Journal of Immunology Research The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Clinical and Experimental Immunomodulation 2014 Tue, 28 Apr 2015 11:36:17 +0000 Lenin Pavón, Oscar Bottasso, Hugo Besedosky, Roger Loria, and Marco A. Velasco-Velázquez Copyright © 2015 Lenin Pavón et al. All rights reserved. Immune Disorders in Hashimoto’s Thyroiditis: What Do We Know So Far? Mon, 27 Apr 2015 13:53:22 +0000 This review of literature attempts to identify the factors that are involved in the pathogenesis of Hashimoto thyroiditis, an immune defect in an individual with genetic susceptibility accompanied with environmental factors. The frequency of Hashimoto’s disease is a growing trend and among Caucasians it is estimated at approximately 5%. The dysfunction of the gland may be clinically evident (0.1–2% of the population) or subclinical (10–15%). The pathology is diagnosed five to ten times more often in women than men and its incidence increases with the age (the peak of the number of cases is between 45 and 65); however, it can also be diagnosed in children. The pathogenesis of Hashimoto’s thyroiditis is still not fully comprehended. In the etiology of Hashimoto thyroiditis excessively stimulated T CD4+ cells are known to play the most important role. Recent research has demonstrated an increasing role of newly discovered cells such as Th17 (CD4+IL-17+) or T regulatory cells (CD4+CD25FoxP3+) in the induction of autoimmune disorders. The process of programmed cell death also plays an equally important role in the pathogenesis and the development of hypothyroidism. Aleksandra Pyzik, Ewelina Grywalska, Beata Matyjaszek-Matuszek, and Jacek Roliński Copyright © 2015 Aleksandra Pyzik et al. All rights reserved. The Alteration and Clinical Significance of Th22/Th17/Th1 Cells in Patients with Chronic Myeloid Leukemia Mon, 27 Apr 2015 12:47:03 +0000 T helper- (Th-) cell immunodeficiency plays important roles in tumor development and their effects in chronic myeloid leukemia (CML) remain unclear. In the present study, we mainly investigated the role of Th22, Th17, and Th1 cell and their related cytokines (IL-22, IL-17, and IFN-r) in the pathophysiology of CML. Bone marrow (BM) and peripheral blood (PB) were extracted from newly diagnosed (ND), chronic phase- (CP-) CML patients, and controls. Th subsets were examined by flow cytometry. Plasma IL-22, IL-17, and IFN-r concentrations were measured by ELISA. AHR and RORC mRNA expressions were examined by RT-PCR. The frequencies of Th22, Th17, and Th1 cells, along with the expression of specific transcription factors RORC and AHR, were significantly decreased in ND patients compared with healthy controls, while all these abnormality recovered in CP patients. In addition, there existed a significantly positive relationship between Th22 and Th17 cells in PB or BM. A significantly negative relationship was found between Th cells (Th22, Th17, or Th1) and BCR-ABL (%) IS or the number of PB white blood cells. All these results demonstrated that Th22, Th17, and Th1 cells might be important therapeutic targets in CML and could facilitate a better outcome for tumor immunotherapy. Ping Chen, Min Wang, Daqi Li, Yan Jia, Na He, Wei Li, Daoxin Ma, and Chunyan Ji Copyright © 2015 Ping Chen et al. All rights reserved. Interactions between MSCs and Immune Cells: Implications for Bone Healing Mon, 27 Apr 2015 11:15:33 +0000 It is estimated that, of the 7.9 million fractures sustained in the United States each year, 5% to 20% result in delayed or impaired healing requiring therapeutic intervention. Following fracture injury, there is an initial inflammatory response that plays a crucial role in bone healing; however, prolonged inflammation is inhibitory for fracture repair. The precise spatial and temporal impact of immune cells and their cytokines on fracture healing remains obscure. Some cytokines are reported to be proosteogenic while others inhibit bone healing. Cell-based therapy utilizing mesenchymal stromal cells (MSCs) is an attractive option for augmenting the fracture repair process. Osteoprogenitor MSCs not only differentiate into bone, but they also exert modulatory effects on immune cells via a variety of mechanisms. In this paper, we review the current literature on both in vitro and in vivo studies on the role of the immune system in fracture repair, the use of MSCs in the enhancement of fracture healing, and interactions between MSCs and immune cells. Insight into this paradigm can provide valuable clues in identifying cellular and noncellular targets that can potentially be modulated to enhance both natural bone healing and bone repair augmented by the exogenous addition of MSCs. Tracy K. Kovach, Abhijit S. Dighe, Peter I. Lobo, and Quanjun Cui Copyright © 2015 Tracy K. Kovach et al. All rights reserved. Human Myeloma Cell Lines Induce Osteoblast Downregulation of CD99 Which Is Involved in Osteoblast Formation and Activity Mon, 27 Apr 2015 09:52:31 +0000 CD99 is a transmembrane glycoprotein expressed in physiological conditions by cells of different tissues, including osteoblasts (OBs). High or low CD99 levels have been detected in various pathological conditions, and the supernatant of some carcinoma cell lines can modulate CD99 expression in OB-like cells. In the present work we demonstrate for the first time that two different human myeloma cell lines (H929 and U266) and, in a less degree, their conditioned media significantly downregulate CD99 expression in normal human OBs during the differentiation process. In the same experimental conditions the OBs display a less differentiated phenotype as demonstrated by the decreased expression of RUNX2 and Collagen I. On the contrary, when CD99 was activated by using a specific agonist antibody, the OBs become more active as demonstrated by the upregulation of Alkaline Phosphatase, Collagen I, RUNX2, and JUND expression. Furthermore, we demonstrate that the activation of CD99 is able to induce the phosphorylation of ERK 1/2 and AKT intracellular signal transduction molecules in the OBs. Angela Oranger, Giacomina Brunetti, Claudia Carbone, Graziana Colaianni, Teresa Mongelli, Isabella Gigante, Roberto Tamma, Giorgio Mori, Adriana Di Benedetto, Marika Sciandra, Selena Ventura, Katia Scotlandi, Silvia Colucci, and Maria Grano Copyright © 2015 Angela Oranger et al. All rights reserved. Muramyl Dipeptide Enhances Lipopolysaccharide-Induced Osteoclast Formation and Bone Resorption through Increased RANKL Expression in Stromal Cells Mon, 27 Apr 2015 09:50:15 +0000 Lipopolysaccharide (LPS) is bacterial cell wall component capable of inducing osteoclast formation and pathological bone resorption. Muramyl dipeptide (MDP), the minimal essential structural unit responsible for the immunological activity of peptidoglycans, is ubiquitously expressed by bacterium. In this study, we investigated the effect of MDP in LPS-induced osteoclast formation and bone resorption. LPS was administered with or without MDP into the supracalvariae of mice. The number of osteoclasts, the level of mRNA for cathepsin K and tartrate-resistant acid phosphatase (TRAP), the ratio of the bone destruction area, the level of tartrate-resistant acid phosphatase form 5b (TRACP 5b), and C-terminal telopeptides fragments of type I collagen as a marker of bone resorption in mice administrated both LPS and MDP were higher than those in mice administrated LPS or MDP alone. On the other hand, MDP had no effect on osteoclastogenesis in parathyroid hormone administrated mice. MDP enhanced LPS-induced receptor activator of NF-κB ligand (RANKL) expression and Toll-like receptor 4 (TLR4) expression in vivo and in stromal cells in vitro. MDP also enhanced LPS-induced mitogen-activated protein kinase (MAPK) signaling, including ERK, p38, and JNK, in stromal cells. These results suggest that MDP might play an important role in pathological bone resorption in bacterial infection diseases. Masahiko Ishida, Hideki Kitaura, Keisuke Kimura, Haruki Sugisawa, Tomo Aonuma, Haruhiko Takada, and Teruko Takano-Yamamoto Copyright © 2015 Masahiko Ishida et al. All rights reserved. Bone-Immune Cell Crosstalk: Bone Diseases Mon, 27 Apr 2015 09:49:24 +0000 Bone diseases are associated with great morbidity; thus, the understanding of the mechanisms leading to their development represents a great challenge to improve bone health. Recent reports suggest that a large number of molecules produced by immune cells affect bone cell activity. However, the mechanisms are incompletely understood. This review aims to shed new lights into the mechanisms of bone diseases involving immune cells. In particular, we focused our attention on the major pathogenic mechanism underlying periodontal disease, psoriatic arthritis, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, metastatic solid tumors, and multiple myeloma. Giorgio Mori, Patrizia D’Amelio, Roberta Faccio, and Giacomina Brunetti Copyright © 2015 Giorgio Mori et al. All rights reserved. Hair Follicle Dermal Sheath Derived Cells Improve Islet Allograft Survival without Systemic Immunosuppression Mon, 27 Apr 2015 08:33:10 +0000 Immunosuppressive drugs successfully prevent rejection of islet allografts in the treatment of type I diabetes. However, the drugs also suppress systemic immunity increasing the risk of opportunistic infection and cancer development in allograft recipients. In this study, we investigated a new treatment for autoimmune diabetes using naturally immune privileged, hair follicle derived, autologous cells to provide localized immune protection of islet allotransplants. Islets from Balb/c mouse donors were cotransplanted with syngeneic hair follicle dermal sheath cup cells (DSCC, group 1) or fibroblasts (FB, group 2) under the kidney capsule of immune-competent, streptozotocin induced, diabetic C57BL/6 recipients. Group 1 allografts survived significantly longer than group 2 (32.2 ± 12.2 versus 14.1 ± 3.3 days, ) without administration of any systemic immunosuppressive agents. DSCC reduced T cell activation in the renal lymph node, prevented graft infiltrates, modulated inflammatory chemokine and cytokine profiles, and preserved better beta cell function in the islet allografts, but no systemic immunosuppression was observed. In summary, DSCC prolong islet allograft survival without systemic immunosuppression by local modulation of alloimmune responses, enhancing of beta cell survival, and promoting of graft revascularization. This novel finding demonstrates the capacity of easily accessible hair follicle cells to be used as local immunosuppression agents in islet transplantation. Xiaojie Wang, Jianqiang Hao, Gigi Leung, Trisia Breitkopf, Eddy Wang, Nicole Kwong, Noushin Akhoundsadegh, Garth L. Warnock, Jerry Shapiro, and Kevin J. McElwee Copyright © 2015 Xiaojie Wang et al. All rights reserved. Herpes Murine Model as a Biological Assay to Test Dialyzable Leukocyte Extracts Activity Thu, 23 Apr 2015 14:22:46 +0000 Human dialyzable leukocyte extracts (DLEs) are heterogeneous mixtures of low-molecular-weight peptides that are released on disruption of peripheral blood leukocytes from healthy donors. DLEs improve clinical responses in infections, allergies, cancer, and immunodeficiencies. Transferon is a human DLE that has been registered as a hemoderivate by Mexican health authorities and commercialized nationally. To develop an animal model that could be used routinely as a quality control assay for Transferon, we standardized and validated a murine model of cutaneous HSV-1 infection. Using this model, we evaluated the activity of 27 Transferon batches. All batches improved the survival of HSV-1-infected mice, wherein average survival rose from 20.9% in control mice to 59.6% in Transferon-treated mice. The activity of Transferon correlated with increased serum levels of IFN- and reduced IL-6 and TNF- concentrations. Our results demonstrate that (i) this mouse model of cutaneous herpes can be used to examine the activity of DLEs, such as Transferon; (ii) the assay can be used as a routine test for batch release; (iii) Transferon is produced with high homogeneity between batches; (iv) Transferon does not have direct virucidal, cytoprotective, or antireplicative effects; and (v) the protective effect of Transferon in vivo correlates with changes in serum cytokines. Nohemí Salinas-Jazmín, Sergio Estrada-Parra, Miguel Angel Becerril-García, Alberto Yairh Limón-Flores, Said Vázquez-Leyva, Emilio Medina-Rivero, Lenin Pavón, Marco Antonio Velasco-Velázquez, and Sonia Mayra Pérez-Tapia Copyright © 2015 Nohemí Salinas-Jazmín et al. All rights reserved. Vitamin D Deficiency Contributes to the Reduction and Impaired Function of Naïve Regulatory T Cell in Chronic Heart Failure Thu, 23 Apr 2015 11:15:18 +0000 The effect of vitamin D pertinent to cardiovascular health on the heart itself is considered to shift toward an anti-inflammatory response in chronic heart failure (CHF); however, its underlying mechanism is not completely understood. In this study, we demonstrated that plasma 25(OH)D level, negatively associated with NT-ProBNP, correlated with the decreased Treg in CHF compared to the patients with other cardiovascular diseases and healthy and older donors. Naïve Treg cell (CD4+CD45RA+FoxpT) subset, rather than whole Treg cells, contributes to the reduction of Treg in CHF. 1,25(OH)2D treatment maintained partial expression of CD45RA on CD4+T cell after αCD3/CD28 monoclonal antibodies activation and ameliorated the impaired CD4+CD45RA+T cell function from CHF patients through upregulating Foxp3 expression and IL-10 secretion in vitro. Low level of vitamin D receptor (VDR) was detected in CD4+CD45RA+T cell of CHF than control, while 1,25(OH)2D treatment increased the VDR expression to exert its immunosuppression on T cell. The results of this study might provide tangible evidence to our knowledge of the impact of vitamin D supplementation on naïve Tregs, which may offer new means of preventing and treating CHF. Yan-hui Ma, Yun-lan Zhou, Chao-yan Yue, Guang-hui Zhang, Lin Deng, Guo-hua Xie, Wei-ping Xu, and Li-song Shen Copyright © 2015 Yan-hui Ma et al. All rights reserved. Crosstalk between the Unfolded Protein Response and NF-κB-Mediated Inflammation in the Progression of Chronic Kidney Disease Tue, 21 Apr 2015 06:13:34 +0000 The chronic inflammatory response is emerging as an important therapeutic target in progressive chronic kidney disease. A key transcription factor in the induction of chronic inflammation is NF-κB. Recent studies have demonstrated that sustained activation of the unfolded protein response (UPR) can initiate this NF-κB signaling phenomenon and thereby induce chronic kidney disease progression. A key factor influencing chronic kidney disease progression is proteinuria and this condition has now been demonstrated to induce sustained UPR activation. This review details the crosstalk between the UPR and NF-κB pathways as pertinent to chronic kidney disease. We present potential tools to study this phenomenon as well as potential therapeutics that are emerging to regulate the UPR. These therapeutics may prevent inflammation specifically induced in the kidney due to proteinuria-induced sustained UPR activation. Zahraa Mohammed-Ali, Gaile L. Cruz, and Jeffrey G. Dickhout Copyright © 2015 Zahraa Mohammed-Ali et al. All rights reserved. The Danger Model Approach to the Pathogenesis of the Rheumatic Diseases Mon, 20 Apr 2015 13:42:02 +0000 The danger model was proposed by Polly Matzinger as complement to the traditional self-non-self- (SNS-) model to explain the immunoreactivity. The danger model proposes a central role of the tissular cells’ discomfort as an element to prime the immune response processes in opposition to the traditional SNS-model where foreignness is a prerequisite. However recent insights in the proteomics of diverse tissular cells have revealed that under stressful conditions they have a significant potential to initiate, coordinate, and perpetuate autoimmune processes, in many cases, ruling over the adaptive immune response cells; this ruling potential can also be confirmed by observations in several genetically manipulated animal models. Here, we review the pathogenesis of rheumatic diseases such as systemic lupus erythematous, rheumatoid arthritis, spondyloarthritis including ankylosing spondylitis, psoriasis, and Crohn’s disease and provide realistic approaches based on the logic of the danger model. We assume that tissular dysfunction is a prerequisite for chronic autoimmunity and propose two genetically conferred hypothetical roles for the tissular cells causing the disease: (A) the Impaired cell and (B) the paranoid cell. Both roles are not mutually exclusive. Some examples in human disease and in animal models are provided based on current evidence. César Pacheco-Tena and Susana Aideé González-Chávez Copyright © 2015 César Pacheco-Tena and Susana Aideé González-Chávez. All rights reserved. Modulation of Th1/Th2 Immune Responses by Killed Propionibacterium acnes and Its Soluble Polysaccharide Fraction in a Type I Hypersensitivity Murine Model: Induction of Different Activation Status of Antigen-Presenting Cells Mon, 20 Apr 2015 12:12:40 +0000 Propionibacterium acnes (P. acnes) is a gram-positive anaerobic bacillus present in normal human skin microbiota, which exerts important immunomodulatory effects, when used as heat- or phenol-killed suspensions. We previously demonstrated that heat-killed P. acnes or its soluble polysaccharide (PS), extracted from the bacterium cell wall, suppressed or potentiated the Th2 response to ovalbumin (OVA) in an immediate hypersensitivity model, depending on the treatment protocol. Herein, we investigated the mechanisms responsible for these effects, using the same model and focusing on the activation status of antigen-presenting cells (APCs). We verified that higher numbers of APCs expressing costimulatory molecules and higher expression levels of these molecules are probably related to potentiation of the Th2 response to OVA induced by P. acnes or PS, while higher expression of toll-like receptors (TLRs) seems to be related to Th2 suppression. In vitro cytokines production in cocultures of dendritic cells and T lymphocytes indicated that P. acnes and PS seem to perform their effects by acting directly on APCs. Our data suggest that P. acnes and PS directly act on APCs, modulating the expression of costimulatory molecules and TLRs, and these differently activated APCs drive distinct T helper patterns to OVA in our model. Carla Cristina Squaiella-Baptistão, Daniela Teixeira, Juliana Sekeres Mussalem, Mayari Eika Ishimura, and Ieda Maria Longo-Maugéri Copyright © 2015 Carla Cristina Squaiella-Baptistão et al. All rights reserved. Vitamin D and Atopic Dermatitis in Childhood Mon, 20 Apr 2015 11:39:57 +0000 Vitamin D features immunomodulatory effects on both the innate and adaptive immune systems, which may explain the growing evidence connecting vitamin D to allergic diseases. A wealth of studies describing a beneficial effect of vitamin D on atopic dermatitis (AD) prevalence and severity are known. However, observations linking high vitamin D levels to an increased risk of developing AD have also been published, effectively creating a controversy. In this paper, we review the existing literature on the association between AD and vitamin D levels, focusing on childhood. As of today, the role of vitamin D in AD is far from clear; additional studies are particularly needed in order to confirm the promising therapeutic role of vitamin D supplementation in childhood AD. Michelangelo Vestita, Angela Filoni, Maurizio Congedo, Caterina Foti, and Domenico Bonamonte Copyright © 2015 Michelangelo Vestita et al. All rights reserved. Impact of Inflammatory Cytokine Gene Polymorphisms on Developing Acute Graft-versus-Host Disease in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation Mon, 20 Apr 2015 09:21:06 +0000 Single nucleotide polymorphisms (SNPs) in gene encoding pro- and anti-inflammatory factors have been associated with the occurrence of aGvHD. We retrospectively tested a wide panel of 38 polymorphisms in 19 immunoregulatory genes, aiming to first establish, in a pediatric HSCT setting, which SNPs were significantly associated with the development of aGvHD. A significant association was found between aGvHD grades II–IV and SNPs of donor IL10-1082GG, and Fas-670CC + CT and recipient IL18-607 TT + TG genotype. aGvHD grades III-IV resulted associated with donor IL10-1082GG, Fas-670CC + CT, and TLR4-3612TT as well as the use of peripheral CD34+ cells as stem cell source. The multivariate analysis confirmed the association between donor IL10-1082GG and Fas-670CC + CT and aGvHD grades II–IV and between donor IL10-1082GG and TLR4-3612TT and aGvHD grades III-IV. In conclusion we found an association between IL10, FAS, and TLR4 in the donor and IL18 in the recipient and an increased risk of developing aGvHD in transplanted children. Knowledge of the SNPs of cytokine genes associated with aGvHD represents a useful tool for an integrated pretransplantation risk assessment and could guide the physicians to an optimal and more accurate HSCT planning. Riccardo Masetti, Daniele Zama, Milena Urbini, Annalisa Astolfi, Virginia Libri, Francesca Vendemini, William Morello, Roberto Rondelli, Arcangelo Prete, and Andrea Pession Copyright © 2015 Riccardo Masetti et al. All rights reserved. Assessment of Physicochemical Properties of Rituximab Related to Its Immunomodulatory Activity Mon, 20 Apr 2015 06:56:25 +0000 Rituximab is a chimeric monoclonal antibody employed for the treatment of CD20-positive B-cell non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis. It binds specifically to the CD20 antigen expressed on pre-B and consequently on mature B-lymphocytes of both normal and malignant cells, inhibiting their proliferation through apoptosis, CDC, and ADCC mechanisms. The immunomodulatory activity of rituximab is closely related to critical quality attributes that characterize its chemical composition and spatial configuration, which determine the recognition of CD20 and the binding to receptors or factors involved in its effector functions, while regulating the potential immunogenic response. Herein, we present a physicochemical and biological characterization followed by a pharmacodynamics and immunogenicity study to demonstrate comparability between two products containing rituximab. The physicochemical and biological characterization revealed that both products fit within the same response intervals exhibiting the same degree of variability. With regard to clinical response, both products depleted CD20+ B-cells until posttreatment recovery and no meaningful differences were found in their pharmacodynamic profiles. The evaluation of anti-chimeric antibodies did not show differential immunogenicity among products. Overall, these data confirm that similarity of critical quality attributes results in a comparable immunomodulatory activity. Mariana P. Miranda-Hernández, Carlos A. López-Morales, Nancy D. Ramírez-Ibáñez, Nelly Piña-Lara, Nestor O. Pérez, Aarón Molina-Pérez, Jorge Revilla-Beltri, Luis F. Flores-Ortiz, and Emilio Medina-Rivero Copyright © 2015 Mariana P. Miranda-Hernández et al. All rights reserved. Modulation of Immune Response by Organophosphorus Pesticides: Fishes as a Potential Model in Immunotoxicology Mon, 20 Apr 2015 06:54:44 +0000 Immune response is modulated by different substances that are present in the environment. Nevertheless, some of these may cause an immunotoxic effect. In this paper, the effect of organophosphorus pesticides (frequent substances spilled in aquatic ecosystems) on the immune system of fishes and in immunotoxicology is reviewed. Furthermore, some cellular and molecular mechanisms that might be involved in immunoregulation mechanisms of organophosphorus pesticides are discussed. K. J. G. Díaz-Resendiz, G. A. Toledo-Ibarra, and M. I. Girón-Pérez Copyright © 2015 K. J. G. Díaz-Resendiz et al. All rights reserved. Inhibins Tune the Thymocyte Selection Process by Regulating Thymic Stromal Cell Differentiation Mon, 20 Apr 2015 06:45:36 +0000 Inhibins and Activins are members of the TGF-β superfamily that regulate the differentiation of several cell types. These ligands were initially identified as hormones that regulate the hypothalamus-pituitary-gonadal axis; however, increasing evidence has demonstrated that they are key regulators in the immune system. We have previously demonstrated that Inhibins are the main Activin ligands expressed in the murine thymus and that they regulate thymocyte differentiation, promoting the DN3-DN4 transition and the selection of SP thymocytes. As Inhibins are mainly produced by thymic stromal cells, which also express Activin receptors and Smad proteins, we hypothesized that Inhibins might play a role in stromal cell differentiation and function. Here, we demonstrate that, in the absence of Inhibins, thymic conventional dendritic cells display reduced levels of MHC Class II (MHCII) and CD86. In addition, the ratio between cTECs and mTECs was affected, indicating that mTEC differentiation was favoured and cTEC diminished in the absence of Inhibins. These changes appeared to impact thymocyte selection leading to a decreased selection of CD4SP thymocytes and increased generation of natural regulatory T cells. These findings demonstrate that Inhibins tune the T cell selection process by regulating both thymocyte and stromal cell differentiation. Ebzadrel Carbajal-Franco, Marisol de la Fuente-Granada, Germán R. Alemán-Muench, Eduardo A. García-Zepeda, and Gloria Soldevila Copyright © 2015 Ebzadrel Carbajal-Franco et al. All rights reserved. Gender-Related Effects of Sex Steroids on Histamine Release and FcεRI Expression in Rat Peritoneal Mast Cells Mon, 20 Apr 2015 06:41:12 +0000 Mast cells (MCs) are versatile effector and regulatory cells in various physiologic, immunologic, and pathologic processes. In addition to the well-characterized IgE/FcεRI-mediated degranulation, a variety of biological substances can induce MCs activation and release of their granule content. Sex steroids, mainly estradiol and progesterone, have been demonstrated to elicit MCs activation. Most published studies have been conducted on MCs lines or freshly isolated peritoneal and bone marrow-derived MC without addressing gender impact on MC response. Our goal was to investigate if the effect of estradiol, progesterone, testosterone, and dihydrotestosterone (DHT) on MCs may differ depending on whether female or male rats are used as MCs donors. Our results demonstrated that effect of sex steroids on MCs histamine release is dose- and gender-dependent and can be direct, synergistic, or inhibitory depending on whether hormones are used alone or to pretreat MCs followed by substance P-stimulation or upon IgE-mediated stimulation. In contrast, sex steroids did not have effect on the MC expression of the IgE high affinity receptor, FcεRI, no matter female or male rats were used. In conclusion, MCs degranulation is modulated by sex hormones in a gender-selective fashion, with MC from females being more susceptible than MC from males to the effects of sex steroids. Samira Muñoz-Cruz, Yolanda Mendoza-Rodríguez, Karen E. Nava-Castro, Lilián Yepez-Mulia, and Jorge Morales-Montor Copyright © 2015 Samira Muñoz-Cruz et al. All rights reserved. The Effects of Bromocriptine on Preventing Postpartum Flare in Systemic Lupus Erythematosus Patients from South China Mon, 20 Apr 2015 06:37:44 +0000 Objective. Prolactin plays an important role on the disease flare of postpartum SLE patients. 76 pregnant SLE patients were enrolled in this study to evaluate the efficacy of bromocriptine (an inhibitor of prolactin secretion) on preventing the postpartum disease relapse. Methods. Patients were randomly divided into the treatment group (bromocriptine, 2.5 mg oral, twice a day for 14 days after delivery) and the control group. All the patients were followed up for 12 months. Clinical features were recorded every 4 weeks. Serum prolactin and estradiol levels were measured at the second week and the second month after delivery. The endpoint of the study was disease relapse and defined when SLEDAI score increased by ≥3 points from the antenatal baseline. Results. (1) Serum levels of prolactin and estradiol decreased significantly in bromocriptine treatment group at the second week () and second month () after delivery compared to control group. (2) The relapse rate of the treatment group was lower than the control group (, ). Conclusions. Two weeks of oral bromocriptine treatment in postpartum SLE patients may relieve the disease from hyperprolactinemia and hyperestrogenemia and may be beneficial in preventing the patients from disease relapse. Qiu Qian, Liang Liuqin, Li Hao, Yuan Shiwen, Zhan Zhongping, Chen Dongying, Lian Fan, Xu Hanshi, Yang Xiuyan, and Ye Yujin Copyright © 2015 Qiu Qian et al. All rights reserved. Epigenetic Control of Interferon-Gamma Expression in CD8 T Cells Mon, 20 Apr 2015 06:33:59 +0000 Interferon- (IFN-) γ is an essential cytokine for immunity against intracellular pathogens and cancer. IFN-γ expression by CD4 T lymphocytes is observed only after T helper (Th) 1 differentiation and there are several studies about the molecular mechanisms that control Ifng expression in these cells. However, naïve CD8 T lymphocytes do not produce large amounts of IFN-γ, but after TCR stimulation there is a progressive acquisition of IFN-γ expression during differentiation into cytotoxic T lymphocytes (CTL) and memory cells, which are capable of producing high levels of this cytokine. Differential gene expression can be regulated from the selective action of transcriptional factors and also from epigenetic mechanisms, such as DNA CpG methylation or posttranslational histone modifications. Recently it has been recognized that epigenetic modification is an integral part of CD8 lymphocyte differentiation. This review will focus on the chromatin status of Ifng promoter in CD8 T cells and possible influences of epigenetic modifications in Ifng gene and conserved noncoding sequences (CNSs) in regulation of IFN-γ production by CD8 T lymphocytes. Patrícia S. de Araújo-Souza, Steffi C. H. Hanschke, and João P. B. Viola Copyright © 2015 Patrícia S. de Araújo-Souza et al. All rights reserved. Lactobacillus acidophilus Suppresses Colitis-Associated Activation of the IL-23/Th17 Axis Mon, 20 Apr 2015 06:33:57 +0000 The aim of this paper is to determine the modulatory effects of Lactobacillus acidophilus on the IL-23/Th17 immune axis in experimental colitis. DSS-induced mouse models of UC were to be saline, hormones, and different concentrations of Lactobacillus acidophilus intervention. The expression of interleukin- (IL-) 17, tumor necrosis factor α (TNFα), IL-23, transforming growth factor β1 (TGFβ1), signal transducer and activator of transcription 3 (STAT3), and phosphorylated (p)-STAT3 was examined by RT-PCR, Western blotting, and immunohistochemical analysis. And the results showed that administration of L. acidophilus suppressed Th17 cell-mediated secretion of proinflammatory cytokine IL-17 through downregulation of IL-23 and TGFβ1 expression and downstream phosphorylation of p-STAT3. Linlin Chen, Yiyou Zou, Jie Peng, Fanggen Lu, Yani Yin, Fujun Li, and Junwen Yang Copyright © 2015 Linlin Chen et al. All rights reserved. The Pharmacodynamic Impact of Apremilast, an Oral Phosphodiesterase 4 Inhibitor, on Circulating Levels of Inflammatory Biomarkers in Patients with Psoriatic Arthritis: Substudy Results from a Phase III, Randomized, Placebo-Controlled Trial (PALACE 1) Mon, 20 Apr 2015 06:32:36 +0000 Apremilast, an oral phosphodiesterase 4 inhibitor, demonstrated effectiveness (versus placebo) for treatment of active psoriatic arthritis in the psoriatic arthritis long-term assessment of clinical efficacy (PALACE) phase III clinical trial program. Pharmacodynamic effects of apremilast on plasma biomarkers associated with inflammation were evaluated in a PALACE 1 substudy. Of 504 patients randomized in PALACE 1, 150 (placebo: ; apremilast 20 mg BID: ; apremilast 30 mg BID: ) provided peripheral blood plasma samples for analysis in a multiplexed cytometric bead array assay measuring 47 proteins associated with systemic inflammatory immune responses. Association between biomarker levels and achievement of 20% improvement from baseline in modified American College of Rheumatology (ACR20) response criteria was assessed by logistic regression. At Week 24, IL-8, TNF-α, IL-6, MIP-1β, MCP-1, and ferritin were significantly reduced from baseline with apremilast 20 mg BID or 30 mg BID versus placebo. ACR20 response correlated with change in TNF-α level with both apremilast doses. At Week 40, IL-17, IL-23, IL-6, and ferritin were significantly decreased and IL-10 and IL-1 receptor antagonists significantly increased with apremilast 30 mg BID versus placebo. In patients with active psoriatic arthritis, apremilast reduced circulating levels of Th1 and Th17 proinflammatory mediators and increased anti-inflammatory mediators. Peter H. Schafer, Peng Chen, Lorraine Fang, Andrew Wang, and Rajesh Chopra Copyright © 2015 Peter H. Schafer et al. All rights reserved. Downmodulation of Vaccine-Induced Immunity and Protection against the Intracellular Bacterium Francisella tularensis by the Inhibitory Receptor FcγRIIB Sun, 19 Apr 2015 17:19:34 +0000 Fc gamma receptor IIB (FcγRIIB) is the only Fc gamma receptor (FcγR) which negatively regulates the immune response, when engaged by antigen- (Ag-) antibody (Ab) complexes. Thus, the generation of Ag-specific IgG in response to infection or immunization has the potential to downmodulate immune protection against infection. Therefore, we sought to determine the impact of FcγRIIB on immune protection against Francisella tularensis (Ft), a Category A biothreat agent. We utilized inactivated Ft (iFt) as an immunogen. Naïve and iFt-immunized FcγRIIB knockout (KO) or wildtype (WT) mice were challenged with Ft-live vaccine strain (LVS). While no significant difference in survival between naïve FcγRIIB KO versus WT mice was observed, iFt-immunized FcγRIIB KO mice were significantly better protected than iFt-immunized WT mice. Ft-specific IgA in serum and bronchial alveolar lavage, as well as IFN-γ, IL-10, and TNF-α production by splenocytes harvested from iFt-immunized FcγRIIB KO, were also significantly elevated. In addition, iFt-immunized FcγRIIB KO mice exhibited a reduction in proinflammatory cytokine levels in vivo at 5 days after challenge, which correlates with increased survival following Ft-LVS challenge in published studies. Thus, these studies demonstrate for the first time the ability of FcγRIIB to regulate vaccine-induced IgA production and downmodulate immunity and protection. The immune mechanisms behind the above observations and their potential impact on vaccine development are discussed. Brian J. Franz, Ying Li, Constantine Bitsaktsis, Bibiana V. Iglesias, Giang Pham, Raju Sunagar, Sudeep Kumar, and Edmund J. Gosselin Copyright © 2015 Brian J. Franz et al. All rights reserved. Immunomodulatory Effects Mediated by Serotonin Sun, 19 Apr 2015 16:57:51 +0000 Serotonin (5-HT) induces concentration-dependent metabolic effects in diverse cell types, including neurons, entherochromaffin cells, adipocytes, pancreatic beta-cells, fibroblasts, smooth muscle cells, epithelial cells, and leukocytes. Three classes of genes regulating 5-HT function are constitutively expressed or induced in these cells: (a) membrane proteins that regulate the response to 5-HT, such as SERT, 5HTR-GPCR, and the 5HT3-ion channels; (b) downstream signaling transduction proteins; and (c) enzymes controlling 5-HT metabolism, such as IDO and MAO, which can generate biologically active catabolites, including melatonin, kynurenines, and kynurenamines. This review covers the clinical and experimental mechanisms involved in 5-HT-induced immunomodulation. These mechanisms are cell-specific and depend on the expression of serotonergic components in immune cells. Consequently, 5-HT can modulate several immunological events, such as chemotaxis, leukocyte activation, proliferation, cytokine secretion, anergy, and apoptosis. The effects of 5-HT on immune cells may be relevant in the clinical outcome of pathologies with an inflammatory component. Major depression, fibromyalgia, Alzheimer disease, psoriasis, arthritis, allergies, and asthma are all associated with changes in the serotonergic system associated with leukocytes. Thus, pharmacological regulation of the serotonergic system may modulate immune function and provide therapeutic alternatives for these diseases. Rodrigo Arreola, Enrique Becerril-Villanueva, Carlos Cruz-Fuentes, Marco Antonio Velasco-Velázquez, María Eugenia Garcés-Alvarez, Gabriela Hurtado-Alvarado, Saray Quintero-Fabian, and Lenin Pavón Copyright © 2015 Rodrigo Arreola et al. All rights reserved. Immunoregulation by Mesenchymal Stem Cells: Biological Aspects and Clinical Applications Sun, 19 Apr 2015 16:54:06 +0000 Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiation into mesenchymal lineages and that can be isolated from various tissues and easily cultivated in vitro. Currently, MSCs are of considerable interest because of the biological characteristics that confer high potential applicability in the clinical treatment of many diseases. Specifically, because of their high immunoregulatory capacity, MSCs are used as tools in cellular therapies for clinical protocols involving immune system alterations. In this review, we discuss the current knowledge about the capacity of MSCs for the immunoregulation of immunocompetent cells and emphasize the effects of MSCs on T cells, principal effectors of the immune response, and the immunosuppressive effects mediated by the secretion of soluble factors and membrane molecules. We also describe the mechanisms of MSC immunoregulatory modulation and the participation of MSCs as immune response regulators in several autoimmune diseases, and we emphasize the clinical application in graft versus host disease (GVHD). Marta E. Castro-Manrreza and Juan J. Montesinos Copyright © 2015 Marta E. Castro-Manrreza and Juan J. Montesinos. All rights reserved. IL-10 and ARG-1 Concentrations in Bone Marrow and Peripheral Blood of Metastatic Neuroblastoma Patients Do Not Associate with Clinical Outcome Sun, 19 Apr 2015 14:16:16 +0000 The expression of the immunosuppressive molecules IL-10 and arginase 1 (ARG-1), and of FOXP3 and CD163, as markers of regulatory T cells (Treg) and macrophages, respectively, was evaluated in bone marrow (BM) and peripheral blood (PB) samples collected at diagnosis from patients with metastatic neuroblastoma (NB). IL-10 and ARG-1 plasma concentrations were measured and the association of each parameter with patients’ outcome was tested. The percentages of immunosuppressive Treg and type-1 regulatory (Tr1) cells were also determined. In both BM and PB samples, IL-10 mRNA expression was higher in metastatic NB patients than in controls. IL-10 plasma concentration was higher in patients with NB regardless of stage. Neither IL-10 expression nor IL-10 plasma concentration significantly associated with patient survival. In PB samples from metastatic NB patients, ARG-1 and CD163 expression was higher than in controls but their expression did not associate with survival. Moreover, ARG-1 plasma concentration was lower than in controls, and no association with patient outcome was found. Finally, in metastatic NB patients, the percentage of circulating Treg was higher than in controls, whereas that of Tr1 cells was lower. In conclusion, although IL-10 concentration and Treg percentage were increased, their contribution to the natural history of metastatic NB appears uncertain. Fabio Morandi, Michela Croce, Giuliana Cangemi, Sebastiano Barco, Valentina Rigo, Barbara Carlini, Loredana Amoroso, Vito Pistoia, Silvano Ferrini, and Maria Valeria Corrias Copyright © 2015 Fabio Morandi et al. All rights reserved. Immunomodulation and Anti-Inflammatory Effects of Garlic Compounds Sun, 19 Apr 2015 14:10:05 +0000 The benefits of garlic to health have been proclaimed for centuries; however, only recently have Allium sativum and its derivatives been proposed as promising candidates for maintaining the homeostasis of the immune system. The complex biochemistry of garlic makes it possible for variations in processing to yield different preparations with differences in final composition and compound proportion. In this review, we assess the most recent experimental results, which indicate that garlic appears to enhance the functioning of the immune system by stimulating certain cell types, such as macrophages, lymphocytes, natural killer (NK) cells, dendritic cells, and eosinophils, by mechanisms including modulation of cytokine secretion, immunoglobulin production, phagocytosis, and macrophage activation. Finally, because immune dysfunction plays an important role in the development and progress of several diseases, we critically examined immunoregulation by garlic extracts and compounds isolated, which can contribute to the treatment and prevention of pathologies such as obesity, metabolic syndrome, cardiovascular disorders, gastric ulcer, and even cancer. We concluded that A. sativum modulates cytokine secretion and that such modulation may provide a mechanism of action for many of their therapeutic effects. Rodrigo Arreola, Saray Quintero-Fabián, Rocío Ivette López-Roa, Enrique Octavio Flores-Gutiérrez, Juan Pablo Reyes-Grajeda, Lucrecia Carrera-Quintanar, and Daniel Ortuño-Sahagún Copyright © 2015 Rodrigo Arreola et al. All rights reserved. Increased Frequency of CD4+ CD25+ FoxP3+ T Regulatory Cells in Pulmonary Tuberculosis Patients Undergoing Specific Treatment and Its Relationship with Their Immune-Endocrine Profile Sun, 19 Apr 2015 14:07:39 +0000 Tuberculosis (TB) is a major health problem requiring an appropriate cell immune response (IR) to be controlled. Since regulatory T cells (Tregs) are relevant in IR regulation, we analyzed Tregs variations throughout the course of TB treatment and its relationship with changes in immune-endocrine mediators dealing with disease immunopathology. The cohort was composed of 41 adult patients, 20 of them completing treatment and follow-up. Patients were bled at diagnosis (T0) and at 2 (T2), 4 (T4), 6 (T6), and 9 months following treatment initiation. Twenty-four age- and sex-matched healthy controls (HCo) were also included. Tregs (flow cytometry) from TB patients were increased at T0 (versus HCo ), showing even higher values at T2 (versus T0 ) and T4 (versus T0 ). While IL-6, IFN-, TGF- (ELISA), and Cortisol (electrochemiluminescence, EQ) were augmented, DHEA-S (EQ) levels were diminished at T0 with respect to HCo, with cytokines and Cortisol returning to normal values at T9. Tregs correlated positively with IFN- (, ) at T2 and negatively at T4 (, ). Lowered levels of proinflammatory cytokines together with an increased frequency of Tregs of patients undergoing specific treatment might reflect a downmodulatory effect of these cells on the accompanying inflammation. Ariana Díaz, Natalia Santucci, Bettina Bongiovanni, Luciano D’Attilio, Claudia Massoni, Susana Lioi, Stella Radcliffe, Griselda Dídoli, Oscar Bottasso, and María Luisa Bay Copyright © 2015 Ariana Díaz et al. All rights reserved. Experimental Autoimmune Encephalomyelitis Development Is Aggravated by Candida albicans Infection Sun, 19 Apr 2015 14:06:11 +0000 Multiple sclerosis (MS) is an inflammatory/autoimmune disease of the central nervous system (CNS) mainly mediated by myelin specific T cells. It is widely believed that environmental factors, including fungal infections, contribute to disease induction or evolution. Even though Candida infection among MS patients has been described, the participation of this fungus in this pathology is not clear. The purpose of this work was to evaluate the effect of a Candida albicans infection on experimental autoimmune encephalomyelitis (EAE) that is a widely accepted model to study MS. Female C57BL/6 mice were infected with C. albicans and 3 days later, animals were submitted to EAE induction by immunization with myelin oligodendrocyte glycoprotein. Previous infection increased the clinical score and also the body weight loss. EAE aggravation was associated with expansion of peripheral CD4+ T cells and production of high levels of TNF-α, IFN-γ IL-6, and IL-17 by spleen and CNS cells. In addition to yeast and hyphae, fungus specific T cells were found in the CNS. These findings suggest that C. albicans infection before EAE induction aggravates EAE, and possibly MS, mainly by CNS dissemination and local induction of encephalitogenic cytokines. Peripheral production of encephalitogenic cytokines could also contribute to disease aggravation. Thais F. C. Fraga-Silva, Luiza A. N. Mimura, Camila M. Marchetti, Fernanda Chiuso-Minicucci, Thais G. D. França, Sofia F. G. Zorzella-Pezavento, James Venturini, Maria S. P. Arruda, and Alexandrina Sartori Copyright © 2015 Thais F. C. Fraga-Silva et al. All rights reserved.