Journal of Immunology Research The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Sildenafil Can Affect Innate and Adaptive Immune System in Both Experimental Animals and Patients Mon, 20 Feb 2017 08:36:10 +0000 Sildenafil, a type 5 phosphodiesterase inhibitor (PDE5-I), is primarily used for treating erectile dysfunction. Sildenafil inhibits the degradation of cyclic guanosine monophosphate (cGMP) by competing with cGMP for binding site of PDE5. cGMP is a secondary messenger activating protein kinases and a common regulator of ion channel conductance, glycogenolysis, and cellular apoptosis. PDE5 inhibitors (PDE-Is) found application in cardiology, nephrology, urology, dermatology, oncology, and gynecology. Positive result of sildenafil treatment is closely connected with its immunomodulatory effects. Sildenafil influences angiogenesis, platelet activation, proliferation of regulatory T cells, and production of proinflammatory cytokines and autoantibodies. Sildenafil action in humans and animals appears to be different. Surprisingly, it also acts differently in males and females organisms. Although the immunomodulatory effects of PDE5 inhibitors appear to be promising, none of them reached the point of being tested in clinical trials. Data on the influence of selective PDE5-Is on the human immune system are limited. The main objective of this review is to discuss the immunomodulatory effects of sildenafil in both patients and experimental animals. This is the first review of the current state of knowledge about the effects of sildenafil on the immune system. Monika Kniotek and Agnieszka Boguska Copyright © 2017 Monika Kniotek and Agnieszka Boguska. All rights reserved. Does the Gut Microbiota Influence Immunity and Inflammation in Multiple Sclerosis Pathophysiology? Mon, 20 Feb 2017 06:25:29 +0000 Aim. Evaluation of the impact of gut microflora on the pathophysiology of MS. Results. The etiopathogenesis of MS is not fully known. Gut microbiota may be of a great importance in the pathogenesis of MS, since recent findings suggest that substitutions of certain microbial population in the gut can lead to proinflammatory state, which can lead to MS in humans. In contrast, other commensal bacteria and their antigenic products may protect against inflammation within the central nervous system. The type of intestinal flora is affected by antibiotics, stress, or diet. The effects on MS through the intestinal microflora can also be achieved by antibiotic therapy and Lactobacillus. EAE, as an animal model of MS, indicates a strong influence of the gut microbiota on the immune system and shows that disturbances in gut physiology may contribute to the development of MS. Conclusions. The relationship between the central nervous system, the immune system, and the gut microbiota relates to the influence of microorganisms in the development of MS. A possible interaction between gut microbiota and the immune system can be perceived through regulation by the endocannabinoid system. It may offer an opportunity to understand the interaction comprised in the gut-immune-brain axis. Monika Adamczyk-Sowa, Aldona Medrek, Paulina Madej, Wirginia Michlicka, and Pawel Dobrakowski Copyright © 2017 Monika Adamczyk-Sowa et al. All rights reserved. IL-10: A Multifunctional Cytokine in Viral Infections Mon, 20 Feb 2017 00:00:00 +0000 The anti-inflammatory master regulator IL-10 is critical to protect the host from tissue damage during acute phases of immune responses. This regulatory mechanism, central to T cell homeostasis, can be hijacked by viruses to evade immunity. IL-10 can be produced by virtually all immune cells, and it can also modulate the function of these cells. Understanding the effects of this multifunctional cytokine is therefore a complex task. In the present review we discuss the factors driving IL-10 production and the cellular sources of the cytokine during antiviral immune responses. We particularly focus on the IL-10 regulatory mechanisms that impact antiviral immune responses and how viruses can use this central regulatory pathway to evade immunity and establish chronic/latent infections. José M. Rojas, Miguel Avia, Verónica Martín, and Noemí Sevilla Copyright © 2017 José M. Rojas et al. All rights reserved. Overview of Celiac Disease in Russia: Regional Data and Estimated Prevalence Mon, 20 Feb 2017 00:00:00 +0000 Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of dietary gluten from some cereals mainly in individuals carrying the HLA-DQ2 and/or HLA-DQ8 haplotypes. As an autoimmune disease, CD is manifested in the small intestine in the form of a progressive and reversible inflammatory lesion due to immune response to self-antigens. Indeed, CD is one of the most challenging medicosocial problems in current gastroenterology. At present, the global CD prevalence is estimated at approximately 1% based on data sent from different locations and available CD screening strategies used. However, it is impossible to estimate global CD prevalence without all the data from the world, including Russia. In this review, we summarize the data on the incidence and prevalence of CD across geographically distinct regions of Russia, which are mostly present in local Russian scientific sources. Our conclusion is that the situation of CD prevalence in Russia is higher than is commonly believed and follows global tendencies that correspond to the epidemiologic situation in Europe, America, and Southwest Asia. Lyudmila V. Savvateeva, Svetlana I. Erdes, Anton S. Antishin, and Andrey A. Zamyatnin Jr. Copyright © 2017 Lyudmila V. Savvateeva et al. All rights reserved. Adrenomedullin Regulates IL-1β Gene Expression in F4/80+ Macrophages during Synovial Inflammation Sun, 19 Feb 2017 07:08:35 +0000 Adrenomedullin (AM) plays an important role in the regulation of inflammatory processes; however, the role and expression of AM in synovial inflammation have not been determined. To investigate the expression and role of AM in inflamed synovial tissue (ST), the gene expression profiles of AM in the ST, including synovial macrophages and fibroblasts, of a murine patellar surgical dislocation model were characterized. In addition, the effects of interleukin- (IL-) 1β and AM in cultured synovial cells were also examined. CD11c+ macrophages were found to be elevated in ST of the surgically dislocated patella. Higher gene expression of CD11c, IL-1β, AM, receptor activity-modifying proteins 2 (RAMP2), and 3 (RAMP3) was also observed in ST obtained from the dislocated side. AM expression was also significantly increased in synovial fibroblasts and macrophages in response to IL-1β treatment. Synovial macrophages also highly expressed RAMP3 compared to fibroblasts and this expression was further stimulated by exogenously added IL-1β. Further, the treatment of the F4/80-positive cell fraction obtained from ST with AM inhibited IL-1β expression. Taken together, these findings demonstrated that AM was produced by synovial fibroblasts and macrophages in inflamed ST and that increased levels of AM may exert anti-inflammatory effects on synovial macrophages. Shotaro Takano, Kentaro Uchida, Masayuki Miyagi, Gen Inoue, Jun Aikawa, Kazuya Iwabuchi, and Masashi Takaso Copyright © 2017 Shotaro Takano et al. All rights reserved. Serum Cytokine Levels and Their Relation to Clinical Features in Patients with Autoimmune Liver Diseases Sun, 19 Feb 2017 00:00:00 +0000 Serum cytokine levels were explored in a combined group of patients with autoimmune liver diseases (AILDs) and separately in patients with autoimmune hepatitis (AIH) and overlap syndrome. Overall, 60 patients with AILD, among them 32 patients with AIH and 28 patients with overlap syndrome, were included in the cross-sectional study. Serum cytokine levels were measured at baseline and compared to those of 21 healthy controls. Patients with AILD had significantly higher levels of IL-6 (0.70 (range 0.17–99.86) in patients with AILD compared to 0.40 (range 0.14–2.65) in controls, ), IL-8 (1.66 (0.45–34.58) versus 0.53 (0.35–2.38), resp., ), and TNF-α (2.61 (0.23–120.88) versus 1.65 (0.21–7.54), resp., ). Adjusted logistic regression analysis revealed a pronounced relation of IL-8 and AILD, 48.36 (3.63–643.60), as well as AIH, 18.54 (1.08–318.54), and overlap syndrome, 23.85 (2.37–240.23), while the associations between the level of other cytokines and AILD were assessed as nonsignificant. In the language of absolute numbers, the increase of IL-8 serum level by 1 pg/mL had increased the chance for a patient to find himself in a group of AILD by 48.36 times. Also, high IL-8 serum levels were strongly related to clinical parameters. Dilyara Akberova, Andrei P. Kiassov, and Diana Abdulganieva Copyright © 2017 Dilyara Akberova et al. All rights reserved. Neutrophils and Immunity: From Bactericidal Action to Being Conquered Sun, 19 Feb 2017 00:00:00 +0000 The neutrophil is the major phagocyte and the final effector cell of the innate immunity, with a primary role in the clearance of extracellular pathogens. Using the broad array of cytokines, extracellular traps, and effector molecules as the humoral arm, neutrophils play a crucial role in the host defense against pathogen infections. On the other hand, the pathogen has the capacity to overcome neutrophil-mediated host defense to establish infection causing human disease. Pathogens, such as S. aureus, have the potential to thwart neutrophil chemotaxis and phagocytosis and thereby succeed in evading killing by neutrophils. Furthermore, S. aureus surviving within neutrophils promotes neutrophil cytolysis, resulting in the release of host-derived molecules that promote local inflammation. Here, we provide a detailed overview of the mechanisms by which neutrophils kill the extracellular pathogens and how pathogens evade neutrophils degradation. This review will provide insights that might be useful for the development of novel therapies against infections caused by antibiotic resistant pathogens. Tie-Shan Teng, Ai-ling Ji, Xin-Ying Ji, and Yan-Zhang Li Copyright © 2017 Tie-Shan Teng et al. All rights reserved. Polymorphisms of IL12RB2 May Affect the Natural History of Primary Biliary Cholangitis: A Single Centre Study Sun, 19 Feb 2017 00:00:00 +0000 Background. Recent GWAS in primary biliary cholangitis (PBC) showed strong associations with SNPs located within interleukin-12 receptor (IL12R) beta-2 (IL12RB2) gene. Aims. We assessed whether genetic variation of IL12RB2 is associated with laboratory and clinical features of PBC. Methods. Genomic DNA was isolated from 306 patients with PBC and 258 age/gender-matched controls. PBC-specific anti-mitochondrial antibodies (AMA) were tested in all subjects by ELISA. Two SNPs, rs3790567 and rs6679356, of IL12RB2 were genotyped using the MGB-TaqMan SNP assay. Results. Despite comparable age at diagnosis of cirrhotic and noncirrhotic PBC patients, allele A of rs3790567 and allele C of rs6679356 were overrepresented in the former rather than the latter group ( and , resp.). The risk of cirrhosis at presentation increased when allele A and allele C coexisted. AMA-M2 titres were significantly higher in AA homozygotes of rs3790567 compared to GG homozygotes ( versus , ) and in rs6679356 when C allele was present (). There were no other significant associations between IL12RB2 polymorphisms and laboratory or clinical features. Conclusion. In this first study analyzing phenotypic features of PBC carriers of the IL12RB2 polymorphisms, we found that carriers are more frequently cirrhotic at diagnosis and have significantly higher titres of AMA. Urszula Wasik, Ewa Wunsch, Gary L. Norman, Eirini I. Rigopoulou, Dimitrios P. Bogdanos, Piotr Milkiewicz, and Małgorzata Milkiewicz Copyright © 2017 Urszula Wasik et al. All rights reserved. Advances in Immunotherapy for Glioblastoma Multiforme Sun, 19 Feb 2017 00:00:00 +0000 Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients with GBM have poor outcomes, even with the current gold-standard first-line treatment: maximal safe resection combined with radiotherapy and temozolomide chemotherapy. Accumulating evidence suggests that advances in antigen-specific cancer vaccines and immune checkpoint blockade in other advanced tumors may provide an appealing promise for immunotherapy in glioma. The future of therapy for GBM will likely incorporate a combinatorial, personalized approach, including current conventional treatments, active immunotherapeutics, plus agents targeting immunosuppressive checkpoints. Boyuan Huang, Hongbo Zhang, Lijuan Gu, Bainxin Ye, Zhihong Jian, Creed Stary, and Xiaoxing Xiong Copyright © 2017 Boyuan Huang et al. All rights reserved. T Lymphocytes and Inflammatory Mediators in the Interplay between Brain and Blood in Alzheimer’s Disease: Potential Pools of New Biomarkers Wed, 15 Feb 2017 13:26:48 +0000 Alzheimer’s disease (AD) is a chronic neurodegenerative disorder and the main cause of dementia. The disease is among the leading medical concerns of the modern world, because only symptomatic therapies are available, and no reliable, easily accessible biomarkers exist for AD detection and monitoring. Therefore extensive research is conducted to elucidate the mechanisms of AD pathogenesis, which seems to be heterogeneous and multifactorial. Recently much attention has been given to the neuroinflammation and activation of glial cells in the AD brain. Reports also highlighted the proinflammatory role of T lymphocytes infiltrating the AD brain. However, in AD molecular and cellular alterations involving T cells and immune mediators occur not only in the brain, but also in the blood and the cerebrospinal fluid (CSF). Here we review alterations concerning T lymphocytes and related immune mediators in the AD brain, CSF, and blood and the mechanisms by which peripheral T cells cross the blood brain barrier and the blood-CSF barrier. This knowledge is relevant for better AD therapies and for identification of novel biomarkers for improved AD diagnostics in the blood and the CSF. The data will be reviewed with the special emphasis on possibilities for development of AD biomarkers. Anna Mietelska-Porowska and Urszula Wojda Copyright © 2017 Anna Mietelska-Porowska and Urszula Wojda. All rights reserved. Generation of Monoclonal Antibodies against Immunoglobulin Proteins of the Domestic Ferret (Mustela putorius furo) Tue, 14 Feb 2017 00:00:00 +0000 The domestic ferret (Mustela putorius furo) serves as an animal model for the study of several viruses that cause human disease, most notably influenza. Despite the importance of this animal model, characterization of the immune response by flow cytometry (FCM) is severely hampered due to the limited number of commercially available reagents. To begin to address this unmet need and to facilitate more in-depth study of ferret B cells including the identification of antibody-secreting cells, eight unique murine monoclonal antibodies (mAb) with specificity for ferret immunoglobulin (Ig) were generated using conventional B cell hybridoma technology. These mAb were screened for reactivity against ferret peripheral blood mononuclear cells by FCM and demonstrate specificity for CD79β+ B cells. Several of these mAb are specific for the light chain of surface B cell receptor (BCR) and enable segregation of kappa and lambda B cells. Additionally, a mAb that yielded surface staining of nearly all surface BCR positive cells (i.e., pan ferret Ig) was generated. Collectively, these MαF-Ig mAb offer advancement compared to the existing portfolio of polyclonal anti-ferret Ig detection reagents and should be applicable to a wide array of immunologic assays including the identification of antibody-secreting cells by FCM. Greg A. Kirchenbaum and Ted M. Ross Copyright © 2017 Greg A. Kirchenbaum and Ted M. Ross. All rights reserved. Computational Approaches to Facilitate Epitope-Based HLA Matching in Solid Organ Transplantation Sun, 12 Feb 2017 00:00:00 +0000 Epitope-based HLA matching has been emerged over the last few years as an improved method for HLA matching in solid organ transplantation. The epitope-based matching concept has been incorporated in both the PIRCHE-II and the HLAMatchmaker algorithm to find the most suitable donor for a recipient. For these algorithms, high-resolution HLA genotype data of both donor and recipient is required. Since high-resolution HLA genotype data is often not available, we developed a computational method which allows epitope-based HLA matching from serological split level HLA typing relying on HLA haplotype frequencies. To validate this method, we simulated a donor-recipient population for which PIRCHE-II and eplet values were calculated when using both high-resolution HLA genotype data and serological split level HLA typing. The majority of the serological split level HLA-determined ln(PIRCHE-II)/ln(eplet) values did not or only slightly deviate from the reference group of high-resolution HLA-determined ln(PIRCHE-II)/ln(eplet) values. This deviation was slightly increased when HLA-C or HLA-DQ was omitted from the input and was substantially decreased when using two-field resolution HLA genotype data of the recipient and serological split level HLA typing of the donor. Thus, our data suggest that our computational approach is a powerful tool to estimate PIRCHE-II/eplet values when high-resolution HLA genotype data is not available. Kirsten Geneugelijk, Jeroen Wissing, Dirk Koppenaal, Matthias Niemann, and Eric Spierings Copyright © 2017 Kirsten Geneugelijk et al. All rights reserved. IL-1β and IL-6 Are Highly Expressed in RF+IgE+ Systemic Lupus Erythematous Subtype Sun, 12 Feb 2017 00:00:00 +0000 Background. Systemic lupus erythematosus (SLE) is an autoimmune disease with great heterogeneity in pathogenesis and clinical symptoms. Rheumatoid factor (RF) is one key indicator for rheumatoid arthritis (RA) while immunoglobulin E (IgE) is associated with type I hypersensitivity. To better categorize SLE subtypes, we determined the dominant cytokines based on familial SLE patients. Methods. RF, IgE, and multiple cytokines (i.e., IL-1β, IL-6, IL-8, IL-10, IL-17, IFN-γ, IP-10, MCP-1, and MIP-1β) were measured in sera of familial SLE patients (), noninherited SLE patients (), and healthy controls (). Results. Three familial SLE patients and 5 noninherited SLE cases are with features of RF+IgE+. These RF+IgE+ SLE patients expressed significantly higher levels of IL-1β and IL-6 than the other SLE patients (). IL-6 correlated with both IgE and IL-1β levels in RF+IgE+ SLE patients (, ; , ), and IgE also correlated with IL-1β (, ). Conclusion. Both IL-1β and IL-6 are highly expressed cytokines in RF+IgE+ SLE subtype which may be related to the pathogenesis of this special SLE subtype and provide accurate treatment strategy by neutralizing IL-1β and IL-6. Yongkang Wu, Bei Cai, Junlong Zhang, Beilei Shen, Zhuochun Huang, Chunyu Tan, Carla C. Baan, and Lanlan Wang Copyright © 2017 Yongkang Wu et al. All rights reserved. RNA-Seq Based Transcriptome Analysis of the Type I Interferon Host Response upon Vaccinia Virus Infection of Mouse Cells Thu, 09 Feb 2017 10:32:37 +0000 Vaccinia virus (VACV) encodes the soluble type I interferon (IFN) binding protein B18 that is secreted from infected cells and also attaches to the cell surface, as an immunomodulatory strategy to inhibit the host IFN response. By using next generation sequencing technologies, we performed a detailed RNA-seq study to dissect at the transcriptional level the modulation of the IFN based host response by VACV and B18. Transcriptome profiling of L929 cells after incubation with purified recombinant B18 protein showed that attachment of B18 to the cell surface does not trigger cell signalling leading to transcriptional activation. Consistent with its ability to bind type I IFN, B18 completely inhibited the IFN-mediated modulation of host gene expression. Addition of UV-inactivated virus particles to cell cultures altered the expression of a set of 53 cellular genes, including genes involved in innate immunity. Differential gene expression analyses of cells infected with replication competent VACV identified the activation of a broad range of host genes involved in multiple cellular pathways. Interestingly, we did not detect an IFN-mediated response among the transcriptional changes induced by VACV, even after the addition of IFN to cells infected with a mutant VACV lacking B18. This is consistent with additional viral mechanisms acting at different levels to block IFN responses during VACV infection. Bruno Hernáez, Graciela Alonso, Juan Manuel Alonso-Lobo, Alberto Rastrojo, Cornelius Fischer, Sascha Sauer, Begoña Aguado, and Antonio Alcamí Copyright © 2017 Bruno Hernáez et al. All rights reserved. Cervical Carcinogenesis and Immune Response Gene Polymorphisms: A Review Thu, 09 Feb 2017 00:00:00 +0000 The local immune response is considered a key determinant in cervical carcinogenesis after persistent infection with oncogenic, high-risk human papillomavirus (HPV) infections. Genetic variation in various immune response genes has been shown to influence risk of developing cervical cancer, as well as progression and survival among cervical cancer patients. We reviewed the literature on associations of immunogenetic single nucleotide polymorphism, allele, genotype, and haplotype distributions with risk and progression of cervical cancer. Studies on HLA and KIR gene polymorphisms were excluded due to the abundance on literature on that subject. We show that multiple genes and loci are associated with variation in risk of cervical cancer. Rather than one single gene being responsible for cervical carcinogenesis, we postulate that variations in the different immune response genes lead to subtle differences in the effectiveness of the antiviral and antitumour immune responses, ultimately leading to differences in risk of developing cervical cancer and progressive disease after HPV infection. Akash M. Mehta, Merel Mooij, Ivan Branković, Sander Ouburg, Servaas A. Morré, and Ekaterina S. Jordanova Copyright © 2017 Akash M. Mehta et al. All rights reserved. TMEM187-IRAK1 Polymorphisms Associated with Rheumatoid Arthritis Susceptibility in Tunisian and French Female Populations: Influence of Geographic Origin Wed, 08 Feb 2017 13:12:59 +0000 Polymorphisms have been identified in the Xq28 locus as risk loci for rheumatoid arthritis (RA). Here, we investigated the association between three polymorphisms in the Xq28 region containing TMEM187 and IRAK1 (rs13397, rs1059703, and rs1059702) in two unstudied populations: Tunisian and French. The rs13397 G and rs1059703 T major alleles were significantly increased in RA patients () compared with age-matched controls () in both Tunisian and French women. These results were confirmed by a meta-analysis replication study including two independent Greek and Korean cohorts. The rs1059702 C major allele was significantly associated with RA, only with French women. In the French population, the GTC haplotype displayed a protective effect against RA, while the ATC, GCC, and GTT haplotypes conferred significant risk for RA. No association for these haplotypes was found in the Tunisian population. Our results replicated for the first time the association of the three Xq28 polymorphisms with RA risk in Tunisian and French populations and suggested that RA susceptibility is associated with TMEM187-IRAK1 polymorphisms in women. Our data further support the involvement of X chromosome in RA susceptibility and evidence ethnicities differences that might be explained by differences in the frequencies of SE HLA-DRB1 alleles between both populations. Olfa Khalifa, Nathalie Balandraud, Nathalie Lambert, Isabelle Auger, Jean Roudier, Audrey Sénéchal, David Geneviève, Christophe Picard, Gérard Lefranc, Isabelle Touitou, Bakridine M’Madi Mrenda, Cécilia Benedito, Etienne Pardoux, Anne-Laure Gagez, Yves-Marie Pers, Christian Jorgensen, Touhami Mahjoub, and Florence Apparailly Copyright © 2017 Olfa Khalifa et al. All rights reserved. Glycomacropeptide Attenuates Inflammation, Pruritus, and Th2 Response Associated with Atopic Dermatitis Induced by 2,4-Dinitrochlorobenzene in Rat Tue, 07 Feb 2017 08:17:44 +0000 Atopic dermatitis (AD) is one of the most common skin diseases, whose incidence is increasing in industrialized countries. The epicutaneous application of a hapten, such as 2,4-dinitrochlorobenzene (DNCB), evokes an experimental murine AD-like reaction. Glycomacropeptide (GMP) is a dairy bioactive peptide derived from hydrolysis of κ-casein by chymosin action. It has anti-inflammatory, prebiotic, and immunomodulatory effects. The present study was aimed to investigate the effect of GMP administration on DNCB-induced AD in rats. The severity of inflammatory process, pruritus, production of cytokines, and total immunoglobulin E (IgE) content were measured, and the histopathological features were analyzed. GMP reduced the intensity of inflammatory process and edema of DNCB-induced dermatitis, with a significant decrease in eosinophils recruitment and mast cells hyperplasia. In addition GMP suppressed the serum levels of total IgE and IL-4, IL-5, and IL-13 expression in AD-lesions. Besides, the levels of IL-10 were significantly increased. Remarkably, GMP administration before AD-induction abolished pruritus in dermatitis-like reactions in the rats. Taken together, these results indicate that GMP has an inhibitory effect on AD by downregulating Th2 dominant immune response, suggesting GMP as a potential effective alternative therapy for the prevention and management of AD. Fabiola Carolina Muñoz, Maritza Montserrat Cervantes, Daniel Cervantes-García, Mariela Jiménez, Javier Ventura-Juárez, and Eva Salinas Copyright © 2017 Fabiola Carolina Muñoz et al. All rights reserved. Analysis of Sera of Recipients with Allograft Rejection Indicates That Keratin 1 Is the Target of Anti-Endothelial Antibodies Tue, 07 Feb 2017 00:00:00 +0000 Anti-endothelial cell antibodies (AECAs) are usually directed against the surface antigens on the vascular endothelial cells. Clinical studies suggest a pathogenic role for nonhuman leukocyte antigen in antibody-mediated rejection; however, the antigens on the donor vascular endothelium that serve as the first-line targets for an immune response during allograft rejection have not been fully identified. Here, we used immunoprecipitation and mass spectrometry to identify antigens from the sera of kidney transplant recipients who were experiencing antibody-mediated rejection. Keratin 1 (KRT1) was identified as a novel antigenic target expressed on endothelial cells. To validate our finding, we produced recombinant proteins representing the three most common alleles of KRT1. The serum used for immunoprecipitation showed a strong reaction to KRT1 recombinants in western blot and ELISA. In the kidney transplant cohort, more AECA-positive recipients than AECA-negative recipients had KRT1 antibodies (32.2% versus 11.9%, ). Sera from 255 renal recipients were tested by ELISA. Of the 77 recipients with deteriorating graft function (serum creatinine > 120 μmol/L), 23 had anti-KRT1 antibodies. KRT1-IgG positivity was, therefore, associated with a higher risk of kidney transplant rejection (29.9% (23/77) versus 16.9% (30/178), ). A better understanding of this antigenic target will improve long-term allograft survival. Xuli Guo, Juan Hu, Weiguang Luo, Qizhi Luo, Jing Guo, Fang Tian, Yingzi Ming, and Yizhou Zou Copyright © 2017 Xuli Guo et al. All rights reserved. Clinical Outcomes of Specific Immunotherapy in Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis Tue, 07 Feb 2017 00:00:00 +0000 Specific immunotherapies, including vaccines with autologous tumor cells and tumor antigen-specific monoclonal antibodies, are important treatments for PC patients. To evaluate the clinical outcomes of PC-specific immunotherapy, we performed a systematic review and meta-analysis of the relevant published clinical trials. The effects of specific immunotherapy were compared with those of nonspecific immunotherapy and the meta-analysis was executed with results regarding the overall survival (OS), immune responses data, and serum cancer markers data. The pooled analysis was performed by using the random-effects model. We found that significantly improved OS was noted for PC patients utilizing specific immunotherapy and an improved immune response was also observed. In conclusion, specific immunotherapy was superior in prolonging the survival time and enhancing immunological responses in PC patients. Jiang Chen, Guo Xiao-Zhong, and Xing-Shun Qi Copyright © 2017 Jiang Chen et al. All rights reserved. Impact of Desensitization on Antiviral Immunity in HLA-Sensitized Kidney Transplant Recipients Mon, 06 Feb 2017 08:06:20 +0000 Viral infections represent significant morbidity and mortality factors in kidney transplant recipients, with CMV, EBV, and BKV infections being most common. Desensitization (DES) with IVIg and rituximab with/without plasma exchange followed by kidney transplantation with alemtuzumab induction increased successful transplant rates in HLA-sensitized patients but may represent an increased risk for viral infections due to severe lymphocyte depletion. Here, we report on the posttransplant viral infection status in 372 DES versus 538 non-DES patients. CMV and EBV viremia were significantly lower in DES patients, while BKV viremia was similar. This trend was observed primarily in CMV sero(−), EBV sero(+), and sero(−) patients. No patient developed PTLD. The incidence of BKAN, allograft, and patient survival was similar in both groups. These viral infections were not associated with subsequent allograft rejection which occurred within 6 months after the infection. Conclusions. The IVIg + rituximab desensitization combined with alemtuzumab induction with triple immunosuppression maintenance does not increase the risk for CMV, EBV, and BKV infections. Possible factors include, in addition to posttransplant antiviral prophylaxis and PCR monitoring, presence of memory T cells and antibodies specific to CMV and likely EBV, NK cell-mediated ADCC despite lymphocyte depletion, elimination of EBV and CMV reservoirs by rituximab and alemtuzumab, and use of IVIg with antiviral properties. Mieko Toyoda, Bong-Ha Shin, Shili Ge, James Mirocha, David Thomas, Maggie Chu, Edgar Rodriguez, Christine Chao, Anna Petrosyan, Odette A. Galera, Ashley Vo, Jua Choi, Alice Peng, Joseph Kahwaji, and Stanley C. Jordan Copyright © 2017 Mieko Toyoda et al. All rights reserved. Manipulation of Innate and Adaptive Immunity through Cancer Vaccines Mon, 06 Feb 2017 00:00:00 +0000 Although cancer immunotherapy has shown significant promise in mediating efficacious responses, it remains encumbered by tumor heterogeneity, loss of tumor-specific antigen targets, and the regulatory milieu both regionally and systemically. Cross talk between the innate and adaptive immune response may be requisite to polarize sustained antigen specific immunity. Cancer vaccines can serve as an essential fulcrum in initiating innate immunity while molding and sustaining adaptive immunity. Although peptide vaccines have shown tepid responses in a therapeutic setting with poor correlates for immune activity, RNA vaccines activate innate immune responses and have shown promising effects in preclinical and clinical studies based on enhanced DC migration. While the mechanistic insights behind the interplay between innate and adaptive immunity may be unique to the immunotherapeutic being investigated, understanding this dynamic is important to coordinate the different arms of the immune response in a focused response against cancer antigens. Elias J. Sayour and Duane A. Mitchell Copyright © 2017 Elias J. Sayour and Duane A. Mitchell. All rights reserved. Endothelial Cells in Antibody-Mediated Rejection of Kidney Transplantation: Pathogenesis Mechanisms and Therapeutic Implications Wed, 01 Feb 2017 11:29:56 +0000 Antibody-mediated rejection (AMR) has been identified as a main obstacle for stable immune tolerance and long survival of kidney allografts. In spite of new insights into the underlying mechanisms of AMR, accurate diagnosis and efficient treatment are still challenges in clinical practice. Endothelium is the first barrier between recipients’ immune systems and grafts in vascularized organ transplants. Considering that endothelial cells express a number of antigens that can be attacked by various allo- and autoantibodies, endothelial cells act as main targets for the recipients’ humoral immune responses. Importantly, emerging evidence has shown that endothelial cells in transplants could also initiate protective mechanisms in response to immune injuries. A better understanding of the role of endothelial cells during the pathogenesis of AMR might provide novel therapeutic targets. In the present review, we summarize the antigens expressed by endothelial cells and also discuss the activation and accommodation of endothelial cells as well as their clinical implications. Collectively, the progress discussed in this review indicates endothelial cells as promising targets to improve current diagnosis and therapeutic regimens for AMR. Shuo Wang, Chao Zhang, Jina Wang, Cheng Yang, Ming Xu, Ruiming Rong, Tongyu Zhu, and Dong Zhu Copyright © 2017 Shuo Wang et al. All rights reserved. The Role of Type III Interferons in Hepatitis C Virus Infection and Therapy Wed, 01 Feb 2017 08:16:19 +0000 The human interferon (IFN) response is a key innate immune mechanism to fight virus infection. IFNs are host-encoded secreted proteins, which induce IFN-stimulated genes (ISGs) with antiviral properties. Among the three classes of IFNs, type III IFNs, also called IFN lambdas (IFNLs), are an essential component of the innate immune response to hepatitis C virus (HCV). In particular, human polymorphisms in IFNL gene loci correlate with hepatitis C disease progression and with treatment response. To date, the underlying mechanisms remain mostly elusive; however it seems clear that viral infection of the liver induces IFNL responses. As IFNL receptors show a more restricted tissue expression than receptors for other classes of IFNs, IFNL treatment has reduced side effects compared to the classical type I IFN treatment. In HCV therapy, however, IFNL will likely not play an important role as highly effective direct acting antivirals (DAA) exist. Here, we will review our current knowledge on IFNL gene expression, protein properties, signaling, ISG induction, and its implications on HCV infection and treatment. Finally, we will discuss the lessons learnt from the HCV and IFNL field for virus infections beyond hepatitis C. Janina Bruening, Bettina Weigel, and Gisa Gerold Copyright © 2017 Janina Bruening et al. All rights reserved. Humoral Responses to Rv1733c, Rv0081, Rv1735c, and Rv1737c DosR Regulon-Encoded Proteins of Mycobacterium tuberculosis in Individuals with Latent Tuberculosis Infection Wed, 01 Feb 2017 08:13:10 +0000 Latent tuberculosis infection (LTBI) is evidence of immunological control of tuberculosis. Dormancy survival regulator (DosR) regulon-encoded proteins may have a role in the maintenance of LTBI. T cell responses to Rv1733c, Rv0081, Rv1735c, and Rv1737c DosR regulon-encoded proteins were found to be most frequent among household contacts of TB cases from Uganda compared to other DosR proteins, but antibody responses were not described. We characterized antibody responses to these proteins in individuals from Uganda. Antibodies to Rv1733c, Rv0081, Rv1735c, and Rv1737c DosR regulon-encoded proteins were measured in 68 uninfected individuals, 62 with LTBI, and 107 with active pulmonary tuberculosis (APTB) cases. There were no differences in the concentrations of antibodies to Rv0081, Rv1735c, and Rv1737c DosR regulon-encoded proteins between individuals with LTBI and APTB and those who were uninfected. LTBI was associated with higher concentrations of antibodies to Rv1733c in female participants [adjusted geometric mean ratio: 1.812, 95% confidence interval (CI): 1.105 2.973, and ] but not in males ( value for interaction = 0.060). Antibodies to the four DosR regulon-encoded proteins investigated may not serve as good biomarkers of LTBI in the general population. More of the M.tb proteome needs to be screened to identify proteins that induce strong antibody responses in LTBI. Simon G. Kimuda, Angela Nalwoga, Jonathan Levin, Kees L. M. C. Franken, Tom H. M. Ottenhoff, Alison M. Elliott, Stephen Cose, and Irene Andia-Biraro Copyright © 2017 Simon G. Kimuda et al. All rights reserved. Genetic Contribution to the Pathogenesis of Primary Biliary Cholangitis Wed, 01 Feb 2017 08:03:35 +0000 Formerly termed primary biliary cirrhosis, primary biliary cholangitis (PBC) is a chronic and progressive cholestatic liver disease characterized by the presence of antimitochondrial antibodies. Ursodeoxycholic acid (UDCA) therapy is the most effective and approved treatment for PBC and leads to a favorable outcome in the vast majority of cases. Although the etiology of PBC has not yet been elucidated, human leukocyte antigen (HLA) class II alleles have been consistently associated with disease onset for decades. Individuals in different geographic regions of the world may have varying susceptibility alleles that reflect indigenous triggering antigens. In this review, we describe the influence of HLA alleles and other gene polymorphisms on PBC along with the results of genome-wide association studies (GWAS) on this disease. Satoru Joshita, Takeji Umemura, Eiji Tanaka, and Masao Ota Copyright © 2017 Satoru Joshita et al. All rights reserved. Treatment of Antibody-Mediated Renal Allograft Rejection: Improving Step by Step Tue, 31 Jan 2017 08:53:26 +0000 Throughout the past years we stepwise modified our immunosuppressive treatment regimen for patients with antibody-mediated rejection (ABMR). Here, we describe three consecutive groups treated with different regimens. From 2005 until 2008, we treated all patients with biopsy-proven ABMR with rituximab (500 mg), low-dose (30 g) intravenous immunoglobulins (IVIG), and plasmapheresis (PPH, 6x) (group RLP, ). Between 2009 and June 2010, patients received bortezomib (1.3 mg/m2, 4x) together with low-dose IVIG and PPH (group BLP, ). In July 2010, we increased the IVIG dose and treated all subsequent patients with bortezomib, high-dose IVIG (1.5 g/kg), and PPH (group BHP, ). Graft survival at three years after treatment was 73% in group BHP as compared to 45% in group BLP and 25% in group RLP. At six months after treatment median serum creatinine was 2.1 mg/dL, 2.9 mg/dL, and 4.2 mg/dL in groups BHP, BLP, and RLP, respectively (). Following treatment, a significant decrease of donor-specific HLA antibody (DSA) mean fluorescence intensity from to () was observed in group BHP, but not in the other groups. Our results indicate that graft survival, graft function, and DSA levels could be improved along with stepwise modifications to our treatment regimen, that is, the introduction of bortezomib and high-dose IVIG treatment. Nils Lachmann, Michael Duerr, Constanze Schönemann, Axel Pruß, Klemens Budde, and Johannes Waiser Copyright © 2017 Nils Lachmann et al. All rights reserved. Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells Mon, 30 Jan 2017 11:31:32 +0000 Immunotoxins as antiviral therapeutics are largely unexplored but have promising prospective due to their high selectivity potential and their unparalleled efficiency. One recent example targeted the virus-encoded G protein-coupled receptor US28 as a strategy for specific and efficient treatment of human cytomegalovirus (HCMV) infections. US28 is expressed on virus-infected cells and scavenge chemokines by rapid internalization. The chemokine-based fusion-toxin protein (FTP) consisted of a variant (F49A) of CX3CL1 specifically targeting US28 linked to the catalytic domain of Pseudomonas exotoxin A (PE). Here, we systematically seek to improve F49A-FTP by modifications in its three structural domains; we generated variants with (1) altered chemokine sequence (K14A, F49L, and F49E), (2) shortened and elongated linker region, and (3) modified toxin domain. Only F49L-FTP displayed higher selectivity in its binding to US28 versus CX3CR1, the endogenous receptor for CX3CL1, but this was not matched by a more selective killing of US28-expressing cells. A longer linker and different toxin variants decreased US28 affinity and selective killing. Thereby, F49A-FTP represents the best candidate for HCMV treatment. Many viruses encode internalizing receptors suggesting that not only HCMV but also, for instance, Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus may be targeted by FTPs. Katja Spiess, Mads G. Jeppesen, Mikkel Malmgaard-Clausen, Karen Krzywkowski, Thomas N. Kledal, and Mette M. Rosenkilde Copyright © 2017 Katja Spiess et al. All rights reserved. Clinical Features and Genetic Analysis of 48 Patients with Chronic Granulomatous Disease in a Single Center Study from Shanghai, China (2005–2015): New Studies and a Literature Review Mon, 30 Jan 2017 00:00:00 +0000 Chronic Granulomatous Disease (CGD) is a rare inherited primary immunodeficiency, which is characterized by recurrent infections due to defective phagocyte NADPH oxidase enzyme. Nowadays, little is known about Chinese CGD patients. Here we report 48 CGD patients in our single center study, which is the largest cohort study from Mainland China. The ratio of male to female was 11 : 1. The mean onset age was 0.29 years old, and 52% patients had an onset within the 1st month of life. The mean diagnosis age was 2.24 years old. 11 patients (23%) had died with an average age of 2.91 years old. 13 patients (28%) had positive family histories. The most prevalent infectious sites were the lungs (77%), followed by gastrointestinal tract (54%), lymph nodes (50%), and skin (46%). In addition, septicopyemia, thrush, and hepatosplenomegaly were also commonly observed, accounting for 23%, 23%, and 40% of the cases. Lesions due to BCG vaccination occurred in more than half of the patients. X-linked CGD due to CYBB gene mutations accounted for 75% of the cases, and 11 of them were novel mutations. Autosomal recessive inheritance accounted for 6% patients, including 1 patient with CYBA, 1 with NCF1, and 1 with NCF2 gene mutations. Jing Wu, Wei-Fan Wang, Yi-Dan Zhang, and Tong-Xin Chen Copyright © 2017 Jing Wu et al. All rights reserved. Mannose-Binding Lectin: Biologic Characteristics and Role in the Susceptibility to Infections and Ischemia-Reperfusion Related Injury in Critically Ill Neonates Thu, 26 Jan 2017 12:27:41 +0000 The mannose-binding lectin (MBL) is a member of the collectin family, belonging to the innate immunity system. Genetic, biologic, and clinical properties of MBL have been widely investigated throughout the last decades, although some interesting aspects of its potential clinical relevance are still poorly understood. Low circulating concentrations of MBL have been associated with increased risk of infection and poor neurologic outcome in neonates. On the other hand, an excessive and uncontrolled inflammatory response by the neonatal intestine after the exposure to luminal bacteria, leading to an increased production of MBL, may be involved in the onset of necrotizing enterocolitis. The purpose of the present review is to summarize the current knowledge about genetic and biologic characteristics of MBL and its role in the susceptibility to infections and to ischemia-reperfusion related tissue injuries to better explore its clinical relevance during the perinatal period and the possible future therapeutic applications. Cinzia Auriti, Giusi Prencipe, Maria Moriondo, Iliana Bersani, Chiara Bertaina, Vito Mondì, and Rita Inglese Copyright © 2017 Cinzia Auriti et al. All rights reserved. Continuous Dual Resetting of the Immune Repertoire as a Basic Principle of the Immune System Function Thu, 26 Jan 2017 10:07:02 +0000 Idiopathic chronic inflammatory conditions (ICIC) such as allergy, asthma, chronic obstructive pulmonary disease, and various autoimmune conditions are a worldwide health problem. Understanding the pathogenesis of ICIC is essential for their successful therapy and prevention. However, efforts are hindered by the lack of comprehensive understanding of the human immune system function. In line with those efforts, described here is a concept of stochastic continuous dual resetting (CDR) of the immune repertoire as a basic principle that governs the function of immunity. The CDR functions as a consequence of system’s thermodynamically determined intrinsic tendency to acquire new states of inner equilibrium and equilibrium against the environment. Consequently, immune repertoire undergoes continuous dual (two-way) resetting: against the physiologic continuous changes of self and against the continuously changing environment. The CDR-based dynamic concept of immunity describes mechanisms of self-regulation, tolerance, and immunosenescence, and emphasizes the significance of immune system’s compartmentalization in the pathogenesis of ICIC. The CDR concept’s relative simplicity and concomitantly documented congruency with empirical, clinical, and experimental data suggest it may represent a plausible theoretical framework to better understand the human immune system function. Silvana Balzar Copyright © 2017 Silvana Balzar. All rights reserved.