquitous as anti-HLA antibodies are found in almost all sera of transplant recipients. Advances in testing assays and amino acid sequencing of HLA along with computer software contributed further to the understanding of antibody-antigen reactivity. It is commonly understood that antibodies bind to HLA antigens. With current knowledge of epitopes, it is more accurate to describe that antibodies bind to their target epitopes on the surface of HLA molecular chains. Epitopes are present on a single HLA (private epitope) or shared by multiple antigens (public epitope). The phenomenon of cross-reactivity in HLA testing, often explained as cross-reactive groups (CREGs) of antigens with antibody, can be clearly explained now by public epitopes. Since 2006, we defined and reported 194 HLA class I unique epitopes, including 56 cryptic epitopes on dissociated HLA class I heavy chains, 83 HLA class II epitopes, 60 epitopes on HLA-DRB1, 15 epitopes on HLA-DQB1, 3 epitopes on HLA-DQA1, 5 epitopes on HLA-DPB1, and 7 MICA epitopes. In this paper, we provide a summary of our findings. Nadim El-Awar, Vadim Jucaud, and Anh Nguyen Copyright © 2017 Nadim El-Awar et al. All rights reserved. Genetics and Molecular Biology of Epstein-Barr Virus-Encoded BART MicroRNA: A Paradigm for Viral Modulation of Host Immune Response Genes and Genome Stability Mon, 22 May 2017 00:00:00 +0000 Epstein-Barr virus, a ubiquitous human herpesvirus, is associated through epidemiologic evidence with common autoimmune syndromes and cancers. However, specific genetic mechanisms of pathogenesis have been difficult to identify. In this review, the author summarizes evidence that recently discovered noncoding RNAs termed microRNA encoded by Epstein-Barr virus BARF (BamHI A right frame) termed BART (BamHI A right transcripts) are modulators of human immune response genes and genome stability in infected and bystander cells. BART expression is apparently regulated by complex feedback loops with the host immune response regulatory NF-κB transcription factors. EBV-encoded BZLF-1 (ZEBRA) protein could also regulate BART since ZEBRA contains a terminal region similar to ankyrin proteins such as IκBα that regulate host NF-κB. BALF-2 (BamHI A left frame transcript), a viral homologue of the immunoglobulin and T cell receptor gene recombinase RAG-1 (recombination-activating gene-1), may also be coregulated with BART since BALF-2 regulatory sequences are located near the BART locus. Viral-encoded microRNA and viral mRNA transferred to bystander cells through vesicles, defective viral particles, or other mechanisms suggest a new paradigm in which bystander or hit-and-run mechanisms enable the virus to transiently or chronically alter human immune response genes as well as the stability of the human genome. David H. Dreyfus Copyright © 2017 David H. Dreyfus. All rights reserved. Targets of Neutrophil Influx and Weaponry: Therapeutic Opportunities for Chronic Obstructive Airway Disease Wed, 17 May 2017 06:19:20 +0000 Neutrophils are important effector cells of antimicrobial immunity in an acute inflammatory response, with a primary role in the clearance of extracellular pathogens. However, in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), there is excessive infiltration and activation of neutrophils, subsequent production of reactive oxygen species, and release of serine proteases, matrix metalloproteinases, and myeloperoxidase—resulting in collateral damage as the cells infiltrate into the tissue. Increased neutrophil survival through dysregulated apoptosis facilitates continued release of neutrophil-derived mediators to perpetuate airway inflammation and tissue injury. Several target mechanisms have been investigated to address pathologic neutrophil biology and thereby provide a novel therapy for respiratory disease. These include neutrophil influx through inhibition of chemokine receptors CXCR2, CXCR1, and PI3Kγ signaling and neutrophil weaponry by protease inhibitors, targeting matrix metalloproteinases and neutrophil serine proteases. In addition, neutrophil function can be modulated using selective PI3Kδ inhibitors. This review highlights the latest advances in targeting neutrophils and their function, discusses the opportunities and risks of neutrophil inhibition, and explores how we might better develop future strategies to regulate neutrophil influx and function for respiratory diseases in dire need of novel effective therapies. Carina Kärrman Mårdh, James Root, Mohib Uddin, Kristina Stenvall, Anna Malmgren, Kostas Karabelas, and Matthew Thomas Copyright © 2017 Carina Kärrman Mårdh et al. All rights reserved. Association of Toll-Like Cell Receptors TLR2 (p.Arg753GLN) and TLR4 (p.Asp299GLY) Polymorphisms with Indicators of General and Local Immunity in Patients with Atopic Dermatitis Tue, 16 May 2017 00:00:00 +0000 A whole group of polymorphisms of genes involved in the formation of the epidermal barrier, immune responses, and their regulation is important in the formation of atopic phenotype. The purpose of the study is to determine the relationship of polymorphisms of genes of Toll-like receptors TLR2 and TLR4 with clinical and immunological parameters in atopic dermatitis patients in a “case-control” study. Polymorphisms of genes TLR2 (p.Arg753Gln) and TLR4 (Asp299Gly) were detected by PCR. Parameters of the state of innate and adaptive immunity were assessed by the level of local production of sIgA, cytokine profile of blood serum for IL-4, IL-10, and IFN-γ. Biological samples from 50 people with allergic pathology, aged 4.5 to 35 years, and 100 healthy individuals (controls) were analyzed. Observed dysregulation of cytokine production (IL-4, IL-10) in patients with heterozygous polymorphic genotypes probably reflects an imbalance of Th1/Th2/Th17 regulation of immune system response in these individuals. Yury A. Tyurin, Anton F. Shamsutdinov, Nikolay N. Kalinin, Alsou A. Sharifullina, and Irina D. Reshetnikova Copyright © 2017 Yury A. Tyurin et al. All rights reserved. Advanced Role of Neutrophils in Common Respiratory Diseases Mon, 15 May 2017 00:00:00 +0000 Respiratory diseases, always being a threat towards the health of people all over the world, are most tightly associated with immune system. Neutrophils serve as an important component of immune defense barrier linking innate and adaptive immunity. They participate in the clearance of exogenous pathogens and endogenous cell debris and play an essential role in the pathogenesis of many respiratory diseases. However, the pathological mechanism of neutrophils remains complex and obscure. The traditional roles of neutrophils in severe asthma, chronic obstructive pulmonary diseases (COPD), pneumonia, lung cancer, pulmonary fibrosis, bronchitis, and bronchiolitis had already been reviewed. With the development of scientific research, the involvement of neutrophils in respiratory diseases is being brought to light with emerging data on neutrophil subsets, trafficking, and cell death mechanism (e.g., NETosis, apoptosis) in diseases. We reviewed all these recent studies here to provide you with the latest advances about the role of neutrophils in respiratory diseases. Jinping Liu, Zhiqiang Pang, Guoqiang Wang, Xuewa Guan, Keyong Fang, Ziyan Wang, and Fang Wang Copyright © 2017 Jinping Liu et al. All rights reserved. Th1/Th2 Balance and Th17/Treg-Mediated Immunity in relation to Murine Resistance to Dextran Sulfate-Induced Colitis Thu, 11 May 2017 00:00:00 +0000 Background. The role of the Th17/Treg balance in the development of experimental colitis remains poorly understood. Methods. We exploited the differential response of BALB/c mice and C57BL/6 mice towards drinking water mediated by dextran sulfate sodium (DSS) challenge. Results. DSS-resistant BALB/c mice were characterized by low levels of IFN-γ and TNF-α but high levels of IL-4, IL-6, IL-10, IL-17A, IL-17F, and colon lamina propria and mesenteric lymph node (MLN) CD4+CD25+FoxP3+ T cells when compared to C57BL/6 mice. Collectively, these data indicate the propensity of BALB/c mice towards a Th2/Th17/Treg-polarized immunity protecting these animals against DSS challenge, whereas Th1-polarization of C57BL/6 mice confers sensitivity to DSS-induced colitis. Conclusions. The intrinsic congenital capacity of mouse strains with respect to T cell proliferation determines sensitivity to experimental colitis. Fangli Yang, Danan Wang, Yan Li, Lixuan Sang, Junfeng Zhu, Jinyan Wang, Bing Wei, Changlong Lu, and Xun Sun Copyright © 2017 Fangli Yang et al. All rights reserved. Mechanisms of Extracellular Immunomodulation Mediated by Infectious Agents Wed, 10 May 2017 00:00:00 +0000 Abel Viejo-Borbolla, Hans-Gerhard Burgert, and Frank A. Schildberg Copyright © 2017 Abel Viejo-Borbolla et al. All rights reserved. Impacts of Anti-dsDNA Antibody on In Vitro Fertilization-Embryo Transfer and Frozen-Thawed Embryo Transfer Sun, 30 Apr 2017 00:00:00 +0000 Our purpose is to explore whether anti-dsDNA antibody, which was demonstrated to enter living cells and induced apoptosis, could adversely affect reproductive outcomes. A total of 259 women receiving the in vitro fertilization-embryo transfer (IVF) cycle were enrolled in this study, including 52 women with positive ANA and anti-dsDNA (ANA+/anti-dsDNA+ group), 86 women with positive ANA and negative anti-dsDNA (ANA+/anti-dsDNA− group), and 121 women with negative ANA and anti-dsDNA (ANA−/anti-dsDNA− group). 136 nonpregnant women among 259 patients in the IVF-ET cycle were enrolled in the hormone replacement therapy frozen-thawed embryo transfer (HRT-TET) cycle. We compared basic characters and IVF outcomes among three groups in fresh embryo transfer and frozen-thawed embryo transfer cycle, respectively. The number of retrieved oocytes, available embryos, and high-quality embryos in the ANA+/anti-dsDNA+ group was lower than those in the other two groups in the fresh embryo transfer cycle. The rates of fertilization, implantation, and clinical pregnancy in the ANA+/anti-dsDNA+ group were the lowest, while the early miscarriage rate was the highest in the ANA+/anti-dsDNA+ group both in the fresh embryo transfer cycle and in the frozen-thawed embryo transfer cycle. Our data suggested that anti-dsDNA antibody may be the essential marker for defective oocytes or embryos in infertile women with any type of ANA. Jiao Fan, Yiping Zhong, and Cuina Chen Copyright © 2017 Jiao Fan et al. All rights reserved. Immune System and Chronic Diseases Sun, 30 Apr 2017 00:00:00 +0000 Margarete Dulce Bagatini, Andréia Machado Cardoso, Alessandra Antunes dos Santos, and Fabiano Barbosa Carvalho Copyright © 2017 Margarete Dulce Bagatini et al. All rights reserved. Plasma Levels of High-Mobility Group Box 1 during Peptide Vaccination in Patients with Recurrent Ovarian Cancer Thu, 27 Apr 2017 00:00:00 +0000 High-mobility group box 1 (HMGB1) is a nuclear protein that is known to be secreted into extracellular fluids from injured cells, activated macrophages, and tumor cells. The clinical correlation of circulating HMGB1 levels with various diseases including cancer has been reported. However, there is no information on HMGB1 levels in cancer patients treated with peptide vaccination. In the present study, we investigated the plasma levels of HMGB1 during personalized peptide vaccination in patients with recurrent ovarian cancer. Frozen plasma samples of 39 patients from previously conducted clinical trials were used in this study. HMGB1 levels were decreased after the 1st cycle of vaccination from their prevaccination levels. However, no correlation was observed between HMGB1 and overall survival (OS). The correlation between plasma HMGB1 levels and other biomarker levels was further analyzed by scatter plot, revealing that HMGB1 levels after the 1st cycle of vaccination were significantly correlated with myeloid-derived suppressor cell (MDSC) frequency after the 1st cycle of vaccination (, ). Chi-square test showed that epitope spreading was significantly related with changes of HMGB1 (). These results suggest that plasma HMGB1 is a possible biomarker for cancer vaccine therapy, although direct correlation with OS has not been obtained. This trial is registered with Clinical Trial Registry under trial numbers UMIN000003083 and UMIN000001482. Kayoko Waki, Kouichiro Kawano, Naotake Tsuda, Kimio Ushijima, Kyogo Itoh, and Akira Yamada Copyright © 2017 Kayoko Waki et al. All rights reserved. Neutrophilic Inflammation in the Immune Responses of Chronic Obstructive Pulmonary Disease: Lessons from Animal Models Thu, 27 Apr 2017 00:00:00 +0000 Chronic obstructive pulmonary disease (COPD) is a major cause of mortality worldwide, which is characterized by chronic bronchitis, destruction of small airways, and enlargement/disorganization of alveoli. It is generally accepted that the neutrophilic airway inflammation observed in the lungs of COPD patients is intrinsically linked to the tissue destruction and alveolar airspace enlargement, leading to disease progression. Animal models play an important role in studying the underlying mechanisms of COPD as they address questions involving integrated whole body responses. This review aims to summarize the current animal models of COPD, focusing on their advantages and disadvantages on immune responses and neutrophilic inflammation. Also, we propose a potential new animal model of COPD, which may mimic the most characteristics of human COPD pathogenesis, including persistent moderate-to-high levels of neutrophilic inflammation. Gang Huang, Xu-Chen Xu, Jie-Sen Zhou, Zhou-Yang Li, Hai-Pin Chen, Yong Wang, Wen Li, Hua-Hao Shen, and Zhi-Hua Chen Copyright © 2017 Gang Huang et al. All rights reserved. Getting “Inside” Type I IFNs: Type I IFNs in Intracellular Bacterial Infections Wed, 26 Apr 2017 00:00:00 +0000 Type I interferons represent a unique and complex group of cytokines, serving many purposes during innate and adaptive immunity. Discovered in the context of viral infections, type I IFNs are now known to have myriad effects in infectious and autoimmune disease settings. Type I IFN signaling during bacterial infections is dependent on many factors including whether the infecting bacterium is intracellular or extracellular, as different signaling pathways are activated. As such, the repercussions of type I IFN induction can positively or negatively impact the disease outcome. This review focuses on type I IFN induction and downstream consequences during infection with the following intracellular bacteria: Chlamydia trachomatis, Listeria monocytogenes, Mycobacterium tuberculosis, Salmonella enterica serovar Typhimurium, Francisella tularensis, Brucella abortus, Legionella pneumophila, and Coxiella burnetii. Intracellular bacterial infections are unique because the bacteria must avoid, circumvent, and even co-opt microbial “sensing” mechanisms in order to reside and replicate within a host cell. Furthermore, life inside a host cell makes intracellular bacteria more difficult to target with antibiotics. Because type I IFNs are important immune effectors, modulating this pathway may improve disease outcomes. But first, it is critical to understand the context-dependent effects of the type I IFN pathway in intracellular bacterial infections. Deann T. Snyder, Jodi F. Hedges, and Mark A. Jutila Copyright © 2017 Deann T. Snyder et al. All rights reserved. Analysis of Serum Cytokines and Single-Nucleotide Polymorphisms of SOD1, SOD2, and CAT in Erysipelas Patients Sun, 23 Apr 2017 00:00:00 +0000 Increased free radical production had been documented in group A (β-hemolytic) streptococcus infection cases. Comparing 71 erysipelas patients to 55 age-matched healthy individuals, we sought for CAT, SOD1, and SOD2 single polymorphism mutation (SNPs) interactions with erysipelas’ predisposition and serum cytokine levels in the acute and recovery phases of erysipelas infection. Whereas female patients had a higher predisposition to erysipelas, male patients were prone to having a facial localization of the infection. The presence of SOD1 G7958, SOD2 T2734, and CAT C262 alleles was linked to erysipelas’ predisposition. T and C alleles of SOD2 T2734C individually were linked to patients with bullous and erythematous erysipelas, respectively. G and A alleles of SOD1 G7958A individually were associated with lower limbs and higher body part localizations of the infection, respectively. Serum levels of IL-1β, CCL11, IL-2Rα, CXCL9, TRAIL, PDGF-BB, and CCL4 were associated with symptoms accompanying the infection, while IL-6, IL-9, IL-10, IL-13, IL-15, IL-17, G-CSF, and VEGF were associated with predisposition and recurrence of erysipelas. While variations of IL-1β, IL-7, IL-8, IL-17, CCL5, and HGF were associated with the SOD2 T2734C SNP, variations of PDFG-BB and CCL2 were associated with the CAT C262T SNP. Charles C. Emene, Irina E. Kravchenko, Gulnaz I. Aibatova, and Albert A. Rizvanov Copyright © 2017 Charles C. Emene et al. All rights reserved. Regulation of Discrete Functional Responses by Syk and Src Family Tyrosine Kinases in Human Neutrophils Sun, 23 Apr 2017 00:00:00 +0000 Neutrophils play a critical role in innate immunity and also influence adaptive immune responses. This occurs in good part through their production of inflammatory and immunomodulatory cytokines, in conjunction with their prolonged survival at inflamed foci. While a picture of the signaling machinery underlying these neutrophil responses is now emerging, much remains to be uncovered. In this study, we report that neutrophils constitutively express various Src family isoforms (STKs), as well as Syk, and that inhibition of these protein tyrosine kinases selectively hinders inflammatory cytokine generation by acting posttranscriptionally. Accordingly, STK or Syk inhibition decreases the phosphorylation of signaling intermediates (e.g., eIF-4E, S6K, and MNK1) involved in translational control. By contrast, delayed apoptosis appears to be independent of either STKs or Syk. Our data therefore significantly extend our understanding of which neutrophil responses are governed by STKs and Syk and pinpoint some signaling intermediates that are likely involved. In view of the foremost role of neutrophils in several chronic inflammatory conditions, our findings identify potential molecular targets that could be exploited for future therapeutic intervention. Thornin Ear, Olga Tatsiy, Frédérick L. Allard, and Patrick P. McDonald Copyright © 2017 Thornin Ear et al. All rights reserved. Diagnostic and Research Aspects of Small Intestinal Disaccharidases in Coeliac Disease Thu, 20 Apr 2017 00:00:00 +0000 Disaccharidases (DS) are brush border enzymes embedded in the microvillous membrane of small intestinal enterocytes. In untreated coeliac disease (CD), a general decrease of DS activities is seen. This manuscript reviews different aspects of DS activities in CD: their utility in the diagnosis and their application to in vitro toxicity testing. The latter has never been established in CD research. However, with the recent advances in small intestinal organoid techniques, DS might be employed as a biomarker for in vitro studies. This includes establishment of self-renewing epithelial cells raised from tissue, which express differentiation markers, including the brush border enzymes. Determining duodenal DS activities may provide additional information during the diagnostic workup of CD: (i) quantify the severity of the observed histological lesions, (ii) provide predictive values for the grade of mucosal villous atrophy, and (iii) aid diagnosing CD where minor histological changes are seen. DS can also provide additional information to assess the response to a gluten-free diet as marked increase of their activities occurs four weeks after commencing it. Various endogenous and exogenous factors affecting DS might also be relevant when considering investigating the role of DS in other conditions including noncoeliac gluten sensitivity and DS deficiencies. Tanja Šuligoj, Paul J. Ciclitira, and Borut Božič Copyright © 2017 Tanja Šuligoj et al. All rights reserved. MRI in Glioma Immunotherapy: Evidence, Pitfalls, and Perspectives Thu, 20 Apr 2017 00:00:00 +0000 Pseudophenomena, that is, imaging alterations due to therapy rather than tumor evolution, have an important impact on the management of glioma patients and the results of clinical trials. RANO (response assessment in neurooncology) criteria, including conventional MRI (cMRI), addressed the issues of pseudoprogression after radiotherapy and concomitant chemotherapy and pseudoresponse during antiangiogenic therapy of glioblastomas (GBM) and other gliomas. The development of cancer immunotherapy forced the identification of further relevant response criteria, summarized by the iRANO working group in 2015. In spite of this, the unequivocal definition of glioma progression by cMRI remains difficult particularly in the setting of immunotherapy approaches provided by checkpoint inhibitors and dendritic cells. Advanced MRI (aMRI) may in principle address this unmet clinical need. Here, we discuss the potential contribution of different aMRI techniques and their indications and pitfalls in relation to biological and imaging features of glioma and immune system interactions. Domenico Aquino, Andrea Gioppo, Gaetano Finocchiaro, Maria Grazia Bruzzone, and Valeria Cuccarini Copyright © 2017 Domenico Aquino et al. All rights reserved. The Role of Proteinase-Activated Receptors 1 and 2 in the Regulation of Periodontal Tissue Metabolism and Disease Wed, 19 Apr 2017 10:03:25 +0000 Proteinase-activated receptors 1 (PAR1) and 2 (PAR2) are the most highly expressed members of the PAR family in the periodontium. These receptors regulate periodontal inflammatory and repair processes through their activation by endogenous and bacterial enzymes. PAR1 is expressed by the periodontal cells such as human gingival fibroblasts, gingival epithelial cells, periodontal ligament cells, osteoblasts, and monocytic cells and can be activated by thrombin, matrix metalloproteinase 1 (MMP-1), MMP-13, fibrin, and gingipains from Porphyromonas gingivalis. PAR2 is expressed by neutrophils, osteoblasts, oral epithelial cells, and human gingival fibroblasts, and its possible activators in the periodontium are gingipains, neutrophil proteinase 3, and mast cell tryptase. The mechanisms through which PARs can respond to periodontal enzymes and result in appropriate immune responses have until recently been poorly understood. This review discusses recent findings that are beginning to identify a cardinal role for PAR1 and PAR2 on periodontal tissue metabolism. E. S. Rovai and M. Holzhausen Copyright © 2017 E. S. Rovai and M. Holzhausen. All rights reserved. Sirtuin 2 Regulates Microvascular Inflammation during Sepsis Wed, 19 Apr 2017 00:00:00 +0000 Objective. Sepsis and septic shock, the leading causes of death in noncoronary intensive care units, kill more than 200,000/year in the US alone. Circulating cell-endothelial cell interactions are the rate determining factor in sepsis inflammation. Sirtuin, a seven-member family of proteins (SIRT1–7), epigenetically controls inflammation. We have studied the roles of SIRTs 1, 3, and 6 in sepsis previously. In this project, we studied the role of SIRT2 on sepsis-related inflammation. Methods. Sepsis was induced in C57Bl/6 (WT), SIRT2 knockout (SIRT2KO), and SIRT2 overexpressing (SIRT2KI) mice by cecal ligation and puncture (CLP). We studied leukocyte/platelet adhesion using intravital microscopy and E-selectin/ICAM-1 adhesion molecule expression in the small intestine with immunohistochemistry (IHC) six hours post-CLP/sham surgery. We also studied 7-day survival rates in WT, SIRT2KO, and SIRT2KI sepsis mice. Results. Compared to WT mice, SIRT2KO mice show exaggeration while SIRT2KI mice show attenuation of cellular adhesion with sepsis in the small intestine. We also show that the small intestinal E-selectin and ICAM-1 expressions increased in SIRT2KO and decreased in SIRT2KI mice versus those in WT sepsis mice. We show that the 7-day survival rate is decreased in SIRT2KO and increased in SIRT2KI sepsis mice. Conclusion. SIRT2 modulates microvascular inflammation in sepsis and affects survival. Nancy Buechler, Xianfeng Wang, Barbara K. Yoza, Charles E. McCall, and Vidula Vachharajani Copyright © 2017 Nancy Buechler et al. All rights reserved. Bacteriophages and Their Immunological Applications against Infectious Threats Tue, 18 Apr 2017 00:00:00 +0000 Bacteriophage therapy dates back almost a century, but the discovery of antibiotics led to a rapid decline in the interests and investments within this field of research. Recently, the novel threat of multidrug-resistant bacteria highlighted the alarming drop in research and development of new antibiotics: 16 molecules were discovered during 1983–87, 10 new therapeutics during the nineties, and only 5 between 2003 and 2007. Phages are therefore being reconsidered as alternative therapeutics. Phage display technique has proved to be extremely promising for the identification of effective antibodies directed against pathogens, as well as for vaccine development. At the same time, conventional phage therapy uses lytic bacteriophages for treatment of infections and recent clinical trials have shown great potential. Moreover, several other approaches have been developed in vitro and in vivo using phage-derived proteins as antibacterial agents. Finally, their use has also been widely considered for public health surveillance, as biosensor phages can be used to detect food and water contaminations and prevent bacterial epidemics. These novel approaches strongly promote the idea that phages and their proteins can be exploited as an effective weapon in the near future, especially in a world which is on the brink of a “postantibiotic era.” Elena Criscuolo, Sara Spadini, Jacopo Lamanna, Mattia Ferro, and Roberto Burioni Copyright © 2017 Elena Criscuolo et al. All rights reserved. Donor-Specific Anti-Human Leukocyte Antigen Antibodies Predict Prolonged Isolated Thrombocytopenia and Inferior Outcomes of Haploidentical Hematopoietic Stem Cell Transplantation Tue, 18 Apr 2017 00:00:00 +0000 Prolonged isolated thrombocytopenia (PT) after allogeneic stem cell transplantation (allo-SCT) has a great impact on transplant outcome. In this study, we performed a retrospective analysis to investigate the association of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) with PT in 394 patients who underwent unmanipulated haploidentical blood and marrow transplantation (HBMT). For HLA antibody positive samples with a median fluorescent intensity (MFI) > 500, DSAs were further examined. A total of 390 patients (99.0%) achieved sustained myeloid engraftment. Of the 394 cases tested, 45 (11.4%) were DSA positive. The cumulative incidence of PT in this cohort of patients was 9.9 ± 1.5%. The incidence of PT was higher in patients with a MFI ≥ 1000 compared with those with a MFI < 1000 (16.8 ± 6.4% versus 7.4 ± 1.4%, ). Multivariate analysis showed that the presence of DSAs (MFI ≥ 1000) was correlated to PT (hazard ratio (HR) 3.262; 95% confidence interval (CI), 1.339–7.946; ) and transplant-related mortality (HR 2.320; 95% CI, 1.169–4.426; ). Our results, for the first time, suggest an association of DSAs with PT after unmanipulated HBMT. It would help screen out the suitable donor and guide intervention. This indicated that DSAs should be incorporated in the algorithm for unmanipulated HBMT. Xiaosu Zhao, Xiangyu Zhao, Mingrui Huo, Qiaozhen Fan, Xuying Pei, Yu Wang, Xiaohui Zhang, Lanping Xu, Xiaojun Huang, Kaiyan Liu, and Yingjun Chang Copyright © 2017 Xiaosu Zhao et al. All rights reserved. New Biomarkers in Autoimmune Disease Wed, 12 Apr 2017 00:00:00 +0000 Guixiu Shi, Zhixin Zhang, and Quanzhen Li Copyright © 2017 Guixiu Shi et al. All rights reserved. Innate-Adaptive Immune Crosstalk 2016 Tue, 11 Apr 2017 00:00:00 +0000 Anil Shanker, Menaka C. Thounaojam, Manoj K. Mishra, and Mikhail M. Dikov Copyright © 2017 Anil Shanker et al. All rights reserved. B-CD8+ T Cell Interactions in the Anti-Idiotypic Response against a Self-Antibody Sun, 09 Apr 2017 00:00:00 +0000 P3 is a murine, germline, IgM mAb that recognizes N-glycolylated gangliosides and other self-antigens. This antibody is able to induce an anti-idiotypic IgG response and B-T idiotypic cascade, even in the absence of any adjuvant or carrier protein. P3 mAb immunization induces the expression of activation markers in a significant percentage of B-1a cells in vivo. Interestingly, transfer of both B-1a and B-2 to BALB/Xid mice was required to recover anti-P3 IgG response in this model. In fact, P3 mAb activated B-2 cells, in vitro, inducing secretion of IFN-γ and IL-4, although this activation was not detected ex vivo. Interestingly, naïve CD8+ T cells increased the expression of activation markers and IFN-γ secretion in the presence of B-1a cells isolated from P3 mAb-immunized mice, even without in vitro restimulation. In contrast, B-2 cells were able to stimulate CD8+ T cells only if P3 was added in vitro. Using bioinformatics, a MHC class I-binding peptide from P3 VH region was identified. P3 mAb was able to induce a specific CTL response in vivo against cells presenting this peptide. Both humoral and CTL anti-idiotypic responses could be mechanisms to protect against the self-reactive antibody, contributing to keeping the tolerance to self-antigens. Darel Martínez, Amaury Pupo, Lianet Cabrera, Judith Raymond, Nichol E. Holodick, and Ana María Hernández Copyright © 2017 Darel Martínez et al. All rights reserved. Understanding the Role of Chemokines and Cytokines in Experimental Models of Herpes Simplex Keratitis Sun, 09 Apr 2017 00:00:00 +0000 Herpes simplex keratitis is a disease of the cornea caused by HSV-1. It is a leading cause of corneal blindness in the world. Underlying molecular mechanism is still unknown, but experimental models have helped give a better understanding of the underlying molecular pathology. Cytokines and chemokines are small proteins released by cells that play an important proinflammatory or anti-inflammatory role in modulating the disease process. Cytokines such as IL-17, IL-6, IL-1α, and IFN-γ and chemokines such as MIP-2, MCP-1, MIP-1α, and MIP-1β have proinflammatory role in the destruction caused by HSV including neutrophil infiltration and corneal inflammation, and other chemokines and cytokines such as IL-10 and CCL3 can have a protective role. Most of the damage results from neutrophil infiltration and neovascularization. While many more studies are needed to better understand the role of these molecules in both experimental models and human corneas, current studies indicate that these molecules hold potential to be targets of future therapy. Tayaba N. Azher, Xiao-Tang Yin, and Patrick M. Stuart Copyright © 2017 Tayaba N. Azher et al. All rights reserved. Interleukin-7 and Immunosenescence Thu, 06 Apr 2017 00:00:00 +0000 The age of an individual is an important, independent risk factor for many of the most common diseases afflicting modern societies. Interleukin-7 (IL-7) plays a central, critical role in the homeostasis of the immune system. Recent studies support a critical role for IL-7 in the maintenance of a vigorous healthspan. We describe the role of IL-7 and its receptor in immunosenescence, the aging of the immune system. An understanding of the role that IL-7 plays in aging may permit parsimonious preventative or therapeutic solutions for diverse conditions. Perhaps IL-7 might be used to “tune” the immune system to optimize human healthspan and longevity. Vanloan Nguyen, Andrew Mendelsohn, and James W. Larrick Copyright © 2017 Vanloan Nguyen et al. All rights reserved.