Journal of Immunology Research The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. OCH Ameliorates Bone Marrow Failure in Mice via Downregulation of T-Bet Expression Thu, 28 Aug 2014 09:46:24 +0000 The aim of this study is to evaluate the immune mechanism of OCH in the treatment of AA (also named bone marrow failure, BMF) induced in mice. OCH at a dose of 400 μg/kg was injected intraperitoneally (I.P.) prior to the induction of BMF. Our study showed that the incidence of BMF was 100% in BMF group and 13% in OCH treatment group. Significant higher level of IL-4 and lower level of IFN-γ were observed in OCH group than that in BMF group () as well as untreated group over BMF (). However, there was no significant difference between OCH and untreated group. Compared with untreated, the expression level of T-bet in OCH and BMF was all significantly higher. However, T-bet expression level was lower in OCH than in BMF. In addition, OCH treatment increased NKT cell fractions of bone marrow and the colonies of CFU-GM. In conclusion, treatment of OCH prior to the induction of BMF could prevent the incidence of BMF possibly through downregulating T-bet expression leading to the transition of immune response from Th1 to Th2, suggesting OCH might be a new therapeutic approach in the treatment of BMF or AA. Xiaohong Qiao, Xiaotian Xie, Wei Shi, Jinqing Tang, Yuexia Shao, and Fuxing Li Copyright © 2014 Xiaohong Qiao et al. All rights reserved. Clinical Biomarkers and Pathogenic-Related Cytokines in Rheumatoid Arthritis Thu, 21 Aug 2014 09:16:34 +0000 Rheumatoid arthritis (RA) is a common autoimmune disease with unknown etiology and pathogenesis. Although major therapeutic advances have been made in recent years, there is no cure for the disease. Current medications mainly reduce inflammation in order to relieve pain and slow joint damage, but many have potentially serious side effects. Therefore, to find specific biomarkers will benefit both RA patients to find relief from the disease and physicians to monitor the disease development. A number of biomarkers have been discovered and used clinically, and others are still under investigation. The autoantibodies, which are widely used in diagnosis and prognosis, novel biomarkers, which reflect clinical disease activity, and newly found biomarkers and pathogenic-related cytokines are discussed in this review. Xiaoyin Niu and Guangjie Chen Copyright © 2014 Xiaoyin Niu and Guangjie Chen. All rights reserved. Cancer Immunology and Cancer Immunodiagnosis Thu, 21 Aug 2014 07:38:23 +0000 Jianying Zhang, Suxia Han, Bin Zhang, and Yi Zhang Copyright © 2014 Jianying Zhang et al. All rights reserved. Clinical Features and Genetic Analysis of 20 Chinese Patients with X-Linked Hyper-IgM Syndrome Wed, 20 Aug 2014 07:29:49 +0000 X-linked hyper-IgM syndrome (XHIGM) is one type of primary immunodeficiency diseases, resulting from defects in the CD40 ligand/CD40 signaling pathways. We retrospectively analyzed the clinical and molecular features of 20 Chinese patients diagnosed and followed up in hospitals affiliated to Shanghai Jiao Tong University School of Medicine from 1999 to 2013. The median onset age of these patients was 8.5 months (range: 20 days–21 months). Half of them had positive family histories, with a shorter diagnosis lag. The most common symptoms were recurrent sinopulmonary infections (18 patients, 90%), neutropenia (14 patients, 70%), oral ulcer (13 patients, 65%), and protracted diarrhea (13 patients, 65%). Six patients had BCGitis. Six patients received hematopoietic stem cell transplantations and four of them had immune reconstructions and clinical remissions. Eighteen unique mutations in CD40L gene were identified in these 20 patients from 19 unrelated families, with 12 novel mutations. We compared with reported mutation results and used bioinformatics software to predict the effects of mutations on the target protein. These mutations reflected the heterogeneity of CD40L gene and expanded our understanding of XHIGM. Lin-Lin Wang, Wei Zhou, Wei Zhao, Zhi-Qing Tian, Wei-Fan Wang, Xiao-Fang Wang, and Tong-Xin Chen Copyright © 2014 Lin-Lin Wang et al. All rights reserved. Cytokine Network Involvement in Subjects Exposed to Benzene Mon, 18 Aug 2014 09:13:49 +0000 Benzene represents an ubiquitous pollutant both in the workplace and in the general environment. Health risk and stress posed by benzene have long been a concern because of the carcinogenic effects of the compound which was classified as a Group 1 carcinogen to humans and animals. There is a close correlation between leukemia, especially acute myeloid leukemia, and benzene exposure. In addition, exposure to benzene can cause harmful effects on immunological, neurological, and reproductive systems. Benzene can directly damage hematopoietic progenitor cells, which in turn could lead to apoptosis or may decrease responsiveness to cytokines and cellular adhesion molecules. Alternatively, benzene toxicity to stromal cells or mature blood cells could disrupt the regulation of hematopoiesis, including hematopoietic commitment, maturation, or mobilization, through the network of cytokines, chemokines, and adhesion molecules. Today there is mounting evidence that benzene may alter the gene expression, production, or processing of several cytokines in vitro and in vivo. The purpose of this review was to systematically analyze the published cases of cytokine effects on human benzene exposure, particularly hematotoxicity, and atopy, and on lungs. Paola Lucia Minciullo, Michele Navarra, Gioacchino Calapai, and Sebastiano Gangemi Copyright © 2014 Paola Lucia Minciullo et al. All rights reserved. Antiphospholipid Syndrome and Antibodies Mon, 18 Aug 2014 08:47:40 +0000 Jozélio Freire de Carvalho, Roger Abramino Levy, and Yehuda Shoenfeld Copyright © 2014 Jozélio Freire de Carvalho et al. All rights reserved. Appropriate Development of the Liver Treg Compartment Is Modulated by the Microbiota and Requires TGF-β and MyD88 Thu, 07 Aug 2014 09:00:14 +0000 Neither the early postnatal development of the liver Treg compartment nor the factors that regulate its development has been characterized. We compared the early developmental patterns of Treg cell accumulation in murine liver, thymus, and spleen. A FoxP3EGFP reporter mouse was employed to identify Treg cells. Mononuclear cells were isolated from organs postnatally, stained for CD4, and examined by flow cytometry to enumerate FoxP3+ cells. To assess roles for TGF-, MyD88, and TLR2, gene-specific knockout pups were generated from heterozygous breeders. To test the role of commensal bacteria, pregnant dams were administered antibiotics during gestation and after parturition. The pattern of appearance of Treg cells differed in liver, spleen, and thymus. Notably, at 1-2 weeks, the frequency of FoxP3+ T cells in liver exceeded that in spleen by 1.5- to 2-fold. The relative increase in liver Treg frequency was transient and was dependent upon TGF- and MyD88, but not TLR2, and was abrogated by antibiotic treatment. A relative increase in liver Treg frequency occurs approximately 1-2 weeks after parturition that appears to be driven by colonization of the intestine with commensal bacteria and is mediated by a pathway that requires TGF- and MyD88, but not TLR2. Ann Maria, Kathryn A. English, and James D. Gorham Copyright © 2014 Ann Maria et al. All rights reserved. The Role of Chemokines in Breast Cancer Pathology and Its Possible Use as Therapeutic Targets Tue, 05 Aug 2014 10:57:25 +0000 Chemokines are small proteins that primarily regulate the traffic of leukocytes under homeostatic conditions and during specific immune responses. The chemokine-chemokine receptor system comprises almost 50 chemokines and approximately 20 chemokine receptors; thus, there is no unique ligand for each receptor and the binding of different chemokines to the same receptor might have disparate effects. Complicating the system further, these effects depend on the cellular milieu. In cancer, although chemokines are associated primarily with the generation of a protumoral microenvironment and organ-directed metastasis, they also mediate other phenomena related to disease progression, such as angiogenesis and even chemoresistance. Therefore, the chemokine system is becoming a target in cancer therapeutics. We review the emerging data and correlations between chemokines/chemokine receptors and breast cancer, their implications in cancer progression, and possible therapeutic strategies that exploit the chemokine system. M. Isabel Palacios-Arreola, Karen E. Nava-Castro, Julieta I. Castro, Eduardo García-Zepeda, Julio C. Carrero, and Jorge Morales-Montor Copyright © 2014 M. Isabel Palacios-Arreola et al. All rights reserved. Congenital Defects in Neutrophil Dynamics Tue, 05 Aug 2014 08:13:53 +0000 Neutrophil granulocytes are key effector cells of the vertebrate immune system. They represent 50–70% of the leukocytes in the human blood and their loss by disease or drug side effect causes devastating bacterial infections. Their high turnover rate, their fine-tuned killing machinery, and their arsenal of toxic vesicles leave them particularly vulnerable to various genetic deficiencies. The aim of this review is to highlight those congenital immunodeficiencies which impede the dynamics of neutrophils, such as migration, cytoskeletal rearrangements, vesicular trafficking, and secretion. Marton Keszei and Lisa S. Westerberg Copyright © 2014 Marton Keszei and Lisa S. Westerberg. All rights reserved. Immunomodulation by Gut Microbiota: Role of Toll-Like Receptor Expressed by T Cells Thu, 24 Jul 2014 08:22:33 +0000 A close relationship exists between gut microbiota and immune responses. An imbalance of this relationship can determine local and systemic immune diseases. In fact the immune system plays an essential role in maintaining the homeostasis with the microbiota that normally resides in the gut, while, at the same time, the gut microbiota influences the immune system, modulating number and function of effector and regulatory T cells. To achieve this aim, mutual regulation between immune system and microbiota is achieved through several mechanisms, including the engagement of toll-like receptors (TLRs), pathogen-specific receptors expressed on numerous cell types. TLRs are able to recognize ligands from commensal or pathogen microbiota to maintain the tolerance or trigger the immune response. In this review, we summarize the latest evidences about the role of TLRs expressed in adaptive T cells, to understand how the immune system promotes intestinal homeostasis, fights invasion by pathogens, and is modulated by the intestinal microbiota. Mariagrazia Valentini, Alessia Piermattei, Gabriele Di Sante, Giuseppe Migliara, Giovanni Delogu, and Francesco Ria Copyright © 2014 Mariagrazia Valentini et al. All rights reserved. Cellular Signaling and Production of Galactose-Deficient IgA1 in IgA Nephropathy, an Autoimmune Disease Wed, 23 Jul 2014 11:14:47 +0000 Immunoglobulin A (IgA) nephropathy (IgAN), the leading cause of primary glomerulonephritis, is characterized by IgA1-containing immunodeposits in the glomeruli. IgAN is a chronic disease, with up to 40% of patients progressing to end-stage renal disease, with no disease-specific treatment. Multiple studies of the origin of the glomerular immunodeposits have linked elevated circulating levels of aberrantly glycosylated IgA1 (galactose-deficient in some O-glycans; Gd-IgA1) with formation of nephritogenic Gd-IgA1-containing immune complexes. Gd-IgA1 is recognized as an autoantigen in susceptible individuals by anti-glycan autoantibodies, resulting in immune complexes that may ultimately deposit in the kidney and induce glomerular injury. Genetic studies have revealed that an elevated level of Gd-IgA1 in the circulation of IgAN patients is a hereditable trait. Moreover, recent genome-wide association studies have identified several immunity-related loci that associated with IgAN. Production of Gd-IgA1 by IgA1-secreting cells of IgAN patients has been attributed to abnormal expression and activity of several key glycosyltransferases. Substantial evidence is emerging that abnormal signaling in IgA1-producing cells is related to the production of Gd-IgA1. As Gd-IgA1 is the key autoantigen in IgAN, understanding the genetic, biochemical, and environmental aspects of the abnormal signaling in IgA1-producing cells will provide insight into possible targets for future disease-specific therapy. Colin Reily, Hiroyuki Ueda, Zhi-Qiang Huang, Jiri Mestecky, Bruce A. Julian, Christopher D. Willey, and Jan Novak Copyright © 2014 Colin Reily et al. All rights reserved. Glycyrrhizin Attenuates Toll Like Receptor-2, -4 and Experimental Vasospasm in a Rat Model Wed, 23 Jul 2014 07:23:00 +0000 Upregulated TLRs are observed in the serum of animals following experimental subarachnoid hemorrhage. This study was to examine glycyrrhizin’s effect on proinflammatory cytokines and TLRs in SAH rats. Administration with glycyrrhizin was initiated 24 hr before and 1 hr later using osmotic minipump. Basilar arteries were harvested to examine TLRs mRNA and protein (rt-PCR and western blot) and CSF cytokines (rt-PCR). Morphologically, deformed endothelium, tortuous elastic lamina, and smooth muscle necrosis were observed in the SAH rats, but were absent in the glycyrrhizin pretreatment group. The TLR-3 protein level was not increased in SAH animals, compared with the controls, while that of TLR-2 and -4 in the SAH only and SAH plus vehicle groups was significantly elevated (). Pretreatment and treatment with glycyrrhizin reduced TLR-2 and -4 by % and %, respectively. Likewise, glycyrrhizin was able to reduce the IL-1β and MCP-1 mRNA levels. This study shows glycyrrhizin exerts anti-inflammatory effects on SAH induced vasospasm and attenuates the ultrashort time expression of TLRs, like TLR-2 and -4. It corresponds to SAH induced early brain injury. These findings offer credit to the antivasospastic effect of glycyrrhizin and its effect on SAH induced early brain injury. Chih-Zen Chang, Shu-Chuan Wu, and Aij-Lie Kwan Copyright © 2014 Chih-Zen Chang et al. All rights reserved. Dose of Incorporated Immunodominant Antigen in Recombinant BCG Impacts Modestly on Th1 Immune Response and Protective Efficiency against Mycobacterium tuberculosis in Mice Wed, 23 Jul 2014 06:32:57 +0000 One approach for improving BCG efficacy is to utilize BCG as vehicle to develop recombinant BCG (rBCG) strains overexpressing Mycobacterium tuberculosis (M. tb) antigens. Also expression level of a candidate antigen should impact the final T cell responses conferred by rBCG. In this study, based on our previously constructed differential expression system, we developed two rBCG strains overexpressing M. tb chimeric antigen Ag856A2 (coding a recombinant ag85a with 2 copies of esat-6 inserted at Acc I site of ag85a) at differential levels under the control of the subtly modified furA promoters. These two rBCG strains were used to vaccinate C57BL/6 mice and exploit dose of incorporated antigen in rBCG to optimize immune response and protective efficiency against M. tb challenge in mouse model. The results showed that rBCG strains overexpressing Ag856A2 at differential levels induced different antigen-specific IFN-γ production and comparable number of M. tb-specific CD4 T cells expressing IL-2. M. tb challenge experiment showed that rBCG strains afforded enhanced but comparable immune protection characterized by reduced bacillary load, lung pathology, and inflammation. These results suggested that the dose of antigens incorporated in rBCG can impact T cell immune responses but imposed no significantly differential protective efficacies. Hui Ma, Kang Wu, Fang Liu, Hua Yang, Han Kang, Ning-Ning Chen, Qin Yuan, Wen-Jiang Zhou, and Xiao-Yong Fan Copyright © 2014 Hui Ma et al. All rights reserved. Airborne Biogenic Particles in the Snow of the Cities of the Russian Far East as Potential Allergic Compounds Tue, 22 Jul 2014 09:36:18 +0000 This paper presents an analysis of airborne biogenic particles (1 mkm–1 mm) found in the snow in several cities of the Russian Far East during 2010–2013. The most common was vegetational terraneous detritus (fragments of tree and grass leaves) followed by animal hair, small insects and their fragments, microorganisms of aeroplankton, and equivocal biological garbage. Specific components were found in samples from locations close to bodies of water such as fragments of algae and mollusc shells and, marine invertebrates (needles of sea urchins and shell debris of arthropods). In most locations across the Far East (Vladivostok, Khabarovsk, Blagoveshchensk, and Ussuriysk), the content of biogenic particles collected in the winter did not exceed 10% of the total particulate matter, with the exception of Birobidzhan and the nature reserve Bastak, where it made up to 20%. Most of all biogenic compounds should be allergic: hair, fragments of tree and grass leaves, insects, and microorganisms. Kirill S. Golokhvast Copyright © 2014 Kirill S. Golokhvast. All rights reserved. Exploring the Innate Immunological Response of an Alternative Nonhuman Primate Model of Infectious Disease; the Common Marmoset Tue, 22 Jul 2014 00:00:00 +0000 The common marmoset (Callithrix jacchus) is increasingly being utilised as a nonhuman primate model for human disease, ranging from autoimmune to infectious disease. In order to fully exploit these models, meaningful comparison to the human host response is necessary. Commercially available reagents, primarily targeted to human cells, were utilised to assess the phenotype and activation status of key immune cell types and cytokines in naive and infected animals. Single cell suspensions of blood, spleen, and lung were examined. Generally, the phenotype of cells was comparable between humans and marmosets, with approximately 63% of all lymphocytes in the blood of marmosets being T cells, 25% B-cells, and 12% NK cells. The percentage of neutrophils in marmoset blood were more similar to human values than mouse values. Comparison of the activation status of cells following experimental systemic or inhalational infection exhibited different trends in different tissues, most obvious in cell types active in the innate immune response. This work significantly enhances the ability to understand the immune response in these animals and fortifies their use as models of infectious disease. M. Nelson and M. Loveday Copyright © 2014 Dstl. All rights reserved. Control of Intracellular Francisella tularensis by Different Cell Types and the Role of Nitric Oxide Mon, 21 Jul 2014 06:17:57 +0000 Reactive nitrogen is critical for the clearance of Francisella tularensis infections. Here we assess the role of nitric oxide in control of intracellular infections in two murine macrophage cell lines of different provenance: the alveolar macrophage cell line, MH-S, and the widely used peritoneal macrophage cell line, J774A.1. Cells were infected with the highly virulent Schu S4 strain or with the avirulent live vaccine strain (LVS) with and without stimuli. Compared to MH-S cells, J774A.1 cells were unresponsive to stimulation and were able to control the intracellular replication of LVS bacteria, but not of Schu S4. In MH-S cells, Schu S4 demonstrated control over cellular NO production. Despite this, MH-S cells stimulated with LPS or LPS and IFN- were able to control intracellular Schu S4 numbers. However, only stimulation with LPS induced significant cellular NO production. Combined stimulation with LPS and IFN- produced a significant reduction in intracellular bacteria that occurred whether high levels of NO were produced or not, indicating that NO secretion is not the only defensive cellular mechanism operating in virulent Francisella infections. Understanding how F. tularensis interacts with host macrophages will help in the rational design of new and effective therapies. Sarah L. Newstead, Amanda J. Gates, M. Gillian Hartley, Caroline A. Rowland, E. Diane Williamson, and Roman A. Lukaszewski Copyright © 2014 Dstl. All rights reserved. Use of Autoantibodies to Detect the Onset of Breast Cancer Mon, 21 Jul 2014 00:00:00 +0000 The widespread use of screening mammography has resulted in increased detection of early-stage breast disease, particularly for in situ carcinoma and early-stage breast cancer. However, the majority of women with abnormalities noted on screening mammograms are not diagnosed with cancer because of several factors, including radiologist assessment, patient age, breast density, malpractice concerns, and quality control procedures. Although magnetic resonance imaging is a highly sensitive detection tool that has become standard for women at very high risk of developing breast cancer, it lacks sufficient specificity and costeffectiveness for use as a general screening tool. Therefore, there is an important need to improve screening and diagnosis of early-invasive and noninvasive tumors, that is, in situ carcinoma. The great potential for molecular tools to improve breast cancer outcomes based on early diagnosis has driven the search for diagnostic biomarkers. Identification of tumor-specific markers capable of eliciting an immune response in the early stages of tumor development seems to provide an effective approach for early diagnosis. The aim of this review is to describe several autoantibodies identified during breast cancer diagnosis. We will focus on these molecules highlighted in the past two years and discuss the potential future use of autoantibodies as biomarkers of early-stage breast cancer. Jérôme Lacombe, Alain Mangé, and Jérôme Solassol Copyright © 2014 Jérôme Lacombe et al. All rights reserved. HLA-G as a Tolerogenic Molecule in Transplantation and Pregnancy Mon, 21 Jul 2014 00:00:00 +0000 HLA-G is a nonclassical HLA class I molecule. In allogeneic situations such as pregnancy or allograft transplantation, the expression of HLA-G has been related to a better acceptance of the fetus or the allograft. Thus, it seems that HLA-G is crucially involved in mechanisms shaping an allogeneic immune response into tolerance. In this contribution we focus on (i) how HLA-G is involved in transplantation and human reproduction, (ii) how HLA-G is regulated by genetic and microenvironmental factors, and (iii) how HLA-G can offer novel perspectives with respect to therapy. Vera Rebmann, Fabiola da Silva Nardi, Bettina Wagner, and Peter A. Horn Copyright © 2014 Vera Rebmann et al. All rights reserved. T CD3+CD8+ Lymphocytes Are More Susceptible for Apoptosis in the First Trimester of Normal Human Pregnancy Sun, 20 Jul 2014 00:00:00 +0000 Aims. Normal human pregnancy is a complex process of many immunoregulatory mechanisms which protect fetus from the activation of the maternal immune system. The aim of the study was to investigate the apoptosis of lymphocytes in peripheral blood of normal pregnant patients and healthy nonpregnant women. Methods. Sixty pregnant women and 17 nonpregnant women were included in the study. Lymphocytes were isolated and labeled with anti-CD3, anti-CD4, and anti-CD8 monoclonal antibodies. Apoptosis was detected by CMXRos staining and analyzed using the flow cytometric method. Results. We found significantly higher apoptosis of total lymphocytes in peripheral blood of pregnant patients when compared to healthy nonpregnant women. The percentage of apoptotic T CD3+CD8+ cells in the first trimester was significantly higher when compared to the third trimester of normal pregnancy. The ratio of T CD3+CD4+ : T CD3+CD8+ apoptotic lymphocytes was significantly lower in the first trimester when compared to other trimesters of pregnancy and to both of the phases of the menstrual cycle. Conclusions. The higher apoptosis of T CD3+CD8+ lymphocytes and the lower ratio of T CD3+CD4+ : T CD3+CD8+ apoptotic cells in the first trimester of normal pregnancy may suggest a higher susceptibility of T CD3+CD8+ cells for apoptosis as a protective mechanism at the early stage of pregnancy. Dorota Darmochwal-Kolarz, Ewelina Sobczak, Piotr Pozarowski, Bogdan Kolarz, Jacek Rolinski, and Jan Oleszczuk Copyright © 2014 Dorota Darmochwal-Kolarz et al. All rights reserved. Clinical, Laboratory, and Therapeutic Analyses of 21 Patients with Neonatal Thrombosis and Antiphospholipid Antibodies: A Literature Review Thu, 17 Jul 2014 10:26:28 +0000 Objectives. A review of the literature reports neonatal thrombosis and antiphospholipid antibodies cases through a retrospective study that focuses on the pathogenesis and main clinical and laboratory manifestations of this disease. Methods. The case reports were selected from PubMed. The keywords used to search were neonatal, antiphospholipid syndrome, thrombosis, and antiphospholipid antibodies. References that were published from 1987 to 2013 were reviewed. Results. Twenty-one cases of neonatal thrombosis and antiphospholipid antibodies were identified. Ten children were born preterm (before 37 weeks). Arterial involvement (17/21) was predominant, of which stroke (12/17) was the most prevalent clinical manifestation. Anti-cardiolipin antibodies were predominant (13/21) in the antiphospholipid antibody profiles. Treatments were based on the use of symptomatics such as antiepileptics (8/21), and 6/21 patients received heparin. There were 4 deaths (4/21); otherwise, the children recovered well, especially the neonates who suffered from strokes (9/12). Conclusion. Neonatal thrombosis and antiphospholipid antibodies are rare. The development of thrombotic manifestations in neonates seems not to be associated exclusively with the aPL, but their etiology may be linked to pre- and perinatal events. We noted good therapeutic responses, especially in stroke patients, who presented with favorable outcomes in 82% of the cases. Marcus Vinicius da Costa Peixoto, Jozélio Freire de Carvalho, and Carlos Ewerton Maia Rodrigues Copyright © 2014 Marcus Vinicius da Costa Peixoto et al. All rights reserved. Tribbles 3 Regulates the Fibrosis Cytokine TGF-β1 through ERK1/2-MAPK Signaling Pathway in Diabetic Nephropathy Wed, 16 Jul 2014 16:21:47 +0000 To reveal the expression and possible role of tribbles homolog 3 (TRB3) in the incidence of type 2 diabetic nephropathy, we used immunohistochemistry, real-time quantitative PCR, western blot analysis, and enzyme-linked immunosorbent assay (ELISA) to study the expression of TRB3, extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK1/2 MAPK), transforming growth factor β1 (TGF-β1), and collagen type IV in kidneys of db/db diabetic mice and in murine renal mesangial cells stimulated with high glucose. The expression of TRB3, TGF-β1, and collagen type IV was increased in kidneys of db/db diabetic mice. TGF-β1 and collagen type IV regulated by high glucose through ERK1/2 MAPK were downregulated by silencing TRB3 in renal mesangial cells. TRB3 may be involved in diabetic nephropathy by regulating the fibrosis cytokine TGF-β1 and collagen type IV through the ERK1/2 MAPK signaling pathway. Luwei Zhang, Jinhang Zhang, Xinnong Liu, Shengli Liu, and Jun Tian Copyright © 2014 Luwei Zhang et al. All rights reserved. Uncomplicated Diverticular Disease: Innate and Adaptive Immunity in Human Gut Mucosa before and after Rifaximin Wed, 16 Jul 2014 07:43:36 +0000 Background/Aim. Uncomplicated diverticular disease (UDD) is a frequent condition in adults. The pathogenesis of symptoms remains unknown. Bacteria are able to interact with Toll-like receptors (TLRs) and to induce inflammation through both innate immunity and T-cell recruitment. We investigated the pattern of TLRs 2 and 4 and the intestinal homing in patients with UDD before and after a course of Rifaximin. Methods. Forty consecutive patients with UDD and 20 healthy asymptomatic subjects were enrolled. Among UDD patients, 20 were assigned to a 2-month course of treatment with Rifaximin 1.2 g/day for 15 days/month and 20 received placebo. Blood sample and colonic biopsies were obtained from patients and controls. The samples were collected and analyzed at baseline and at the end of treatment. Flow cytometry was performed using monoclonal antibodies (CD3, CD4, CD8, CD103, TCR-gamma/delta, CD14, TLR2, and TLR4). Results. In UDD, TLR2 and TLR4 expression on immune cell subpopulations from blood and mucosa of the affected colon are altered as compared with controls. Rifaximin treatment induced significant modifications of altered conditions. Conclusions. Our data show the role of TLRs in the development of inflammation in UDD. TLRs distribution is altered in UDD and these alterations are reversed after antibiotic treatment. This trial is registered with NCT02068482. Rossella Cianci, Simona Frosali, Danilo Pagliari, Paola Cesaro, Lucio Petruzziello, Fabio Casciano, Raffaele Landolfi, Guido Costamagna, and Franco Pandolfi Copyright © 2014 Rossella Cianci et al. All rights reserved. SOCS1 and Regulation of Regulatory T Cells Plasticity Tue, 15 Jul 2014 12:01:38 +0000 Several reports have suggested that natural regulatory T cells (Tregs) lose Forkhead box P3 (Foxp3) expression and suppression activity under certain inflammatory conditions. Treg plasticity has been studied because it may be associated with the pathogenesis of autoimmunity. Some studies showed that a minor uncommitted Foxp3+ T cell population, which lacks hypomethylation at Treg-specific demethylation regions (TSDRs), may convert to effector/helper T cells. Suppressor of cytokine signaling 1 (SOCS1), a negative regulator of cytokine signaling, has been reported to play an important role in Treg cell integrity and function by protecting the cells from excessive inflammatory cytokines. In this review, we discuss Treg plasticity and maintenance of suppression functions in both physiological and pathological settings. In addition, we discuss molecular mechanisms of maintaining Treg plasticity by SOCS1 and other molecules. Such information will be useful for therapy of autoimmune diseases and reinforcement of antitumor immunity. Reiko Takahashi and Akihiko Yoshimura Copyright © 2014 Reiko Takahashi and Akihiko Yoshimura. All rights reserved. The Relevance of HLA Sequencing in Population Genetics Studies Tue, 15 Jul 2014 00:00:00 +0000 Next generation sequencing (NGS) is currently being adapted by different biotechnological platforms to the standard typing method for HLA polymorphism, the huge diversity of which makes this initiative particularly challenging. Boosting the molecular characterization of the HLA genes through efficient, rapid, and low-cost technologies is expected to amplify the success of tissue transplantation by enabling us to find donor-recipient matching for rare phenotypes. But the application of NGS technologies to the molecular mapping of the MHC region also anticipates essential changes in population genetic studies. Huge amounts of HLA sequence data will be available in the next years for different populations, with the potential to change our understanding of HLA variation in humans. In this review, we first explain how HLA sequencing allows a better assessment of the HLA diversity in human populations, taking also into account the methodological difficulties it introduces at the statistical level; secondly, we show how analyzing HLA sequence variation may improve our comprehension of population genetic relationships by facilitating the identification of demographic events that marked human evolution; finally, we discuss the interest of both HLA and genome-wide sequencing and genotyping in detecting functionally significant SNPs in the MHC region, the latter having also contributed to the makeup of the HLA molecular diversity observed today. Alicia Sanchez-Mazas and Diogo Meyer Copyright © 2014 Alicia Sanchez-Mazas and Diogo Meyer. All rights reserved. Cellular Factors Targeting APCs to Modulate Adaptive T Cell Immunity Mon, 14 Jul 2014 11:29:04 +0000 The fate of adaptive T cell immunity is determined by multiple cellular and molecular factors, among which the cytokine milieu plays the most important role in this process. Depending on the cytokines present during the initial T cell activation, T cells become effector cells that produce different effector molecules and execute adaptive immune functions. Studies thus far have primarily focused on defining how these factors control T cell differentiation by targeting T cells themselves. However, other non-T cells, particularly APCs, also express receptors for the factors and are capable of responding to them. In this review, we will discuss how APCs, by responding to those cytokines, influence T cell differentiation and adaptive immunity. Anabelle Visperas, Jeongsu Do, and Booki Min Copyright © 2014 Anabelle Visperas et al. All rights reserved. Activation Effects of Polysaccharides of Flammulina velutipes Mycorrhizae on the T Lymphocyte Immune Function Mon, 14 Jul 2014 09:54:09 +0000 Flammulina velutipes mycorrhizae have increasingly been produced with increasing of F. velutipes production. A mouse model was thus used to examine potential effect of F. velutipes mycorrhizae on the immune function. Fifty female Wistar mice (5-weeks-old) weighed 15–20 g were randomly allocated into five groups. Polysaccharide of F. velutipes mycorrhizae were treated with mice and mice spleen lymphocytes. The levels of CD3+, CD4+, and CD8+ T lymphocyte, interleukin-2 (IL-2), and tumor necrosis factor-a (TNF-) were determined. The results showed that the proportions of CD3+, and CD4+ T lymphocyte, the ratio of CD4+/CD8+, and the levels of IL-2 and TNF-a were significantly increased in polysaccharide of F. velutipes mycorrhizae, while the proportion of CD8+ T lymphocyte was decreased in polysaccharide of F. velutipes mycorrhizae-dose dependent manner. Our findings indicated that a long term exposure of polysaccharide of F. velutipes mycorrhizae could activate the T lymphocyte immune function. Polysaccharide of F. velutipes mycorrhizae was expected to develop into the immune health products. Zheng-Fei Yan, Nai-Xu Liu, Xin-Xin Mao, Yu Li, and Chang-Tian Li Copyright © 2014 Zheng-Fei Yan et al. All rights reserved. IL-6 as a Druggable Target in Psoriasis: Focus on Pustular Variants Sun, 13 Jul 2014 08:25:49 +0000 Psoriasis vulgaris (PV) is a cutaneous inflammatory disorder stemming from abnormal, persistent activation of the interleukin- (IL-)23/Th17 axis. Pustular psoriasis (PP) is a clinicopathological variant of psoriasis, histopathologically defined by the predominance of intraepidermal collections of neutrophils. Although PP pathogenesis is thought to largely follow that of (PV), recent evidences point to a more central role for IL-1, IL-36, and IL-6 in the development of PP. We review the role of IL-6 in the pathogenesis of PV and PP, focusing on its cross-talk with cytokines of the IL-23/Th17 axis. Clinical inhibitors of IL-6 signaling, including tocilizumab, have shown significant effectiveness in the treatment of several inflammatory rheumatic diseases, including rheumatoid arthritis and juvenile idiopathic arthritis; accordingly, anti-IL-6 agents may potentially represent future promising therapies for the treatment of PP. Andrea Saggini, Sergio Chimenti, and Andrea Chiricozzi Copyright © 2014 Andrea Saggini et al. All rights reserved. Cardiovascular Risk Factors in the Antiphospholipid Syndrome Sun, 13 Jul 2014 07:56:18 +0000 A major cause of morbidity and mortality in the context of the antiphospholipid syndrome (APS) is the occurrence of thrombotic events. Besides the pathogenic roles of antiphospholipid antibodies (aPL), other risk factors and medical conditions, which are conditions for traditional risk of an individual without the APS, can coexist in this patient, raising their risk of developing thrombosis. Therefore, the clinical and laboratory investigation of comorbidities known to increase cardiovascular risk in patients with antiphospholipid antibody syndrome is crucial for the adoption of a more complete and effective treatment. Experimental models and clinical studies show evidence of association between APS and premature formation of atherosclerotic plaques. Atherosclerosis has major traditional risk factors: hypertension, diabetes mellitus, obesity, dyslipidemia, smoking, and sedentary lifestyle that may be implicated in vascular involvement in patients with APS. The influence of nontraditional risk factors as hyperhomocysteinemia, increased lipoprotein a, and anti-oxLDL in the development of thromboembolic events in APS patients has been studied in scientific literature. Metabolic syndrome with all its components also has been recently studied in antiphospholipid syndrome and is associated with arterial events. Felipe Freire da Silva, Roger Abramino Levy, and Jozélio Freire de Carvalho Copyright © 2014 Felipe Freire da Silva et al. All rights reserved. Potential and Limitation of HLA-Based Banking of Human Pluripotent Stem Cells for Cell Therapy Wed, 09 Jul 2014 08:53:33 +0000 Great hopes have been placed on human pluripotent stem (hPS) cells for therapy. Tissues or organs derived from hPS cells could be the best solution to cure many different human diseases, especially those who do not respond to standard medication or drugs, such as neurodegenerative diseases, heart failure, or diabetes. The origin of hPS is critical and the idea of creating a bank of well-characterized hPS cells has emerged, like the one that already exists for cord blood. However, the main obstacle in transplantation is the rejection of tissues or organ by the receiver, due to the three main immunological barriers: the human leukocyte antigen (HLA), the ABO blood group, and minor antigens. The problem could be circumvented by using autologous stem cells, like induced pluripotent stem (iPS) cells, derived directly from the patient. But iPS cells have limitations, especially regarding the disease of the recipient and possible difficulties to handle or prepare autologous iPS cells. Finally, reaching standards of good clinical or manufacturing practices could be challenging. That is why well-characterized and universal hPS cells could be a better solution. In this review, we will discuss the interest and the feasibility to establish hPS cells bank, as well as some economics and ethical issues. Casimir de Rham and Jean Villard Copyright © 2014 Casimir de Rham and Jean Villard. All rights reserved. Glioma-Associated Antigen HEATR1 Induces Functional Cytotoxic T Lymphocytes in Patients with Glioma Wed, 09 Jul 2014 07:33:26 +0000 A2B5+ glioblastoma (GBM) cells have glioma stem-like cell (GSC) properties that are crucial to chemotherapy resistance and GBM relapse. T-cell-based antigens derived from A2B5+ GBM cells provide important information for immunotherapy. Here, we show that HEAT repeat containing 1 (HEATR1) expression in GBM tissues was significantly higher than that in control brain tissues. Furthermore, HEATR1 expression in A2B5+ U87 cells was higher than that in A2B5−U87 cells (). Six peptides of HEATR1 presented by HLA-A02 were selected for testing of their ability to induce T-cell responses in patients with GBM. When peripheral blood mononuclear cells from healthy donors () and patients with glioma () were stimulated with the peptide mixture, eight patients with malignant gliomas had positive reactivity with a significantly increased number of responding T-cells. The peptides HEATR1682–690, HEATR11126–1134, and HEATR1757–765 had high affinity for binding to HLA-A02:01 and a strong capacity to induce CTL response. CTLs against HEATR1 peptides were capable of recognizing and lysing GBM cells and GSCs. These data are the first to demonstrate that HEATR1 could induce specific CTL responses targeting both GBM cells and GSCs, implicating that HEATR1 peptide-based immunotherapy could be a novel promising strategy for treating patients with GBM. Zhe Bao Wu, Chao Qiu, An Li Zhang, Lin Cai, Shao Jian Lin, Yu Yao, Qi Sheng Tang, Ming Xu, Wei Hua, Yi Wei Chu, Ying Mao, Jian Hong Zhu, Jianqing Xu, and Liang Fu Zhou Copyright © 2014 Zhe Bao Wu et al. All rights reserved.