Journal of Immunology Research The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Reestablishment of Active Immunity against HBV Graft Reinfection after Liver Transplantation for HBV-Related End Stage Liver Disease Thu, 18 Dec 2014 00:10:56 +0000 Background. The aim of this study was to establish a hepatitis B virus (HBV) vaccination protocol among orthotopic liver transplantation (OLT) recipients under the coverage of a low-dose hepatitis B immunoglobulin (HBIG) combined with an antiviral agent prophylaxis protocol. Method. Two hundred OLT recipients were included in this study. The vaccine was injected at months 0, 1, 2, and 6. Low-dose HBIG combined with antiviral agent prophylaxis protocol was continued before reestablishment of active immunity against HBV in order to maintain a steady anti-HBs titer. Results. Active immunity against HBV was reestablished in 50 patients, for an overall response rate of 25%. Of the 50 patients, 24 discontinued HBIG without any HBV graft reinfection during a follow-up period of 26.13 ± 7.05 months. 21 patients discontinued both HBIG and antiviral agents during a follow-up period of 39.86 ± 15.47 months, and 4 patients among them appeared to be HBsAg positive. There was no recipient death or graft loss because of HBV reinfection. Conclusions. Vaccination preventing HBV reinfection for OLT recipients is feasible. The strategy withdrawal of HBIG with induction of active immunity against hepatitis B is reasonable for long-term survivors of OLT; however, discontinuation nucleoside analogues should be cautious. Shi-Chun Lu, Tao Jiang, Wei Lai, Yuan Liu, Jing Zhang, Dao-Bing Zeng, Chuan-Yun Li, Meng-Long Wang, Dong-Dong Lin, Yue Zhu, You-Ping Li, and Ning Li Copyright © 2014 Shi-Chun Lu et al. All rights reserved. The Secretion of IL-22 from Mucosal NKp44+ NK Cells Is Associated with Microbial Translocation and Virus Infection in SIV/SHIV-Infected Chinese Macaques Tue, 16 Dec 2014 13:06:52 +0000 Microbial translocation (MT) causes systemic immune activation in chronic human immunodeficiency virus (HIV) infection. The role of a novel subtype of innate lymphoid cells, the NKp44+ NK cells, in HIV/simian immunodeficiency virus- (SIV-) induced MT remains unknown. In this study, 12 simian-human immunodeficiency virus- (SHIV-) infected macaques were chosen and split into two groups based on the MT level. Blood and Peripheral lymphoid tissue were sampled for flow cytometric analysis, viral load detection, and interleukin testing. Then, six naive Chinese macaques were used to determine the dynamics of cytokine secretion from mucosal NKp44+ NK cells in different phases of SIV infection. As a result, the degranulation capacity and IL-22 production of mucosal NKp44+ NK cells were associated with the MT level in the SHIV-infected macaques. And the number of mucosal NKp44+ NK cells and IL-22 secretion by these cells were lower in the chronic phase than in the early acute phase of SIV infection. The number of mucosal NKp44+ NK cells and interleukin-22 (IL-22) secretion by these cells increased before MT occurred. Therefore, we conclude that a decline in IL-22 production from mucosal NKp44+ NK cells induced by virus infection may be one of the causes of microbial translocation in HIV/SIV infection. Wei Wang, Fangxin Wu, Zhe Cong, Kejian Liu, Chuan Qin, and Qiang Wei Copyright © 2014 Wei Wang et al. All rights reserved. Daily Intake of Probiotics with High IFN-γ/IL-10 Ratio Increases the Cytotoxicity of Human Natural Killer Cells: A Personalized Probiotic Approach Thu, 11 Dec 2014 06:05:52 +0000 A personalized probiotic microfluidic chip system has been established and used to screen the probiotics which had the highest value of IFN-γ/IL-10 or IL-10/IFN-γ among six probiotics, including L. paracasei BRAP01, L. acidophilus AD300, B. longum BA100, E. faecium BR0085, L. rhamnosus AD500, and L. reuteri BR101. One hundred volunteers were included and their PBMCs were collected and stimulated by the six probiotics. People who belonged to the IFN-γ group took the probiotics that exerted the highest ratio of IFN-γ/IL-10 and vice versa in IL-10 group. A significant increase in NK cytotoxicity of 69 volunteers in the IFN-γ group was observed compared to the IL-10 group () and control group (). The result also showed that L. paracasei BRAP01 and L. acidophilus AD300 were the two dominant inducers in IFN-γ group which yielded higher value of IFN-γ/IL-10 than the other 4 probiotics, while L. reuteri BR101 was the most effective agent on the ratio of IL-10/IFN-γ in the IL-10 group. Our finding highlighted the concept of personalized probiotics and also provided a good foundation to investigate the probiotics with NK activity. Yu-Hsuan Ho, Yu-Chiu Lu, Hung-Cheng Chang, Shin-Yi Lee, Min-Fen Tsai, Yu-Ting Huang, and Ting-Yuan Hsu Copyright © 2014 Yu-Hsuan Ho et al. All rights reserved. A Micropolymorphism Altering the Residue Triad 97/114/156 Determines the Relative Levels of Tapasin Independence and Distinct Peptide Profiles for HLA-A24 Allotypes Thu, 04 Dec 2014 13:31:44 +0000 While many HLA class I molecules interact directly with the peptide loading complex (PLC) for conventional loading of peptides certain class I molecules are able to present peptides in a way that circumvents the PLC components. We investigated micropolymorphisms at position 156 of HLA-A24 allotypes and their effects on PLC dependence for assembly and peptide binding specificities. HLA-A24: and HLA-A24: showed high levels of cell surface expression while HLA-A24: was expressed at low levels in tapasin deficient cells. Peptides presented by these allelic variants showed distinct differences in features and repertoire. Immunoprecipitation experiments demonstrated all the HLA-A24/156 variants to associate at similar levels with tapasin when present. Structurally, HLA-A24:02 contains the residue triad Met97/His114/Gln156 and a Trp156 or Leu156 polymorphism provides tapasin independence by stabilizing these triad residues, thus generating an energetically stable and a more peptide receptive environment. Micropolymorphisms at position 156 can influence the generic peptide loading pathway for HLA-A24 by altering their tapasin dependence for peptide selection. The trade-off for this tapasin independence could be the presentation of unusual ligands by these alleles, imposing significant risk following hematopoietic stem cell transplantation (HSCT). Soumya Badrinath, Heike Kunze-Schumacher, Rainer Blasczyk, Trevor Huyton, and Christina Bade-Doeding Copyright © 2014 Soumya Badrinath et al. All rights reserved. Long-Lasting Production of New T and B Cells and T-Cell Repertoire Diversity in Patients with Primary Immunodeficiency Who Had Undergone Stem Cell Transplantation: A Single-Centre Experience Mon, 01 Dec 2014 10:07:45 +0000 Levels of Kappa-deleting recombination excision circles (KRECs), T-cell receptor excision circles (TRECs), and T-cell repertoire diversity were evaluated in 1038 samples of 124 children with primary immunodeficiency, of whom 102 (54 with severe combined immunodeficiency and 48 with other types of immunodeficiency) underwent hematopoietic stem cell transplantation. Twenty-two not transplanted patients with primary immunodeficiency were used as controls. Only data of patients from whom at least five samples were sent to the clinical laboratory for routine monitoring of lymphocyte reconstitutions were included in the analysis. The mean time of the follow-up was 8 years. The long-lasting posttransplantation kinetics of KREC and TREC production occurred similarly in patients with severe combined immunodeficiency and with other types of immunodeficiency and, in both groups, the T-cell reconstitution was more efficient than in nontransplanted children. Although thymic output decreased in older transplanted patients, the degree of T-cell repertoire diversity, after an initial increase, remained stable during the observation period. However, the presence of graft-versus-host disease and ablative conditioning seemed to play a role in the time-related shaping of T-cell repertoire. Overall, our data suggest that long-term B- and T-cell reconstitution was equally achieved in children with severe combined immunodeficiency and with other types of primary immunodeficiency. Monica Valotti, Alessandra Sottini, Arnalda Lanfranchi, Federica Bolda, Federico Serana, Diego Bertoli, Viviana Giustini, Marion Vaglio Tessitore, Luigi Caimi, and Luisa Imberti Copyright © 2014 Monica Valotti et al. All rights reserved. Inflammation and ER Stress Downregulate BDH2 Expression and Dysregulate Intracellular Iron in Macrophages Mon, 01 Dec 2014 08:37:43 +0000 Macrophages play a very important role in host defense and in iron homeostasis by engulfing senescent red blood cells and recycling iron. Hepcidin is the master iron regulating hormone that limits dietary iron absorption from the gut and limits iron egress from macrophages. Upon infection macrophages retain iron to limit its bioavailability which limits bacterial growth. Recently, a short chain butyrate dehydrogenase type 2 (BDH2) protein was reported to contain an iron responsive element and to mediate cellular iron trafficking by catalyzing the synthesis of the mammalian siderophore that binds labile iron; therefore, BDH2 plays a crucial role in intracellular iron homeostasis. However, BDH2 expression and regulation in macrophages have not yet been described. Here we show that LPS-induced inflammation combined with ER stress led to massive BDH2 downregulation, increased the expression of ER stress markers, upregulated hepcidin expression, downregulated ferroportin expression, caused iron retention in macrophages, and dysregulated cytokine release from macrophages. We also show that ER stress combined with inflammation synergistically upregulated the expression of the iron carrier protein NGAL and the stress-inducible heme degrading enzyme heme oxygenase-1 (HO-1) leading to iron liberation. This is the first report to show that inflammation and ER stress downregulate the expression of BDH2 in human THP-1 macrophages. Susu M. Zughaier, Brandon B. Stauffer, and Nael A. McCarty Copyright © 2014 Susu M. Zughaier et al. All rights reserved. Autoantibodies Targeting AT1 Receptor from Patients with Acute Coronary Syndrome Upregulate Proinflammatory Cytokines Expression in Endothelial Cells Involving NF-κB Pathway Sun, 30 Nov 2014 11:36:12 +0000 Our study intended to prove whether agonistic autoantibodies to angiotensin II type 1 receptor (AT1-AAs) exist in patients with coronary heart disease (CHD) and affect the human endothelial cell (HEC) by upregulating proinflammatory cytokines expression involved in NF-κB pathway. Antibodies were determined by chronotropic responses of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists (valsartan and AT1-EC2) as described previously. Interleukin-6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemotactic protein-1 (MCP-1) expression were improved at both mRNA and protein levels in HEC, while NF-κB in the DNA level was improved detected by electrophoretic mobility shift assays (EMSA). These improvements could be inhibited by specific AT1 receptor blocker valsartan, NF-κB blocker pyrrolidine dithiocarbamate (PDTC), and specific short peptides from the second extracellular loop of AT1 receptor. These results suggested that AT1-AAs, via the AT1 receptor, induce expression of proinflammatory cytokines involved in the activation of NF-κB. AT1-AAs may play a great role in the pathogenesis of the acute coronary syndrome by mediating vascular inflammatory effects involved in the NF-κB pathway. Weijuan Li, Zhi Li, Yaoqi Chen, Songhai Li, Yuanyuan Lv, Wenping Zhou, Mengyang Liao, Feng Zhu, Zihua Zhou, Xiang Cheng, Qiutang Zeng, Yuhua Liao, and Yumiao Wei Copyright © 2014 Weijuan Li et al. All rights reserved. Inhibition of Neutrophil Collagenase/MMP-8 and Gelatinase B/MMP-9 and Protection against Endotoxin Shock Wed, 26 Nov 2014 13:05:53 +0000 Endotoxin shock is a life-threatening disorder, associated with the rapid release of neutrophil enzymes, including neutrophil collagenase/matrix metalloproteinase-8 (MMP-8) and gelatinase B/matrix metalloproteinase-9 (MMP-9). After activation, these enzymes cleave extracellular matrix components and cytokines and thus may contribute to shock syndrome development. MMP inhibitors have been suggested as immunotherapy of endotoxin shock. However, little is known about the therapeutic time window of MMP inhibition. Here, a sublethal endotoxin shock mouse model was used to evaluate the effect of an MMP inhibiting peptide (P2) after intravenous or intraperitoneal injection and to study the time window between LPS and inhibitor injections. With the use of a specific ELISA the plasma P2 concentrations were monitored. Whereas we corroborated the treatment strategy of MMP targeting in endotoxin shock with a new inhibitor, we also demonstrated that the time window, within which effective MMP inhibition increased the survival rates, is rather limited. Zheng Qiu, Jianghai Chen, Hanmei Xu, Philippe E. Van den Steen, Ghislain Opdenakker, Min Wang, and Jialiang Hu Copyright © 2014 Zheng Qiu et al. All rights reserved. Association of TNF-α with Impaired Migration Capacity of Mesenchymal Stem Cells in Patients with Systemic Lupus Erythematosus Mon, 24 Nov 2014 07:17:31 +0000 Previous studies indicated that bone marrow mesenchymal stem cells (BMSCs) from patients with systemic lupus erythematosus (SLE) exhibited impaired capacities of proliferation, differentiation, and immune modulation. Considering that migration capacity is important for the exertion of BMSCs functions, the defects in migration might contribute to BMSCs dysfunction in SLE patients. In this study, we showed that the migration capacity of SLE BMSCs was remarkably impaired in comparison with those of healthy controls. Increased tumor necrosis factor α (TNF-α) in SLE serum significantly inhibited the migration capacity and in vivo homing capacity of SLE BMSCs via a specific TNF receptor I (TNFRI) manner, in which decreased HGF mRNA production caused by the activation of I kappa B kinase beta (IKK-β) pathway is partially involved. To our knowledge, this is the first report to discuss the possible mechanisms for impaired migration of BMSCs in SLE patients. Our results suggest that inhibition of TNF-α pathway might be helpful for accelerating BMSCs migration to the inflammatory microenvironment in SLE patients, thereby having a potential role in SLE treatment. Linyu Geng, Xia Li, Xuebing Feng, Jiyun Zhang, Dandan Wang, Jinyun Chen, Rui Liu, Haifeng Chen, and Lingyun Sun Copyright © 2014 Linyu Geng et al. All rights reserved. TNFα Promotes Th17 Cell Differentiation through IL-6 and IL-1β Produced by Monocytes in Rheumatoid Arthritis Tue, 11 Nov 2014 00:00:00 +0000 TNFα plays an important role in autoimmune pathogenesis and is the main therapeutic target of rheumatoid arthritis. However, its underlying mechanism is not completely understood. In this study, we described that Th17 cells were accumulated in synovial fluid, which was attributable to TNFα aberrantly produced in rheumatoid synovium. Interestingly, TNFα cannot induce IL-17 production of CD4+ T cells directly, but through the monocytes high levels of IL-1β and IL-6 in a TNFRI and TNFRII dependent manner from the active RA patients are produced. TNFα was shown to enhance the phosphorylation level of STAT3 and the expression level of transcription factor RORC of CD4+ T cells when cultured with CD14+ monocytes. Treatment with an approved TNFα blocking antibody showed marked reduction in the levels of IL-6, IL-1β, and IL-17 and the expression level of STAT3 phosphorylation in relation to Th17 cell differentiation in patients with rheumatoid arthritis. The study provides new evidence supporting the critical role of TNFα in the pathogenic Th17 cell differentiation in rheumatoid arthritis. Yingxia Zheng, Lei Sun, Ting Jiang, Dongqing Zhang, Dongyi He, and Hong Nie Copyright © 2014 Yingxia Zheng et al. All rights reserved. A Circulating Subpopulation of Monocytic Myeloid-Derived Suppressor Cells as an Independent Prognostic/Predictive Factor in Untreated Non-Small Lung Cancer Patients Tue, 11 Nov 2014 00:00:00 +0000 Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of cells with immunosuppressive properties and might confer to worse prognosis in cancer patients. The presence of phenotypically newly described subpopulations of MDSCs and their association with the clinical outcome were investigated in non-small cell lung cancer (NSCLC) patients. The percentages and correlation between MDSCs and distinct immune cells in the peripheral blood of 110 chemotherapy-naive patients before treatment and healthy controls were investigated using flow cytometry. Two monocytic [CD14+CD15−CD11b+CD33+HLA-DR−Lin− and CD14+CD15+CD11b+CD33+HLA-DR−Lin−] and a granulocytic [CD14−CD15+CD11b+CD33+HLA-DR−Lin−] subpopulations of MDSCs were identified, expressing inducible nitric oxide synthase, and reactive oxygen species, respectively. Increased percentages of both monocytic-MDSCs’ subpopulations were inversely correlated to dendritic/monocyte levels , while granulocytic-MDSCs were inversely correlated to CD4+ T cells . Increased percentages of monocytic-MDSCs were associated with worse response to treatment and patients with normal levels of CD14+CD15+CD11b+CD33+HLA-DR−Lin− had longer overall survival and progression free-survival compared to those with high levels and , resp.). Multivariate analysis revealed that the increased percentages of CD14+CD15+CD11b+CD33+HLA-DR−Lin− MDSCs were independently associated with decreased progression free-survival and overall survival. The data provide evidence that increased percentages of new monocytic-MDSCs’ subpopulations in advanced NSCLC patients are associated with an unfavourable clinical outcome. Eleni-Kyriaki Vetsika, Filippos Koinis, Marianthi Gioulbasani, Despoina Aggouraki, Anna Koutoulaki, Eirini Skalidaki, Dimitris Mavroudis, Vassilis Georgoulias, and Athanasios Kotsakis Copyright © 2014 Eleni-Kyriaki Vetsika et al. All rights reserved. Expression of TNF-α, April and BCMA in Behcet’s Disease Wed, 05 Nov 2014 06:53:45 +0000 Background. Tumor necrosis factor-alpha (TNF-α) is an important proinflammatory cytokine which plays an important role in the immunopathogenesis of Behcet’s disease (BD). B cell activating factor (BAFF) and its homolog A proliferation inducing ligand (APRIL) are members of the tumor necrosis factor family. BAFF binds to 3 receptors, B cell activating factor receptor (BAFF-R), transmembrane activator and calcium modulator ligand interactor (TACI), and B cell maturation antigen (BCMA) that are expressed by B cells. Objective. Estimation of the serum levels of TNF-α, APRIL, BAFF, and BCMA in patients with BD in an effort to evaluate their degree of involvement in the pathogenesis and development of BD. Patients and Methods. This study included 30 male patients fulfilling the international study group criteria for the diagnosis of BD. Twenty age-matched healthy male volunteers served as control. Serum samples were used for quantification of TNF-α, APRIL, BCMA, BAFF, and hsCRP using ELISA techniques. Results. The mean serum levels of TNF-α, APRIL, BCMA, and BAFF were more elevated in cases than in controls in a statistically significant manner . Positive correlation was observed between hs-CRP and BDCAF (Behcet’s disease current activity forum) index (r 0.68, . None of the TNF family members tested was affected by a positive pathergy test. Conclusions. Patients have significantly higher levels of TNF family members’ (TNF-α, BAFF, APRIL, and BCMA) compared to controls which might contribute to the pathogenesis of BD. Olfat G. Shaker, Shereen O. Tawfic, Amira M. El-Tawdy, Mohamed H. M. El-Komy, Manal El Menyawi, and Ahmed A. Heikal Copyright © 2014 Olfat G. Shaker et al. All rights reserved. CD8+ TIL Recruitment May Revert the Association of MAGE A3 with Aggressive Features in Thyroid Tumors Tue, 04 Nov 2014 06:52:11 +0000 Background. We aimed to investigate a possible role of MAGE A3 and its associations with infiltrated immune cells in thyroid malignancy, analyzing their utility as a diagnostic and prognostic marker. Materials and Methods. We studied 195 malignant tissues: 154 PTCs and 41 FTCs; 102 benign tissues: 51 follicular adenomas and 51 goiter and 17 normal thyroid tissues. MAGE A3 and immune cell markers (CD4 and CD8) were evaluated using immunohistochemistry and compared with clinical pathological features. Results. The semiquantitative analysis and ACIS III analysis showed similar results. MAGE A3 was expressed in more malignant than in benign lesions (), also helping to discriminate follicular-patterned lesions. It was also higher in tumors in which there was extrathyroidal invasion () and in patients with stage II disease (). MAGE A3+ tumors were more likely to present CD8+ TIL (), and these tumors were associated with less aggressive features, that is, extrathyroidal invasion and small size. There was a trend of MAGE A3+ CD8+ tumors to evolve free of disease. Conclusion. We demonstrated that MAGE A3 and CD8+ TIL infiltration may play an important role in malignant thyroid nodules, presenting an interesting perspective for new researches on DTC immunotherapy. Mariana Bonjiorno Martins, Marjory Alana Marcello, Fernando de Assis Batista, Lucas Leite Cunha, Elaine Cristina Morari, Fernando Augusto Soares, José Vassallo, and Laura Sterian Ward Copyright © 2014 Mariana Bonjiorno Martins et al. All rights reserved. GK-1 Improves the Immune Response Induced by Bone Marrow Dendritic Cells Loaded with MAGE-AX in Mice with Melanoma Thu, 30 Oct 2014 00:00:00 +0000 The aim of dendritic cell (DC) vaccination in cancer is to induce tumor-specific effector T cells that may reduce and control tumor mass. Immunostimulants that could drive a desired immune response are necessary to be found in order to generate a long lasting tumor immune response. GK-1 peptide, derived from Taenia crassiceps, induces not only increase in TNFα, IFNγ, and MCP-1 production in cocultures of DCs and T lymphocytes but also immunological protection against influenza virus. Moreover, the aim of this investigation is the use of GK-1 as a bone marrow DCs (BMDCs) immunostimulant targeted with MAGE antigen; thus, BMDC may be used as immunotherapy against murine melanoma. GK-1 induced in BMDCs a meaningful increment of CD86 and IL-12. In addition, the use of BMDCs TNFα/GK-1/MAGE-AX induced the highest survival and the smallest tumors in mice. Besides, the treatment helped to increase CD8 lymphocytes levels and to produce IFNγ in lymph nodes. Moreover, the histopathological analysis showed that BMDCs treated with GK-1/TNFα and loaded with MAGE-AX induced the apparition of more apoptotic and necrotic areas in tumors than in mice without treatment. These results highlight the properties of GK-1 as an immunostimulant of DCs and suggest as a potential candidate the use of this immunotherapy against cancer disease. Gabriela Piñón-Zárate, Miguel Ángel Herrera-Enríquez, Beatriz Hernández-Téllez, Katia Jarquín-Yáñez, and Andrés Eliú Castell-Rodríguez Copyright © 2014 Gabriela Piñón-Zárate et al. All rights reserved. Proatherogenic Oxidized Low-Density Lipoprotein/2-Glycoprotein I Complexes in Arterial and Venous Disease Tue, 28 Oct 2014 00:00:00 +0000 OxLDL/2GPI complexes have been implicated in the initiation and progression of atherosclerosis and associated with disease severity and adverse outcomes. We investigate the significance of anti-oxLDL/2GPI antibodies and oxLDL/2GPI complexes in patients with arterial and idiopathic venous disease. A cohort of 61 arterial disease patients, 32 idiopathic venous disease patients, and 53 healthy controls was studied. Because statins influence oxLDL/2GPI, these complexes were analyzed on subjects not taking statins. Arterial and venous groups expressed higher levels of IgG anti-oxLDL/2GPI antibodies than controls without any other significant clinical association. OxLDL/2GPI complexes were significantly elevated in arterial (0.69 U/mL, ) and venous disease (0.54 U/mL, ) than controls (0.39 U/mL). Among arterial diseases, oxLDL/β2GPI was 0.85 U/mL for carotid artery disease, 0.72 U/mL for peripheral artery disease, and 0.52 U/mL for abdominal aortic aneurysm. There was a significant association with male gender, age, hypertension, and history of thrombosis. Subjects with oxLDL/β2GPI above the median (0.25 U/mL) were more likely to have arterial (OR 4.5, ) or venous disease (OR 4.1, ). Multivariate regression indicated that males (), high cholesterol (), and carotid disease () were significant predictors of oxLDL/β2GPI. The coexistence of oxLDL/2GPI in arterial and venous disease may suggest a common oxidative mechanism that independently predicts carotid artery disease. Jeffrey S. Berger, Caron B. Rockman, Kirk E. Guyer, and Luis R. Lopez Copyright © 2014 Jeffrey S. Berger et al. All rights reserved. Tolerogenic Splenic IDO+ Dendritic Cells from the Mice Treated with Induced-Treg Cells Suppress Collagen-Induced Arthritis Mon, 27 Oct 2014 12:45:19 +0000 TGF-β-induced regulatory T cells (iTregs) retain Foxp3 expression and immune-suppressive activity in collagen-induced arthritis (CIA). However, the mechanisms whereby transferred iTregs suppress immune responses, particularly the interplay between iTregs and dendritic cells (DCs) in vivo, remain incompletely understood. In this study, we found that after treatment with iTregs, splenic CD11c+DCs, termed “DCiTreg,” expressed tolerogenic phenotypes, secreted high levels of IL-10, TGF-β, and IDO, and showed potent immunosuppressive activity in vitro. After reinfusion with DCiTreg, marked antiarthritic activity improved clinical scores and histological end-points were observed. The serological levels of inflammatory cytokines and anti-CII antibodies were low and TGF-β production was high in the DCiTreg-treated group. DCiTreg also induced new iTregs in vivo. Moreover, the inhibitory activity of DCiTreg on CIA was lost following pretreatment with the inhibitor of indoleamine 2,3-dioxygenase (IDO). Collectively, these findings suggest that transferred iTregs could induce tolerogenic characteristics in splenic DCs and these cells could effectively dampen CIA in an IDO-dependent manner. Thus, the potential therapeutic effects of iTregs in CIA are likely maintained through the generation of tolerogenic DCs in vivo. Jie Yang, Yiming Yang, Huahua Fan, and Hejian Zou Copyright © 2014 Jie Yang et al. All rights reserved. HLA-E: A Novel Player for Histocompatibility Mon, 20 Oct 2014 13:42:49 +0000 The classical class I human leukocyte antigens (HLA-A, -B, and -C) present allele-specific self- or pathogenic peptides originated by intracellular processing to CD8+ immune effector cells. Even a single mismatch in the heavy chain (hc) of an HLA class I molecule can impact on the peptide binding profile. Since HLA class I molecules are highly polymorphic and most of their polymorphisms affect the peptide binding region (PBR), it becomes obvious that systematic HLA matching is crucial in determining the outcome of transplantation. The opposite holds true for the nonclassical HLA class I molecule HLA-E. HLA-E polymorphism is restricted to two functional versions and is thought to present a limited set of highly conserved peptides derived from class I leader sequences. However, HLA-E appears to be a ligand for the innate and adaptive immune system, where the immunological response to peptide-HLA-E complexes is dictated through the sequence of the bound peptide. Structural investigations clearly demonstrate how subtle amino acid differences impact the strength and response of the cognate CD94/NKG2 or T cell receptor. Thomas Kraemer, Rainer Blasczyk, and Christina Bade-Doeding Copyright © 2014 Thomas Kraemer et al. All rights reserved. Immune Dysfunction in Rett Syndrome Patients Revealed by High Levels of Serum Anti-N(Glc) IgM Antibody Fraction Wed, 15 Oct 2014 06:54:13 +0000 Rett syndrome (RTT), a neurodevelopmental disorder affecting exclusively (99%) female infants, is associated with loss-of-function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2) and, more rarely, cyclin-dependent kinase-like 5 (CDKL5) and forkhead box protein G1 (FOXG1). In this study, we aimed to evaluate the function of the immune system by measuring serum immunoglobulins (IgG and IgM) in RTT patients () and, by comparison, in age-matched children affected by non-RTT pervasive developmental disorders (non-RTT PDD) () and healthy age-matched controls (). To determine immunoglobulins we used both a conventional agglutination assay and a novel ELISA based on antibody recognition by a surrogate antigen probe, CSF114(Glc), a synthetic N-glucosylated peptide. Both assays provided evidence for an increase in IgM titer, but not in IgG, in RTT patients relative to both healthy controls and non-RTT PDD patients. The significant difference in IgM titers between RTT patients and healthy subjects in the CSF114(Glc) assay () suggests that this procedure specifically detects a fraction of IgM antibodies likely to be relevant for the RTT disease. These findings offer a new insight into the mechanism underlying the Rett disease as they unveil the possible involvement of the immune system in this pathology. Anna Maria Papini, Francesca Nuti, Feliciana Real-Fernandez, Giada Rossi, Caterina Tiberi, Giuseppina Sabatino, Shashank Pandey, Silvia Leoncini, Cinzia Signorini, Alessandra Pecorelli, Roberto Guerranti, Solange Lavielle, Lucia Ciccoli, Paolo Rovero, Claudio De Felice, and Joussef Hayek Copyright © 2014 Anna Maria Papini et al. All rights reserved. Alpha/Beta T-Cell Depleted Grafts as an Immunological Booster to Treat Graft Failure after Hematopoietic Stem Cell Transplantation with HLA-Matched Related and Unrelated Donors Mon, 13 Oct 2014 12:06:11 +0000 Allogeneic hematopoietic stem cell transplantation is associated with several complications and risk factors, for example, graft versus host disease (GVHD), viral infections, relapse, and graft rejection. While high levels of CD3+ cells in grafts can contribute to GVHD, they also promote the graft versus leukemia (GVL) effect. Infusions of extra lymphocytes from the original stem cell donor can be used as a treatment after transplantation for relapse or poor immune reconstitution but also they increase the risk for GVHD. In peripheral blood, 95% of T-cells express the T-cell receptor and the remaining T-cells express the T-cell receptor. As T-cells are the primary mediators of GVHD, depleting them from the graft should reduce this risk. In this pilot study, five patients transplanted with HLA-matched related and unrelated donors were treated with T-cell depleted stem cell boosts. The majority of T-cells in the grafts expressed and/or . Most patients receiving -depleted stem cell boosts increased their levels of white blood cells, platelets, and/or granulocytes 30 days after infusion. No signs of GVHD or other side effects were detected. A larger pool of patients with longer follow-up time is needed to confirm the data in this study. E. Rådestad, H. Wikell, M. Engström, E. Watz, B. Sundberg, S. Thunberg, M. Uzunel, J. Mattsson, and M. Uhlin Copyright © 2014 E. Rådestad et al. All rights reserved. Clinical Relevance of HLA Antibody Monitoring after Kidney Transplantation Mon, 13 Oct 2014 10:45:28 +0000 In kidney transplantation, antibody-mediated allograft injury caused by donor HLA-specific antibodies (DSA) has recently been identified as one of the major causes of late graft loss. This paper gives a brief overview on the impact of DSA development on graft outcome in organ transplantation with a focus on risk factors for de novo alloantibody induction and recently published guidelines for monitoring of DSA during the posttransplant phase. Christian Morath, Gerhard Opelz, Martin Zeier, and Caner Süsal Copyright © 2014 Christian Morath et al. All rights reserved. Immunomodulation by Trypanosoma cruzi: Toward Understanding the Association of Dendritic Cells with Infecting TcI and TcII Populations Mon, 13 Oct 2014 07:31:29 +0000 Dendritic cells (DCs) are major immune components, and depending on how these cells are modulated, the protective host immune response changes drastically. Trypanosoma cruzi is a parasite with high genetic variability and modulates DCs by interfering with their capacity for antigen recognition, migration, and maturation. Despite recent efforts, the association between DCs and T. cruzi I (TcI) and TcII populations is unknown. Herein, it was demonstrated that AQ1.7 and MUTUM TcI strains present low rates of invasion of bone marrow-derived DCs, whereas the 1849 and 2369 TcII strains present higher rates. Whereas the four strains similarly induced the expression of PD-L1, the production and expression of IL-10 and TLR-2, respectively, in DCs were differentially increased. The production of TNF-α, IL-12, IL-6, and CCL2 and the expression of CD40, CD80, MHC-II, CCR5, and CCR7 changed depending on the strain. The 2369 strain yielded the most remarkable results because greater invasion correlated with an increase in the levels of anti-inflammatory molecules IL-10 and PD-L1 but not with a change in the levels of TNF-α, MHC-II, or CD40 molecules. These results suggest that T. cruzi strains belonging to different populations have evolved specific evasion strategies that subvert DCs and consequently the host response. Thiago Alvares da Costa, Marcos Vinicius Silva, Maria Tays Mendes, Tamires Marielem Carvalho-Costa, Lara Rocha Batista, Eliane Lages-Silva, Virmondes Rodrigues, Carlo Jose Oliveira, and Luis Eduardo Ramirez Copyright © 2014 Thiago Alvares da Costa et al. All rights reserved. Effects of Awakening and the Use of Topical Dexamethasone and Levofloxacin on the Cytokine Levels in Tears Following Corneal Transplantation Sun, 12 Oct 2014 00:00:00 +0000 Objectives. To study the short-term effect of eye opening and use of topical dexamethasone phosphate 0.1% and levofloxacin 0.5% on the cytokine levels in human tears. Methods. Prospective experimental design was used for tear collection from eyes of 10 healthy controls and 20 patients four days after penetrating keratoplasty (PKP) at awakening and after instilling dexamethasone or levofloxacin. The concentrations of different cytokines were measured by cytometric bead array. Results. At eye opening, IL-6 levels were higher in the PKP group as compared to the controls. Thirty minutes later, the released levels of IL-10, IL-13, IL-17, IFNγ, and CCL5 increased in controls, while CXCL8 decreased in both control and PKP groups. The release of the cytokines remained stable after 30 mins except for IFNγ, which showed a decrease in the controls following levofloxacin instillation. No short-term effects of the topically used dexamethasone and levofloxacin could be detected on the cytokine levels in controls and after PKP. Conclusions. Evidence of changes in the levels and time course of tear cytokines after awakening or eye opening could be established and the short-term confounding effects of dexamethasone and levofloxacin on the levels of released cytokines in human tears could be excluded. Mariann Fodor, Goran Petrovski, Dorottya Pásztor, Péter Gogolák, Éva Rajnavölgyi, and András Berta Copyright © 2014 Mariann Fodor et al. All rights reserved. Immune and Inflammatory Processes in Obesity, Insulin Resistance, Diabetes, and Related Cardiometabolic Complications Sun, 21 Sep 2014 10:57:48 +0000 Joseph Fomusi Ndisang, Sharad Rastogi, and Alfredo Vannacci Copyright © 2014 Joseph Fomusi Ndisang et al. All rights reserved. Powering the Immune System: Mitochondria in Immune Function and Deficiency Sun, 21 Sep 2014 06:18:15 +0000 Mitochondria are critical subcellular organelles that are required for several metabolic processes, including oxidative phosphorylation, as well as signaling and tissue-specific processes. Current understanding of the role of mitochondria in both the innate and adaptive immune systems is expanding. Concurrently, immunodeficiencies arising from perturbation of mitochondrial elements are increasingly recognized. Recent observations of immune dysfunction and increased incidence of infection in patients with primary mitochondrial disorders further support an important role for mitochondria in the proper function of the immune system. Here we review current findings. Melissa A. Walker, Stefano Volpi, Katherine B. Sims, Jolan E. Walter, and Elisabetta Traggiai Copyright © 2014 Melissa A. Walker et al. All rights reserved. The Central Role of the Gut Microbiota in Chronic Inflammatory Diseases Thu, 18 Sep 2014 11:09:08 +0000 The commensal microbiota is in constant interaction with the immune system, teaching immune cells to respond to antigens. Studies in mice have demonstrated that manipulation of the intestinal microbiota alters host immune cell homeostasis. Additionally, metagenomic-sequencing analysis has revealed alterations in intestinal microbiota in patients suffering from inflammatory bowel disease, asthma, and obesity. Perturbations in the microbiota composition result in a deficient immune response and impaired tolerance to commensal microorganisms. Due to altered microbiota composition which is associated to some inflammatory diseases, several strategies, such as the administration of probiotics, diet, and antibiotic usage, have been utilized to prevent or ameliorate chronic inflammatory diseases. The purpose of this review is to present and discuss recent evidence showing that the gut microbiota controls immune system function and onset, development, and resolution of some common inflammatory diseases. Caroline Marcantonio Ferreira, Angélica Thomaz Vieira, Marco Aurelio Ramirez Vinolo, Fernando A. Oliveira, Rui Curi, and Flaviano dos Santos Martins Copyright © 2014 Caroline Marcantonio Ferreira et al. All rights reserved. Association of Helicobacter pylori and iNOS Production by Macrophages and Lymphocytes in the Gastric Mucosa in Chronic Gastritis Thu, 18 Sep 2014 09:11:48 +0000 Helicobacter pylori is one of the most common causes of chronic gastritis. With the development of the disease cellular inflammatory infiltrates composed of lymphocytes, plasma cells, and macrophages are formed in epithelium and lamina propria of the stomach. These cells are capable of secreting a number of active substances, including inducible nitric oxide synthase (iNOS). We examined the relationship between H. pylori and secretion of iNOS by cells of inflammatory infiltrates in chronic gastritis by light microscopy and immunohistochemistry. The data obtained indicate that stimulation of H. pylori immune system cells of the host organism during development of chronic gastritis causes increase in number of macrophages and lymphocytes in the inflammatory infiltrate of the gastric mucosa. This is accompanied with increased expression of inducible NO-synthase with excess free radicals in the tissues, which leads to secondary alterations and exacerbates the inflammation with impaired regeneration processes. Lilia A. Cherdantseva, Oksana V. Potapova, Tatyana V. Sharkova, Yana Yu. Belyaeva, and Vyacheslav A. Shkurupiy Copyright © 2014 Lilia A. Cherdantseva et al. All rights reserved. The Impact of “Omic” and Imaging Technologies on Assessing the Host Immune Response to Biodefence Agents Tue, 16 Sep 2014 08:33:18 +0000 Understanding the interactions between host and pathogen is important for the development and assessment of medical countermeasures to infectious agents, including potential biodefence pathogens such as Bacillus anthracis, Ebola virus, and Francisella tularensis. This review focuses on technological advances which allow this interaction to be studied in much greater detail. Namely, the use of “omic” technologies (next generation sequencing, DNA, and protein microarrays) for dissecting the underlying host response to infection at the molecular level; optical imaging techniques (flow cytometry and fluorescence microscopy) for assessing cellular responses to infection; and biophotonic imaging for visualising the infectious disease process. All of these technologies hold great promise for important breakthroughs in the rational development of vaccines and therapeutics for biodefence agents. Julia A. Tree, Helen Flick-Smith, Michael J. Elmore, and Caroline A. Rowland Copyright © 2014. All rights reserved. The Role of Inflammatory, Anti-Inflammatory, and Regulatory Cytokines in Patients Infected with Cutaneous Leishmaniasis in Amazonas State, Brazil Thu, 11 Sep 2014 09:45:26 +0000 The authors discuss in this paper the role of inflammatory, anti-inflammatory, and regulatory cytokines in patients infected with different species of Leishmania in Amazonas State, Brazil. A comparative analysis was made of serum concentrations of these cytokines in the peripheral blood of 33 patients infected with cutaneous leishmaniasis. The isolates were identified as Leishmania guyanensis, L. naiffi, and L. amazonensis. Most (64%) of the patients were male ranging in age from 18 to 58 years. Protein expression profiles of IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α, and IL-17 cytokines were shown to vary significantly between infected and noninfected (control group) individuals and according to the Leishmania species. Infection caused by L. guyanensis accounted for 73% of the cases and patients with this parasite also showed higher concentrations of IL-2, IFN-γ, IL-4, and IL-17 when compared to infection by L. amazonensis. Patients with infection caused by L. naiffi showed higher concentration of the cytokines analyzed when compared to uninfected patients; however, there was no statistically significant difference with the other species analyzed. Thaís Tibery Espir, Luanda de Paula Figueira, Maricleide de Farias Naiff, Allyson Guimarães da Costa, Marcelo Ramalho-Ortigão, Adriana Malheiro, and Antonia Maria Ramos Franco Copyright © 2014 Thaís Tibery Espir et al. All rights reserved. Comparisons of CVID and IgGSD: Referring Physicians, Autoimmune Conditions, Pneumovax Reactivity, Immunoglobulin Levels, Blood Lymphocyte Subsets, and HLA-A and -B Typing in 432 Adult Index Patients Thu, 11 Sep 2014 08:29:32 +0000 Common variable immunodeficiency (CVID) and immunoglobulin (Ig) G subclass deficiency (IgGSD) are heterogeneous disorders characterized by respiratory tract infections, selective Ig isotype deficiencies, and impaired antibody responses to polysaccharide antigens. Using univariable analyses, we compared observations in 34 CVID and 398 IgGSD adult index patients (81.9% women) referred to a hematology/oncology practice. Similarities included specialties of referring physicians, mean ages, proportions of women, reactivity to Pneumovax, median serum IgG3 and IgG4 levels, median blood CD56+/CD16+ lymphocyte levels, positivity for HLA-A and -B types, and frequencies of selected HLA-A, -B haplotypes. Dissimilarities included greater prevalence of autoimmune conditions, lower median IgG, IgA, and IgM, and lower median CD19+, CD3+/CD4+, and CD3+/CD8+ blood lymphocytes in CVID patients. Prevalence of Sjögren’s syndrome and hypothyroidism was significantly greater in CVID patients. Combined subnormal IgG1/IgG3 occurred in 59% and 29% of CVID and IgGSD patients, respectively. Isolated subnormal IgG3 occurred in 121 IgGSD patients (88% women). Logistic regression on CVID (versus IgGSD) revealed a significant positive association with autoimmune conditions and significant negative associations with IgG1, IgG3, and IgA and CD56+/CD16+ lymphocyte levels, but the odds ratio was increased for autoimmune conditions alone (6.9 (95% CI 1.3, 35.5)). James C. Barton, Luigi F. Bertoli, and J. Clayborn Barton Copyright © 2014 James C. Barton et al. All rights reserved. Pathophysiological Roles of Cytokine-Chemokine Immune Network Thu, 11 Sep 2014 07:27:43 +0000 Jong-Young Kwak, Mizuko Mamura, Jana Barlic-Dicen, and Evelin Grage-Griebenow Copyright © 2014 Jong-Young Kwak et al. All rights reserved.