http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2013 , Hindawi Publishing Corporation . All rights reserved. Thu, 23 May 2013 15:54:29 +0000 http://www.hindawi.com/journals/cdi/2013/852418/ Bacterial translocation across the damaged mucosal epithelium has emerged as a major paradigm for chronic immune activation observed during HIV infection. T helper 17 (Th17) cells are a unique lineage of T helper cells that are enriched in mucosal tissues and are thought to play a central role in protecting the integrity of the mucosal barrier and maintaining immune homeostasis at mucosal sites. Th17 cells are lost very early during the course of HIV infection, and their loss has been shown to correlate with bacterial translocation. Interestingly, Th17 cells are unable to completely recover from the early destruction even after successful antiretroviral therapy (ART). Here, we review some of the potential mechanisms for the loss and dysregulation of Th17 cells during HIV infection. Sandra L. Bixler and Joseph J. Mattapallil Copyright © 2013 Sandra L. Bixler and Joseph J. Mattapallil. All rights reserved. Thu, 23 May 2013 15:36:10 +0000 http://www.hindawi.com/journals/cdi/2013/575936/ In the last years, new evidences of the relationship between immune system and bone have been accumulated both in animal models and in humans affected by bone disease, such as rheumatoid arthritis, bone metastasis, periodontitis, and osteoporosis. Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone tissue with a subsequent increase in bone fragility and susceptibility to fractures. The combined effects of estrogen deprivation and raising of FSH production occurring in menopause cause a marked stimulation of bone resorption and a rapid bone loss which is central for the onset of postmenopausal osteoporosis. This review focuses on the role of immune system in postmenopausal osteoporosis and on therapeutic strategies targeting osteoimmunology pathways. Maria Felicia Faienza, Annamaria Ventura, Flaviana Marzano, and Luciano Cavallo Copyright © 2013 Maria Felicia Faienza et al. All rights reserved. Thu, 23 May 2013 15:11:40 +0000 http://www.hindawi.com/journals/cdi/2013/186872/ MicroRNAs (miRNAs) are an abundant class of small noncoding RNA molecules that play an important role in the regulation of gene expression at the posttranscriptional level. Due to their ability to simultaneously modulate the fate of different genes, these molecules are particularly well suited to act as key regulators during immune cell differentiation and activation, and their dysfunction can contribute to pathological conditions associated with neuroinflammation. Recent studies have addressed the role of miRNAs in the differentiation of progenitor cells into microglia and in the activation process, aiming at clarifying the origin of adult microglia cells and the contribution of the central nervous system (CNS) environment to microglia phenotype, in health and disease. Altered expression of several miRNAs has been associated with Alzheimer’s disease, multiple sclerosis, and ischemic injury, hence strongly advocating the use of these small molecules as disease markers and new therapeutic targets. This review summarizes the recent advances in the field of miRNA-mediated regulation of microglia development and activation. We discuss the role of specific miRNAs in the maintenance and switching of microglia activation states and illustrate the potential of this class of nucleic acids both as biomarkers of inflammation and new therapeutic tools for the modulation of microglia behavior in the CNS. J. Guedes, A. L. C. Cardoso, and M. C. Pedroso de Lima Copyright © 2013 J. Guedes et al. All rights reserved. Thu, 23 May 2013 13:54:10 +0000 http://www.hindawi.com/journals/cdi/2013/181849/ Tumor necrosis factor-α (TNF-α) is a cytokine produced by monocytes, macrophages, and T cells and is induced by pathogens, endotoxins, or related substances. TNF-α may play a key role in bone metabolism and is important in inflammatory bone diseases such as rheumatoid arthritis. Cells directly involved in osteoclastogenesis include macrophages, which are osteoclast precursor cells, osteoblasts, or stromal cells. These cells express receptor activator of NF-κB ligand (RANKL) to induce osteoclastogenesis, and T cells, which secrete RANKL, promote osteoclastogenesis during inflammation. Elucidating the detailed effects of TNF-α on bone metabolism may enable the identification of therapeutic targets that can efficiently suppress bone destruction in inflammatory bone diseases. TNF-α is considered to act by directly increasing RANK expression in macrophages and by increasing RANKL in stromal cells. Inflammatory cytokines such as interleukin- (IL-) 12, IL-18, and interferon-γ (IFN-γ) strongly inhibit osteoclast formation. IL-12, IL-18, and IFN-γ induce apoptosis in bone marrow cells treated with TNF-α  in vitro, and osteoclastogenesis is inhibited by the interactions of TNF-α-induced Fas and Fas ligand induced by IL-12, IL-18, and IFN-γ. This review describes and discusses the role of cells concerned with osteoclast formation and immunological reactions in TNF-α-mediated osteoclastogenesis in vitro and in vivo. Hideki Kitaura, Keisuke Kimura, Masahiko Ishida, Haruka Kohara, Masako Yoshimatsu, and Teruko Takano-Yamamoto Copyright © 2013 Hideki Kitaura et al. All rights reserved. Thu, 23 May 2013 13:36:28 +0000 http://www.hindawi.com/journals/cdi/2013/503754/ Periodontal disease (PD), or periodontitis, is defined as a bacterially induced disease of the tooth-supporting (periodontal) tissues. It is characterized by inflammation and bone loss; therefore understanding how they are linked would help to address the most efficacious therapeutic approach. Bacterial infection is the primary etiology but is not sufficient to induce the disease initiation or progression. Indeed, bacteria-derived factors stimulate a local inflammatory reaction and activation of the innate immune system. The innate response involves the recognition of microbial components by host cells, and this event is mediated by toll-like receptors (TLRs) expressed by resident cells and leukocytes. Activation of these cells leads to the release of proinflammatory cytokines and recruitment of phagocytes and lymphocytes. Activation of T and B cells initiates the adaptive immunity with Th1 Th2 Th17 Treg response and antibodies production respectively. In this inflammatory scenario, cytokines involved in bone regulation and maintenance have considerable relevance because tissue destruction is believed to be the consequence of host inflammatory response to the bacterial challenge. In the present review, we summarize host factors including cell populations, cytokines, and mechanisms involved in the destruction of the supporting tissues of the tooth and discuss treatment perspectives based on this knowledge. Adriana Di Benedetto, Isabella Gigante, Silvia Colucci, and Maria Grano Copyright © 2013 Adriana Di Benedetto et al. All rights reserved. Thu, 23 May 2013 13:09:21 +0000 http://www.hindawi.com/journals/cdi/2013/475415/ Necrotizing enterocolitis (NEC) is a challenging disease to treat, and caring for patients afflicted by it remains both frustrating and difficult. While NEC may develop quickly and without warning, it may also develop slowly, insidiously, and appear to take the caregiver by surprise. In seeking to understand the molecular and cellular processes that lead to NEC development, we have identified a critical role for the receptor for bacterial lipopolysaccharide (LPS) toll like receptor 4 (TLR4) in the pathogenesis of NEC, as its activation within the intestinal epithelium of the premature infant leads to mucosal injury and reduced epithelial repair. The expression and function of TLR4 were found to be particularly elevated within the intestinal mucosa of the premature as compared with the full-term infant, predisposing to NEC development. Importantly, factors within both the enterocyte itself, such as heat shock protein 70 (Hsp70), and in the extracellular environment, such as amniotic fluid, can curtail the extent of TLR4 signaling and reduce the propensity for NEC development. This review will highlight the critical TLR4-mediated steps that lead to NEC development, with a focus on the proinflammatory responses of TLR4 signaling that have such devastating consequences in the premature host. David J. Hackam, Amin Afrazi, Misty Good, and Chhinder P. Sodhi Copyright © 2013 David J. Hackam et al. All rights reserved. Thu, 23 May 2013 09:21:59 +0000 http://www.hindawi.com/journals/cdi/2013/981468/ Regulatory T cells (Tregs) play a crucial role in immune homeostasis. Treg induction is a strategy that parasites have evolved to modulate the host’s inflammatory environment, facilitating their establishment and permanence. In human Taenia solium neurocysticercosis (NC), the concurrence of increased peripheral and central Treg levels and their capacity to inhibit T cell activation and proliferation support their role in controlling neuroinflammation. This study is aimed at identifing possible mechanisms of Treg induction in human NC. Monocyte-derived dendritic cells (DC) from healthy human donors, cocultivated with autologous CD4+ naïve cells either in the presence or absence of cysticerci, promoted CD25highFoxp3+ Treg differentiation. An increased Treg induction was observed when cysticerci were present. Moreover, an augmentation of suppressive-related molecules (SLAMF1, B7-H1, and CD205) was found in parasite-induced DC differentiation. Increased Tregs and a higher in vivo DC expression of the regulatory molecules SLAMF1 and CD205 in NC patients were also found. SLAMF1 gene was downregulated in NC patients with extraparenchymal cysticerci, exhibiting higher inflammation levels than patients with parenchymal parasites. Our findings suggest that cysticerci may modulate DC to favor a suppressive environment, which may help parasite establishment, minimizing the excessive inflammation, which may lead to tissue damage. Laura Adalid-Peralta, Asiel Arce-Sillas, Gladis Fragoso, Graciela Cárdenas, Marcos Rosetti, Didier Casanova-Hernández, Claudia Rangel-Escareño, Laura Uribe-Figueroa, Agnes Fleury, and Edda Sciutto Copyright © 2013 Laura Adalid-Peralta et al. All rights reserved. Wed, 22 May 2013 16:35:12 +0000 http://www.hindawi.com/journals/cdi/2013/586076/ Neonates, especially those born prematurely, are at high risk of morbidity and mortality from sepsis. Multiple factors, including prematurity, invasive life-saving medical interventions, and immaturity of the innate immune system, put these infants at greater risk of developing infection. Although advanced neonatal care enables us to save even the most preterm neonates, the very interventions sustaining those who are hospitalized concurrently expose them to serious infections due to common nosocomial pathogens, particularly coagulase-negative staphylococci bacteria (CoNS). Moreover, the health burden from infection in these infants remains unacceptably high despite continuing efforts. In this paper, we review the epidemiology, immunological risk factors, diagnosis, prevention, treatment, and outcomes of neonatal infection due to the predominant neonatal pathogen CoNS. Elizabeth A. Marchant, Guilaine K. Boyce, Manish Sadarangani, and Pascal M. Lavoie Copyright © 2013 Elizabeth A. Marchant et al. All rights reserved. Wed, 22 May 2013 13:24:48 +0000 http://www.hindawi.com/journals/cdi/2013/937846/ The goal of the present work was to identify the candidate genetic markers predictive of alloimmunization in sickle cell disease (SCD). Red blood cell (RBC) transfusion is indicated for acute treatment, prevention, and abrogation of some complications of SCD. A well-known consequence of multiple RBC transfusions is alloimmunization. Given that a subset of SCD patients develop multiple RBC allo-/autoantibodies, while others do not in a similar multiple transfusional setting, we investigated a possible genetic basis for alloimmunization. Biomarker(s) which predicts (predict) susceptibility to alloimmunization could identify patients at risk before the onset of a transfusion program and thus may have important implications for clinical management. In addition, such markers could shed light on the mechanism(s) underlying alloimmunization. We genotyped 27 single nucleotide polymorphisms (SNPs) in the CD81, CHRNA10, and ARHG genes in two groups of SCD patients. One group (35) of patients developed alloantibodies, and another (40) had no alloantibodies despite having received multiple transfusions. Two SNPs in the CD81 gene, that encodes molecule involved in the signal modulation of B lymphocytes, show a strong association with alloimmunization. If confirmed in prospective studies with larger cohorts, the two SNPs identified in this retrospective study could serve as predictive biomarkers for alloimmunization. Zohreh Tatari-Calderone, Ryad Tamouza, Gama P. Le Bouder, Ramita Dewan, Naomi L. C. Luban, Jacqueline Lasserre, Jacqueline Maury, François Lionnet, Rajagopal Krishnamoorthy, Robert Girot, and Stanislav Vukmanovic Copyright © 2013 Zohreh Tatari-Calderone et al. All rights reserved. Wed, 22 May 2013 09:31:38 +0000 http://www.hindawi.com/journals/cdi/2013/701305/ Rheumatoid arthritis (RA) and Langerhans cell histiocytosis (LCH) are common and rare diseases, respectively. They associate myeloid cell recruitment and survival in inflammatory conditions with tissue destruction and bone resorption. Manipulating dendritic cell (DC), and, especially, regulating their half-life and fusion, is a challenge. Indeed, these myeloid cells display pathogenic roles in both diseases and may be an important source of precursors for differentiation of osteoclasts, the bone-resorbing multinucleated giant cells. We have recently documented that the proinflammatory cytokine IL-17A regulates long-term survival of DC by inducing BCL2A1 expression, in addition to the constitutive MCL1 expression. We summarize bibliography of the BCL2 family members and their therapeutic targeting, with a special emphasis on MCL1 and BCL2A1, discussing their potential impact on RA and LCH. Our recent knowledge in the survival pathway, which is activated to perform DC fusion in the presence of IL-17A, suggests that targeting MCL1 and BCL2A1 in infiltrating DC may affect the clinical outcomes in RA and LCH. The development of new therapies, interfering with MCL1 and BCL2A1 expression, to target long-term surviving inflammatory DC should be translated into preclinical studies with the aim to increase the well-being of patients with RA and LCH. Selma Olsson Åkefeldt, Mohamad Bachar Ismail, Hélène Valentin, Maurizio Aricò, Jan-Inge Henter, and Christine Delprat Copyright © 2013 Selma Olsson Åkefeldt et al. All rights reserved. Wed, 22 May 2013 08:05:37 +0000 http://www.hindawi.com/journals/cdi/2013/806025/ Dendritic cells (DCs) are essential for the maintenance of homeostasis in the organism, and they do that by modulating lymphocyte priming, expansion, and response patterns according to signals they receive from the environment. The induction of suppressive lymphocytes by DCs is essential to hinder the development of autoimmune diseases but can be reverted against homeostasis when in the context of neoplasia. In this setting, the induction of suppressive or regulatory T cells contributes to the establishment of a state of tolerance towards the tumor, allowing it to grow unchecked by an otherwise functional immune system. Besides affecting its local environment, tumor also has been described as potent sources of anti-inflammatory/suppressive factors, which may act systemically, generating defects in the differentiation and maturation of immune cells, far beyond the immediate vicinity of the tumor mass. Cytokines, as IL-10 and TGF-beta, as well as cell surface molecules like PD-L1 and ICOS seem to be significantly involved in the redirection of DCs towards tolerance induction, and recent data suggest that tumor cells may, indeed, modulate distinct DCs subpopulations through the involvement of these molecules. It is to be expected that the identification of such molecules should provide molecular targets for more effective immunotherapeutic approaches to cancer. Rodrigo Nalio Ramos, Cristiano Jacob de Moraes, Bruna Zelante, and José Alexandre M. Barbuto Copyright © 2013 Rodrigo Nalio Ramos et al. All rights reserved. Mon, 20 May 2013 16:54:43 +0000 http://www.hindawi.com/journals/cdi/2013/496974/ New-onset diabetes mellitus after transplantation (NODAT) may complicate 2–50% of kidney transplantation, and it is associated with reduced graft and patient survivals. In this retrospective study, we applied a conversion protocol to sirolimus in a cohort of kidney transplant recipients with NODAT. Among 344 kidney transplant recipients, 29 patients developed a NODAT (6.6%) and continued with a reduced dose of calcineurin inhibitors (CNI) (8 patients, Group A) or were converted to sirolimus (SIR) (21 patients, Group B). NODAT resolved in 37.5% and in 80% patients in Group A and Group B, respectively. In Group A, patient and graft survivals were 100% and 75%, respectively, not significantly different from Group B (83.4% and 68%, resp., ). Graft function improved after conversion to sirolimus therapy: serum creatinine was 1.8 ± 0.7 mg/dL at the time of conversion and 1.6 ± 0.4 mg/dL five years after conversion to sirolimus therapy (), while in the group of patients remaining with a reduced dose of CNI, serum creatinine was 1.7 ± 0.6 mg/dL at the time of conversion and 1.65 ± 0.6 mg/dL at five-year followup (). This study demonstrated that the conversion from CNI to SIR in patients could improve significantly the metabolic parameters of patients with NODAT, without increasing the risk of acute graft rejection. Massimiliano Veroux, Tiziano Tallarita, Daniela Corona, Nunziata Sinagra, Alessia Giaquinta, Domenico Zerbo, Carmela Guerrieri, Antonino D'Assoro, Sebastiano Cimino, and Pierfrancesco Veroux Copyright © 2013 Massimiliano Veroux et al. All rights reserved. Wed, 15 May 2013 17:08:57 +0000 http://www.hindawi.com/journals/cdi/2013/412768/ Since its identification, the RANKL cytokine has been demonstrated to play a crucial role in bone homeostasis and lymphoid tissue organization. Genetic defects impairing its function lead to a peculiar form of autosomal recessive osteopetrosis (ARO), a rare genetic bone disease presenting early in life and characterized by increased bone density due to failure in bone resorption by the osteoclasts. Hematopoietic stem cell transplantation (HSCT) is the only option for the majority of patients affected by this life-threatening disease. However, the RANKL-dependent ARO does not gain any benefit from this approach, because the genetic defect is not intrinsic to the hematopoietic osteoclast lineage but rather to the mesenchymal one. Of note, we recently provided proof of concept of the efficacy of a pharmacological RANKL-based therapy to cure this form of the disease. Here we provide an overview of the diverse roles of RANKL in the bone and immune systems and review the clinical features of RANKL-deficient ARO patients and the results of our preclinical studies. We emphasize that these patients present a continuous worsening of the disease in the absence of a cure and strongly wish that the therapy we propose will be further developed. Nadia Lo Iacono, Alessandra Pangrazio, Mario Abinun, Robbert Bredius, Marco Zecca, Harry C. Blair, Paolo Vezzoni, Anna Villa, and Cristina Sobacchi Copyright © 2013 Nadia Lo Iacono et al. All rights reserved. Wed, 15 May 2013 14:28:44 +0000 http://www.hindawi.com/journals/cdi/2013/972865/ In general, immunological tolerance is acquired upon treatment with non-specific immunosuppressive drugs. This indiscriminate immunosuppression of the patient often causes serious side-effects, such as opportunistic infectious diseases. Therefore, the need for antigen-specific modulation of pathogenic immune responses is of crucial importance in the treatment of inflammatory diseases. In this perspective, dendritic cells (DCs) can have an important immune-regulatory function, besides their notorious antigen-presenting capacity. DCs appear to be essential for both central and peripheral tolerance. In the thymus, DCs are involved in clonal deletion of autoreactive immature T cells by presenting self-antigens. Additionally, tolerance is achieved by their interactions with T cells in the periphery and subsequent induction of T cell anergy, T cell deletion, and induction of regulatory T cells (Treg). Various studies have described, modulation of DC characteristics with the purpose to induce antigen-specific tolerance in autoimmune diseases, graft-versus-host-disease (GVHD), and transplantations. Promising results in animal models have prompted researchers to initiate first-in-men clinical trials. The purpose of current review is to provide an overview of the role of DCs in the immunopathogenesis of autoimmunity, as well as recent concepts of dendritic cell-based therapeutic opportunities in autoimmune diseases. Chun Yuen J. Chung, Dirk Ysebaert, Zwi N. Berneman, and Nathalie Cools Copyright © 2013 Chun Yuen J. Chung et al. All rights reserved. Mon, 13 May 2013 13:52:42 +0000 http://www.hindawi.com/journals/cdi/2013/781320/ One of the challenges faced by the infant immune system is learning to distinguish the myriad of foreign but nonthreatening antigens encountered from those expressed by true pathogens. This balance is reflected in the diminished production of proinflammatory cytokines by both innate and adaptive immune cells in the infant. A downside of this bias is that several factors critical for controlling Mycobacterium tuberculosis infection are significantly restricted in infants, including TNF, IL-1, and IL-12. Furthermore, infant T cells are inherently less capable of differentiating into IFN-γ-producing T cells. As a result, infected infants are 5–10 times more likely than adults to develop active tuberculosis (TB) and have higher rates of severe disseminated disease, including miliary TB and meningitis. Infant TB is a fundamentally different disease than TB in immune competent adults. Immunotherapeutics, therefore, should be specifically evaluated in infants before they are routinely employed to treat TB in this age group. Modalities aimed at reducing inflammation, which may be beneficial for adjunctive therapy of some forms of TB in older children and adults, may be of no benefit or even harmful in infants who manifest much less inflammatory disease. Koen Vanden Driessche, Alexander Persson, Ben J. Marais, Pamela J. Fink, and Kevin B. Urdahl Copyright © 2013 Koen Vanden Driessche et al. All rights reserved. Sun, 12 May 2013 18:16:29 +0000 http://www.hindawi.com/journals/cdi/2013/210506/ One of the greatest advances in medicine during the past century is the introduction of organ transplantation. This therapeutic strategy designed to treat organ failure and organ dysfunction allows to prolong the survival of many patients that are faced with no other treatment option. Today, organ transplantation between genetically dissimilar individuals (allogeneic grafting) is a procedure widely used as a therapeutic alternative in cases of organ failure, hematological disease treatment, and some malignancies. Despite the potential of organ transplantation, the administration of immunosuppressive drugs required for allograft acceptance induces severe immunosuppression in transplanted patients, which leads to serious side effects such as infection with opportunistic pathogens and the occurrence of neoplasias, in addition to the known intrinsic toxicity of these drugs. To solve this setback in allotransplantation, researchers have focused on manipulating the immune response in order to create a state of tolerance rather than unspecific immunosuppression. Here, we describe the different treatments and some of the novel immunotherapeutic strategies undertaken to induce transplantation tolerance. Paulina Ruiz, Paula Maldonado, Yessia Hidalgo, Alejandra Gleisner, Daniela Sauma, Cinthia Silva, Juan Jose Saez, Sarah Nuñez, Mario Rosemblatt, and Maria Rosa Bono Copyright © 2013 Paulina Ruiz et al. All rights reserved. Sun, 12 May 2013 12:36:09 +0000 http://www.hindawi.com/journals/cdi/2013/545621/ Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become a valuable strategy for some intractable diseases, a number of problems remain to be resolved. We have developed a new HSCT method, HSCT + thymus transplantation (TT) from the same donor, which induces elevated T cell function with mild graft-versus-host disease (GVHD) in comparison to conventional HSCT alone and HSCT + donor lymphocyte infusion (HSCT + DLI). This new method is effective in the treatment of several intractable diseases and conditions, such as autoimmune diseases in aging, advanced malignant tumors, exposure to supralethal irradiation, multiple organ transplantation from different donors, and type 2 diabetes mellitus, for which conventional methods are ineffective. Our findings suggest that allo-HSCT + TT is preferable to conventional allo-HSCT alone or allo-HSCT + DLI. This method may become a valuable next-generation HSCT technique. Naoki Hosaka Copyright © 2013 Naoki Hosaka. All rights reserved. Wed, 08 May 2013 17:47:15 +0000 http://www.hindawi.com/journals/cdi/2013/679804/ Regulatory T cells are a specific subset of lymphocytes that suppress immune responses and play a crucial role in the maintenance of self-tolerance. They can be generated in the thymus as well as in the periphery through differentiation of naïve CD4+ T cells. The forkhead box P3 transcription factor (Foxp3) is a crucial molecule regulating the generation and function of Tregs. Here we show that the foxp3 gene promoter becomes hyperacetylated in in vitro differentiated Tregs compared to naïve CD4+ T cells. We also show that the histone deacetylase inhibitor TSA stimulated the in vitro differentiation of naïve CD4+ T cells into Tregs and that this induction was accompanied by a global increase in histone H3 acetylation. Importantly, we also demonstrated that Tregs generated in the presence of TSA have phenotypical and functional differences from the Tregs generated in the absence of TSA. Thus, TSA-generated Tregs showed increased suppressive activities, which could potentially be explained by a mechanism involving the ectonucleotidases CD39 and CD73. Our data show that TSA could potentially be used to enhance the differentiation and suppressive function of CD4+Foxp3+ Treg cells. Cristian Doñas, Macarena Fritz, Valeria Manríquez, Gabriela Tejón, María Rosa Bono, Alejandra Loyola, and Mario Rosemblatt Copyright © 2013 Cristian Doñas et al. All rights reserved. Wed, 08 May 2013 13:28:39 +0000 http://www.hindawi.com/journals/cdi/2013/608951/ Growing evidence suggests that cellular adoptive immunotherapy is becoming an attractive though challenging approach in regulating tumor immunity and alloresponses in clinical transplantation. Naturally arising CD4+CD25+Foxp3+ regulatory T cells (Treg) have emerged as a key component in this regard. Over the last decade, a large body of evidence from preclinical models has demonstrated their crucial role in auto- and tumor immunity and has opened the door to their “first-in-man” clinical application. Initial studies in clinical allogeneic stem cell transplantation are very encouraging and may pave the way for other applications. Further improvements in Treg ex vivo or in vivo expansion technologies will simplify their global clinical application. In this review, we discuss the current knowledge of Treg biology and their potential for cell-based immunotherapy in allogeneic stem cell transplantation. Maria Michael, Avichai Shimoni, and Arnon Nagler Copyright © 2013 Maria Michael et al. All rights reserved. Tue, 07 May 2013 09:07:59 +0000 http://www.hindawi.com/journals/cdi/2013/389807/ Hepatic stellate cells (HSCs) interact with immune cells to actively participate in regulating immune response in the liver which is mediated by the effector molecules, including B7-H1. We demonstrated here that expression of B7-H1 on HSCs was markedly enhanced by interferon-(IFN-) γ stimulation. IFN-γ stimulated HSCs inhibited T-cell proliferation via induction of T-cell apoptosis (22.1% ± 1.6%). This immunosuppressive effect was inhibited by preincubation with an anti-B7-H1 antibody, or inhibitor of the MEK/ERK pathway inhibited IFN-γ mediated expression of B7-H1. Thus, regulation of B7-H1 expression on HSCs by IFN-γ represents an important mechanism that regulates immune responses in the liver favoring tolerogenicity rather than immunogenicity. Involvement of MEK/ERK pathway provides a novel target for therapeutic approaches. Xiaodong Gu, Yan Wang, Jianbin Xiang, Zongyou Chen, Lianfu Wang, Lina Lu, and Shiguang Qian Copyright © 2013 Xiaodong Gu et al. All rights reserved. Thu, 02 May 2013 10:00:51 +0000 http://www.hindawi.com/journals/cdi/2013/270301/ The intestinal tract is engaged in a relationship with a dense and complex microbial ecosystem, the microbiota. The establishment of this symbiosis is essential for host physiology, metabolism, and immune homeostasis. Because newborns are essentially sterile, the first exposure to microorganisms and environmental endotoxins during the neonatal period is followed by a crucial sequence of active events leading to immune tolerance and homeostasis. Contact with potent immunostimulatory molecules starts immediately at birth, and the discrimination between commensal bacteria and invading pathogens is essential to avoid an inappropriate immune stimulation and/or host infection. The dysregulation of these tight interactions between host and microbiota can be responsible for important health disorders, including inflammation and sepsis. This review summarizes the molecular events leading to the establishment of postnatal immune tolerance and how pathogens can avoid host immunity and induce neonatal infections and sepsis. Emilie Tourneur and Cecilia Chassin Copyright © 2013 Emilie Tourneur and Cecilia Chassin. All rights reserved. Thu, 02 May 2013 09:49:29 +0000 http://www.hindawi.com/journals/cdi/2013/373579/ JC and BK polyomaviruses were discovered over 40 years ago and have become increasingly prevalent causes of morbidity and mortality in a variety of distinct, immunocompromised patient cohorts. The recent discoveries of eight new members of the Polyomaviridae family that are capable of infecting humans suggest that there are more to be discovered and raise the possibility that they may play a more significant role in human disease than previously understood. In spite of this, there remains a dearth of specific therapeutic options for human polyomavirus infections and an incomplete understanding of the relationship between the virus and the host immune system. This review summarises the human polyomaviruses with particular emphasis on pathogenesis in those directly implicated in disease aetiology and the therapeutic options available for treatment in the immunocompromised host. Cillian F. De Gascun and Michael J. Carr Copyright © 2013 Cillian F. De Gascun and Michael J. Carr. All rights reserved. Sun, 28 Apr 2013 17:24:53 +0000 http://www.hindawi.com/journals/cdi/2013/146219/ Neuromyelitis optica (NMO) is an autoimmune disease in which a specific biomarker named NMO-IgG and directed against aquaporin-4 (AQP4) has been found. A correlation between disease activity and anti-AQP4 antibody (Ab) serum concentration or complement-mediated cytotoxicity has been reported, but the usefulness of longitudinal evaluation of these parameters remains to be evaluated in actual clinical practice. Thirty serum samples from 10 NMO patients positive for NMO-IgG were collected from 2006 to 2011. Anti-AQP4 Ab serum concentration and complement-mediated cytotoxicity were measured by flow cytometry using two quantitative cell-based assays (CBA) and compared with clinical parameters. We found a strong correlation between serum anti-AQP4 Ab concentration and complement-mediated cytotoxicity (). Nevertheless, neither relapse nor worsening of impairment level was closely associated with a significant increase in serum Ab concentration or cytotoxicity. These results suggest that complement-mediated serum cytotoxicity assessment does not provide extra insight compared to anti-AQP4 Ab serum concentration. Furthermore, none of these parameters appears closely related to disease activity and/or severity. Therefore, in clinical practice, serum anti-AQP4 reactivity seems not helpful as a predictive biomarker in the followup of NMO patients as a means of predicting the onset of a relapse and adapting the treatment accordingly. Jean-Baptiste Chanson, Melissa Alame, Nicolas Collongues, Frédéric Blanc, Marie Fleury, Gabrielle Rudolf, Jérôme de Seze, and Thierry Vincent Copyright © 2013 Jean-Baptiste Chanson et al. All rights reserved. Sun, 28 Apr 2013 16:00:11 +0000 http://www.hindawi.com/journals/cdi/2013/510547/ Background. Previous studies reported associations between specific alleles of non-HLA immunoregulatory genes and higher fatigue scores in patients with primary biliary cirrhosis (PBC). Aim. To study the relationship between variables of health-related quality of life (HRQoL) and single nucleotide polymorphisms of TRAF1-C5, a member of the tumor necrosis factor receptor family. Patients and Methods. TRAF1-C5 gene polymorphisms, rs2900180 and rs3761847, were analysed in 120 Caucasian PBCs. The HRQoL was assessed with SF-36, PBC-40, and PBC-27 questionnaires. Results. We found a negative association between TT genotype of rs2900180 and SF-36’s domains vitality (), mental health (), and mental component summary score (). GG homozygotes of rs3761847 had lower vitality (), mental health (), mental component summary score () and impairment of social functioning (). Allelic analysis has shown that T allele of rs2900180 and G allele of rs3761847 related to SF-36’s vitality ( and ), social functioning ( and ), mental health ( and ), and mental component summary score ( and ), respectively. Genotyping and allelic analysis did not reveal correlation with PBC-40 and PBC-27 domains. Conclusion. The association between rs2900180 and rs3761847 polymorphisms and HRQoL variables indicates that TRAF1 is involved in the induction of impaired QoL in PBC. Joanna Raszeja-Wyszomirska, Ewa Wunsch, Agnieszka Kempinska-Podhorodecka, Daniel S. Smyk, Dimitrios P. Bogdanos, Malgorzata Milkiewicz, and Piotr Milkiewicz Copyright © 2013 Joanna Raszeja-Wyszomirska et al. All rights reserved. Wed, 24 Apr 2013 15:44:30 +0000 http://www.hindawi.com/journals/cdi/2013/315024/ Bone metastases are a dismal consequence for different types of solid tumors, such as breast, prostate, lung, and kidney cancer. The mechanisms regulating the interactions among bone, immune system, and tumor cells have been deeply investigated, and many studies are ongoing to define the specific role of the different cells in the bone metastatic process. The affinity of some tumors to growth in bone results from the special microenvironment provided by bone. Moreover, immune system and bone have a bidirectional relationship: bone cells express surface molecules ruling the expansion of hemopoietic stem cells from which all cells of the mammalian immune system derive, and various immunoregulatory cytokines influence the fate of bone cells. The last findings allow to extend the concept of vicious cycle and add T cells as mediators of the tumor growth in bone. Ilaria Roato Copyright © 2013 Ilaria Roato. All rights reserved. Tue, 23 Apr 2013 16:05:30 +0000 http://www.hindawi.com/journals/cdi/2013/608456/ Protein toxins are important virulence factors contributing to neonatal sepsis. The major pathogens of neonatal sepsis, group B Streptococci, Escherichia coli, Listeria monocytogenes, and Staphylococcus aureus, secrete toxins of different molecular nature, which are key for defining the disease. Amongst these toxins are pore-forming exotoxins that are expressed as soluble monomers prior to engagement of the target cell membrane with subsequent formation of an aqueous membrane pore. Membrane pore formation is not only a means for immediate lysis of the targeted cell but also a general mechanism that contributes to penetration of epithelial barriers and evasion of the immune system, thus creating survival niches for the pathogens. Pore-forming toxins, however, can also contribute to the induction of inflammation and hence to the manifestation of sepsis. Clearly, pore-forming toxins are not the sole factors that drive sepsis progression, but they often act in concert with other bacterial effectors, especially in the initial stages of neonatal sepsis manifestation. Andreas F.-P. Sonnen and Philipp Henneke Copyright © 2013 Andreas F.-P. Sonnen and Philipp Henneke. All rights reserved. Tue, 23 Apr 2013 09:15:03 +0000 http://www.hindawi.com/journals/cdi/2013/952469/ The recruitment and activation of regulatory T cells (Tregs) in the micro-environment of malignant brain tumors has detrimental effects on antitumoral immune responses. Hence, local elimination of Tregs within the tumor micro-environment represents a highly valuable tool from both a fundamental and clinical perspective. In the syngeneic experimental GL261 murine glioma model, Tregs were prophylactically eliminated through treatment with PC61, an anti-CD25 mAb. This resulted in specific elimination of CD4+CD25hiFoxp3+ Treg within brain-infiltrating lymphocytes and complete protection against subsequent orthotopic GL261 tumor challenge. Interestingly, PC61-treated mice also showed a pronounced infiltration of CD11b+ myeloid cells in the brain. Phenotypically, these cells could not be considered as Gr-1+ myeloid-derived suppressor cells (MDSC) but were identified as F4/80+ macrophages and granulocytes. Wim Maes, Tina Verschuere, Anaïs Van Hoylandt, Louis Boon, and Stefaan Van Gool Copyright © 2013 Wim Maes et al. All rights reserved. Tue, 23 Apr 2013 08:54:22 +0000 http://www.hindawi.com/journals/cdi/2013/890517/ Hepatitis C virus (HCV) is a small-enveloped RNA virus belonging to the Flaviviridae family. Since first identified in 1989, HCV has been estimated to infect 170 million people worldwide. Mostly chronic hepatitis C virus has a uniform natural history, from liver cirrhosis to the development of hepatocellular carcinoma. The current therapy for HCV infection consists of a combination of Pegylated interferon and ribavirin. On the other hand, HCV-related liver disease is also the leading indication for liver transplantation. However, posttransplant HCV re-infection of the graft has been reported to be universal. Furthermore, the graft after HCV re-infection often results in accelerated progression to liver failure. In addition, treatment of recurrent HCV infection after liver transplantation is often compromised by enhanced adverse effects and limited efficacy of interferon-based therapies. Taken together, poor outcome after HCV re-infection, regardless of grafts or recipients, poses a major issue for the hepatologists and transplant surgeons. The aim of this paper is to review several specific aspects regarding HCV re-infection after transplant: risk factors, current therapeutics for HCV in different stages of liver transplantation, cellular function of HCV proteins, and molecular mechanisms of HCV entry. Hopefully, this paper will inspire new strategies and novel inhibitors against recurrent HCV infection after liver transplantation and greatly improve its overall outcome. Shih-Hsien Hsu, Ming-Lun Yeh, and Shen-Nien Wang Copyright © 2013 Shih-Hsien Hsu et al. All rights reserved. Mon, 22 Apr 2013 15:13:38 +0000 http://www.hindawi.com/journals/cdi/2013/107321/ Osteoblasts support hematopoietic cell development, including B lymphopoiesis. We have previously shown that the nuclear factor of activated T cells (NFAT) negatively regulates osteoblast differentiation and bone formation. Interestingly, in smooth muscle, NFAT has been shown to regulate the expression of vascular cellular adhesion molecule-1 (VCAM-1), a mediator of cell adhesion and signaling during leukocyte development. To examine whether NFAT signaling in osteoblasts regulates hematopoietic development in vivo, we generated a mouse model expressing dominant-negative NFAT driven by the 2.3 kb fragment of the collagen-I promoter to disrupt NFAT activity in osteoblasts (dnNFAdnNFATOB). Bone histomorphometry showed that dnNFAdnNFATOB mice have significant increases in bone volume (44%) and mineral apposition rate (131%) and decreased trabecular thickness (18%). In the bone microenvironment, dnNFAdnNFATOB mice displayed a significant increase (87%) in Lineage−cKit+Sca-1+ (LSK) cells and significant decreases in B220+CD19−IgM− pre-pro-B cells (41%) and B220+CD19+IgM+ immature B cells (40%). Concurrent with these findings, LSK cell differentiation into B220+ cells was inhibited when cocultured on differentiated primary osteoblasts harvested from dnNFAdnNFATOB mice. Gene expression and protein levels of VCAM-1 in osteoblasts decreased in dnNFAdnNFATOB mice compared to controls. These data suggest that osteoblast-specific NFAT activity mediates early B lymphopoiesis, possibly by regulating VCAM-1 expression on osteoblasts. Cheryl L. Sesler and Majd Zayzafoon Copyright © 2013 Cheryl L. Sesler and Majd Zayzafoon. All rights reserved. Mon, 22 Apr 2013 10:43:52 +0000 http://www.hindawi.com/journals/cdi/2013/968041/ CUZD1, the CUB, and zona pellucida-like domains-containing protein 1, is a newly identified antigen of pancreatic autoantibodies (PAB) giving a reticulogranular pattern in patients with inflammatory bowel diseases, and in particular Crohn’s disease. The exact mechanisms by which this pancreatic antigen becomes the target of IBD-specific pancreatic autoantibodies are unclear. At the same time, evolving data strongly support a role for CUZD1 in carcinogenesis. Human CUZD1 is mapped at chromosome 10q26.13 and the loss of this region is a frequent event in various malignant tumours. mRNA overexpression of CUZD1 has been noted in ovarian cancer and serum levels of CUZD1 are elevated in women with ovarian cancer and patients suffering from pancreatic cancer. CUZD1 appears to be one of the relatively few biomarkers that serve as both cancer biomarker and autoantigen of autoantibodies in an autoimmune disease unrelated to cancerous organs. This review discusses the role of CUZD1 in cancer and autoimmunity. We anticipate that a better understanding of the function of CUZD1 will help us to understand how it becomes the focus of an autoimmune attack specifically targeting the intestine and its enigmatic role in carcinogenesis. Christos Liaskos, Eirini I. Rigopoulou, Timoklia Orfanidou, Dimitrios P. Bogdanos, and Christos N. Papandreou Copyright © 2013 Christos Liaskos et al. All rights reserved.