Journal of Immunology Research The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Evaluation of T Cell Immunity against Human Cytomegalovirus: Impact on Patient Management and Risk Assessment of Vertical Transmission Thu, 01 Dec 2016 12:12:18 +0000 Cytomegalovirus (CMV) is one of the most common infectious agents, infecting the general population at an early age without causing morbidity most of the time. However, on particular occasions, it may represent a serious risk, as active infection is associated with rejection and disease after solid organ transplantation or fetal transmission during pregnancy. Several methods for CMV diagnosis are available on the market, but because infection is so common, careful selection is needed to discriminate primary infection from reactivation. This review focuses on methods based on CMV-specific T cell reactivity to help monitor the consequences of CMV infection/reactivation in specific categories of patients. This review makes an attempt at discussing the pros and cons of the methods available. Giulia Freer, Paola Quaranta, and Mauro Pistello Copyright © 2016 Giulia Freer et al. All rights reserved. Antigen-Specific IFN-γ Responses Correlate with the Activity of M. tuberculosis Infection but Are Not Associated with the Severity of Tuberculosis Disease Wed, 30 Nov 2016 14:20:01 +0000 IFN-γ is a key cytokine in antituberculosis (TB) defense. However, how the levels of its secretion affect M. tuberculosis (Mtb) infection is not clear. We have analyzed associations between IFN-γ responses measured in QuantiFERON®-TB Gold In-tube (QFT) assay, TB disease severity, and Mtb infection activity. TB severity was evaluated based on the results of radiological, microbiological, and clinical examinations. Antigen-driven IFN-γ secretion did not correlate with TB severity. Mitogen-induced IFN-γ secretion correlated inversely with the form of pulmonary pathology and the area of affected pulmonary tissue; the levels of spontaneous IFN-γ secretion correlated with patients’ age ( = 0.395, = 0.001). Mtb infection activity was evaluated based on radiological data of lung tissue infiltration, destruction, dissemination or calcification, and condensation. The rate of positive QFT results and the levels of antigen-driven IFN-γ secretion increased in a row: patients with residual TB lesions < patients with low TB activity < patients with high TB activity. Thus, antigen-driven IFN-γ secretion and QFT results did not associate with TB severity but associated with the infection activity. The results suggest that quantitative parameters of IFN-γ secretion play a minor role in determining the course of TB disease but mirror the activity of the infectious process. Irina Yu. Nikitina, Alexander V. Panteleev, Ekaterina V. Sosunova, Natalya L. Karpina, Tatef R. Bagdasarian, Irina A. Burmistrova, Sofia N. Andreevskaya, Larisa N. Chernousova, Irina A. Vasilyeva, and Irina V. Lyadova Copyright © 2016 Irina Yu. Nikitina et al. All rights reserved. Influence of the Expression of Inflammatory Markers on Kidney after Fetal Programming in an Experimental Model of Renal Failure Mon, 28 Nov 2016 12:29:11 +0000 Objective. To evaluate the expression of inflammatory markers in experimental renal failure after fetal programming. Methods. The offspring aged two and five months were divided into four groups: CC (control dams, control offspring); DC (diabetic dams, control offspring); CFA (control dams, folic acid offspring, 250 mg/Kg); and DFA (diabetic dams, folic acid offspring). Gene expression of inflammatory markers MCP-1, IL-1, NOS3, TGF-β, TNF-α, and VEGF was evaluated by RT-PCR. Results. MCP-1 was increased in the CFA and DFA groups at two and five months of age, as well as in DC5 when compared to CC5. There was a higher expression of IL-1 in the CFA2, DFA2, and DC2 groups. There was a decrease in NOS3 and an increase in TNF-α in DFA5 in relation to CFA5. The gene expression of TGF-β increased in cases that had received folic acid at two and five months, and VEGF decreased in the CFA5 and DFA5 groups. DC5 showed increased VEGF expression in comparison with CC5. Conclusions. Gestational diabetes mellitus and folic acid both change the expression of inflammatory markers, thus demonstrating that the exposure to harmful agents in adulthood has a more severe impact in cases which underwent fetal reprogramming. Carlos Donizete Pereira Júnior, Camila Souza de Oliveira Guimarães, Aline Cristina Souza da Silva, Aldo Rogelis Aquiles Rodrigues, Maria Aparecida da Glória, Vicente de Paula Antunes Teixeira, Niels Olsen Saraiva Câmara, Lenaldo Branco Rocha, Marlene Antônia dos Reis, Juliana Reis Machado, Laura Penna Rocha, Fernanda Rodrigues Helmo, and Rosana Rosa Miranda Corrêa Copyright © 2016 Carlos Donizete Pereira Júnior et al. All rights reserved. The Pathophysiological Impact of HLA Class Ia and HLA-G Expression and Regulatory T Cells in Malignant Melanoma: A Review Wed, 23 Nov 2016 13:49:33 +0000 Malignant melanoma, a very common type of cancer, is a rapidly growing cancer of the skin with an increase in incidence among the Caucasian population. The disease is seen through all age groups and is very common in the younger age groups. Several studies have examined the risk factors and pathophysiological mechanisms of malignant melanoma, which have enlightened our understanding of the development of the disease, but we have still to fully understand the complex immunological interactions. The examination of the interaction between the human leucocyte antigen (HLA) system and prognostic outcome has shown interesting results, and a correlation between the down- or upregulation of these antigens and prognosis has been seen through many different types of cancer. In malignant melanoma, HLA class Ia has been seen to influence the effects of pharmaceutical drug treatment as well as the overall prognosis, and the HLA class Ib and regulatory T cells have been correlated with tumor progression. Although there is still no standardized immunological treatment worldwide, the interaction between the human leucocyte antigen (HLA) system and tumor progression seems to be a promising focus in the way of optimizing the treatment of malignant melanoma. Lasse Lindholm Johansen, Jørgen Lock-Andersen, and Thomas Vauvert F. Hviid Copyright © 2016 Lasse Lindholm Johansen et al. All rights reserved. Association of Serum CXCL13 with Intrarenal Ectopic Lymphoid Tissue Formation in Lupus Nephritis Sun, 20 Nov 2016 08:31:25 +0000 Aims. To assess the concentrations of serum CXCL13 and intrarenal ectopic lymphoid tissue (ELT) profiles and their correlation in the patients with lupus nephritis (LN). Methods. Serum CXCL13 levels were measured using enzyme-linked immunosorbent assays (ELISA). The expression of CD3, CD20, and CD21 in renal biopsy specimens was tested using immunohistochemical methods. Results. Serum CXCL13 levels were significantly higher in the LN group than those in the SLE group without LN and also in the type III and IV LN patients than in type V LN patients. LN patients with positive CD20 expression (CD20+ LN) had a longer disease course and poorer response to combination therapy and higher serum CXCL13 levels than CD20− LN patients. Moreover, the serum CXCL13 level was positively correlated with the number of B cells/HP in the renal tissue of LN patients. The coexpression patterns of CD3, CD20, and CD21 in the renal tissue of LN patients with different WHO pathological types were significantly different. Serum CXCL13 levels were significantly higher in ELT-2 type LN patients than in 0 or 1 type LN patients. Conclusions. This study suggested that increased serum levels of CXCL13 might be involved in renal ELT formation and renal impairment process in LN. De Ning He, Wen Li Chen, Kang Xia Long, Xiao Zhang, and Guang Fu Dong Copyright © 2016 De Ning He et al. All rights reserved. Complement Receptor Type 1 Suppresses Human B Cell Functions in SLE Patients Thu, 17 Nov 2016 09:21:15 +0000 Complement receptors (CRs) play an integral role in innate immunity and also function to initiate and shape the adaptive immune response. Our earlier results showed that complement receptor type 1 (CR1, CD35) is a potent inhibitor of the B cell receptor- (BCR-) induced functions of human B lymphocytes. Here we show that this inhibition occurs already at the initial steps of B cell activation since ligation of CR1 reduces the BCR-induced phosphorylation of key signaling molecules such as Syk and mitogen activated protein kinases (MAPKs). Furthermore, our data give evidence that although B lymphocytes of active systemic lupus erythematosus (SLE) patients express lower level of CR1, the inhibitory capacity of this complement receptor is still maintained and its ligand-induced clustering results in significant inhibition of the main B cell functions, similar to that found in the case of healthy individuals. Since we have found that reduced CR1 expression of SLE patients does not affect the inhibitory capacity of the receptor, our results further support the therapeutical potential of CD35 targeting the decrease of B cell activation and autoantibody production in autoimmune patients. Mariann Kremlitzka, Bernadett Mácsik-Valent, Anna Polgár, Emese Kiss, Gyula Poór, and Anna Erdei Copyright © 2016 Mariann Kremlitzka et al. All rights reserved. New Mechanisms of Tumor-Associated Macrophages on Promoting Tumor Progression: Recent Research Advances and Potential Targets for Tumor Immunotherapy Wed, 16 Nov 2016 11:11:54 +0000 The majority of basic and clinical studies have shown a protumor function of tumor-associated macrophages (TAMs), which represent a large proportion of matrix cells. TAMs promote tumorigenesis, and their number is related to the malignancy degree and poor prognosis of many kinds of tumors. Macrophage plasticity makes it possible to change the tumor microenvironment and remodel antitumor immunity during cancer immunotherapy. Increasing numbers of studies have revealed the effects of TAMs on the tumor microenvironment, for example, via promotion of tumor growth and tumorigenesis and through an increase in the number of cancer stem cells or via facilitation of angiogenesis, lymphangiogenesis, and metastasis. Investigators also proposed tumor-immunological treatments targeting TAMs by inhibiting TAM recruitment and differentiation, by regulating TAM polarization, and by blocking factors and pathways associated with the protumor function of TAMs. This comprehensive review presents recent research on TAMs in relation to prediction of poor outcomes, remodeling of the tumor immune microenvironment, and immunological targeted therapies. Qiujun Guo, Zhichao Jin, Yuan Yuan, Rui Liu, Tao Xu, Huamin Wei, Xinyao Xu, Shulin He, Shuntai Chen, Zhan Shi, Wei Hou, and Baojin Hua Copyright © 2016 Qiujun Guo et al. All rights reserved. Overexpression of MMP-3 and uPA with Diminished PAI-1 Related to Metastasis in Ductal Breast Cancer Patients Attending a Public Hospital in Mexico City Tue, 15 Nov 2016 11:13:48 +0000 Extracellular matrix metalloproteases and the fibrinolytic system are important protease systems interacting with each other in charge of remodeling and recycling of tissues. Their role in tumor invasion and metastasis is often discussed. In this study several metalloproteases such as MMP-1, MMP-3, MMP-9, and TIMP-1 together with molecules from the fibrinolytic system like uPA, its receptor uPAR, and its inhibitor, PAI-1, were studied by immune-histochemistry to establish a comparison with and without metastasis. From the (118) primary tumors of Mexican patients with ductal breast cancer studied, 56% were grade II and 69% were size T2; the group with metastatic ganglia included 64 samples (54.3%). In patients with metastasis the estimated expression of MMP-3 and uPA (resp., 28% and 45%) was higher than that from no metastatic tumors; it means there is higher expression of both markers in metastatic tumors (). At the same time, metastatic tumors showed statistically significant lower signal of PAI-1 (24%) than tumors without metastasis (). We concluded that overexpression of MMP-3 and uPA, altogether with diminished expression of PAI-1 from metastatic tumors, might be a crucial step towards metastasis in ductal breast cancer. Nevertheless, additional studies in different populations are necessary to establish a pattern. Luis Miguel Barajas-Castañeda, Evelin Cortés-Gutiérrez, Francisco Mario García-Rodríguez, Rafael Campos-Rodríguez, Eleazar Lara-Padilla, Fernando Enríquez-Rincón, María Eugenia Castro-Mussot, and Paula Figueroa-Arredondo Copyright © 2016 Luis Miguel Barajas-Castañeda et al. All rights reserved. The Suppressed Induction of Human Mature Cytotoxic T Lymphocytes Caused by Asbestos Is Not due to Interleukin-2 Insufficiency Tue, 15 Nov 2016 08:51:00 +0000 We previously reported that exposure to chrysotile B (CB) asbestos suppressed the induction of mature cytotoxic T lymphocytes (CTLs) during mixed lymphocyte reaction assays (MLRs) with a decrease in the proliferation of immature CTLs. However, the mechanism responsible for the effect of asbestos fibers on the differentiation of CTLs remains unclear. Since interleukin-2 (IL-2) is a regulator of T lymphocyte proliferation, we examined the effect of IL-2 addition on suppressed CTL differentiation in CB-exposed cultures using flow cytometry (FCM). When IL-2 was added at 1 ng/mL on the second day of MLRs, the asbestos-caused decreases in the proliferation and percentages of CD25+ and CD45RO+ cells in CD8+ lymphocytes were not recovered by IL-2 addition, although the decrease in percentage of granzyme B+ cells was partially recovered. CD8+ lymphocytes from the IL-2-treated culture with asbestos showed the same degree of cytotoxicity as those in cultures without IL-2 or asbestos. These findings indicate that IL-2 insufficiency is not the main cause for the suppressed induction of CTLs by asbestos exposure, although they suggest a potential for the improvement of such suppressed CTL functions. Secretory factors other than IL-2 in addition to membrane-bound stimulatory molecules may play a role in asbestos-caused suppressed CTL differentiation. Naoko Kumagai-Takei, Yasumitsu Nishimura, Hidenori Matsuzaki, Suni Lee, Kei Yoshitome, Hiroaki Hayashi, and Takemi Otsuki Copyright © 2016 Naoko Kumagai-Takei et al. All rights reserved. Donor Cell Composition and Reactivity Predict Risk of Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation Mon, 14 Nov 2016 09:19:57 +0000 Background. Graft-versus-host disease (GVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). We designed a functional assay for assessment of individual risk for acute GVHD. Study Design and Methods. Blood samples were collected from patients and donors before HSCT. Two groups of seven patients each were selected, one in which individuals developed acute GVHD grades II–IV and one in which none showed any clinical signs of GVHD. Peripheral blood mononuclear cells (PBMCs) isolated from donors were incubated in mixed lymphocyte cultures (MLCs) with recipient PBMCs. The cells were characterized by flow cytometry before and after MLC. Results. Samples from donors in the GVHD group contained significantly lower frequencies of naïve T-cells and T-cells expressing NK-cell markers CD56 and CD94. Donor samples in this group also exhibited lower frequencies of naïve CD95+ T-cells compared to controls. After MLC, there were dissimilarities in the CD4/CD8 T-cell ratio and frequency of CD69+ T-cells between the two patient groups, with the non-GVHD group showing higher frequencies of CD8+ and CD69+ T-cells. Conclusion. We conclude that a thorough flow cytometric analysis of donor cells for phenotype and allogeneic reactivity may be of value when assessing pretransplant risk for severe acute GVHD. Darius Sairafi, Arwen Stikvoort, Jens Gertow, Jonas Mattsson, and Michael Uhlin Copyright © 2016 Darius Sairafi et al. All rights reserved. Serum Levels of Soluble ST2 and IL-10 Are Associated with Disease Severity in Patients with IgA Nephropathy Wed, 09 Nov 2016 13:52:53 +0000 Background. The IL-33/ST2 axis is involved in humoral immune responses. Method. The concentrations of sera IL-33 and sST2 in 74 patients and 34 healthy controls (HC) were measured by ELISA. Clinical and laboratory data were examined. The potential association between sera IL-33 and sST2 and the clinical parameters in IgAN patients were analyzed. Results. No difference was discovered in IL-33 concentrations between IgAN patients and HCs; however, the sST2 were significantly higher in each stage of IgAN progression than in the HC. The concentration of sST2 was positively correlated with IL-33 levels in IgAN patients. Higher levels of sera IL-2, IL-4, IL-10, IL-17A, and IFN-γ were detected in patients compared to the HC. The concentration of serum sST2 was positively correlated with the levels of IL-10 in IgAN patients. Furthermore, serum sST2 was negatively correlated with the values of eGFR and serum calcium. Serum sST2 was positively correlated with 24-hour urinary protein, serum phosphorus, and serum IgA; however, serum IL-33 was not associated with these. Following treatment, serum sST2 was significantly decreased, while sera IL-4 and IL-10 were significantly increased. Conclusions. Increased sST2 and IL-10 but not IL-33 may be involved in the pathogenic process of IgAN. Zhihui Zhang, Haifeng Wang, Li Zhang, Rebecca Crew, Nan Zhang, Xiaolei Liu, and Yanfang Jiang Copyright © 2016 Zhihui Zhang et al. All rights reserved. Attention Deficit Disorder and Allergic Rhinitis: Are They Related? Mon, 31 Oct 2016 13:44:43 +0000 The association between ADHD and allergy remains controversial. Our previous findings suggest that nerve growth factor may link the nervous and immune systems. The primary objective of this study was to determine if a combination of cetirizine + methylphenidate is effective in children with comorbid ADHD and allergic rhinitis. We also examined the role of nerve growth factor in these comorbidities. Our randomized, double-blind, placebo-controlled, crossover study enrolled 38 children diagnosed with comorbid ADHD and allergy using cetirizine (), sustained-release methylphenidate (), or cetirizine + methylphenidate (). Endpoints compared baseline to posttreatment evaluations for allergic rhinitis and ADHD scores. Serum nerve growth factor levels were measured using ELISA. For allergy endpoints, combination therapy produced results superior to individual therapy. For ADHD, similar scores were achieved for individual therapy; however, combination therapy resulted in improved scores. Nerve growth factor levels were downregulated following this trend. We conclude that ADHD and allergic rhinitis may have common mechanism and represent a comorbid condition that links the nervous system to the immune system. Further studies are needed. Isaac Melamed and Melinda Heffron Copyright © 2016 Isaac Melamed and Melinda Heffron. All rights reserved. Bone Marrow Mesenchymal Stem Cells Enhance the Differentiation of Human Switched Memory B Lymphocytes into Plasma Cells in Serum-Free Medium Mon, 31 Oct 2016 13:11:30 +0000 The differentiation of human B lymphocytes into plasma cells is one of the most stirring questions with regard to adaptive immunity. However, the terminal differentiation and survival of plasma cells are still topics with much to be discovered, especially when targeting switched memory B lymphocytes. Plasma cells can migrate to the bone marrow in response to a CXCL12 gradient and survive for several years while secreting antibodies. In this study, we aimed to get closer to niches favoring plasma cell survival. We tested low oxygen concentrations and coculture with mesenchymal stem cells (MSC) from human bone marrow. Besides, all cultures were performed using an animal protein-free medium. Overall, our model enables the generation of high proportions of CD38+CD138+CD31+ plasma cells (≥50%) when CD40-activated switched memory B lymphocytes were cultured in direct contact with mesenchymal stem cells. In these cultures, the secretion of CXCL12 and TGF-β, usually found in the bone marrow, was linked to the presence of MSC. The level of oxygen appeared less impactful than the contact with MSC. This study shows for the first time that expanded switched memory B lymphocytes can be differentiated into plasma cells using exclusively a serum-free medium. Guillaume Bonnaure, Catherine Gervais-St-Amour, and Sonia Néron Copyright © 2016 Guillaume Bonnaure et al. All rights reserved. Roles of Zinc Signaling in the Immune System Mon, 31 Oct 2016 11:50:15 +0000 Zinc (Zn) is an essential micronutrient for basic cell activities such as cell growth, differentiation, and survival. Zn deficiency depresses both innate and adaptive immune responses. However, the precise physiological mechanisms of the Zn-mediated regulation of the immune system have been largely unclear. Zn homeostasis is tightly controlled by the coordinated activity of Zn transporters and metallothioneins, which regulate the transport, distribution, and storage of Zn. There is growing evidence that Zn behaves like a signaling molecule, facilitating the transduction of a variety of signaling cascades in response to extracellular stimuli. In this review, we highlight the emerging functional roles of Zn and Zn transporters in immunity, focusing on how crosstalk between Zn and immune-related signaling guides the normal development and function of immune cells. Shintaro Hojyo and Toshiyuki Fukada Copyright © 2016 Shintaro Hojyo and Toshiyuki Fukada. All rights reserved. Minor Antigen Disparities Impede Induction of Long Lasting Chimerism and Tolerance through Bone Marrow Transplantation with Costimulation Blockade Mon, 31 Oct 2016 09:26:32 +0000 Mixed chimerism and tolerance can be successfully induced in rodents through allogeneic bone marrow transplantation (BMT) with costimulation blockade (CB), but varying success rates have been reported with distinct models and protocols. We therefore investigated the impact of minor antigen disparities on the induction of mixed chimerism and tolerance. C57BL/6 () mice received nonmyeloablative total body irradiation (3 Gy), costimulation blockade (anti-CD40L mAb and CTLA4Ig), and bone marrow cells (BMC) from either of three donor strains: Balb/c () (MHC plus multiple minor histocompatibility antigen (mHAg) mismatched), B10.D2 () or B10.A () (both MHC mismatched, but mHAg matched). Macrochimerism was followed over time by flow cytometry and tolerance was tested by skin grafting. 20 of 21 recipients of B10.D2 BMC but only 13 of 18 of Balb/c BMC and 13 of 20 of B10.A BMC developed stable long-term multilineage chimerism ( for each donor strain versus B10.D2). Significantly superior donor skin graft survival was observed in successfully established long-term chimeras after mHAg matched BMT compared to mHAg mismatched BMT (). Both minor and major antigen disparities pose a substantial barrier for the induction of chimerism while the maintenance of tolerance after nonmyeloablative BMT and costimulation blockade is negatively influenced by minor antigen disparities.         Sinda Bigenzahn, Ines Pree, Christoph Klaus, Nina Pilat, Benedikt Mahr, Elisabeth Schwaiger, Patrick Nierlich, Friedrich Wrba, and Thomas Wekerle Copyright © 2016 Sinda Bigenzahn et al. All rights reserved. CXCR3, CCR5, and CRTH2 Chemokine Receptor Expression in Lymphocytes Infiltrating Thyroid Nodules with Coincident Hashimoto’s Thyroiditis Obtained by Fine Needle Aspiration Biopsy Mon, 31 Oct 2016 08:11:48 +0000 Objective. To determine the expression of chemokine receptors in lymphocytes from thyroid nodules and peripheral blood in patients with and without Hashimoto’s thyroiditis (HT). Patients and Methods. The study included 46 women with thyroid nodules and HT and 60 women with thyroid nodules without HT (controls) who underwent a fine needle aspiration biopsy (FNAB). Expression of chemokine receptors CXCR3, CCR5, and CRTH2 was assessed by flow cytometry in lymphocytes from FNAB samples and from peripheral blood. Results. The percentage of CRTH2+ lymphocytes was higher in nodules with HT in comparison with controls, both in FNAB samples (13.95 versus 6.7%, ) and in peripheral blood (6.7 versus 5.13%, ), and positively correlated with serum antibodies to thyroid peroxidase (; ) and negatively correlated with thyroid volume (; ). Lymphocytes from neoplastic nodules showed a higher expression of both CXCR3 and CCR5 than those from hyperplastic ones. Conclusion. Flow cytometry performed in FNAB samples may serve as a good tool in investigation of intrathyroidal expression of immunological parameters. In our study, the CRTH2 expression on thyroid-infiltrating lymphocytes as well as on lymphocytes from peripheral blood was increased in HT as compared to controls. Jan Jiskra, Marie Antošová, Jan Krátký, Hana Vítková, Zdeňka Límanová, Helena Marečková, and Eliška Potluková Copyright © 2016 Jan Jiskra et al. All rights reserved. F4/80+ Host Macrophages Are a Barrier to Murine Embryonic Stem Cell-Derived Hematopoietic Progenitor Engraftment In Vivo Sun, 30 Oct 2016 12:55:05 +0000 Understanding how embryonic stem cells and their derivatives interact with the adult host immune system is critical to developing their therapeutic potential. Murine embryonic stem cell-derived hematopoietic progenitors (ESHPs) were generated via coculture with the bone marrow stromal cell line, OP9, and then transplanted into NOD.SCID.Common Gamma Chain (NSG) knockout mice, which lack B, T, and natural killer cells. Compared to control mice transplanted with adult lineage-negative bone marrow (Lin− BM) progenitors, ESHP-transplanted mice attained a low but significant level of donor hematopoietic chimerism. Based on our previous studies, we hypothesized that macrophages might contribute to the low engraftment of ESHPs in vivo. Enlarged spleens were observed in ESHP-transplanted mice and found to contain higher numbers of host F4/80+ macrophages compared to BM-transplanted controls. In vivo depletion of host macrophages using clodronate-loaded liposomes improved the ESHP-derived hematopoietic chimerism in the spleen but not in the BM. F4/80+ macrophages demonstrated a striking propensity to phagocytose ESHP targets in vitro. Taken together, these results suggest that macrophages are a barrier to both syngeneic and allogeneic ESHP engraftment in vivo. Heather L. Thompson, Nico van Rooijen, Bryce T. McLelland, and Jennifer O. Manilay Copyright © 2016 Heather L. Thompson et al. All rights reserved. The Role of TLR4 on B Cell Activation and Anti-GPI Antibody Production in the Antiphospholipid Syndrome Thu, 27 Oct 2016 14:15:22 +0000 High titer of anti-β2-glycoprotein I antibodies (anti-β2GPI Ab) plays a pathogenic role in antiphospholipid syndrome (APS). Numerous studies have focused on the pathological mechanism in APS; however, little attention is paid to the immune mechanism of production of anti-β2GPI antibodies in APS. Our previous study demonstrated that Toll-like receptor 4 (TLR4) plays a vital role in the maturation of bone marrow-derived dendritic cells (BMDCs) from the mice immunized with human β2-glycoprotein I (β2GPI). TLR4 is required for the activation of B cells and the production of autoantibody in mice treated with β2GPI. However, TLR4 provides a third signal for B cell activation and then promotes B cells better receiving signals from both B cell antigen receptor (BCR) and CD40, thus promoting B cell activation, surface molecules expression, anti-β2GPI Ab production, and cytokines secretion and making B cell functioning like an antigen presenting cell (APC). At the same time, TLR4 also promotes B cells producing antibodies by upregulating the expression of B-cell activating factor (BAFF). In this paper, we aim to review the functions of TLR4 in B cell immune response and antibody production in autoimmune disease APS and try to find a new way for the prevention and treatment of APS. Si Cheng, Haibo Wang, and Hong Zhou Copyright © 2016 Si Cheng et al. All rights reserved. The Crosstalk between Myeloid Derived Suppressor Cells and Immune Cells: To Establish Immune Tolerance in Transplantation Thu, 27 Oct 2016 09:30:50 +0000 Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of myeloid precursor and progenitor cells and endowed with a robust immunosuppressive activity in multiple pathophysiological conditions. Recent studies have uncovered the crosstalk between MDSCs and immune cells (i.e., natural killer cells, dendritic cells, macrophages, natural killer T cells, and regulatory T cells) and its role in the establishment and maintenance of immune tolerant microenvironment in transplantation. Considering their strong immunosuppressive capability, MDSCs could become a prospective clinical regimen during transplantation tolerance induction, resulting in long-term graft survival with decreased or without immunosuppressive drugs. The review summarized recent research advances in this field and looked ahead at the research directions in the future. Chao Zhang, Shuo Wang, Cheng Yang, and Ruiming Rong Copyright © 2016 Chao Zhang et al. All rights reserved. CD63 Promotes Hemocyte-Mediated Phagocytosis in the Clam, Paphia undulata Thu, 27 Oct 2016 08:29:25 +0000 As one of the surface membrane proteins of tetraspanin family, CD63 plays a crucial role in cellular trafficking and endocytosis, which also is associated with activation of a wide variety of immune cells. Here, the homolog of CD63 was characterized from one marine mollusk, Paphia undulata, which is designated as Pu-CD63. The complete cDNA of Pu-CD63 is 1,738 bp in length with an open reading frame (ORF) of 849 bp, encoding a 282 amino acid protein with four putative hydrophobic transmembrane helixes. Bioinformatic analysis revealed that Pu-CD63 contains one putative YXXØ consensus motif of “110-YVII-113” and one N-glycosylation site “155-NGT-157” within the large extracellular loop (LEL) region, supporting its conserved function in plasma membrane and endosomal/lysosomal trafficking. Moreover, temporal expression profile analysis demonstrates a drastic induction in the expression of CD63 in hemocytes after pathogenic challenge with either V. parahaemolyticus or V. alginolyticus. By performing dsRNA-mediate RNAi knockdowns of CD63, a dramatic reduction in hemocytes phagocytic activity to pathogenic Vibrio is recorded by flow cytometry, revealing the definite role of Pu-CD63 in promoting hemocyte-mediated phagocytosis. Therefore, our work has greatly enhanced our understanding about primitive character of innate immunity in marine mollusk. Mingjia Yu, Shanjun Yang, Hongxia Sun, and Qiang Xia Copyright © 2016 Mingjia Yu et al. All rights reserved. Early Differentiation of Human CD11c+NK Cells with γδ T Cell Activation Properties Is Promoted by Dialyzable Leukocyte Extracts Tue, 25 Oct 2016 13:28:35 +0000 Reconstitution of the hematopoietic system during immune responses and immunological and neoplastic diseases or upon transplantation depends on the emergent differentiation of hematopoietic stem/progenitor cells within the bone marrow. Although in the last decade the use of dialyzable leukocyte extracts (DLE) as supportive therapy in both infectious and malignant settings has increased, its activity on the earliest stages of human hematopoietic development remains poorly understood. Here, we have examined the ability of DLE to promote replenishment of functional lymphoid lineages from CD34+ cells. Our findings suggest that DLE increases their differentiation toward a conspicuous CD56+CD16+CD11c+ NK-like cell population endowed with properties such as IFNy production, tumor cell cytotoxicity, and the capability of inducing γδ T lymphocyte proliferation. Of note, long-term coculture controlled systems showed the bystander effect of DLE-stromal cells by providing NK progenitors with signals to overproduce this cell subset. Thus, by direct effect on progenitor cells and through activation and remodeling of the supporting hematopoietic microenvironment, DLE may contribute a robust innate immune response by promoting the emerging lymphopoiesis of functional CD11c+ NK cells in a partially TLR-related manner. Unraveling the identity and mechanisms of the involved DLE components may be fundamental to advance the NK cell-based therapy field. Dalia Ramírez-Ramírez, Eduardo Vadillo, Lourdes Andrea Arriaga-Pizano, Héctor Mayani, Sergio Estrada-Parra, Marco Antonio Velasco-Velázquez, Sonia Mayra Pérez-Tapia, and Rosana Pelayo Copyright © 2016 Dalia Ramírez-Ramírez et al. All rights reserved. State of the Art, Unresolved Issues, and Future Research Directions in the Fight against Hepatitis C Virus: Perspectives for Screening, Diagnostics of Resistances, and Immunization Mon, 24 Oct 2016 07:33:56 +0000 Hepatitis C virus (HCV) still represents a major public health threat, with a dramatic burden from both epidemiological and clinical points of view. New generation of direct-acting antiviral agents (DAAs) has been recently introduced in clinical practice promising to cure HCV and to overcome the issues related to the interferon-based therapies. However, the emergence of drug resistance and the suboptimal activity of DAAs therapies against diverse HCV genotypes have been observed, determining treatment failure and hampering an effective control of HCV spread worldwide. Moreover, these treatments remain poorly accessible, particularly in low-income countries. Finally, effective screening strategy is crucial to early identifying and treating all HCV chronically infected patients. For all these reasons, even though new drugs may contribute to impacting HCV spread worldwide a preventive HCV vaccine remains a cornerstone in the road to significantly reduce the HCV spread globally, with the ultimate goal of its eradication. Advances in molecular vaccinology, together with a strong financial, political, and societal support, will enable reaching this fundamental success in the coming years. In this comprehensive review, the state of the art about these major topics in the fight against HCV and the future of research in these fields are discussed. Cecilia Trucchi, Andrea Orsi, Cristiano Alicino, Laura Sticchi, Giancarlo Icardi, and Filippo Ansaldi Copyright © 2016 Cecilia Trucchi et al. All rights reserved. Low Dose BCG Infection as a Model for Macrophage Activation Maintaining Cell Viability Wed, 19 Oct 2016 13:11:49 +0000 Mycobacterium bovis BCG, the current vaccine against tuberculosis, is ingested by macrophages promoting the development of effector functions including cell death and microbicidal mechanisms. Despite accumulating reports on M. tuberculosis, mechanisms of BCG/macrophage interaction remain relatively undefined. In vivo, few bacilli are sufficient to establish a mycobacterial infection; however, in vitro studies systematically use high mycobacterium doses. In this study, we analyze macrophage/BCG interactions and microenvironment upon infection with low BCG doses and propose an in vitro model to study cell activation without affecting viability. We show that RAW macrophages infected with BCG at MOI 1 activated higher and sustained levels of proinflammatory cytokines and transcription factors while MOI 0.1 was more efficient for early stimulation of IL-1β, MCP-1, and KC. Both BCG infection doses induced iNOS and NO in a dose-dependent manner and maintained nuclear and mitochondrial structures. Microenvironment generated by MOI 1 induced macrophage proliferation but not MOI 0.1 infection. In conclusion, BCG infection at low dose is an efficient in vitro model to study macrophage/BCG interactions that maintains macrophage viability and mitochondrial structures. This represents a novel model that can be applied to BCG research fields including mycobacterial infections, cancer immunotherapy, and prevention of autoimmunity and allergies. Leslie Chávez-Galán, Dominique Vesin, Denis Martinvalet, and Irene Garcia Copyright © 2016 Leslie Chávez-Galán et al. All rights reserved. Impact of Ivabradine on Inflammatory Markers in Chronic Heart Failure Sun, 16 Oct 2016 08:59:49 +0000 Background. Inflammation plays a crucial role in the progression of chronic heart failure (CHF). Ivabradine is known to reduce the morbidity and mortality of patients with CHF under certain conditions. Beyond the reduction of heart rate, only limited knowledge exists about potential anti-inflammatory effects of ivabradine that might contribute to its benefit in CHF. Thus, the present study aimed to investigate the effect of ivabradine on systemic inflammation. Methods. In the present study, 33 patients with CHF due to dilated, ischemic, and hypertensive cardiomyopathy were treated with ivabradine according to the guidelines of the European Society of Cardiology (ESC). A number of circulating dendritic cells as well as inflammatory mediators were investigated using FACS analysis and ELISA, respectively, before and during ivabradine therapy. Results. Treatment with ivabradine resulted in a significant improvement of CHF symptoms as well as an increase in left ventricular ejection fraction. Moreover, ivabradine treatment led to a significant reduction of TNF-alpha (TNF-α) serum levels and a reconstitution of circulating dendritic cells which are known to be reduced in patients with CHF. Conclusion. We show that treatment with ivabradine in patients with CHF resulted in an improvement of HF symptoms and ejection fraction as well as a normalization of inflammatory mediators. Ilonka Rohm, Daniel Kretzschmar, Rudin Pistulli, Marcus Franz, P. Christian Schulze, Christian Stumpf, and Atilla Yilmaz Copyright © 2016 Ilonka Rohm et al. All rights reserved. Link-Polymorphism of 5-HTT Promoter Region Is Associated with Autoantibodies in Patients with Systemic Lupus Erythematosus Thu, 13 Oct 2016 07:23:39 +0000 Serotonin transporter linked polymorphic region (5-HTTLPR) was reported to associate with depression in systemic lupus erythematosus (SLE) patients by our team. To explore whether 5-HTTLPR plays a role in the pathogenesis of SLE, we tested 138 SLE patients and 138 age and sex matched health controls (HCs) for 5-HTTLPR by polymerase chain reaction (PCR) and agarose gel electrophoresis. Interestingly, the results suggest that the frequencies of SS genotype and S allele in SLE patients with positive anti-Sm antibody and anti-U1RNP antibody were both significantly higher than the other genotypes and alleles. However, the frequencies of 5-HTTLPR genotypes and alleles were of no significant difference between SLE patients and HCs. This suggested that 5-HTTLPR was not a high-risk susceptible gene in SLE but might relate to SLE by affecting production of some autoantibodies, especially anti-Sm and anti-U1RNP antibody. Shu Li, Shuang Liu, Fan Chen, Yuqi Cheng, Ru Bai, Aiyun Lai, Zhaoping Lu, and Jian Xu Copyright © 2016 Shu Li et al. All rights reserved. Crosstalk between Innate Lymphoid Cells and Other Immune Cells in the Tumor Microenvironment Wed, 12 Oct 2016 09:37:07 +0000 Our knowledge and understanding of the tumor microenvironment (TME) have been recently expanded with the recognition of the important role of innate lymphoid cells (ILC). Three different groups of ILC have been described based on their ability to produce cytokines that mediate the interactions between innate and adaptive immune cells in a variety of immune responses in infection, allergy, and autoimmunity. However, recent evidence from experimental models and clinical studies has demonstrated that ILC contribute to the mechanisms that generate suppressive or tolerant environments that allow tumor regression or progression. Defining the complex network of interactions and crosstalk of ILC with other immune cells and understanding the specific contributions of each type of ILC leading to tumor development will allow the manipulation of their function and will be important to develop new interventions and therapeutic strategies. Fabian Flores-Borja, Sheeba Irshad, Peter Gordon, Felix Wong, Ibrahim Sheriff, Andrew Tutt, and Tony Ng Copyright © 2016 Fabian Flores-Borja et al. All rights reserved. Upregulation of Soluble HLA-G in Chronic Left Ventricular Systolic Dysfunction Sun, 09 Oct 2016 09:58:12 +0000 Left ventricular systolic dysfunction (LVSD) defined by ejection fraction (EF) <40% is common, serious but treatable, and correct diagnosis is the cornerstone of effective treatment. Biomarkers may help to diagnose LVSD and give insight into the pathophysiology. The immune system is activated in LVSD, and the immunomodulatory molecule human leukocyte antigen-G (HLA-G) may be involved. The primary aim was to measure soluble HLA-G (sHLA-G) in the blood in different stages of LVSD (<30% and 30–40%), in the midrange EF 40–50%, and in preserved EF ≥ 50% and to validate sHLA-G as a LVSD biomarker. The secondary aim was to examine associations between HLA-G gene polymorphisms influencing expression levels and LVSD. The 260 study participants were ≥75 years old, many with risk factors for heart disease or with known heart disease. Soluble HLA-G was significantly and uniformly higher in the groups with EF < 50% (<30, 30–40, and 40–50%) compared to EF > 50% (). N-terminal fragment-pro-B-type natriuretic peptide (NT-proBNP) and uric acid values were inversely related to EF. According to Receiver Operating Characteristic (ROC) curves NT-proBNP outperformed both sHLA-G and uric acid as biomarkers of LVSD. Soluble HLA-G in blood plasma was elevated in LVSD regardless of EF. A novel finding was that a combined 14 bp ins-del/+3142 SNP HLA-G haplotype was associated with EF < 40%. Line Lisbeth Olesen and Thomas Vauvert F. Hviid Copyright © 2016 Line Lisbeth Olesen and Thomas Vauvert F. Hviid. All rights reserved. Serum HMGB1 Serves as a Novel Laboratory Indicator Reflecting Disease Activity and Treatment Response in Ankylosing Spondylitis Patients Wed, 05 Oct 2016 06:11:15 +0000 Objective. High mobility group box 1 (HMGB1) is a late inflammatory factor participating in the pathogenesis of various autoimmune and inflammatory diseases. In the current study, we analyzed the association between serum levels of HMGB1 and clinical features of AS patients before and during treatment. Methods. Serum HMGB1 was detected in 147 AS patients and 61 healthy controls using ELISA. We evaluated the association between HMGB1 and extra-articular manifestations as well as disease severity indices. Among these AS patients, 41 patients received close follow-up at 1, 3, and 6 months after treatment. This group comprised 25 patients treated with anti-TNF-α biologics and 16 patients receiving oral NSAIDs plus sulfasalazine. Results. The serum HMGB1 of AS patients was significantly higher than in healthy controls and positively correlated with BASDAI, BASFI, ASDAS-ESR, ASDAS-CRP, ESR, and CRP, but not with HLA-B27, anterior uveitis, and recurrent diarrhea. There was no significant difference between patients with radiographic damage of hip joints and those without. We observed that serum HMGB1 paralleled disease activity after treatment. Conclusion. Serum level of HMGB1 is higher in AS patients, and to some extent, HMGB1 can reflect the activity of AS and be used as a laboratory indicator to reflect the therapeutic response. Chenqiong Wang, Ye Miao, Xuefen Wu, Yishu Huang, Mengchen Sun, Yingzi Zhu, Fang Zheng, Wei Sun, and Lingli Dong Copyright © 2016 Chenqiong Wang et al. All rights reserved. Immunomodulatory Effects Mediated by Dopamine Tue, 04 Oct 2016 09:51:05 +0000 Dopamine (DA), a neurotransmitter in the central nervous system (CNS), has modulatory functions at the systemic level. The peripheral and central nervous systems have independent dopaminergic system (DAS) that share mechanisms and molecular machinery. In the past century, experimental evidence has accumulated on the proteins knowledge that is involved in the synthesis, reuptake, and transportation of DA in leukocytes and the differential expression of the D1-like (D1R and D5R) and D2-like receptors (D2R, D3R, and D4R). The expression of these components depends on the state of cellular activation and the concentration and time of exposure to DA. Receptors that are expressed in leukocytes are linked to signaling pathways that are mediated by changes in cAMP concentration, which in turn triggers changes in phenotype and cellular function. According to the leukocyte lineage, the effects of DA are associated with such processes as respiratory burst, cytokine and antibody secretion, chemotaxis, apoptosis, and cytotoxicity. In clinical conditions such as schizophrenia, Parkinson disease, Tourette syndrome, and multiple sclerosis (MS), there are evident alterations during immune responses in leukocytes, in which changes in DA receptor density have been observed. Several groups have proposed that these findings are useful in establishing clinical status and clinical markers. Rodrigo Arreola, Samantha Alvarez-Herrera, Gilberto Pérez-Sánchez, Enrique Becerril-Villanueva, Carlos Cruz-Fuentes, Enrique Octavio Flores-Gutierrez, María Eugenia Garcés-Alvarez, Dora Luz de la Cruz-Aguilera, Emilio Medina-Rivero, Gabriela Hurtado-Alvarado, Saray Quintero-Fabián, and Lenin Pavón Copyright © 2016 Rodrigo Arreola et al. All rights reserved. The CXCL10/CXCR3 Axis and Cardiac Inflammation: Implications for Immunotherapy to Treat Infectious and Noninfectious Diseases of the Heart Mon, 03 Oct 2016 13:14:13 +0000 Accumulating evidence reveals involvement of T lymphocytes and adaptive immunity in the chronic inflammation associated with infectious and noninfectious diseases of the heart, including coronary artery disease, Kawasaki disease, myocarditis, dilated cardiomyopathies, Chagas, hypertensive left ventricular (LV) hypertrophy, and nonischemic heart failure. Chemokine CXCL10 is elevated in cardiovascular diseases, along with increased cardiac infiltration of proinflammatory Th1 and cytotoxic T cells. CXCL10 is a chemoattractant for these T cells and polarizing factor for the proinflammatory phenotype. Thus, targeting the CXCL10 receptor CXCR3 is a promising therapeutic approach to treating cardiac inflammation. Due to biased signaling CXCR3 also couples to anti-inflammatory signaling and immunosuppressive regulatory T cell formation when activated by CXCL11. Numbers and functionality of regulatory T cells are reduced in patients with cardiac inflammation, supporting the utility of biased agonists or biologicals to simultaneously block the pro-inflammatory and activate the anti-inflammatory actions of CXCR3. Other immunotherapy strategies to boost regulatory T cell actions include intravenous immunoglobulin (IVIG) therapy, adoptive transfer, immunoadsorption, and low-dose interleukin-2/interleukin-2 antibody complexes. Pharmacological approaches include sphingosine 1-phosphate receptor 1 agonists and vitamin D supplementation. A combined strategy of switching CXCR3 signaling from pro- to anti-inflammatory and improving Treg functionality is predicted to synergistically lessen adverse cardiac remodeling. Raffaele Altara, Ziad Mallat, George W. Booz, and Fouad A. Zouein Copyright © 2016 Raffaele Altara et al. All rights reserved.