Journal of Immunology Research The latest articles from Hindawi © 2019 , Hindawi Limited . All rights reserved. The Effects of Immunosuppressive Factors on Primary Dendritic Cells from C57BL/6 and CBA Mice Thu, 18 Apr 2019 10:05:12 +0000 Introduction. Dendritic cells (DCs) control immune responses by modulating T and B cells towards effector or tolerogenic responses. In this study, we evaluated the effects of different immunosuppressive molecules on the phenotypic and functional characteristics of primary dendritic cells from C57BL/6 and CBA mice. Methods. DCs were derived from bone marrow cells in the presence of rmGM-CSF and rmIL-4. DCs were then treated with different types of immunosuppressive molecules (rmIL-10, rmTGF-β, and BAY 11-7082) and cocultured with syngeneic splenocytes. The amount of CD4+CD25hiFoxP3+ Tregs, IL-10 expression, and proliferation were evaluated. Results. Tolerogenic factors were found to have different effects on DCs C57Bl/6 mice. In C57Bl/6 mice, BAY 11-7082 alone had no effect on the expression of DC maturation molecules (CD80, CD86). Transforming growth factor beta (TGF-β), alone and in combination with BAY 11-7082, reduced the expression of these molecules. Cocultivation of DCs with splenocytes in the presence of TGF-β and BAY 11-7082 favored regulatory T cell (CD4+CD25hiFoxP3+) differentiation and disfavored differentiation of CD4+ T cells producing IL-10. In CBA mice, we found that rmIL-10 and rmTGF-β have a weak effect on maturation of DCs and their functional properties to induce Treg cells and IL-10 production. Conclusion. These results indicate that TGF-β and IL-10 have different effects on the phenotypic and functional characteristics of DCs and that the NF-κB inhibitor, BAY 11-7082, has no synergistic effect on these treatments. In mice with an opposite nature of the immune response, the effects of immunoregulatory cytokines (IL-10 and TGF-b) differ on maturation of dendritic cells. Vasiliy V. Kurilin, Julia N. Khantakova, Valeriy P. Tereschenko, Julia A. Lopatnikova, Irina A. Obleukhova, and Sergey V. Sennikov Copyright © 2019 Vasiliy V. Kurilin et al. All rights reserved. Novel Immune Microlens Imaging for Detection of Antigen and Antibody Thu, 18 Apr 2019 09:05:14 +0000 Detection and analysis of antigen-antibody reaction is one of the most critical detection techniques in the fields of medicine, biology, environmental science, and food safety. Traditional and classical methods for detecting antigen and antibody encounter many problems, such as time-consuming, high cost, and low accuracy. A novel immune microsphere imaging technique by the microlens is used to test the changes of refractive index before and after antigen-antibody reaction. It can quickly perform qualitative and quantitative determination for antigen-antibody reaction without any labeling, premodification, postwashing, and expensive enzymes. Here, we feature and discuss its principle and advantages, structure of a microlens immunoassay instrument, and potential in measuring clinical samples. It is promising to be developed for application to diagnosis of clinical diseases. Jiahui Liang, Xiaotian Ye, Jiang He, Jing Liu, Yaoxiong Huang, and Feiyue Xing Copyright © 2019 Jiahui Liang et al. All rights reserved. Immunity in the Cervix: Interphase between Immune and Cervical Epithelial Cells Wed, 17 Apr 2019 13:05:15 +0000 The cervix is divided into two morphologically and immunologically distinct regions, namely, (1) the microbe-laden ectocervix, which is proximal to the vagina, and (2) the “sterile” endocervix, which is distal to the uterus. The two cervical regions are bordered by the cervical transformation zone (CTZ), an area of changing cells, and are predominantly composed of cervical epithelial cells. Epithelial cells are known to play a crucial role in the initiation, maintenance, and regulation of innate and adaptive response in collaboration with immune cells in several tissue types, including the cervix, and their dysfunction can lead to a spectrum of clinical syndromes. For instance, epithelial cells block progression and neutralize or kill microorganisms through multiple ways. These (ways) include mounting physical (intercellular junctions, secretion of mucus) and immune barriers (pathogen-recognition receptor-mediated pathways), which collectively and ultimately lead to the release of specific chemokines and or cytokines. The cytokines subsequently recruit subsets of immune cells appropriate to a particular immune context and response, such as dendritic cells (DCs), T, B, and natural killer (NK) cells. The immune response, as most biological processes in the female reproductive tract (FRT), is mainly regulated by estrogen and progesterone and their (immune cells) responses vary during different physiological phases of reproduction, such as menstrual cycle, pregnancy, and post menopause. The purpose of the present review is to compare the immunological profile of the mucosae and immune cells in the ecto- and endocervix and their interphase during the different phases of female reproduction. Jorgelina Barrios De Tomasi, Michael Makokha Opata, and Chishimba Nathan Mowa Copyright © 2019 Jorgelina Barrios De Tomasi et al. All rights reserved. Expressions of MMP-12, TIMP-4, and Neutrophil Elastase in PBMCs and Exhaled Breath Condensate in Patients with COPD and Their Relationships with Disease Severity and Acute Exacerbations Wed, 17 Apr 2019 08:05:22 +0000 Objective. The purpose of this study was to compare matrix metalloproteinase-12 (MMP-12), neutrophil elastase (NE), and tissue inhibitor of metalloproteinase-4 (TIMP-4) in peripheral blood of patients with chronic obstructive pulmonary disease (COPD) and controls. At the same time, MMP-12, NE, and TIMP-4 in exhaled breath condensate (EBC) were also evaluated. Methods. Peripheral blood and EBC samples from COPD patients and healthy controls were collected. In serum and EBC, MMP-12, NE, and TIMP-4 proteins were detected by enzyme-linked immunoassays. The mRNA expression levels of MMP-12, NE, and TIMP-4 in peripheral blood mononuclear cells (PBMCs) were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Results. The concentration of TIMP-4 protein in EBC was lower in patients with COPD (). MMP-12 (), NE (), and TIMP-4 () proteins in serum of patients with COPD showed higher levels of concentration. The mRNA of MMP-12 (), NE (), and TIMP-4 () in PBMCs of COPD patients showed higher expression levels. Compared with stable patients, mRNA expression level of NE () in PBMCs of patients with acute exacerbation of COPD was increased. There were differences in the ratio of MMP-12/TIMP-4 in PBMC (), serum (), and EBC () samples between COPD patients and healthy controls. The mRNA expression of MMP-12 (,) and NE (,) in COPD patients was negatively correlated with pulmonary function. However, the mRNA expression of TIMP-4 (,) in PBMCs was not correlated with the FEV1 of the pulmonary function. Serum MMP-12 level was positively correlated with the MMP-12 level in EBC (). The level of TIMP-4 in serum was not correlated with the level in the EBC sample ().Conclusion. The expression levels of MMP-12, NE, and TIMP-4 in PBMCs and serum were elevated in COPD patients. In PBMCs of COPD patients, the mRNA expression level of NE may predict acute exacerbation, and MMP-12 mRNA expression level may be used to reflect the severity of airflow limitation. However, to better assess their diagnostic or prognostic value, larger studies are necessary. Wendong Hao, Manxiang Li, Yunqing Zhang, Cailian Zhang, and Yani Xue Copyright © 2019 Wendong Hao et al. All rights reserved. Cutting Edge: Probiotics and Fecal Microbiota Transplantation in Immunomodulation Tue, 16 Apr 2019 16:05:04 +0000 Probiotics are commensal or nonpathogenic microbes that confer beneficial effects on the host through several mechanisms such as competitive exclusion, antibacterial effects, and modulation of immune responses. Some probiotics have been found to regulate immune responses via immune regulatory mechanisms. T regulatory (Treg) cells, T helper cell balances, dendritic cells, macrophages, B cells, and natural killer (NK) cells can be considered as the most determinant dysregulated mediators in immunomodulatory status. Recently, fecal microbiota transplantation (FMT) has been defined as the transfer of distal gut microbial communities from a healthy individual to a patient’s intestinal tract to cure some immune disorders (mainly inflammatory bowel diseases). The aim of this review was followed through the recent literature survey on immunomodulatory effects and mechanisms of probiotics and FMT and also efficacy and safety of probiotics and FMT in clinical trials and applications. Wenjie Zeng, Jie Shen, Tao Bo, Liangxin Peng, Hongbo Xu, Moussa Ide Nasser, Quan Zhuang, and Mingyi Zhao Copyright © 2019 Wenjie Zeng et al. All rights reserved. Curcumin Provides Hepatoprotection against Amoebic Liver Abscess Induced by Entamoeba histolytica in Hamster: Involvement of Nrf2/HO-1 and NF-κB/IL-1β Signaling Pathways Mon, 15 Apr 2019 10:05:09 +0000 Amoebic liver abscess (ALA) is the most common extraintestinal amoebiasis caused by Entamoeba histolytica (E. histolytica). However, despite current knowledge and scientific advances about this infection, there are no effective treatments to prevent it. Herein, the antiamoebic capacity of curcumin in a hamster model was evaluated. Curcumin (150 mg/kg, p.o., daily during 10 days before infection) considerably prevents liver damage induced at 12 and 48 h post-intrahepatic inoculation of trophozoites and decreases ALT, ALP, and γ-GTP activities, and macroscopic and microscopic observations were consistent with these results. On the other hand, after one week of intraportal inoculation, liver damage was prevented by curcumin (150 mg/kg, p.o., daily, 20 days before amoebic inoculation and during the week of infection); liver/body weight ratios and tissue and histological stains showed normal appearance; in addition, the increases in ALT, ALP, and γ-GTP activities were prevented; the depletion of glycogen content induced by the amoebic damage was partially but significantly prevented, while NF-κB activity was inhibited and the expression of IL-1β was reduced; Nrf2 production showed a tendency to increase it, and HO-1 protein was overexpressed. These results suggest for the first time that curcumin can be a compound with antiamoebic effect in the liver, suggesting that its daily use could help greatly decrease the incidence of this type of infection. José Roberto Macías-Pérez, Liseth Rubí Aldaba-Muruato, Sandra Luz Martínez-Hernández, Martín Humberto Muñoz-Ortega, Julieta Pulido-Ortega, and Javier Ventura-Juárez Copyright © 2019 José Roberto Macías-Pérez et al. All rights reserved. CD33 (Siglec-3) Inhibitory Function: Role in the NKG2D/DAP10 Activating Pathway Mon, 15 Apr 2019 09:05:29 +0000 CD33 (siglec-3), a well-known target in leukemia therapy, is an inhibitory sialoadhesin expressed in human leukocytes of the myeloid lineage and some lymphoid subsets, including NK cells. It may constitute a control mechanism of the innate immune system; nevertheless, its role as an inhibitory receptor remains elusive. Using human NK cells as a cellular model, we analyzed CD33 inhibitory function upon different activating receptors. In high-cytotoxicity NKL cells, CD33 displayed a prominent inhibition on cytotoxicity triggered by the activating receptors NKG2D and, in a lower extent, 2B4, whereas it did not inhibit NKp46-induced cytotoxicity. NKp46 was partially inhibited by CD33 only when low-cytotoxicity NKL cells were tested. CD33 triggering did not inhibit IFN-γ secretion, contrasting with ILT-2 and CD94/NKG2A inhibitory receptors that inhibited cytotoxicity and IFN-γ secretion induced by all activating receptors tested. CD33-mediated inhibition of NKG2D-induced triggering involved Vav1 dephosphorylation. Our results support the role of CD33 as an inhibitory receptor preferentially regulating the NKG2D/DAP10 cytotoxic signaling pathway, which could be involved in self-tolerance and tumor and infected cell recognition. Trinidad Hernández-Caselles, Rubén Corral-San Miguel, Antonio José Ruiz-Alcaraz, and Pilar García-Peñarrubia Copyright © 2019 Trinidad Hernández-Caselles et al. All rights reserved. Intracellular Pathogens: Host Immunity and Microbial Persistence Strategies Sun, 14 Apr 2019 13:05:19 +0000 Infectious diseases caused by pathogens including viruses, bacteria, fungi, and parasites are ranked as the second leading cause of death worldwide by the World Health Organization. Despite tremendous improvements in global public health since 1950, a number of challenges remain to either prevent or eradicate infectious diseases. Many pathogens can cause acute infections that are effectively cleared by the host immunity, but a subcategory of these pathogens called “intracellular pathogens” can establish persistent and sometimes lifelong infections. Several of these intracellular pathogens manage to evade the host immune monitoring and cause disease by replicating inside the host cells. These pathogens have evolved diverse immune escape strategies and overcome immune responses by residing and multiplying inside host immune cells, primarily macrophages. While these intracellular pathogens that cause persistent infections are phylogenetically diverse and engage in diverse immune evasion and persistence strategies, they share common pathogen type-specific mechanisms during host-pathogen interaction inside host cells. Likewise, the host immune system is also equipped with a diverse range of effector functions to fight against the establishment of pathogen persistence and subsequent host damage. This article provides an overview of the immune effector functions used by the host to counter pathogens and various persistence strategies used by intracellular pathogens to counter host immunity, which enables their extended period of colonization in the host. The improved understanding of persistent intracellular pathogen-derived infections will contribute to develop improved disease diagnostics, therapeutics, and prophylactics. Aneesh Thakur, Heidi Mikkelsen, and Gregers Jungersen Copyright © 2019 Aneesh Thakur et al. All rights reserved. Intrapulmonary Autoantibodies to HSP72 Are Associated with Improved Outcomes in IPF Thu, 11 Apr 2019 00:05:10 +0000 Rationale. Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease, with high mortality. Currently, the aetiology and the pathology of IPF are poorly understood, with both innate and adaptive responses previously being implicated in the disease pathogenesis. Heat shock proteins (Hsp) and antibodies to Hsp in patients with IPF have been suggested as therapeutic targets and prognostic biomarkers, respectively. We aimed to study the relationship between the expression of Hsp72 and anti-Hsp72 antibodies in the BAL fluid and serum Aw disease progression in patients with IPF. Methods. A novel indirect ELISA to measure anti-Hsp72 IgG was developed and together with commercially available ELISAs used to detect Hsp72 IgG, Hsp72 IgGAM, and Hsp72 antigen, in the serum and BALf of a cohort of IPF () and other interstitial lung disease (ILD) patients (). Immunohistochemistry was used to detect Hsp72 in lung tissue. The cytokine expression from monocyte-derived macrophages was measured by ELISA. Results. Anti-Hsp72 IgG was detectable in the serum and BALf of IPF () and other ILDs (). Total immunoglobulin concentrations in the BALf showed an excessive adaptive response in IPF compared to other ILDs and healthy controls (). Immunohistochemistry detection of C4d and Hsp72 showed that these antibodies may be targeting high expressing Hsp72 type II alveolar epithelial cells. However, detection of anti-Hsp72 antibodies in the BALf revealed that increasing concentrations were associated with improved patient survival (adjusted HR 0.62, 95% CI 0.45-0.85; ).In vitro experiments demonstrate that anti-Hsp72 complexes stimulate macrophages to secrete CXCL8 and CCL18. Conclusion. Our results indicate that intrapulmonary anti-Hsp72 antibodies are associated with improved outcomes in IPF. These may represent natural autoantibodies, and anti-Hsp72 IgM and IgA may provide a beneficial role in disease pathogenesis, though the mechanism of action for this has yet to be determined. Ross Mills, Abhinav Mathur, Lisa M. Nicol, Jeremy J. Walker, Alexander A. Przybylski, Alison C. Mackinnon, Sarah E. M. Howie, William A. H. Wallace, Ian Dransfield, and Nik Hirani Copyright © 2019 Ross Mills et al. All rights reserved. Influence of Interleukin-8 and Neutrophil Extracellular Trap (NET) Formation in the Tumor Microenvironment: Is There a Pathogenic Role? Wed, 10 Apr 2019 19:05:02 +0000 In this review, we will highlight several studies that revolve around interleukin-8 (IL-8) and show the multiple facets that could take in the tumor microenvironment. Chemokines that attract neutrophils (to a large extent, IL-8) can have a bimodal behavior inducing the migration of them in the first place and later favoring the formation of NETs in the place of emission focus of the chemokine. Also, this mechanism occurs when neutrophils migrate to tumor cells and where the extrusion of NETs in the tumor is observed. A possible participation of NETs in cancer progression was considered; however, until now, it is difficult to decide if NETosis plays a pro- or antitumor role, although it is necessary to emphasize that there is more experimentation focused on the protumorigenic aspect of the NETs. The formation of NETs has a relevant role in the inhibition of the immune response against the tumor generated by neutrophils and in turn favoring the processes involved in the development of tumor metastasis. It is striking that we do not have more complete information about the effects of circulating chemokines on neutrophils in cancer patients and hence the suitability of this review. No one has observed to date the impact that it could have on other cell populations to inhibit the arrival of neutrophils and the formation/elimination of NETs. However, the extent to which NETs affect the function of other cells of the immune system in the tumor context has not been directly demonstrated. It is necessary to identify possible combinations of immunotherapy that involve the modulation of neutrophil activity with other strategies (immunomodulatory antibodies or adoptive cell therapy). Therefore, knowing the mechanisms by which tumors take advantage of this ability of neutrophils to form NETs is very important in the search for antitumor therapies and thus be able to take advantage of the possible immunotherapeutic combinations that we currently have in clinical practice. Manuela Gonzalez-Aparicio and Carlos Alfaro Copyright © 2019 Manuela Gonzalez-Aparicio and Carlos Alfaro. All rights reserved. CD80 Expression Correlates with IL-6 Production in THP-1-Like Macrophages Costimulated with LPS and Dialyzable Leukocyte Extract (Transferon®) Wed, 10 Apr 2019 12:05:09 +0000 Transferon® is a complex drug based on a mixture of low molecular weight peptides. This biotherapeutic is employed as a coadjuvant in clinical trials of several diseases, including viral infections and allergies. Given that macrophages play key roles in pathogen recognition, phagocytosis, processing, and antigen presentation, we evaluated the effect of Transferon® on phenotype and function of macrophage-like cells derived from THP-1 monocytes. We determined the surface expression of CD80 and CD86 by flow cytometry and IL-1β, TNF-α, and IL-6 levels by ELISA. Transferon® alone did not alter the steady state of PMA-differentiated macrophage-like THP-1 cells. On the contrary, simultaneous stimulation of cells with Transferon® and LPS elicited a significant increase in CD80 () and CD86 () expression, as well as in IL-6 production () compared to the LPS control. CD80 expression and IL-6 production exhibited a positive correlation (,) in cells exposed to Transferon® and LPS. Our results suggest that the administration of Transferon® induces the expression of costimulatory molecules and the secretion of cytokines in LPS-activated macrophages. Further studies are necessary to determine the implication of these findings in the therapeutic properties of Transferon®. Alexis P. Jiménez-Uribe, Hugo Valencia-Martínez, Gregorio Carballo-Uicab, Luis Vallejo-Castillo, Emilio Medina-Rivero, Rommel Chacón-Salinas, Lenin Pavón, Marco A. Velasco-Velázquez, Gabriela Mellado-Sánchez, Sergio Estrada-Parra, and Sonia M. Pérez-Tapia Copyright © 2019 Alexis P. Jiménez-Uribe et al. All rights reserved. Calcitriol Inhibits the Proliferation of Triple-Negative Breast Cancer Cells through a Mechanism Involving the Proinflammatory Cytokines IL-1β and TNF-α Wed, 10 Apr 2019 08:05:14 +0000 Triple-negative breast cancer (TNBC) is one of the most aggressive tumors, with poor prognosis and high metastatic capacity. The aggressive behavior may involve inflammatory processes characterized by deregulation of molecules related to the immunological responses in which interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) are involved. It is known that calcitriol, the active vitamin D metabolite, modulates the synthesis of immunological mediators; however, its role in the regulation of IL-1β and TNF-α in TNBC has been scarcely studied. In the present study, we showed that TNBC cell lines SUM-229PE and HCC1806 expressed vitamin D, IL-1β, and TNF-α receptors. Moreover, calcitriol, its analogue EB1089, IL-1β, and TNF-α inhibited cell proliferation. In addition, we showed that synthesis of both IL-1β and TNF-α was stimulated by calcitriol and its analogue. Interestingly, the antiproliferative activity of calcitriol was significantly abrogated when the cells were treated with anti-IL-1β receptor 1 (IL-1R1) and anti-TNF-α receptor type 1 (TNFR1) antibodies. Furthermore, the combination of calcitriol with TNF-α resulted in a greater antiproliferative effect than either agent alone, in the two TNBC cell lines and an estrogen receptor-positive cell line. In summary, this study demonstrated that calcitriol exerted its antiproliferative effects in part by inducing the synthesis of IL-1β and TNF-α through IL-1R1 and TNFR1, respectively, in TNBC cells, highlighting immunomodulatory and antiproliferative functions of calcitriol in TNBC tumors. Isela Martínez-Reza, Lorenza Díaz, David Barrera, Mariana Segovia-Mendoza, Sigifredo Pedraza-Sánchez, Giovanny Soca-Chafre, Fernando Larrea, and Rocío García-Becerra Copyright © 2019 Isela Martínez-Reza et al. All rights reserved. The IL-1B Gene Polymorphisms rs16944 and rs1143627 Contribute to an Increased Risk of Coronary Artery Lesions in Southern Chinese Children with Kawasaki Disease Tue, 09 Apr 2019 12:05:09 +0000 Background. Kawasaki disease (KD) is a systemic form of self-limited vasculitis in children less than five years old, and the main complication is coronary artery injury. However, the etiology of KD remains unclear. The IL-1B polymorphisms rs16944 GG and rs1143627 AA and their diplotype GA/GA have been associated with significantly increased risk of intravenous immunoglobulin (IVIG) resistance in a Taiwanese population, but the relationship between rs16944 A/G and rs1143627 G/A and coronary artery lesions (CALs) in patients with KD has not been investigated. The present study is aimed at investigating whether the rs16944 A/G and rs1143627 G/A polymorphisms in IL-1B were associated with KD susceptibility and CALs in a southern Chinese population. Methods and Results. We recruited 719 patients with KD and 1401 healthy children. Multiplex PCR was used to assess the genotypes of single nucleotide polymorphisms (SNPs), including two SNPs of IL-1B, rs16944 A/G and rs1143627 G/A. According to the results, no significant association was observed between the IL-1B (rs16944 and rs1143627) polymorphisms and KD risk in the patients compared with the healthy controls in our southern Chinese population. However, in further stratified analysis, we found that children younger than 12 months with the rs16944 GG and rs1143627 AA genotypes of IL-1B had a higher risk of CALs than those with the AA/AG genotypes of rs16944 and GG/AG genotypes of rs1143627 (, 95% -3.95, , adjusted , 95% -4.04, ).Conclusions. Our results indicated that there was no association between the rs16944 A/G and rs1143627 G/A gene polymorphisms and KD susceptibility. However, the rs16944 GG and rs1143627 AA genotypes of IL-1B may significantly impact the risk of CAL formation in children younger than 12 months, which may contribute to the pathogenesis of KD. These findings need further validation in multicenter studies with larger sample sizes. Lan Yan Fu, Xiantao Qiu, Qiu Lian Deng, Ping Huang, Lei Pi, Yufen Xu, Di Che, Huazhong Zhou, Zhaoliang Lu, Yaqian Tan, Zhiyong Jiang, Li Zhang, Techang Liu, and Xiaoqiong Gu Copyright © 2019 Lan Yan Fu et al. All rights reserved. pDC Activation by TLR7/8 Ligand CL097 Compared to TLR7 Ligand IMQ or TLR9 Ligand CpG Tue, 09 Apr 2019 07:05:03 +0000 Plasmacytoid dendritic cells (pDCs) express high levels of the toll-like receptors (TLRs) TLR7 and TLR9. In response to TLR7 and TLR9 ligands, pDCs are primary producers of type I interferons. Our previous study demonstrated that pDCs activated by the TLR7 ligand imiquimod (IMQ) and the TLR9 ligand CpG A can kill breast cancer cells in vitro and inhibit tumor growth in vivo. Moreover, we observed a distinctive morphological, phenotypic change in pDCs after activation by IMQ and CpG A. However, the effect of other TLR7 and TLR9 ligands on pDCs remains less understood. In this study, we treat pDCs with the TLR7 ligand IMQ, TLR7/8 ligands (CL097 and CL075), and three TLR9 ligands (different types of CpGs). The size of pDCs increased significantly after activation by TLR7, or TLR7/8 ligands. TLR7, TLR7/8, and TLR9 ligands similarly modulated cytokine release, as well as protein expression of pDC markers, costimulatory molecules, and cytotoxic molecules. Interestingly, TLR7/8 ligands, especially CL097, induced stronger responses. These results are relevant to the further study of the role and mechanism of pDC-induced antitumor effects and may aid in the development of a new strategy for future tumor immunotherapy. Jing Wu, Shuang Li, Tete Li, Xinping Lv, Mingyou Zhang, Guoxia Zang, Chong Qi, Yong-Jun Liu, Liang Xu, and Jingtao Chen Copyright © 2019 Jing Wu et al. All rights reserved. Middle East Respiratory Syndrome Coronavirus (MERS-CoV): Infection, Immunological Response, and Vaccine Development Sun, 07 Apr 2019 07:05:27 +0000 Middle East respiratory syndrome coronavirus (MERS-CoV) first emerged in late 2012. Since its emergence, a total of 2279 patients from 27 countries have been infected across the globe according to a World Health Organization (WHO) report (Feb. 12th, 2019). Approximately 806 patients have died. The virus uses its spike proteins as adhesive factors that are proinflammatory for host entry through a specific receptor called dipeptidyl peptidase-4 (DPP4). This receptor is considered a key factor in the signaling and activation of the acquired and innate immune responses in infected patients. Using potent antigens in combination with strong adjuvants may effectively trigger the activation of specific MERS-CoV cellular responses as well as the production of neutralizing antibodies. Unfortunately, to date, there is no effective approved treatment or vaccine for MERS-CoV. Thus, there are urgent needs for the development of novel MERS-CoV therapies as well as vaccines to help minimize the spread of the virus from infected patients, thereby mitigating the risk of any potential pandemics. Our main goals are to highlight and describe the current knowledge of both the innate and adaptive immune responses to MERS-CoV and the current state of MERS-CoV vaccine development. We believe this study will increase our understanding of the mechanisms that enhance the MERS-CoV immune response and subsequently contribute to the control of MERS-CoV infections. Ayman Mubarak, Wael Alturaiki, and Maged Gomaa Hemida Copyright © 2019 Ayman Mubarak et al. All rights reserved. Manipulation of Type I Interferon Signaling by HIV and AIDS-Associated Viruses Thu, 04 Apr 2019 23:05:02 +0000 Type I Interferons were first described for their profound antiviral abilities in cell culture and animal models, and later, they were translated into potent antiviral therapeutics. However, as additional studies into the function of Type I Interferons progressed, it was also seen that pathogenic viruses have coevolved to encode potent mechanisms allowing them to evade or suppress the impact of Type I Interferons on their replication. For chronic viral infections, such as HIV and many of the AIDS-associated viruses, including HTLV, HCV, KSHV, and EBV, the clinical efficacy of Type I Interferons is limited by these mechanisms. Here, we review some of the ways that HIV and AIDS-associated viruses thrive in Type I Interferon-rich environments via mechanisms that block the function of this important antiviral cytokine. Overall, a better understanding of these mechanisms creates avenues to better understand the innate immune response to these viruses as well as plan the development of antivirals that would allow the natural antiviral effect of Type I Interferons to manifest during these infections. Buyuan He, James T. Tran, and David Jesse Sanchez Copyright © 2019 Buyuan He et al. All rights reserved. Increased Serum Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) Levels in FSGS: A Meta-Analysis Thu, 04 Apr 2019 12:05:19 +0000 Introduction. The soluble urokinase-type plasminogen activator receptor (suPAR) has been found to be elevated in primary focal segmental glomerulosclerosis (pFSGS). However, its usefulness as a biomarker for FSGS remains controversial. We conducted a meta-analysis aiming at investigating the significance of suPAR in diagnosing pFSGS. Methods. Electronic databases (PubMed and EMBASE) were searched to identify studies comparing suPAR levels in FSGS patients and controls, from the earliest available date to May 1, 2018. A random-effects model with standardized mean difference (SMD) was used for meta-analyses. Risk of bias was assessed using the Newcastle-Ottawa quality assessment scale. Results. A total of 187 articles were screened, and the final analysis included 13 articles. In comparison to healthy controls, serum suPAR levels were significantly increased in pFSGS patients (SMD, 1.07, 95% confidence interval (CI) 0.65 to 1.48; ;,). Higher suPAR levels were also found in patients with pFSGS compared to those with minimal change disease (SMD 0.53, 95% CI 0.22 to 0.84). Of note, such a difference was not found in pediatric groups (SMD 0.42, 95% CI -0.13 to 0.96) while it was more evidently noted in adult patients (SMD 1.32, 95% CI 0.90 to 1.74). Serum suPAR levels did not differ between pFSGS patients in remission compared to those in active proteinuric state (SMD 0.29, 95% CI -0.30 to 0.88). Comparison with membranous nephropathy and IgA nephropathy showed no significant difference. Conclusions. Our meta-analysis demonstrated that, in comparison to both healthy controls and controls with minimal change disease, suPAR levels were significantly higher in adult patients with pFSGS. suPAR levels did not differ between pFSGS patients during the initial period of diagnosis and those in remission. Jiwon M. Lee, Jae Won Yang, Andreas Kronbichler, Michael Eisenhut, Gaeun Kim, Keum Hwa Lee, and Jae Il Shin Copyright © 2019 Jiwon M. Lee et al. All rights reserved. Interleukin 6 Function in the Skin and Isolated Keratinocytes Is Modulated by Hyperglycemia Wed, 03 Apr 2019 13:05:17 +0000 Diabetes currently affects over twenty-five million Americans. Annual health care cost of diabetes exceeds $254 billion and is associated with a distinct set of diabetic complications that include delayed wound healing and diabetic ulcers. Interleukin 6 (IL-6) plays an important role in wound healing and is known to be elevated in the serum of both type I and type II diabetes patients. This study assesses the expression and function of IL-6 in the hyperglycemic epidermis and keratinocyte culture. Streptozotocin-treated mice were wounded six weeks after induction of hyperglycemia. Wound closure, protein, and mRNA expression were assessed up to 13 days of postwounding. Wound closure was delayed 4-5 days in hyperglycemic animals. Hyperglycemic wounds displayed greater IL-6 and IL-6Rα protein expression at 1, 7, and 10 days of postwounding compared to euglycemic control. However, IL-6Rα mRNA expression was reduced at all time points beyond day 1, while IL-6 mRNA expression did not significantly differ at any time point. SOCS3 mRNA expression was higher in the hyperglycemic skin at every time point. Imaging of fluorescent immunohistology also revealed significantly lower expression of SOCS3, but higher nuclear pSTAT3 in the epidermis of the hyperglycemic skin. Primary mouse keratinocytes cultured in high glucose for 7 days displayed 2-fold higher IL-6Rα mRNA and higher rmIL-6-induced nuclear pSTAT3, but lower SOCS3 basal levels compared to normal glucose-cultured cells. Thus, it appears that delayed diabetic skin wound healing is associated with increased induction and expression of IL-6 and its receptor, but its function in epidermal keratinocytes may be impaired. Eric G. Lee, Lerin R. Luckett-Chastain, Kaitlin N. Calhoun, Benjamin Frempah, Anja Bastian, and Randle M. Gallucci Copyright © 2019 Eric G. Lee et al. All rights reserved. Decreased Frequencies of Th17 and Tc17 Cells in Patients Infected with Avian Influenza A (H7N9) Virus Tue, 02 Apr 2019 13:05:11 +0000 The outbreak of avian influenza A (H7N9) virus infection, with a high mortality rate, has caused concern worldwide. Although interleukin-17- (IL-17-) secreting CD4+ T (Th17) and CD8+ T (Tc17) cells have been proven to play crucial roles in influenza virus infection, the changes and roles of Th17 and Tc17 cells in immune responses to H7N9 infection remain controversial. In this study, we found that the frequencies of Th17 and Tc17 cells among human peripheral blood mononuclear cells (PBMCs) as well as IL-17A protein and mRNA levels were markedly decreased in patients with acute H7N9 virus infection. A positive correlation was found between the serum IL-17A level and the frequency of these two cell groups. In vitro infection experiments revealed decreased Th17 and Tc17 cell frequency and IL-17A levels at various time points postinfection. In addition, Th17 cells were the predominant sources of IL-17A in PBMCs of patients infected with H7N9 virus. Taken together, our results indicate immune disorder in acute H7N9 infection and a restored Th17 and Tc17 cell frequency might serve as a biomarker for predicting recovery in patients infected with this virus. Jiaqi Bao, Dawei Cui, Xiaochen Wang, Qianda Zou, Dejian Zhao, Shufa Zheng, Fei Yu, Li Huang, Yuejiao Dong, Xianzhi Yang, Guoliang Xie, Weizhen Chen, and Yu Chen Copyright © 2019 Jiaqi Bao et al. All rights reserved. Genetic Predisposition to Hepatocarcinogenesis in Inbred and Outbred Mouse Lines Selected for High or Low Inflammatory Response Sun, 31 Mar 2019 08:05:19 +0000 AIRmax and AIRmin mouse strains phenotypically selected for high and low acute inflammatory responsiveness (AIR) are, respectively, susceptible or resistant to developing hepatocellular carcinoma (HCC) induced by the chemical carcinogens urethane and diethylnitrosamine (DEN). Early production of TNF-α, IL-1β, and IL-6 in the liver after DEN treatment correlated with tumor development in AIRmax mice. Transcriptome analysis of livers from untreated AIRmax and AIRmin mice showed specific gene expression profiles in each line, which might play a role in their differential susceptibility to HCC. Linkage analysis with SNP markers in F2 (AIRmax×AIRmin) intercross mice revealed two quantitative trait loci (QTL) in chromosomes 2 and 9, which are significantly associated with the number and progression of urethane-induced liver tumors. An independent linkage analysis with an intercross population from A/J and C57BL/6J inbred mice mapped regions in chromosomes 1 and 7 associated with the progression of urethane-induced liver tumors, evidencing the heterogeneity of HCC genetic control. Lilian Rego de Carvalho, Andrea Borrego, José Ricardo Jensen, Wafa Hanna Koury Cabrera, Aline Marques Santos, Orlando Garcia Ribeiro, Nancy Starobinas, Marcelo De Franco, Tommaso A. Dragani, Giacomo Manenti, and Olga Célia Martinez Ibañez Copyright © 2019 Lilian Rego de Carvalho et al. All rights reserved. Cell Counts, rather than Proportion, of CD8/PD-1 Tumor-Infiltrating Lymphocytes in a Tumor Microenvironment Associated with Pathological Characteristics of Chinese Invasive Ductal Breast Cancer Sun, 31 Mar 2019 00:05:36 +0000 Objective. This study is aimed at investigating the association of exhausted CD8+ tumor-infiltrating lymphocytes with clinic-pathological factors. Methods. 133 patients diagnosed with primary invasive ductal breast cancer were recruited into the cross-sectional study consecutively. Immunohistochemistry was used to detect biomarker expression on formalin-fixed and paraffin-embedded sections. Double staining of CD8 and PD-1 was conducted on lymphocytes. Results. The proportion of CD8+/PD-1- TILs was 16% among patients with axillary lymph node metastasis, significantly lower than those without metastasis (24%). The expression of CK7, CK20, or Ki-67 was not related with the proportion of phenotypes of CD8/PD-1 TILs. Younger patients had more cell counts of CD8+/PD-1- TILs than elderly patients (18/HPF vs. 9/HPF, ). Patients with axillary lymph node metastasis had less CD8+/PD-1- TILs than those without metastasis (11/HPF vs. 27/HPF, ). Median counts of CD8+/PD-1- TILs among patients with CK20 and E-Cad expression were 33/HPF and 14/HPF, significantly higher than those among patients with negative CK20 (16/HPF) and E-Cad expression (6/HPF). Ki-67 index had a significant correlation with cell counts of CD8+/PD-1+ TILs and CD8+/PD-1- TILs, and the correlation coefficients were 0.19 and 0.21 (), respectively. Conclusion. The proportion of CD8+/PD-1- TILs was related with metastatic status of the axillary lymph node but cell counts of CD8+/PD-1- TILs were related with metastatic status of the axillary lymph node and expression of CK7, CK20, E-Cad, and Ki-67. Absolute cell counts, not proportion of CD8/PD-1 TILs, were more likely to distinguish clinic and pathologic characteristics of breast cancer. Qingkun Song, Feng Shi, Maya Adair, Hong Chang, Xiudong Guan, Yanjie Zhao, Yuchen Li, Guangjiang Wu, and Jiangping Wu Copyright © 2019 Qingkun Song et al. All rights reserved. Enhanced Antitumor Immune Response in 2-5 Oligoadenylate Synthetase-Like 1- (OASL1-) Deficient Mice upon Cisplatin Chemotherapy and Radiotherapy Sun, 31 Mar 2019 00:05:33 +0000 Type I interferon (IFN-I) plays a critical role in the antitumor immune response. In our previous study, we showed that IFN-I-inducible 2-5 oligoadenylate synthetase-like 1 (OASL1) negatively regulated IFN-I production upon tumor challenge similar to that of viral infection. Thus, OASL1-deficient (Oasl1−/−) mice were more resistant to implanted tumor growth than wild-type (WT) mice. In this study, we investigated whether targeting or suppressing OASL1 could show synergistic effects on tumor clearance with conventional cancer therapies (such as chemotherapy and radiotherapy) using Oasl1−/− mice and a transplantable lung metastatic tumor cell model. Upon treatment with the anticancer drug cisplatin, we found that Oasl1−/− mice showed enhanced resistance to injected tumors compared to untreated Oasl1−/− mice. Similarly, irradiated Oasl1−/− mice showed better resistance to tumor challenge than untreated Oasl1−/− mice. Additionally, we found that Oasl1−/− mice applied with both types of the cancer therapies contained more cytotoxic effector cells, such as CD8+ T cells and NK cells, and produced more cytotoxic effector cytokine IFN-γ as well as IFN-I in their tumor-containing lungs compared to untreated Oasl1−/− mice. Collectively, these results show that targeting OASL1 together with conventional cancer therapies could be an effective strategy to enhance treatment efficacy. Chan Kyu Sim, Jung Hoon Lee, In-Jeoung Baek, Sang-Wook Lee, and Myeong Sup Lee Copyright © 2019 Chan Kyu Sim et al. All rights reserved. Anti-GAPDH Autoantibody Is Associated with Increased Disease Activity and Intracranial Pressure in Systemic Lupus Erythematosus Sun, 31 Mar 2019 00:05:32 +0000 Objective. Systemic lupus erythematosus (SLE) is an immune disease characterized by multiorgan involvement. Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most devastating complications of SLE, which lacks efficient diagnostic biomarkers. The recent studies on the anti-GAPDH autoantibodies suggested its potential pathogenic roles in NPSLE. However, the clinical relevance of the anti-GAPDH autoantibodies in patients with SLE is still elusive. In this study, we sought to determine the serum levels of the anti-GAPDH autoantibodies in patients with SLE to investigate the clinical significance of the anti-GAPDH autoantibodies in SLE. Methods. Concentrations of the glyceraldehyde 3-phosphate dehydrogenase autoantibodies (anti-GAPDH autoantibodies) in the serum of 130 SLE patients and 55 healthy individuals were determined by enzyme-linked immunosorbent assay (ELISA). Among the 130 SLE patients, 95 were SLE patients without neuropsychiatric symptoms and 35 had NPSLE. White blood cell (WBC) count, hemoglobin (HB), platelet count (PLT), IgG, IgA, IgM, anti-dsDNA, C3, C4, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), RF, anti-cardiolipin (Acl), ANA, AnuA, anti-SSA, anti-SSB, β2-GPI, urinalysis, and 24 h urine protein were measured by standard laboratory techniques. Systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index scores were evaluated accordingly. Results. The serum levels of the anti-GAPDH autoantibodies were significantly elevated in the SLE patients, especially in the patients with NPSLE (). Elevated serum anti-GAPDH was correlated with increased SLEDAI-2K (), ESR, IgG, and IgM and associated with increased intracranial pressure and incidence of cerebrovascular lesions, but it was protective for seizure disorder incidence. Conclusions. Serum anti-GAPDH autoantibody was increased in both groups of SLE patients with or without neuropsychiatric symptoms and associated with disease severity. It could become an indicator of tissue damages in the brain for the future clinical practice. Jingjing Sun, Xue Li, Haotian Zhou, Xiaoyun Liu, Jingjing Jia, Qizhi Xie, Sijia Peng, Xiaolin Sun, Qingwen Wang, and Li Yi Copyright © 2019 Jingjing Sun et al. All rights reserved. Corrigendum to “Combination Therapy with EpCAM-CAR-NK-92 Cells and Regorafenib against Human Colorectal Cancer Models” Wed, 27 Mar 2019 09:05:24 +0000 Qing Zhang, Haixu Zhang, Jiage Ding, Hongyan Liu, Huizhong Li, Hailong Li, Mengmeng Lu, Yangna Miao, Liantao Li, and Junnian Zheng Copyright © 2019 Qing Zhang et al. All rights reserved. Absence of Nonclassical Monocytes in Hemolytic Patients: Free Hb and NO-Mediated Mechanism Wed, 27 Mar 2019 08:05:23 +0000 In a recent work, we have described the kinetics among the monocyte subsets in the peripheral blood of hemolytic patients including paroxysmal nocturnal hemoglobinuria (PNH) and sickle cell disease (SCD). After engulfing Hb-activated platelets, classical monocytes (CD14+CD16-) significantly transformed into highly inflammatory (CD14+CD16hi) subsets in vitro. An estimated 40% of total circulating monocytes in PNH and 70% in SCD patients existed as CD14+CD16hi subsets. In this study, we show that the nonclassical (CD14dimCD16+) monocyte subsets are nearly absent in patients with PNH or SCD, compared to 10-12% cells in healthy individuals. In mechanism, we have described the unique role of both free Hb and nitric oxide (NO) in reducing number of nonclassical subsets more than classical monocytes. After engulfing Hb-activated platelets, the monocytes including nonclassical subsets acquired rapid cell death within 12 h in vitro. Further, the treatment to monocytes either with the secretome of Hb-activated platelets containing NO and free Hb or purified free Hb along with GSNO (a physiological NO donor) enhanced rapid cell death. Besides, our data from both PNH and SCD patients exhibited a direct correlation between intracellular NO and cell death marker 7AAD in monocytes from the peripheral blood. Our data together suggest that due to the immune surveillance nature, the nonclassical or patrolling monocytes are encountered frequently by Hb-activated platelets, free Hb, and NO in the circulation of hemolytic patients and are predisposed to die rapidly. Rashi Singhal, Deepak K. Rathore, Teena Bhakuni, Tulika Seth, and Prasenjit Guchhait Copyright © 2019 Rashi Singhal et al. All rights reserved. Characteristics of Immunobiology in the Tumor Microenvironment- Development of Immunotherapies Sun, 24 Mar 2019 13:05:13 +0000 Jian Song, Zenghui Teng, and Weidong Cao Copyright © 2019 Jian Song et al. All rights reserved. Alterations of Hematologic and Hematopoietic Parameters in Mice Exposed to Pulsed Electromagnetic Field Sun, 24 Mar 2019 12:05:22 +0000 Effects of pulsed electromagnetic field (PEMF) on hematology and hematopoiesis might vary with different PEMF parameters. The purpose of this study was to evaluate the possible effects of PEMF exposure at different pulses on hematologic and hematopoietic parameters in mice. Groups of male BALB/c mice were whole body exposed or were sham exposed (control) to PEMF at 100, 1000, and 10000 pulses. After PEMF exposure, blood samples and bone marrow cells of mice were collected for hematologic examinations, bone marrow nucleated cell counting, colony-forming units of granulocyte-macrophage (CFU-GM) colony assay, and serum granulocyte-macrophage colony-stimulating factor (GM-CSF) assay. Compared with the control group, white blood cells (WBC) and lymphocytes (LYM) in the 100 and 1000 pulses exposed groups were significantly increased but not changed in the 10000 pulses exposed group. Red blood cells (RBC), hemoglobin (HGB), and platelets (PLT) were not changed in all exposed groups. There was no significant difference in mouse bone marrow nucleated cell number between the control group and each exposed group 7 days after PEMF exposure. The CFU-GM clone number of bone marrow cells and serum GM-CSF level were significantly increased in the 100 and 1000 pulses exposed group but not changed in the 10000 pulses exposed group. Our results indicated that the PEMF exposure at fewer pulses may induce statistically significant alterations in some hematologic and hematopoietic parameters of mice but no changes can be found in the more pulses PEMF-exposed groups. Kangchu Li, Zenghui Teng, Zhaohui Liu, Yuxing Zhang, Kaiping Long, Qimei Liao, Ansheng Ni, Guirong Ding, and Shirong Ma Copyright © 2019 Kangchu Li et al. All rights reserved. Reverse Immunology Approach to Define a New HIV-gp41-Neutralizing Epitope Sun, 24 Mar 2019 12:05:21 +0000 The design of immunogens susceptible to elicit potent and broadly neutralizing antibodies against the human immunodeficiency virus type 1 (HIV-1) remains a veritable challenge in the course of vaccine development. Viral envelope proteins adopt different conformational states during the entry process, allowing the presentation of transient neutralizing epitopes. We focused on the highly conserved 3S motif of gp41, which is exposed to the surface envelope in its trimeric prefusion state. Vaccination with a W614A-modified 3S peptide induces in animals neutralizing anti-HIV-1 antibodies among which we selected clone F8. We used F8 as bait to select for W614A-3S phage-peptide mimics. Binding and molecular docking studies revealed that F8 interacts similarly with W614A-3S and a Mim_F8-1 mimotope, despite their lack of sequence homology, suggesting structural mimicry. Finally, vaccination of mice with the purified Mim_F8-1 phage elicited HIV-1-neutralizing antibodies that bound to the cognate W614A-3S motif. Collectively, our findings provide new insights into the molecular design of immunogens to elicit antibodies with neutralizing properties. Karim Dorgham, Nicolas Pietrancosta, Amel Affoune, Olivier Lucar, Tahar Bouceba, Solenne Chardonnet, Cedric Pionneau, Christophe Piesse, Delphine Sterlin, Pablo Guardado-Calvo, Philippe Karoyan, Patrice Debré, Guy Gorochov, and Vincent Vieillard Copyright © 2019 Karim Dorgham et al. All rights reserved. Expression of LAIR-1 (CD305) on Human Blood Monocytes as a Marker of Hepatic Cirrhosis Progression Sun, 24 Mar 2019 10:05:09 +0000 Background and Aim. The presumed role of the inhibitory receptor LAIR-1 (CD305) in the inflammatory response suggests that it might contribute to the pathophysiology of chronic inflammatory diseases such as liver cirrhosis. We studied the LAIR-1 expression on liver macrophages and blood monocytes related to the progression of liver cirrhosis. Methods. The expression of LAIR-1 was analyzed by immunohistochemistry, flow cytometry, and Western blot. Results. We found a decreased number of macrophages expressing LAIR-1 in cirrhotic liver that could be due to a high presence of collagen, ligand of LAIR-1, in the fibrotic tissue which could downregulate its expression or interfere with the immunostaining. The expression of LAIR-1 decreased after cell differentiation, and the total content, but not the cell surface expression, increased after activation in the HL-60 human macrophage in vitro model. Blood monocytes exhibited higher LAIR-1 expression levels in cirrhotic patients, which were evident even in early clinical stages in all monocyte subsets, and greater in the “intermediate” inflammatory monocyte subpopulation. The in vitro activation of human blood monocytes did not increase its expression on the cell surface suggesting that the in vivo increase of LAIR-1 must be the result of a specific combination of stimuli present in cirrhotic patients. This represents an exclusive feature of liver cirrhosis, since blood monocytes from other chronic inflammatory pathologies showed similar or lower LAIR-1 levels compared with those of healthy controls. Conclusions. These results may indicate that monocyte LAIR-1 expression is a new biomarker to early detect liver damage caused by chronic inflammation in liver cirrhosis. María Martínez-Esparza, Antonio José Ruiz-Alcaraz, Violeta Carmona-Martínez, María Dolores Fernández-Fernández, Gonzalo Antón, María Muñoz-Tornero, Miriam Lencina, Inmaculada Pagán, Jesús de la Peña, and Pilar García-Peñarrubia Copyright © 2019 María Martínez-Esparza et al. All rights reserved. Multifaceted Roles of Neutrophils in Autoimmune Diseases Wed, 20 Mar 2019 13:05:16 +0000 Yi Zhao, Tony N. Marion, and Qian Wang Copyright © 2019 Yi Zhao et al. All rights reserved.