Journal of Immunology Research The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Gamma-Irradiated Bacille Calmette-Guérin Vaccination Does Not Modulate the Innate Immune Response during Experimental Human Endotoxemia in Adult Males Thu, 26 Mar 2015 12:24:53 +0000 Bacille Calmette-Guérin (BCG) vaccine exerts nonspecific immunostimulatory effects and may therefore represent a novel therapeutic option to treat sepsis-induced immunoparalysis. We investigated whether BCG vaccination modulates the systemic innate immune response in humans in vivo during experimental endotoxemia. We used inactivated gamma-irradiated BCG vaccine because of the potential risk of disseminated disease with the live vaccine in immunoparalyzed patients. In a randomized double-blind placebo-controlled study, healthy male volunteers were vaccinated with gamma-irradiated BCG () or placebo () and received 1 ng/kg lipopolysaccharide (LPS) intravenously on day 5 after vaccination to assess the in vivo immune response. Peripheral blood mononuclear cells were stimulated with various related and unrelated pathogens 5, 8 to 10, and 25 to 35 days after vaccination to assess ex vivo immune responses. BCG vaccination resulted in a scar in 90% of vaccinated subjects. LPS administration elicited a profound systemic immune response, characterized by increased levels of pro- and anti-inflammatory cytokines, hemodynamic changes, and flu-like symptoms. However, BCG modulated neither this in vivo immune response, nor ex vivo leukocyte responses at any time point. In conclusion, gamma-irradiated BCG is unlikely to represent an effective treatment option to restore immunocompetence in patients with sepsis-induced immunoparalysis. This trial is registered with NCT02085590. Linda A. C. Hamers, Matthijs Kox, Rob J. W. Arts, Bastiaan Blok, Jenneke Leentjens, Mihai G. Netea, and Peter Pickkers Copyright © 2015 Linda A. C. Hamers et al. All rights reserved. Immunodiagnostic Significance of Anti-RA33 Autoantibodies in Saudi Patients with Rheumatoid Arthritis Wed, 25 Mar 2015 09:08:51 +0000 The primary objective of this study was to evaluate and compare the immunodiagnostic significance and utility of anti-RA33 with anti-CCP, RF, and CRP in Saudi patients with rheumatoid arthritis. Methods. This was a prospective controlled clinical study conducted at King Abdul Aziz University Tertiary Medical Centre. The sera of 41 RA patients, 31 non-RA patients, and 29 healthy controls were collected. Anti-RA33 and anti-CCP were measured using commercially available ELISA principle kits. RF and CRP were measured using nephelometry. Results. Anti-RA33 antibodies had the lowest positive and negative predictive values and showed a sensitivity of 7.32% with 95.12% specificity. Of the other three markers (including anti-CCP antibodies, CRP, and RF), only anti-CCP showed specificity of 90.46% with sensitivity of 63.41% compared to non-RA patients + healthy control. There was a significant correlation with rheumatoid factor positivity with anti-CCP. With respect to CRP, a notable correlation was seen only with anti-RA33. Conclusion. Compared to rheumatoid factor, anti-CCP antibodies, and C-reactive proteins, the anti-RA33 autoantibodies seem to be not representing as an important additional immunodiagnostic marker in Saudi patients with established RA. RA33 may have more interest in early RA or less severe RA and other systemic connective tissue disorders. Jamil A. Al-Mughales Copyright © 2015 Jamil A. Al-Mughales. All rights reserved. A Novel PET Imaging Using 64Cu-Labeled Monoclonal Antibody against Mesothelin Commonly Expressed on Cancer Cells Wed, 25 Mar 2015 08:21:30 +0000 Mesothelin (MSLN) is a 40-kDa cell differentiation-associated glycoprotein appearing with carcinogenesis and is highly expressed in many human cancers, including the majority of pancreatic adenocarcinomas, ovarian cancers, and mesotheliomas, while its expression in normal tissue is limited to mesothelial cells lining the pleura, pericardium, and peritoneum. Clone 11-25 is a murine hybridoma secreting monoclonal antibody (mAb) against human MSLN. In this study, we applied the 11-25 mAb to in vivo imaging to detect MSLN-expressing tumors. In in vitro and ex vivo immunochemical studies, we demonstrated specificity of 11-25 mAb to membranous MSLN expressed on several pancreatic cancer cells. We showed the accumulation of Alexa Fluor 750-labeled 11-25 mAb in MSLN-expressing tumor xenografts in athymic nude mice. Then, 11-25 mAb was labeled with 64Cu via a chelating agent DOTA and was used in both in vitro cell binding assay and in vivo positron emission tomography (PET) imaging in the tumor-bearing mice. We confirmed that 64Cu-labeled 11-25 mAb highly accumulated in MSLN-expressing tumors as compared to MSLN-negative ones. The 64Cu-labeled 11-25 mAb is potentially useful as a PET probe capable of being used for wide range of tumors, rather than 18F-FDG that occasionally provides nonspecific accumulation into the inflammatory lesions. Kazuko Kobayashi, Takanori Sasaki, Fumiaki Takenaka, Hiromasa Yakushiji, Yoshihiro Fujii, Yoshiro Kishi, Shoichi Kita, Lianhua Shen, Hiromi Kumon, and Eiji Matsuura Copyright © 2015 Kazuko Kobayashi et al. All rights reserved. MBL2 Genotypes and Their Associations with MBL Levels and NICU Morbidity in a Cohort of Greek Neonates Tue, 24 Mar 2015 06:42:13 +0000 The objective of this study was to assess the frequency of MBL2 genotypes and their associations with MBL levels and various morbidities of a neonatal intensive care unit (NICU). One hundred and thirty-four (134) NICU (83 term and 51 preterm) and 150 healthy neonates were enrolled in the study. MBL2 genotype and MBL serum levels at birth were determined prospectively by PCR-RFLP-sequencing and enzyme-linked immunosorbent assay, respectively. NICU neonates displayed significantly lower MBL serum levels compared to healthy ones. MBL deficiency, defined as the low MBL2 expression group (XA/O and O/O), was significantly associated with an increased risk of respiratory morbidity, especially transient tachypnea of the newborn and respiratory distress syndrome (RDS). Moreover, an increase of 100 ng/mL of serum MBL levels decreases by 5% the risk of total respiratory morbidity and by 7% the risk of RDS, after correction for prematurity and sex and regardless of the presence of infections. Our study further supports the notion that neonates with MBL deficiency and low MBL serum levels at birth may be at higher risk of developing severe respiratory complications. Matthaios Speletas, Antonios Gounaris, Eirini Sevdali, Maria Kompoti, Katerina Konstantinidi, Rozeta Sokou, Elena Tsitsami, and Anastasios E. Germenis Copyright © 2015 Matthaios Speletas et al. All rights reserved. “New” Antigenic Targets and Methodological Approaches for Refining Laboratory Diagnosis of Antiphospholipid Syndrome Thu, 19 Mar 2015 07:33:39 +0000 Antiphospholipid antibodies (aPLs) are a heterogeneous group of antibodies directed against phospholipids or protein/phospholipid complexes. Currently, aPLs are assessed using either “solid-phase” assays that identify anticardiolipin antibodies and anti-β2-glycoprotein I antibodies or “liquid-phase” assay that identifies lupus anticoagulant. However, in the last few years, “new” antigenic targets and methodological approaches have been employed for refining laboratory diagnosis of antiphospholipid syndrome (APS). In this review the potential diagnostic value of antibodies to domains of β2-GPI, prothrombin/phosphatidylserine, vimentin/cardiolipin, protein S, protein C, annexin A2, annexin A5, and phospholipid antigens is discussed. Moreover, new technical approaches, including chemiluminescence, multiline dot assay, and thin layer chromatography (TLC) immunostaining, which utilize different supports for detection of aPL, have been developed. A special focus has been dedicated on “seronegative” APS, that is, those patients with a clinical profile suggestive of APS (thromboses, recurrent miscarriages, or foetal loss), who are persistently negative for the routinely used aPL. Recent findings suggest that, in sera from patients with SN-APS, antibodies may be detected using “new” antigenic targets (mainly vimentin/cardiolipin) or methodological approaches different from traditional techniques (TLC immunostaining). Thus, APS represents a mosaic, in which antibodies against different antigenic targets may be detected thanks to the continuously evolving new technologies. Roberta Misasi, Antonella Capozzi, Agostina Longo, Serena Recalchi, Emanuela Lococo, Cristiano Alessandri, Fabrizio Conti, Guido Valesini, and Maurizio Sorice Copyright © 2015 Roberta Misasi et al. All rights reserved. Effect of TACI Signaling on Humoral Immunity and Autoimmune Diseases Tue, 17 Mar 2015 14:20:26 +0000 Transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) is one of the receptors of B cell activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL). TACI is a regulator in the immune responses. TACI inhibits B cell expansion and promotes the differentiation and survival of plasma cells. The mechanisms underlying these effects probably involve changed expressions of some crucial molecules, such as B lymphocyte induced maturation protein-1 (Blimp-1) and inducible T-cell costimulator ligand (ICOSL) in B cells and/or plasma cells. However, abnormal TACI signaling may relate to autoimmune disorders. Common variable immune deficiency (CVID) patients with heterozygous mutations in TACI alleles increase susceptibility to autoimmune diseases. Taci−/− mice and BAFF transgenic mice both develop signs of human SLE. These findings that indicate inappropriate levels of TACI signaling may disrupt immune system balance, thereby promoting the development of autoimmune diseases. In this review, we summarize the basic characteristics of the TACI ligands BAFF and APRIL, and detail the research findings on the role of TACI in humoral immunity. We also discuss the possible mechanisms underlying the susceptibility of CVID patients with TACI mutations to autoimmune diseases and the role of TACI in the pathogenesis of SLE. Yi Zhang, Jun Li, Ya-Min Zhang, Xiao-Ming Zhang, and Juan Tao Copyright © 2015 Yi Zhang et al. All rights reserved. Growth Modeling of the Maternal Cytokine Milieu throughout Normal Pregnancy: Macrophage-Derived Chemokine Decreases as Inflammation/Counterregulation Increases Tue, 17 Mar 2015 07:29:12 +0000 Several recent studies have shown differences in the maternal immune milieu at different phases of pregnancy, but most studies have been cross-sectional or of relatively few time points. Levels of 42 cytokines were determined using a multiplex bead-based assay on archived serum from a cohort of pregnant women at median of 18 time points tested, from the first trimester through to parturition, per woman. Unconditional growth modeling was then used to determine time-dependent changes in levels of these cytokines. Macrophage-derived chemokine (MDC, aka CCL22) decreases as pregnancy progresses. IL-1β, IL-6, IL-8, IL-12p70, IL-13, IL-15, IP-10, and FLT3-ligand increase as a function of gestational weeks, and IFNα2, IL-1ra, IL-3, IL-9, IL-12p40, and soluble CD40 ligand increase as a function of trimester. As pregnancy normally progresses, a maternal shift away from a type 2-biased immune response and toward an inflammatory/counterregulatory response is observed. Shernan G. Holtan, Yiyi Chen, Rajani Kaimal, Douglas J. Creedon, Elizabeth Ann L. Enninga, Wendy K. Nevala, and Svetomir N. Markovic Copyright © 2015 Shernan G. Holtan et al. All rights reserved. HIV Vaccine Research: The Challenge and the Way Forward Sun, 15 Mar 2015 09:00:23 +0000 Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) is a worldwide epidemic, with over 35 million people infected currently. Therefore, the development of a safe and effective HIV-1 vaccine is on top of the global health priority. In the past few years, there have been many promising advances in the prevention of HIV/AIDS, among which the RV144 Thai trial has been encouraging and suggests optimization of the current vaccine strategies or search for novel strategies. Here we reviewed the brief history of HIV-1 vaccine, analyzed key challenges existing now, and illustrated future research priority/directions for a therapeutic or prophylactic HIV-1 vaccine, with the hope of accelerating the speed of vaccine development. We believe that an effective HIV-1 vaccine, together with other prevention approaches, will bring an end to this epidemic in the near future. Hai-Bo Wang, Qiu-Hua Mo, and Ze Yang Copyright © 2015 Hai-Bo Wang et al. All rights reserved. Vaccines and Therapies for Biodefence Agents Sun, 08 Mar 2015 13:02:10 +0000 Julia A. Tree, E. Diane Williamson, Caroline A. Rowland, and Louise M. Pitt Copyright © 2015 Julia A. Tree et al. All rights reserved. The Story of CD4+CD28− T Cells Revisited: Solved or Still Ongoing? Thu, 05 Mar 2015 13:52:33 +0000 CD4+CD28− T cells are a unique type of proinflammatory T cells characterised by blockade of costimulatory CD28 receptor expression at the transcriptional level, which is still reversible by IL-12. In healthy individuals older than 65 years, these cells may accumulate to up to 50% of total CD4+ T lymphocytes as in many immune-mediated diseases, immunodeficiency, and specific infectious diseases. Here we focus on CD4+CD28− T cells in chronic immune-mediated diseases, summarizing various phenotypic and functional characteristics, which vary depending on the underlying disease, disease activity, and concurrent treatment. CD4+CD28− T cells present as effector/memory cells with increased replicative history and oligoclonality but reduced apoptosis. As an alternative costimulatory signal instead of CD28, not only natural killer cell receptors and Toll-like receptors, but also CD47, CTLA-4, OX40, and 4-1BB have to be considered. The proinflammatory and cytotoxic capacities of these cells indicate an involvement in progression and maintenance of chronic immune-mediated disease. So far it has been shown that treatment with TNF-α blockers, abatacept, statins, and polyclonal antilymphocyte globulins (ATG) mediates reduction of the CD4+CD28− T cell level. The clinical relevance of targeting CD4+CD28− T cells as a therapeutic option has not been examined so far. Kathrin Maly and Michael Schirmer Copyright © 2015 Kathrin Maly and Michael Schirmer. All rights reserved. Significance of Circulating and Crevicular Matrix Metalloproteinase-9 in Rheumatoid Arthritis-Chronic Periodontitis Association Tue, 03 Mar 2015 11:07:13 +0000 In the recent years, statistically significant associations between rheumatoid arthritis (RA) and periodontal disease have been identified. Emerging as a chronic inflammatory joint disease, RA displays various features and pathogenetic events similar to chronic periodontitis (CP). The purpose of this study was to evaluate the utility of determining systemic and crevicular levels of metalloproteinase-9 (MMP-9) as potential biomarkers for association between RA and CP. A total of fifty-six patients were included in the study. The subjects were categorized into four groups as follows: healthy-control (), active RA (), CP (), and RA-CP association (). Assessment of serum and crevicular concentrations of total MMP-9 (active and pro-MMP-9) was based on ELISA technique. The results of this study showed statistically significant differences of serum MMP-9 between patients groups and control. Serum levels of MMP-9 were similar in RA and RA-CP associated patients. Gingival crevicular fluid (GCF) recorded increased MMP-9 levels in RA-CP association subjects as compared to CP. Considering that RA-CP association is characterized by a disregulation of the inflammatory response, MMP-9 may play a role in the pathogenesis of RA-CP association. MMP-9 is therefore a sensitive tool in the diagnosis and management of patients affected by this binomial association. Isabela Silosi, Manole Cojocaru, Lili Foia, Mihail Virgil Boldeanu, Florin Petrescu, Petra Surlin, and Viorel Biciusca Copyright © 2015 Isabela Silosi et al. All rights reserved. Intestinal Microbiota as Modulators of the Immune System Mon, 02 Mar 2015 09:35:03 +0000 Borja Sánchez, Miguel Gueimonde, Amado Salvador Peña, and David Bernardo Copyright © 2015 Borja Sánchez et al. All rights reserved. Effective Binding of a Phosphatidylserine-Targeting Antibody to Ebola Virus Infected Cells and Purified Virions Sun, 01 Mar 2015 11:12:35 +0000 Ebola virus is responsible for causing severe hemorrhagic fevers, with case fatality rates of up to 90%. Currently, no antiviral or vaccine is licensed against Ebola virus. A phosphatidylserine-targeting antibody (PGN401, bavituximab) has previously been shown to have broad-spectrum antiviral activity. Here, we demonstrate that PGN401 specifically binds to Ebola virus and recognizes infected cells. Our study provides the first evidence of phosphatidylserine-targeting antibody reactivity against Ebola virus. S. D. Dowall, V. A. Graham, K. Corbin-Lickfett, C. Empig, K. Schlunegger, C. B. Bruce, L. Easterbrook, and R. Hewson Copyright © 2015 S. D. Dowall et al. All rights reserved. Neutrophil Migration in the Activation of the Innate Immune Response to Different Flavobacterium psychrophilum Vaccines in Zebrafish (Danio rerio) Sat, 28 Feb 2015 12:41:48 +0000 Flavobacterium psychrophilum is a Gram-negative bacterium, responsible for the bacterial cold-water disease and the rainbow trout fry syndrome in freshwater salmonid fish. At present, there is only one commercial vaccine in Chile, made with two Chilean F. psychrophilum isolates and another licensed in Europe. The present study analyzed neutrophil migration, as a marker of innate immune activation, in zebrafish (Danio rerio) in response to different F. psychrophilum bath vaccines, which is the first step in evaluating vaccine effectiveness and efficiency in fish. Results indicated that bacterins of the LM-02-Fp isolate were more immunogenic than those from the LM-13-Fp isolate. However, no differences were observed between the same bacteria inactivated by either formaldehyde or heat. Importantly, the same vaccine formulation without an adjuvant only triggered a mild neutrophil migration compared to the complete vaccine. Observations also found that, after a year of storage at 4°C, the activation of the innate immune system by the different vaccines was considerably decreased. Finally, new vaccine formulations prepared with heat and formaldehyde inactivated LM-02-Fp were significantly more efficient than the available commercial vaccine in regard to stimulating the innate immune system. Camila J. Solís, Matías Poblete-Morales, Sergio Cabral, Juan A. Valdés, Ariel E. Reyes, Ruben Avendaño-Herrera, and Carmen G. Feijóo Copyright © 2015 Camila J. Solís et al. All rights reserved. Connexin 43 Communication Channels in Follicular Dendritic Cell Development and in Follicular Lymphomas Thu, 26 Feb 2015 12:34:35 +0000 Follicular dendritic cells (FDC) show homo- and heterocellular metabolic coupling through connexin 43 (Cx43) gap junctions and support B cell selection and maturation in germinal centers. In follicular lymphomas B cells escape apoptosis while FDC develop abnormally. Here we tested Cx43 channels in reactive FDC development and follicular lymphomas. In culture, the treatment of FDC-B cell clusters (resembling to “ex vivo” germinal centers) with Gap27 peptide, mimicking the 2nd extracellular loop of Cx43 protein, significantly impaired FDC-B cell cluster formation and cell survival. In untreated cultures of intact clusters, cell proliferation showed a moderate reduction. In tissues, Cx43 protein levels run parallel with the density of FDC both in reactive germinal centers and in malformed follicles of follicular lymphomas and showed strong upregulation in newly generated and/or degrading bi-/multinuclear FDC of rudimentary processes. However, the inverse correlation between Cx43 expression and B cell proliferation seen in reactive germinal centers was not detected in follicular lymphomas. Furthermore, Cx43 levels were not associated with either lymphoma grade or bone marrow involvement. Our results suggest that Cx43 channels are critical in FDC and “ex vivo” germinal center development and in the persistence of FDC in follicular lymphomas but do not affect tumor progression. Hajnalka Rajnai, Ivett Teleki, Gergo Kiszner, Nora Meggyesházi, Peter Balla, Tamas Vancsik, Gyorgyi Muzes, Judit Csomor, Andras Matolcsy, and Tibor Krenacs Copyright © 2015 Hajnalka Rajnai et al. All rights reserved. The Value of a Panel of Autoantibodies for Predicting the Activity of Lupus Nephritis at Time of Renal Biopsy Thu, 26 Feb 2015 12:05:48 +0000 Few studies have correlated serum biomarkers with renal histology, the gold standard for renal activity, in lupus nephritis (LN). We tested a panel of autoantibodies and complement at the time of kidney biopsy and after treatment. Anti-dsDNA, anti-nucleosome, anti-ribosome P, and anti-C1q antibodies and C3/C4 were measured in 107 patients with LN at the time of renal biopsy and after 6–12 months and were correlated with clinical/histological parameters. At multivariate analysis, high titers of anti-C1q antibodies or of anti-dsDNA antibodies (, OR = 8.67, CI: 2.03–37.3) were the independent predictors that discriminate proliferative from nonproliferative LN. All the immunological parameters, except anti-ribosome, showed a significant correlation with activity index but not with chronicity index. Only anti-C1q showed a significant correlation with the amount of proteinuria (, ). None of the immunological parameters were predictive of remission at 6 and 12 months. We found that anti-C1q alone or in combination with anti-dsDNA emerged as the most reliable test in differentiating proliferative and nonproliferative LN. Anti-C1q was the only test correlated with the clinical presentation of LN. After treatment, the titre of the autoantibodies was significantly reduced, but none was predictive of remission. Gabriella Moroni, Silvana Quaglini, Antonella Radice, Barbara Trezzi, Francesca Raffiotta, Piergiorgio Messa, and Renato Alberto Sinico Copyright © 2015 Gabriella Moroni et al. All rights reserved. PGE2-Induced IDO1 Inhibits the Capacity of Fully Mature DCs to Elicit an In Vitro Antileukemic Immune Response Thu, 26 Feb 2015 08:49:55 +0000 In the last years, dendritic cells (DC) have been evaluated for antitumor vaccination. Although DC-based vaccines have raised great expectations, their clinical translation has been largely disappointing. For these results, several explanations have been proposed. In particular, the concomitant expression by DCs of tolerogenic pathways, such as the immunosuppressive agent indoleamine 2,3-dioxygenase-1 (IDO1), has been demonstrated. The aim of this study is to evaluate both the stimulatory and the tolerogenic feature of monocyte-derived DCs (Mo-DCs) after maturation with PGE2. In particular, the role of IDO1 expression in PGE2-matured Mo-DCs has been addressed. Here we show that PGE2, which is required for full maturation of DCs, is one mediator of DC tolerance by enhancing IDO1. PGE2-mediated expression of IDO1 results in the production of kynurenine, in the generation of Tregs, and in the inhibition of either the allogeneic or the autologous antigen-specific stimulatory capacity of DCs. When pulsed with leukemic lysates and matured with PGE2, DCs are impaired in the induction of IFN-γ secreting CD4+ and CD8+ T cells due to IDO1 upregulation. Moreover, the inhibition of IDO1 enhances the antileukemic response. Overall, these results point toward the use of IDO1 inhibitors to enhance the vaccination capacity of DCs, matured with PGE2. Sara Trabanelli, Mariangela Lecciso, Valentina Salvestrini, Michele Cavo, Darina Očadlíková, Roberto M. Lemoli, and Antonio Curti Copyright © 2015 Sara Trabanelli et al. All rights reserved. Correlation between Genetic Variations and Serum Level of Interleukin 28B with Virus Genotypes and Disease Progression in Chronic Hepatitis C Virus Infection Wed, 25 Feb 2015 14:00:40 +0000 Recent studies have demonstrated that polymorphisms near the interleukin-28B (IL-28B) gene could predict the response to Peg-IFN-a/RBV combination therapy in HCV-infected patients. The aim of the study was to correlate the serum level of IL28B in HCV-infected patients with virus genotype/subgenotype and disease progression. IL28B serum level was detected and variations at five single nucleotide polymorphisms (SNPs) in IL28B gene region were genotyped and analyzed. The variation of IL28B genetic polymorphisms was found to be strongly associated with HCV infection when healthy control group was compared to HCV-infected patients with all values <0.0001. Functional analysis revealed that subjects carrying rs8099917-GG genotype had higher serum level of IL28B than those with GT or TT genotypes . Also, patients who were presented with cirrhosis (Cirr) only or with cirrhosis plus hepatocellular carcinoma (Cirr+HCC) had higher levels of serum IL28B when compared to chronic HCV-infected patients ( and 0.003, resp.). No significant association was found when serum levels of IL28B were compared to virus genotypes/subgenotypes. This study indicates that variation at SNP rs8099917 could predict the serum levels of IL28B in HCV-infected patients. Furthermore, IL28B serum level may serve as a useful marker for the development of HCV-associated sequelae. Ahmed Al-Qahtani, Mashael Al-Anazi, Ayman A. Abdo, Faisal M. Sanai, Waleed Al-Hamoudi, Khalid A. Alswat, Hamad I. Al-Ashgar, Mohammed Q. Khan, Ali Albenmousa, Nisreen Khalaf, Nisha Viswan, and Mohammed N. Al-Ahdal Copyright © 2015 Ahmed Al-Qahtani et al. All rights reserved. Impact of Kefir Derived Lactobacillus kefiri on the Mucosal Immune Response and Gut Microbiota Tue, 24 Feb 2015 10:02:25 +0000 The evaluation of the impact of probiotics on host health could help to understand how they can be used in the prevention of diseases. On the basis of our previous studies and in vitro assays on PBMC and Caco-2 ccl20:luc reporter system presented in this work, the strain Lactobacillus kefiri CIDCA 8348 was selected and administrated to healthy Swiss mice daily for 21 days. The probiotic treatment increased IgA in feces and reduced expression of proinflammatory mediators in Peyer Patches and mesenteric lymph nodes, where it also increased IL-10. In ileum IL-10, CXCL-1 and mucin 6 genes were upregulated; meanwhile in colon mucin 4 was induced whereas IFN-γ, GM-CSF, and IL-1β genes were downregulated. Moreover, ileum and colon explants showed the anti-inflammatory effect of L. kefiri since the LPS-induced increment of IL-6 and GM-CSF levels in control mice was significantly attenuated in L. kefiri treated mice. Regarding fecal microbiota, DGGE profiles allowed differentiation of experimental groups in two separated clusters. Quantitative PCR analysis of different bacterial groups revealed only significant changes in Lactobacillus population. In conclusion, L. kefiri is a good candidate to be used in gut inflammatory disorders. P. Carasi, S. M. Racedo, C. Jacquot, D. E. Romanin, M. A. Serradell, and M. C. Urdaci Copyright © 2015 P. Carasi et al. All rights reserved. Toll-Like Receptor Mediated Modulation of T Cell Response by Commensal Intestinal Microbiota as a Trigger for Autoimmune Arthritis Mon, 23 Feb 2015 06:51:35 +0000 In autoimmune diseases, a disturbance of the balance between T helper 17 (Th17) and regulatory T cells (Tregs) is often observed. This disturbed balance is also the case in rheumatoid arthritis (RA). Genetic predisposition to RA confers the presence of several polymorphisms mainly regulating activation of T lymphocytes. However, the presence of susceptibility factors is neither necessary nor sufficient to explain the disease development, emphasizing the importance of environmental factors. Multiple studies have shown that commensal gut microbiota is of great influence on immune homeostasis and can trigger the development of autoimmune diseases by favoring induction of Th17 cells over Tregs. However the mechanism by which intestinal microbiota influences the Th cell balance is not completely understood. Here we review the current evidence supporting the involvement of commensal intestinal microbiota in rheumatoid arthritis, along with a potential role of Toll-like receptors (TLRs) in modulating the relevant Th cell responses to trigger autoimmunity. A better understanding of TLR triggering by intestinal microbiota and subsequent T cell activation might offer new perspectives for manipulating the T cell response in RA patients and may lead to the discovery of new therapeutic targets or even preventive measures. Rebecca Rogier, Marije I. Koenders, and Shahla Abdollahi-Roodsaz Copyright © 2015 Rebecca Rogier et al. All rights reserved. Administration of Bifidobacterium breve PS12929 and Lactobacillus salivarius PS12934, Two Strains Isolated from Human Milk, to Very Low and Extremely Low Birth Weight Preterm Infants: A Pilot Study Sun, 22 Feb 2015 16:43:10 +0000 The preterm infant gut has been described as immature and colonized by an aberrant microbiota. Therefore, the use of probiotics is an attractive practice in hospitals to try to reduce morbidity and mortality in this population. The objective of this pilot study was to elucidate if administration of two probiotic strains isolated from human milk to preterm infants led to their presence in feces. In addition, the evolution of a wide spectrum of immunological compounds, including the inflammatory biomarker calprotectin, in both blood and fecal samples was also assessed. For this purpose, five preterm infants received two daily doses (~109 CFU) of a 1 : 1 mixture of Bifidobacterium breve PS12929 and Lactobacillus salivarius PS12934. Bacterial growth was detected by culture-dependent techniques in all the fecal samples. The phylum Firmicutes dominated in nearly all fecal samples while L. salivarius PS12934 was detected in all the infants at numerous sample collection points and B. breve PS12929 appeared in five fecal samples. Finally, a noticeable decrease in the fecal calprotectin levels was observed along time. Laura Moles, Esperanza Escribano, Javier de Andrés, María Teresa Montes, Juan M. Rodríguez, Esther Jiménez, Miguel Sáenz de Pipaón, and Irene Espinosa-Martos Copyright © 2015 Laura Moles et al. All rights reserved. Lactic Acid Bacteria Strains Exert Immunostimulatory Effect on H. pylori-Induced Dendritic Cells Sun, 22 Feb 2015 14:06:20 +0000 The aim of this study was to find out if selected lactic acid bacteria (LAB) strains (antagonistic or nonantagonistic against H. pylori in vitro) would differ in their abilities to modulate the DCs maturation profiles reflected by their phenotype and cytokine expression patterns. Methods. Monocyte-derived DCs maturation was elicited by their direct exposure to the LAB strains of L. rhamnosus 900 or L. paracasei 915 (antagonistic and nonantagonistic to H. pylori, resp.), in the presence or absence of H. pylori strain cagA+. The DCs maturation profile was assessed on the basis of surface markers expression and cytokines production. Results. We observed that the LAB strains and the mixtures of LAB with H. pylori are able to induce mature DCs. At the same time, the L. paracasei 915 leads to high IL-10/IL-12p70 cytokine ratio, in contrast to L. rhamnosus 900. Conclusions. This study showed that the analyzed lactobacilli strains are more potent stimulators of DC maturation than H. pylori. Interestingly from the two chosen LAB strains the antagonistic to H. pylori-L. rhamnosus strain 900 has more proinflammatory and probably antibactericidal properties. Małgorzata Wiese, Andrzej Eljaszewicz, Anna Helmin-Basa, Marek Andryszczyk, Ilona Motyl, Jolanta Wieczyńska, Lidia Gackowska, Izabela Kubiszewska, Milena Januszewska, and Jacek Michałkiewicz Copyright © 2015 Małgorzata Wiese et al. All rights reserved. CD69 Is the Crucial Regulator of Intestinal Inflammation: A New Target Molecule for IBD Treatment? Sun, 22 Feb 2015 09:52:03 +0000 CD69 has been identified as an early activation marker of lymphocytes. However, recent work has indicated that CD69 plays an essential role for the regulation of inflammatory processes. Particularly, CD69 is highly expressed by lymphocytes at mucosal sites being constantly exposed to the intestinal microflora (one of the nature’s most complex and most densely populated microbial habitats) and food antigens, while only a small number of circulating leukocytes express this molecule. In this review we will discuss the role of CD69 in mucosal tissue and consider CD69 as a potential target for the development of novel treatments of intestinal inflammation. Katarina Radulovic and Jan Hendrik Niess Copyright © 2015 Katarina Radulovic and Jan Hendrik Niess. All rights reserved. The Multifaceted Role of Commensal Microbiota in Homeostasis and Gastrointestinal Diseases Sun, 22 Feb 2015 09:23:25 +0000 The gastrointestinal tract houses a complex and diverse community of microbes. In recent years, an increased understanding of the importance of intestinal microbiota for human physiology has been gained. In the steady state, commensal microorganisms have a symbiotic relationship with the host and possess critical and distinct functions, including directly influencing immunity. This means that recognition of commensal antigens is necessary for the development of complete immune responses. Therefore, the immune system must face the challenge of maintaining mucosal homeostasis while dealing with undue passage of commensal or pathogenic microbes, as well as the host nutritional status or drug use. Disruption of this fine balance has been associated with the development of several intestinal inflammatory diseases. In this review, we discuss the mechanisms involved in the modulation of host-microbe interactions and how the breakdown of this homeostatic association can lead to intestinal inflammation and pathology. Marcelo José Barbosa Silva, Matheus Batista Heitor Carneiro, Brunna dos Anjos Pultz, Danielle Pereira Silva, Mateus Eustáquio de Moura Lopes, and Liliane Martins dos Santos Copyright © 2015 Marcelo José Barbosa Silva et al. All rights reserved. HIV and the Gut Microbiota, Partners in Crime: Breaking the Vicious Cycle to Unearth New Therapeutic Targets Sun, 22 Feb 2015 08:46:43 +0000 The gut microbiota plays a key role in health and immune system education and surveillance. The delicate balance between microbial growth and containment is controlled by the immune system. However, this balance is disrupted in cases of chronic viral infections such as HIV. This virus is capable of drastically altering the immune system and gastrointestinal environment leading to significant changes to the gut microbiota and mucosal permeability resulting in microbial translocation from the gut into the peripheral blood. The changes made locally in the gut have far-reaching consequences on the other organs of the body starting in the liver, where microbes and their products are normally filtered out, and extending to the blood and even brain. Microbial translocation and their downstream effects such as increased indolamine 2,3-dioxygenase (IDO) enzyme expression and activity create a self-sustaining feedback loop which enhances HIV disease progression and constitute a vicious cycle of inflammation and immune activation combining viral and bacterial factors. Understanding this self-perpetuating cycle could be a key element in developing new therapies aimed at the gut microbiota and its fallout after infection. Kishanda Vyboh, Mohammad-Ali Jenabian, Vikram Mehraj, and Jean-Pierre Routy Copyright © 2015 Kishanda Vyboh et al. All rights reserved. Statins Increase the Frequency of Circulating CD4+FOXP3+ Regulatory T Cells in Healthy Individuals Sun, 22 Feb 2015 07:59:04 +0000 Statins have been shown to modulate the number and the suppressive function of CD4+FOXP3+ T cells (Treg) in inflammatory conditions. However, it is not well established whether statin could also affect Treg in absence of inflammation. To address this question, eighteen normocholesterolemic male subjects were treated with lovastatin or atorvastatin daily for 45 days. The frequency and phenotype of circulating Treg were evaluated at days 0, 7, 30, and 45. mRNA levels of FOXP3, IDO, TGF-β, and IL-10 were measured in CD4+ T cells. We found that both statins significantly increased Treg frequency and FOXP3 mRNA levels at day 30. At day 45, Treg numbers returned to baseline values; however, TGF-β and FOXP3 mRNA levels remained high, accompanied by increased percentages of CTLA-4- and GITR-expressing Treg. Treg Ki-67 expression was decreased upon statin treatment. Treg frequency positively correlated with plasma levels of high-density lipoprotein cholesterol (HDL-c), suggesting a role for HDL-c in Treg homeostasis. Therefore, statins appear to have inflammation-independent immune-modulatory effects. Thus, the increase in Treg cells frequency likely contributes to immunomodulatory effect of statins, even in healthy individuals. Ana Lucía Rodríguez-Perea, Carlos J. Montoya, Sven Olek, Claire A. Chougnet, and Paula A. Velilla Copyright © 2015 Ana Lucía Rodríguez-Perea et al. All rights reserved. Intestinal Microbiota as Modulators of the Immune System and Neuroimmune System: Impact on the Host Health and Homeostasis Sun, 22 Feb 2015 07:32:53 +0000 Many immune-based intestinal disorders, such as ulcerative colitis and Crohn’s disease, as well as other illnesses, may have the intestines as an initial cause or aggravator in the development of diseases, even apparently not correlating directly to the intestine. Diabetes, obesity, multiple sclerosis, depression, and anxiety are examples of other illnesses discussed in the literature. In parallel, importance of the gut microbiota in intestinal homeostasis and immunologic conflict between tolerance towards commensal microorganisms and combat of pathogens is well known. Recent researches show that the immune system, when altered by the gut microbiota, influences the state in which these diseases are presented in the patient directly and indirectly. At the present moment, a considerable number of investigations about this subject have been performed and published. However, due to difficulties on correlating information, several speculations and hypotheses are generated. Thus, the present review aims at bringing together how these interactions work—gut microbiota, immune system, and their influence in the neuroimmune system. Carlos Magno da Costa Maranduba, Sandra Bertelli Ribeiro De Castro, Gustavo Torres de Souza, Cristiano Rossato, Francisco Carlos da Guia, Maria Anete Santana Valente, João Vitor Paes Rettore, Claudinéia Pereira Maranduba, Camila Maurmann de Souza, Antônio Márcio Resende do Carmo, Gilson Costa Macedo, and Fernando de Sá Silva Copyright © 2015 Carlos Magno da Costa Maranduba et al. All rights reserved. Meta-Analysis: Diagnostic Accuracy of Anti-Cyclic Citrullinated Peptide Antibody for Juvenile Idiopathic Arthritis Thu, 19 Feb 2015 11:48:00 +0000 Objective. To estimate the diagnostic accuracy of the anti-CCP test in JIA and to evaluate factors associated with higher accuracy. Methods. Two investigators performed an extensive search of the literature published between January 2000 and January 2014. The included articles were assessed by the Quality Assessment of Diagnostic Accuracy Studies tool. The meta-analysis was performed using a summary ROC (SROC) curve and a bivariate random-effect model to estimate sensitivity and specificity across studies. Results. The bivariate meta-analysis yielded a pooled sensitivity and specificity of 10% (95% confidence interval (CI): 6.0%–15.0%) and 99.0% (95% CI: 98.0%–100.0%). The area under the SROC curve was 0.96. Sensitivity estimates were highly heterogeneous, which was partially explained by the higher sensitivity in the rheumatoid factor-positive polyarthritis (RF+ PA) subtype (48.0%; 95% CI: 31.0%–65.0%) than in the other subtypes (17.0%; 95% CI: 14.0%–20.0%) and the higher sensitivity of the Inova assay (17.0%; 95% CI: 14.0%–20.%%) than the other assays (0.05%; 95% CI: 2.0%–11.0%). Conclusions. Anti-CCP antibody test has a high specificity for the diagnosis of JIA. The sensitivity of this test is low and varies across populations but is higher in RF+ PA than in other JIA subtypes. Yan Wang, Fengyan Pei, Xingjuan Wang, Zhiyu Sun, Chengjin Hu, and Hengli Dou Copyright © 2015 Yan Wang et al. All rights reserved. Fas Ligand DNA Enhances a Vaccination Effect by Coadministered DNA Encoding a Tumor Antigen through Augmenting Production of Antibody against the Tumor Antigen Wed, 18 Feb 2015 16:44:01 +0000 Interaction of Fas and Fas ligand (FasL) plays an important role in the regulation of immune responses by inducing apoptosis of activated cells; however, a possible role of FasL in DNA vaccination has not been well understood. We examined whether administration of DNA encoding FasL gene enhanced antitumor effects in mice that were vaccinated with DNA expressing a putative tumor antigen gene, β-galactosidase (β-gal). Growth of β-gal-positive Colon 26 tumors was retarded in the syngeneic mice immunized with β-gal and FasL DNA compared with those vaccinated with β-gal or FasL DNA. We did not detect increased numbers of β-gal-specific CD8+ T cells in lymph node of mice that received combination of β-gal and FasL DNA, but amounts of anti-β-gal antibody increased with the combination but not with β-gal or FasL DNA injection alone. Subtype analysis of anti-β-gal antibody produced by the combination of β-gal and FasL DNA or β-gal DNA injection showed that IgG2a amounts were greater in mice injected with both DNA than those with β-gal DNA alone, but IgG2b amounts were lower in both DNA-injected than β-gal DNA-injected mice. These data suggest that FasL is involved in boosting humoral immunity against a gene product encoded by coinjected DNA and enhances the vaccination effects. Boya Zhong, Guangyu Ma, Ayako Sato, Osamu Shimozato, Hongdan Liu, Quanhai Li, Masato Shingyoji, Yuji Tada, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima, and Masatoshi Tagawa Copyright © 2015 Boya Zhong et al. All rights reserved. TRAIL Modulates the Immune System and Protects against the Development of Diabetes Wed, 18 Feb 2015 06:32:06 +0000 TRAIL or tumor necrosis factor (TNF) related apoptosis-inducing ligand is a member of the TNF superfamily of proteins, whose best characterized function is the induction of apoptosis in tumor, infected, or transformed cells through activation of specific receptors. In nontransformed cells, however, the actions of TRAIL are less well characterized. Recent studies suggest that TRAIL may be implicated in the development and progression of diabetes. Here we review TRAIL biological actions, its effects on the immune system, and how and to what extent it has been shown to protect against diabetes. Fleur Bossi, Stella Bernardi, Giorgio Zauli, Paola Secchiero, and Bruno Fabris Copyright © 2015 Fleur Bossi et al. All rights reserved.