Journal of Immunology Research The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. The Bidirectional Relationship between Sleep and Immunity against Infections Mon, 31 Aug 2015 12:07:21 +0000 Sleep is considered an important modulator of the immune response. Thus, a lack of sleep can weaken immunity, increasing organism susceptibility to infection. For instance, shorter sleep durations are associated with a rise in suffering from the common cold. The function of sleep in altering immune responses must be determined to understand how sleep deprivation increases the susceptibility to viral, bacterial, and parasitic infections. There are several explanations for greater susceptibility to infections after reduced sleep, such as impaired mitogenic proliferation of lymphocytes, decreased HLA-DR expression, the upregulation of CD14+, and variations in CD4+ and CD8+ T lymphocytes, which have been observed during partial sleep deprivation. Also, steroid hormones, in addition to regulating sexual behavior, influence sleep. Thus, we hypothesize that sleep and the immune-endocrine system have a bidirectional relationship in governing various physiological processes, including immunity to infections. This review discusses the evidence on the bidirectional effects of the immune response against viral, bacterial, and parasitic infections on sleep patterns and how the lack of sleep affects the immune response against such agents. Because sleep is essential in the maintenance of homeostasis, these situations must be adapted to elicit changes in sleep patterns and other physiological parameters during the immune response to infections to which the organism is continuously exposed. Elizabeth G. Ibarra-Coronado, Ana Ma. Pantaleón-Martínez, Javier Velazquéz-Moctezuma, Oscar Prospéro-García, Mónica Méndez-Díaz, Mayra Pérez-Tapia, Lenin Pavón, and Jorge Morales-Montor Copyright © 2015 Elizabeth G. Ibarra-Coronado et al. All rights reserved. Local and Systemic IKK and NF-B Signaling Associated with Sjögren’s Syndrome Immunopathogenesis Wed, 26 Aug 2015 12:40:51 +0000 The activated NF-κB signaling pathway plays an important role in pathogenesis of primary Sjögren’s syndrome (pSS). The inhibitor of κB (IκB) kinase (IKK) family such as IKKα, IKKβ, IKKγ, and IKKε, is required for this signaling. Our aim was to investigate the role of IKKα/β/γ/ε in patients with untreated pSS. In minor salivary glands from pSS patients, phosphorylated IKKε (pIKKε), pIκBα, and pNF-κB p65 (p-p65) were highly expressed in ductal epithelium and infiltrating mononuclear cells by immunohistochemistry, compared to healthy individuals. pIKKα/β and pIKKγ were both negative. And pIKKε positively related to expression of p-p65. Furthermore, pIKKε and p-p65 expression significantly correlated with biopsy focus score and overall disease activity. Meanwhile, in peripheral blood mononuclear cells from pSS patients, pIKKε, total IKKε, pIKKα/β, and p-p65 were significantly increased by western blot, compared to healthy controls. However, there was no difference in IKKγ and IκBα between pSS patients and healthy individuals. These results demonstrated an abnormality of IKKε, IκBα, and NF-κB in pSS, suggesting a potential target of treatment for pSS based on the downregulation of IKKε expression and deregulation of NF-κB pathway. Weiqian Chen, Jin Lin, Heng Cao, Danyi Xu, Bei Xu, Liqin Xu, Lihuan Yue, Chuanyin Sun, Guolin Wu, and Wenbin Qian Copyright © 2015 Weiqian Chen et al. All rights reserved. Vaccines of the Future: The Role of Inflammation and Adjuvanticity Wed, 26 Aug 2015 11:19:52 +0000 Cheol-Heui Yun, Luciana C. C. Leite, Aldo Tagliabue, and Diana Boraschi Copyright © 2015 Cheol-Heui Yun et al. All rights reserved. Serum Calprotectin: A Potential Biomarker for Neonatal Sepsis Wed, 26 Aug 2015 08:00:58 +0000 Introduction. The correct diagnosis of neonatal sepsis is a relevant problem because sepsis is one of the most important causes of neonatal morbidity, mortality, and prolonged hospital stay. Calprotectin is an antimicrobial, calcium and zinc binding heterocomplex protein that could be used as a nonspecific marker for activation of granulocytes and mononuclear phagocytes. Calprotectin has been proposed for the diagnosis of inflammatory conditions. Our aim is to study serum calprotectin as a biomarker for neonatal sepsis diagnosis. Methods. 41 (20 females, 21 males) infants who underwent blood culture due to suspected sepsis were enrolled in the study. Serum calprotectin was measured by a commercial ELISA assay (Calprest, Eurospital, Trieste, Italy). Statistical analysis was performed using the statistical software package Stata 13.1 (Stata Corporation, College Station, Texas, USA). Results. 8 neonates (19.51%) showed sepsis with positive culture and 33 (80.49%) showed suspected sepsis. The optimal cut-off for calprotectin is 2.2 μg/mL with a sensitivity of 62.5% and a specificity of 69.7%. Conclusions. Calprotectin may be considered a promising early, sensitive, specific marker of sepsis thanks to the importance of calprotectin in defense mechanisms and physiological functions of the immune system. Lidia Decembrino, Mara De Amici, Margherita Pozzi, Annalisa De Silvestri, and Mauro Stronati Copyright © 2015 Lidia Decembrino et al. All rights reserved. Stimulation of Innate and Adaptive Immunity by Using Filamentous Bacteriophage fd Targeted to DEC-205 Wed, 26 Aug 2015 07:13:56 +0000 The filamentous bacteriophage fd, codisplaying antigenic determinants and a single chain antibody fragment directed against the dendritic cell receptor DEC-205, is a promising vaccine candidate for its safety and its ability to elicit innate and adaptive immune response in absence of adjuvants. By using a system vaccinology approach based on RNA-Sequencing (RNA-Seq) analysis, we describe a relevant gene modulation in dendritic cells pulsed with anti-DEC-205 bacteriophages fd. RNA-Seq data analysis indicates that the bacteriophage fd virions are sensed as a pathogen by dendritic cells; they activate the danger receptors that trigger an innate immune response and thus confer a strong adjuvanticity that is needed to obtain a long-lasting adaptive immune response. Luciana D’Apice, Valerio Costa, Rossella Sartorius, Maria Trovato, Marianna Aprile, and Piergiuseppe De Berardinis Copyright © 2015 Luciana D’Apice et al. All rights reserved. Targeted Collection of Plasmid DNA in Large and Growing Animal Muscles 6 Weeks after DNA Vaccination with and without Electroporation Tue, 25 Aug 2015 08:23:09 +0000 DNA vaccination has been developed in the last two decades in human and animal species as a promising alternative to conventional vaccination. It consists in the injection, in the muscle, for example, of plasmid DNA encoding the vaccinating polypeptide. Electroporation which forces the entrance of the plasmid DNA in cells at the injection point has been described as a powerful and promising strategy to enhance DNA vaccine efficacy. Due to the fact that the vaccine is composed of DNA, close attention on the fate of the plasmid DNA upon vaccination has to be taken into account, especially at the injection point. To perform such studies, the muscle injection point has to be precisely recovered and collected several weeks after injection. This is even more difficult for large and growing animals. A technique has been developed to localize precisely and collect efficiently the muscle injection points in growing piglets 6 weeks after DNA vaccination accompanied or not by electroporation. Electroporation did not significantly increase the level of remaining plasmids compared to nonelectroporated piglets, and, in all the cases, the levels were below the limit recommended by the FDA to research integration events of plasmid DNA into the host DNA. Daniel Dory, Vincent Le Moigne, Roland Cariolet, Véronique Béven, André Keranflec’h, and André Jestin Copyright © 2015 Daniel Dory et al. All rights reserved. Application of “Systems Vaccinology” to Evaluate Inflammation and Reactogenicity of Adjuvanted Preventative Vaccines Tue, 25 Aug 2015 08:07:58 +0000 Advances in “omics” technology (transcriptomics, proteomics, metabolomics, genomics/epigenomics, etc.) allied with statistical and bioinformatics tools are providing insights into basic mechanisms of vaccine and adjuvant efficacy or inflammation/reactogenicity. Predictive biomarkers of relatively frequent inflammatory reactogenicity may be identified in systems vaccinology studies involving tens or hundreds of participants and used to screen new vaccines and adjuvants in in vitro, ex vivo, animal, or human models. The identification of rare events (such as those observed with initial rotavirus vaccine or suspected autoimmune complications) will require interrogation of large data sets and population-based research before application of systems vaccinology. The Innovative Medicine Initiative funded public-private project BIOVACSAFE is an initial attempt to systematically identify biomarkers of relatively common inflammatory events after adjuvanted immunization using human, animal, and population-based models. Discriminatory profiles or biomarkers are being identified, which require validation in large trials involving thousands of participants before they can be generalized. Ultimately, it is to be hoped that the knowledge gained from such initiatives will provide tools to the industry, academia, and regulators to select optimal noninflammatory but immunogenic and effective vaccine adjuvant combinations, thereby shortening product development cycles and identifying unsuitable vaccine candidates that would fail in expensive late stage development or postmarketing. David J. M. Lewis and Mark P. Lythgoe Copyright © 2015 David J. M. Lewis and Mark P. Lythgoe. All rights reserved. Extracellular Vesicles: Role in Inflammatory Responses and Potential Uses in Vaccination in Cancer and Infectious Diseases Tue, 25 Aug 2015 08:03:06 +0000 Almost all cells and organisms release membrane structures containing proteins, lipids, and nucleic acids called extracellular vesicles (EVs), which have a wide range of functions concerning intercellular communication and signaling events. Recently, the characterization and understanding of their biological role have become a main research area due to their potential role in vaccination, as biomarkers antigens, early diagnostic tools, and therapeutic applications. Here, we will overview the recent advances and studies of Evs shed by tumor cells, bacteria, parasites, and fungi, focusing on their inflammatory role and their potential use in vaccination and diagnostic of cancer and infectious diseases. João Henrique Campos, Rodrigo Pedro Soares, Kleber Ribeiro, André Cronemberger Andrade, Wagner Luiz Batista, and Ana Claudia Torrecilhas Copyright © 2015 João Henrique Campos et al. All rights reserved. Are the Two Human Papillomavirus Vaccines Really Similar? A Systematic Review of Available Evidence: Efficacy of the Two Vaccines against HPV Tue, 25 Aug 2015 07:58:08 +0000 Background. When the bivalent and the quadrivalent HPV vaccines were marketed they were presented as having comparable efficacy against cervical cancer. Differences between the vaccines are HPV types included and formulation of the adjuvant. Method. A systematic review was conducted to assess the efficacy of the two vaccines against cervical cancer. Outcomes considered were CIN2+, CIN3+, and AIS. Results. Nine reports (38,419 women) were included. At enrolment mean age of women was 20 years, 90% had negative cytology, and 80% were seronegative and/or DNA negative for HPV 16 or 18 (naïve women). In the TVC-naïve, VE against CIN2+ was 58% (95% CI: 35, 72); heterogeneity was detected, VE being 65% (95% CI: 54, 74) for the bivalent and 43% (95% CI: 23, 57) for the quadrivalent. VE against CIN3+ was 78% (95% CI: <0, 97); heterogeneity was substantial, VE being 93% (95% CI: 77, 98) for the bivalent and 43% (95% CI: 12, 63) for the quadrivalent. VE in the TVC was much lower. No sufficient data were available on AIS. Conclusions. In naïve girls bivalent vaccine shows higher efficacy, even if the number of events detected is low. In women already infected the benefit of the vaccination seems negligible. Simona Di Mario, Vittorio Basevi, Pier Luigi Lopalco, Sara Balduzzi, Roberto D’Amico, and Nicola Magrini Copyright © 2015 Simona Di Mario et al. All rights reserved. Development of Nonaggregating Poly-A Tailed Immunostimulatory A/D Type CpG Oligodeoxynucleotides Applicable for Clinical Use Tue, 25 Aug 2015 07:52:00 +0000 Immunostimulatory CpG ODNs have been developed and utilized as TLR9-dependent innate immune activators and vaccine adjuvants. Four different types of immunostimulatory CpG ODNs (A/D, B/K, C, and P type) have been reported. A/D type ODNs are characterized by high IFN-α production but intrinsically form aggregates, hindering its good manufacturing practice grade preparation. In this study, we developed several D35-derived ODNs (a commonly used A/D type ODN), which were modified with the addition of a phosphorothioate polynucleotide tail (such as dAs40), and examined their physical properties, solubility in saline, immunostimulatory activity on human PBMCs, and vaccine adjuvant potential in monkeys. We found that two modified ODNs including D35-dAs40 and D35core-dAs40 were immunostimulatory, similar to original D35 in human PBMCs, resulting in high IFN-α secretion in a dose-dependent manner. Physical property analysis by dynamic light scattering revealed that both D35-dAs40 and D35core-dAs40 did not form aggregates in saline, which is currently impossible for the original D35. Furthermore, D35-dAs40 and D35core-dAs40 worked as better vaccine adjuvant in monkeys. These results suggested that D35-dAs40 and D35core-dAs40 are two promising prototypes of nonaggregating A/D type ODN with advantages of ease of drug preparation for clinical applications as vaccine adjuvants or IFN-α inducing immunomodifiers. Taiki Aoshi, Yasunari Haseda, Kouji Kobiyama, Hirotaka Narita, Hideaki Sato, Hirokazu Nankai, Shinichi Mochizuki, Kazuo Sakurai, Yuko Katakai, Yasuhiro Yasutomi, Etsushi Kuroda, Cevayir Coban, and Ken J. Ishii Copyright © 2015 Taiki Aoshi et al. All rights reserved. Adsorption of Toll-Like Receptor 4 Agonist to Alum-Based Tetanus Toxoid Vaccine Dampens Pro-T Helper 2 Activities and Enhances Antibody Responses Tue, 25 Aug 2015 07:46:43 +0000 Aluminum salts gels (alum) are TLR-independent adjuvants and have been used to boost antibody responses in alum-based vaccines such as diphtheria, pertussis, and tetanus toxoid (DPT) triple vaccine. However, the pro-Th2 activity of alum-based vaccine formulations has not been fully appreciated. Here we found that alum-based tetanus toxoid (TT) vaccine was biased toward a Th-2 profile as shown by TT-induced airway eosinophilic inflammation, type 2 cytokine production, and high levels of IgE anaphylactic antibodies. The adsorption into alum of prototypic TLR4 agonists such as lipopolysaccharides (LPS) derived from Escherichia coli consistently dampened TT-induced Th2 activities without inducing IFNγ or Th1-like responses in the lung. Conversely, adsorption of monophosphoryl lipid A (MPLA) extracted from Salmonella minnesota, which is a TIR-domain-containing adapter-inducing interferon-β- (TRIF-) biased TLR4 agonist, was less effective in decreasing Th-2 responses. Importantly, in a situation with antigenic competition (OVA plus TT), TT-specific IgG1 or IgG2a was decreased compared with TT sensitization. Notably, LPS increased the production of IgG1 and IgG2a TT-specific antibodies. In conclusion, the addition of LPS induces a more robust IgG1 and IgG2a TT-specific antibody production and concomitantly decreases Th2-cellular and humoral responses, indicating a potential use of alum/TLR-based vaccines. Juliana Bortolatto, Luciana Mirotti, Dunia Rodriguez, Eliane Gomes, and Momtchilo Russo Copyright © 2015 Juliana Bortolatto et al. All rights reserved. Non-CpG Oligonucleotides Exert Adjuvant Effects by Enhancing Cognate B Cell-T Cell Interactions, Leading to B Cell Activation, Differentiation, and Isotype Switching Tue, 25 Aug 2015 07:16:54 +0000 Natural and synthetic nucleic acids are known to exert immunomodulatory properties. Notably, nucleic acids are known to modulate immune function via several different pathways and various cell types, necessitating a complex interpretation of their effects. In this study we set out to compare the effects of a CpG motif containing oligodeoxynucleotide (ODN) with those of a control and an inhibitory non-CpG ODN during cognate B cell-T cell interactions. We employed an antigen presentation system using splenocytes from TCR transgenic DO11.10 mice and the ovalbumin peptide recognized by the TCR as model antigen. We followed early activation events by measuring CD69 expression, late activation by MHC class II expression, cell division and antibody production of switched, and nonswitched isotypes. We found that both of the tested non-CpG ODN exerted significant immunomodulatory effects on early T cell and on late B cell activation events. Importantly, a synergism between non-CpG effects and T cell help acting on B cells was observed, resulting in enhanced IgG production following cognate T cell-B cell interactions. We propose that non-CpG ODN may perform as better adjuvants when a strong antigen-independent immune activation, elicited by CpG ODNs, is undesirable. Melinda Herbáth, Krisztián Papp, Anna Erdei, and József Prechl Copyright © 2015 Melinda Herbáth et al. All rights reserved. Innate Immune Memory: The Latest Frontier of Adjuvanticity Tue, 25 Aug 2015 07:10:21 +0000 Recent findings in the field of immune memory have demonstrated that B and T cell mediated immunity following infections are enhanced by the so-called trained immunity. This effect has been most extensively investigated for the tuberculosis vaccine strain Bacillus Calmette-Guérin (BCG). Epidemiological studies suggest that this vaccine is associated with a substantial reduction in overall child mortality that cannot be solely explained by prevention of the target disease but that it seems to rely on inducing resistance to other infections. Upon infection or vaccination, monocytes/macrophages can be functionally reprogrammed so as to display an enhanced defensive response against unrelated infections. Epigenetic modifications seem to play a key role in the induction of this “innate memory.” These findings are revolutionising our knowledge of the immune system, introducing the concept of memory also for mammalian innate immunity. Thus, vaccines are likely to nonspecifically affect the overall immunological status of individuals in a clinically relevant manner. As a consequence, future vaccine strategies ought to take into account the contribution of innate memory through appropriate design of formulations and administration scheduling. Elfi Töpfer, Diana Boraschi, and Paola Italiani Copyright © 2015 Elfi Töpfer et al. All rights reserved. Possible Triggering Effect of Influenza Vaccination on Psoriasis Tue, 25 Aug 2015 07:10:16 +0000 Psoriasis is a chronic, recurrent, immune-mediated inflammatory disease and it can be provoked or exacerbated by a variety of different environmental factors, particularly infections and drugs. In addition, a possible association between vaccination and the new onset and/or exacerbation of psoriasis has been reported by a number of different authors. The aim of this study is to investigate the effects of influenza vaccination on patients with psoriasis. Here, we report the findings from 43 patients suffering from psoriasis (clinical phenotypes as mixed guttate/plaque lesions, palmoplantar or scalp psoriasis) whose diseases had been triggered after influenza vaccination applied in the 2009-2010 season. The short time intervals between vaccination and psoriasis flares in our patients and the lack of other possible triggers suggest that influenza vaccinations may have provocative effects on psoriasis. However, further large and controlled studies need to be carried out to confirm this relationship. Ali Tahsin Gunes, Emel Fetil, Sevgi Akarsu, Ozlem Ozbagcivan, and Lale Babayeva Copyright © 2015 Ali Tahsin Gunes et al. All rights reserved. Differential Immune Response against Recombinant Leishmania donovani Peroxidoxin 1 and Peroxidoxin 2 Proteins in BALB/c Mice Tue, 25 Aug 2015 06:29:54 +0000 We assessed the immune response against recombinant proteins of two related, albeit functionally different, peroxidoxins from Leishmania donovani: peroxidoxin 1 (LdPxn1) and peroxidoxin 2 (LdPxn2) in BALB/c mice. We also evaluated the effect of coadministration of TLR agonists (CpG ODN and GLA-SE) on the antigen-specific immune response. Immunization with recombinant LdPxn1 alone induced a predominantly Th2 type immune response that is associated with the production of high level of IgG1 and no IgG2a isotype while rLdPxn2 resulted in a mixed Th1/Th2 response characterized by the production of antigen-specific IgG2a in addition to IgG1 isotype. Antigen-stimulated spleen cells from mice that were immunized with rLdPxn1 produced low level of IL-10 and IL-4 and no IFN-γ, whereas cells from mice immunized with rLdPxn2 secreted high level of IFN-γ, low IL-4, and no IL-10. Coadministration of CpG ODN or GLA-SE with rLdPxn1 skewed the immune response towards a Th 1 type as indicated by robust production of IgG2a isotype. Furthermore, the presence of TLR agonists together with rLdPxn1 antigen enhanced the production of IFN-γ and to a lesser extent of IL-10. TLR agonists also enhanced a more polarized Th 1 type immune response against rLdPxn2. Nada S. Daifalla, Abebe Genetu Bayih, and Lashitew Gedamu Copyright © 2015 Nada S. Daifalla et al. All rights reserved. Mesenchymal Stromal Cell-Derived Factors Promote Tissue Repair in a Small-for-Size Ischemic Liver Model but Do Not Protect against Early Effects of Ischemia and Reperfusion Injury Mon, 24 Aug 2015 12:27:34 +0000 Loss of liver mass and ischemia/reperfusion injury (IRI) are major contributors to postresectional liver failure and small-for-size syndrome. Mesenchymal stromal cell- (MSC-) secreted factors are described to stimulate regeneration after partial hepatectomy. This study investigates if liver-derived MSC-secreted factors also promote liver regeneration after resection in the presence of IRI. C57BL/6 mice underwent IRI of 70% of their liver mass, alone or combined with 50% partial hepatectomy (PH). Mice were treated with MSC-conditioned medium (MSC-CM) or unconditioned medium (UM) and sacrificed after 6 or 24 hours (IRI group) or after 48 hours (IRI + PH group). Blood and liver tissue were analyzed for tissue injury, hepatocyte proliferation, and gene expression. In the IRI alone model, serum ALT and AST levels, hepatic tissue damage, and inflammatory cytokine gene expression showed no significant differences between both treatment groups. In the IRI + PH model, significant reduction in hepatic tissue damage as well as a significant increase in hepatocyte proliferation was observed after MSC-CM treatment. Conclusion. Mesenchymal stromal cell-derived factors promote tissue regeneration of small-for-size livers exposed to ischemic conditions but do not protect against early ischemia and reperfusion injury itself. MSC-derived factors therefore represent a promising treatment strategy for small-for-size syndrome and postresectional liver failure. Suomi M. G. Fouraschen, Joshua H. Wolf, Luc J. W. van der Laan, Petra E. de Ruiter, Wayne W. Hancock, Job P. van Kooten, Monique M. A. Verstegen, Kim M. Olthoff, and Jeroen de Jonge Copyright © 2015 Suomi M. G. Fouraschen et al. All rights reserved. Immune Homeostasis in Epithelial Cells: Evidence and Role of Inflammasome Signaling Reviewed Wed, 19 Aug 2015 11:29:17 +0000 The epithelium regulates the interaction between the noxious xenogenous, as well as the microbial environment and the immune system, not only by providing a barrier but also by expressing a number of immunoregulatory membrane receptors, and intracellular danger sensors and their downstream effectors. Amongst these are a number of inflammasome sensor subtypes, which have been initially characterized in myeloid cells and described to be activated upon assembly into multiprotein complexes by microbial and environmental triggers. This review compiles a vast amount of literature that supports a pivotal role for inflammasomes in the various epithelial barriers of the human body as essential factors maintaining immune signaling and homeostasis. Paul M. Peeters, Emiel F. Wouters, and Niki L. Reynaert Copyright © 2015 Paul M. Peeters et al. All rights reserved. Immunological Features and Clinical Benefits of Conjugate Vaccines against Bacteria Tue, 18 Aug 2015 11:54:22 +0000 Paolo Durando, Saul N. Faust, and Antoni Torres Copyright © 2015 Paolo Durando et al. All rights reserved. Coinfection by Hepatitis C Is Strongly Associated with Abnormal CD4/CD8 Ratio in HIV Patients under Stable ART in Salvador, Brazil Tue, 18 Aug 2015 06:15:23 +0000 Proper immune restoration (CD4 count >500 and normal CD4/8 ratio) is reached only by a fraction of HIV patients, despite stable viral suppression. Methods. We present a case-control study to compare HIV patients with viral suppression >1 year, according to immune restoration pattern: adequate response (AR) defined by CD4 > 500 cells/mm3 and CD4/8 ratio >1; partial response (PR = patients with CD4 > 500, but CD4/8 ratio <1); inadequate response (IR = CD4 < 500 cells). Results. We evaluated 293 consecutive patients (89 AR, 112 PR, and 92 IR), 70% males. Male gender (), lower mean CD4 nadir (), higher baseline VL (), previous diagnosis of Tb (), or HCV () was associated with IR. Likelihood of AR/PR was similar regardless of gender, after adjusting for nadir CD4+ cells count. Longer time under suppressive ART was also associated with a greater chance of AR, but logistic regression identified coinfection by HCV as the main factor associated with abnormal CD4/CD8 ratio. Conclusion. Early initiation of ART and longer time since first undetectable PVL were predictors of AR. Previous HCV diagnosis significantly increases the risk of abnormal CD4/CD8 ratio. Clara Brites-Alves, Eduardo Martins Netto, and Carlos Brites Copyright © 2015 Clara Brites-Alves et al. All rights reserved. Impacts of the 13-Valent Pneumococcal Conjugate Vaccine in Children Mon, 17 Aug 2015 13:52:46 +0000 Applications of the heptavalent pneumococcal conjugate vaccine (PCV7) in the pediatric immunization schedule have dramatically reduced the incidence of pneumococcal diseases in both vaccinated children and unvaccinated individuals of all ages. However, increased infections caused by non-PCV7 serotypes have been reported by several groups. To overcome this problem, new vaccines covering more serotypes including the emerging serotypes have been developed. The 13-valent pneumococcal conjugate vaccine (PCV13) currently covers the 7 PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) and 6 additional serotypes 1, 3, 5, 6A, 7F, and 19A. After the first year of PCV13 applications in the immunization schedule in young children, global evaluation studies demonstrated that PCV13 provided a wider coverage and more effective prevention than PCV7 against invasive pneumococcal diseases (IPDs), mucosal pneumococcal diseases, and pneumococcal carriage. We reviewed the effects of PCV13 in the control of pneumococcal diseases in children based on previous studies. Susanna Esposito and Nicola Principi Copyright © 2015 Susanna Esposito and Nicola Principi. All rights reserved. How the Knowledge of Interactions between Meningococcus and the Human Immune System Has Been Used to Prepare Effective Neisseria meningitidis Vaccines Mon, 17 Aug 2015 08:34:35 +0000 In the last decades, tremendous advancement in dissecting the mechanisms of pathogenicity of Neisseria meningitidis at a molecular level has been achieved, exploiting converging approaches of different disciplines, ranging from pathology to microbiology, immunology, and omics sciences (such as genomics and proteomics). Here, we review the molecular biology of the infectious agent and, in particular, its interactions with the immune system, focusing on both the innate and the adaptive responses. Meningococci exploit different mechanisms and complex machineries in order to subvert the immune system and to avoid being killed. Capsular polysaccharide and lipooligosaccharide glycan composition, in particular, play a major role in circumventing immune response. The understanding of these mechanisms has opened new horizons in the field of vaccinology. Nowadays different licensed meningococcal vaccines are available and used: conjugate meningococcal C vaccines, tetravalent conjugate vaccines, an affordable conjugate vaccine against the N. menigitidis serogroup A, and universal vaccines based on multiple antigens each one with a different and peculiar function against meningococcal group B strains. R. Gasparini, D. Panatto, N. L. Bragazzi, P. L. Lai, A. Bechini, M. Levi, P. Durando, and D. Amicizia Copyright © 2015 R. Gasparini et al. All rights reserved. Estimation of the Impact of Meningococcal Serogroup C Universal Vaccination in Italy and Suggestions for the Multicomponent Serogroup B Vaccine Introduction Mon, 17 Aug 2015 08:32:04 +0000 In Italy, the meningococcal C conjugate vaccine (MenC) has been offered in most regions since 2009-2010. The incidence of Invasive Meningococcal Disease (IMD) was 0.25 confirmed cases per 100,000 in 2011, but this may be considerably underestimated due to underdetection and underreporting. This study estimates the impact of the MenC universal vaccination (URV) in the Puglia region by assessing the completeness of three registration sources (notifications, hospitalizations, and laboratory surveillance). Capture-recapture analysis was performed on meningococcal meningitis collected within 2001–2013. The impact of URV among 18-year-olds was assessed by attributable benefit, preventable fraction, and prevented fraction. Missed opportunities for vaccination were evaluated from surveillance of IMD. The proportion of detected serogroups was applied to the number of IMD in the postvaccination period to compute the cases still preventable. The sensitivity of the three sources was 36.7% (95% CI: 17.5%–57.9%) and registrations lost nearly 28 cases/year in the period. Attributable benefit of URV was −0.5 cases per 100,000, preventable fraction 19.6%, and prevented fraction 31.3%. Three adolescent cases missed the opportunity to be vaccinated. The multicomponent serogroup B meningococcal vaccine has the potential to further prevent at least three other cases/year. Vaccination strategy against serogroup B together with existing programmes makes IMD a 100% vaccine-preventable disease. Domenico Martinelli, Francesca Fortunato, Maria Giovanna Cappelli, Vanessa Cozza, Maria Chironna, and Rosa Prato Copyright © 2015 Domenico Martinelli et al. All rights reserved. Meningococcal Antigen Typing System Development and Application to the Evaluation of Effectiveness of Meningococcal B Vaccine and Possible Use for Other Purposes Mon, 17 Aug 2015 06:45:22 +0000 Development of the 4-component meningococcal serogroup B vaccine (4CMenB) has required new assays for the reliable evaluation of the expression and cross-reactivity of those specific antigen variants that are predicted to be targeted by bactericidal antibodies elicited by the vaccine in different isolates. Existing laboratory techniques, such as multilocus sequence typing, are poorly suited to this purpose, since they do not provide information on the contribution of single vaccine components and therefore cannot be applied to estimate the potential coverage of the multicomponent vaccine. The hSBA, the only correlate of protection against invasive meningococcal disease accepted thus far, cannot conveniently be used to test large number of strains. To overcome these issues, the meningococcal antigen typing system (MATS) has been specifically developed in order to predict 4CMenB coverage of individual meningococcus serogroup B strains. To date, MATS has proved advantageous for several reasons, including its ability to assess both qualitative and quantitative aspects of surface antigens of single strains in a highly reproducible, rapid, and resource-saving manner, while its shortcomings include a possible underestimation of 4CMenB coverage and the use of pooled sera to calculate the positive bactericidal threshold. This paper provides an overview of MATS development and its field application. Alexander Domnich, Roberto Gasparini, Daniela Amicizia, Giuseppe Boccadifuoco, Marzia Monica Giuliani, and Donatella Panatto Copyright © 2015 Alexander Domnich et al. All rights reserved. Meningococcal B Vaccination (4CMenB) in Infants and Toddlers Mon, 17 Aug 2015 06:39:34 +0000 Neisseria meningitidis is a Gram-negative pathogen that actively invades its human host and leads to the development of life-threatening pathologies. One of the leading causes of death in the world, N. meningitidis can be responsible for nearly 1,000 new infections per 100,000 subjects during an epidemic period. The bacterial species are classified into 12 serogroups, five of which (A, B, C, W, and Y) cause the majority of meningitides. The three purified protein conjugate vaccines currently available target serogroups A, C, W, and Y. Serogroup B has long been a challenge but the discovery of the complete genome sequence of an MenB strain has allowed the development of a specific four-component vaccine (4CMenB). This review describes the pathogenetic role of N. meningitidis and the recent literature concerning the new meningococcal vaccine. Susanna Esposito, Claudia Tagliabue, and Samantha Bosis Copyright © 2015 Susanna Esposito et al. All rights reserved. Nasopharyngeal Bacterial Carriage in the Conjugate Vaccine Era with a Focus on Pneumococci Sun, 16 Aug 2015 14:15:37 +0000 Seven-valent pneumococcal conjugate vaccine (PCV7) was included in the UK national immunisation program in 2006, and this was replaced by thirteen-valent PCV in 2010. During this time, the carriage of vaccine-type Streptococcus pneumoniae decreased but pneumococcal carriage remained stable due to increases in non-vaccine-type S. pneumoniae. Carriage studies have been undertaken in various countries to monitor vaccine-type replacement and to help predict the serotypes, which may cause invasive disease. There has been less focus on how conjugate vaccines indirectly affect colonization of other nasopharyngeal bacteria. If the nasopharynx is treated as a niche, then bacterial dynamics are accepted to occur. Alterations in these dynamics have been shown due to seasonal changes, antibiotic use, and sibling/day care interaction. It has been shown that, following PCV7 introduction, an eradication of pneumococcal vaccine types has resulted in increases in the abundance of other respiratory pathogens including Haemophilus influenzae and Staphylococcus aureus. These changes are difficult to attribute to PCV7 introduction alone and these studies do not account for further changes due to PCV13 implementation. This review aims to describe nasopharyngeal cocarriage of respiratory pathogens in the PCV era. V. T. Devine, J. M. Jefferies, S. C. Clarke, and S. N. Faust Copyright © 2015 V. T. Devine et al. All rights reserved. Impact of Pneumococcal Conjugate Universal Routine Vaccination on Pneumococcal Disease in Italian Children Sun, 16 Aug 2015 14:13:33 +0000 In Italy, the effectiveness of pneumococcal universal vaccination in preventing vaccine-type invasive pneumococcal disease (IPD) in the PCV7/PCV13 shifting period was estimated to be 84.3% (95% CI: 84.0–84.6%) in children <5 years. This study aims at corroborating the estimation of both the effectiveness (VE) of PCVs and its impact in reducing pneumococcal diseases. A 1 : 3 matched-case-control study was conducted among children <5 years old hospitalized for IPD or pneumococcal pneumonia (PP) between 2006 and 2012 in the Puglia region. Moreover, hospitalizations for pneumococcal outcomes in the pre- and postvaccination period and the hospitalization risk ratios (HRRs) with 95% CIs were computed in Italy and in the first eight regions that introduced PCVs in 2006. The overall effectiveness of PCVs was 75% (95% CI: 61%–84%); it was 69% (95% CI: 30%–88%) against IPD and 77% (95% CI: 61%–87%) against PP. PCVs showed a significant impact on IPD and acute otitis media either at a national level or in those regions with a longer vaccination history, with a nearly 40% reduction of hospitalizations for both outcomes. Our findings provide further evidence of the effectiveness of PCVs against pneumococcal diseases and its impact on nasopharyngeal carriage in children <5 years, indicating the importance of maintaining high immunization coverage. Francesca Fortunato, Domenico Martinelli, Maria Giovanna Cappelli, Vanessa Cozza, and Rosa Prato Copyright © 2015 Francesca Fortunato et al. All rights reserved. Human Leukocyte Antigen Diversity: A Southern African Perspective Wed, 12 Aug 2015 11:26:53 +0000 Despite the increasingly well-documented evidence of high genetic, ethnic, and linguistic diversity amongst African populations, there is limited data on human leukocyte antigen (HLA) diversity in these populations. HLA is part of the host defense mechanism mediated through antigen presentation to effector cells of the immune system. With the high disease burden in southern Africa, HLA diversity data is increasingly important in the design of population-specific vaccines and the improvement of transplantation therapeutic interventions. This review highlights the paucity of HLA diversity data amongst southern African populations and defines a need for information of this kind. This information will support disease association studies, provide guidance in vaccine design, and improve transplantation outcomes. Mqondisi Tshabalala, Juanita Mellet, and Michael S. Pepper Copyright © 2015 Mqondisi Tshabalala et al. All rights reserved. Exposure of Monocytes to Lipoarabinomannan Promotes Their Differentiation into Functionally and Phenotypically Immature Macrophages Tue, 11 Aug 2015 09:55:45 +0000 Lipoarabinomannan (LAM) is a lipid virulence factor secreted by Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis. LAM can be measured in the urine or serum of tuberculosis patients (TB-patients). Circulating monocytes are the precursor cells of alveolar macrophages and might be exposed to LAM in patients with active TB. We speculated that exposing monocytes to LAM could produce phenotypically and functionally immature macrophages. To test our hypothesis, human monocytes were stimulated with LAM (24–120 hours) and various readouts were measured. The study showed that when monocytes were exposed to LAM, the frequency of CD68+, CD33+, and CD86+ macrophages decreased, suggesting that monocyte differentiation into mature macrophages was affected. Regarding functionality markers, TLR2+ and TLR4+ macrophages also decreased, but the percentage of MMR+ expression did not change. LAM-exposed monocytes generated macrophages that were less efficient in producing proinflammatory cytokines such as TNF- and IFN-; however, their phagocytic capacity was not modified. Taken together, these data indicate that LAM exposure influenced monocyte differentiation and produced poorly functional macrophages with a different phenotype. These results may help us understand how mycobacteria can limit the quality of the innate and adaptive immune responses. Leslie Chávez-Galán, Ranferi Ocaña-Guzmán, Luis Torre-Bouscoulet, Carolina García-de-Alba, and Isabel Sada-Ovalle Copyright © 2015 Leslie Chávez-Galán et al. All rights reserved. SP140L, an Evolutionarily Recent Member of the SP100 Family, Is an Autoantigen in Primary Biliary Cirrhosis Tue, 11 Aug 2015 08:23:03 +0000 The SP100 family members comprise a set of closely related genes on chromosome 2q37.1. The widely expressed SP100 and the leukocyte-specific proteins SP110 and SP140 have been associated with transcriptional regulation and various human diseases. Here, we have characterized the SP100 family member SP140L. The genome sequence analysis showed the formation of SP140L gene through rearrangements of the two neighboring genes, SP100 and SP140, during the evolution of higher primates. The SP140L expression is interferon-inducible with high transcript levels in B cells and other peripheral blood mononuclear cells. Subcellularly, SP140L colocalizes with SP100 and SP140 in nuclear structures that are devoid of SP110, PML, or p300 proteins. Similarly to SP100 and SP140 protein, we detected serum autoantibodies to SP140L in patients with primary biliary cirrhosis using luciferase immunoprecipitation system and immunoblotting assays. In conclusion, our results show that SP140L is phylogenetically recent member of SP100 proteins and acts as an autoantigen in primary biliary cirrhosis patients. Mario Saare, Uku Hämarik, Rainis Venta, Marina Panarina, Chiara Zucchelli, Maire Pihlap, Anu Remm, Kai Kisand, Urve Toots, Kaidi Möll, Riina Salupere, Giovanna Musco, Raivo Uibo, and Pärt Peterson Copyright © 2015 Mario Saare et al. All rights reserved. The Maternal Cytokine and Chemokine Profile of Naturally Conceived Gestations Is Mainly Preserved during In Vitro Fertilization and Egg Donation Pregnancies Sun, 09 Aug 2015 12:26:10 +0000 This prospective longitudinal study aimed at comparing maternal immune response among naturally conceived (NC; ), in vitro fertilization (IVF; ), and egg donation (ED; ) pregnancies. The main outcome measures were, firstly, to follow up plasma levels of interleukin (IL) 1beta, IL2, IL4, IL5, IL6, IL8, IL10, IL17, interferon gamma, tumor necrosis factor-alpha (TNFα), transforming growth factor-beta (TGFβ), regulated upon activation normal T-cell expressed and secreted (RANTES), stromal cell-derived factor 1 alpha (SDF1α), and decidual granulocyte-macrophage colony-stimulating factor (GM-CSF) during the three trimesters of pregnancy during the three trimesters of pregnancy; secondly, to evaluate if the cytokine and chemokine pattern of ED pregnant women differs from that of those with autologous oocytes and, thirdly, to assess if women with preeclampsia show different cytokine and chemokine profile throughout pregnancy versus women with uneventful pregnancies. Pregnant women in the three study groups displayed similar cytokine and chemokine pattern throughout pregnancy. The levels of all quantified cytokines and chemokines, except RANTES, TNFα, IL8, TGFβ, and SDF1α, rose in the second trimester compared with the first, and these higher values remained in the third trimester. ED pregnancies showed lower SDF1α levels in the third trimester compared with NC and IVF pregnancies. Patients who developed preeclampsia displayed higher SDF1α plasma levels in the third trimester. Alicia Martínez-Varea, Begoña Pellicer, Vicente Serra, David Hervás-Marín, Alicia Martínez-Romero, José Bellver, Alfredo Perales-Marín, and Antonio Pellicer Copyright © 2015 Alicia Martínez-Varea et al. All rights reserved.