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  • IL10 promoter haplotypes may contribute to altered cytokine expression and systemic inflammation in celiac disease
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-24
    S.R. Hofmann, M.W. Laass, A. Fehrs, D. Schuppan, V.F. Zevallos, D. Salminger, K. Mäbert, C.M. Hedrich

    Celiac disease (CD) is an autoimmune/inflammatory condition triggered by dietary gluten intake in genetically predisposed individuals. Though associations with MHC class II HLA-DQ2 or -DQ8 are the primary and necessary genetic predisposition for CD, >97% of genetically predisposed individuals never develop CD.Cytokines were measured in the serum of CD patients and controls. Possible associations with IL10 promoter variants were investigated. Cytokine expression from PBMCs was monitored in response to gluten exposure, or CD3/TCR complex stimulation in the absence or presence of recombinant IL-10.Serum cytokines varied between patients with CD at the time of diagnosis, after dietary elimination of gluten, and healthy controls. Serum IL-17A reflected disease activity. Reduced IL-10 serum levels and altered IL-10 expression by PBMCs coincided with IL10 promoter haplotypes that encode for “low” IL-10 expression (ATA).Increased prevalence of ATA IL10 promoter haplotypes and subsequently reduced IL-10 expression may be an immunological cofactor in individuals genetically predisposed for the development of CD. Resulting cytokine imbalances may be utilized as disease biomarkers in CD.

  • Estrogen receptor β activation stimulates the development of experimental autoimmune thyroiditis through up-regulation of Th17-type responses
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-23
    Juan Qin, Li Li, Qian Jin, Dan Guo, Miao Liu, Chenling Fan, Jing Li, Zhongyan Shan, Weiping Teng

    Estrogens play important roles in autoimmune thyroiditis, but it remains unknown which estrogen receptor (ER) subtype (α or β) mediates the stimulatory effects. Herein we treated ovariectomized mice with ERα or ERβ selective agonist followed by thyroglobulin-immunization to induce experimental autoimmune thyroiditis (EAT), and observed the aggravation of EAT after diarylpropionitrile (DPN, ERβ selective agonist) administration. The mRNA levels of interleukin(IL)-17A, IL-21 and RORγt and percentages of T helper (Th) 17 cells were up-regulated in the splenocytes of DPN-treated mice. Activated ERβ was found not only binding to IL-17A and IL-21 gene promoters directly, but also indirectly binding to IL-21 and RORγt gene promoters through interactions with NF-κB. The expressions of co-stimulatory molecules were increased on antigen-presenting cells (APCs), after DPN administration. It suggests that ERβ is the predominant ER subtype responsible for EAT development, and its activation may enhance Th17-type responses through genomic pathways and alteration of APCs' activities.

  • Progressive severe B cell and NK cell deficiency with T cell senescence in adult CD40L deficiency
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-21
    Vassilios Lougaris, Gaetana Lanzi, Manuela Baronio, Luisa Gazzurelli, Donatella Vairo, Tiziana Lorenzini, Raffaele Badolato, Lucia Dora Notarangelo, Andrea Boschi, Daniele Moratto, Alessandro Plebani

    Highlights • CD40 Ligand deficiency may result in severe B and NK loss over time. • T cell senescence is a novel finding in adult CD40 Ligand deficiency. • Long term follow-up of CD40 Ligand deficiency may reveal novel immunological findings. • CD40 Ligand deficient patients not undergoing HSCT should be closely monitored.

  • Dysfunction of CD3−CD16+CD56dim and CD3−CD16−CD56bright NK cell subsets in RR-MS patients
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-12
    Ilhan Tahrali, Umut Can Kucuksezer, Ayse Altintas, Ugur Uygunoglu, Nilgun Akdeniz, Esin Aktas Cetin, Gunnur Deniz

    Multiple sclerosis (MS), is a chronic inflammatory disease of central nervous system with unclear etiology. Relapsing-remitting (RR)-MS is the most frequent subtype of disease. Natural Killer (NK) cells have roles in cytotoxicity and immune regulation by cytokine secretions, with uncertain contribution to MS pathogenesis. This study aimed to explore contribution of NK cells to MS pathogenesis. Percentages of CD3−CD16+CD56+ total NK cells, CD3−CD16+CD56dim and CD3−CD16−CD56bright NK cell subsets, NK cytotoxicity and intracellular IFN-γ, IL-10 and IL-22 levels were investigated in patients with RR-MS and clinically isolated syndrome (CIS) as well as healthy subjects. Findings support the possible contribution of NK cells to RR-MS immunopathogenesis. Decreased IFN-γ and increased IL-22 production might have detrimental effects on the clinical course of RR-MS. Impaired cytotoxicity is correlated with disease duration in RR-MS. Moreover, NK cell ratios and EDSS values are negatively correlated in CIS revealing a possible protective role in converting to RR-MS.

  • Rapamycin attenuates Th2-driven experimental allergic conjunctivitis
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-09
    Soojung Shin, Ji Hyun Lee, Hyun Jung Lee, Sun Young Chang, So-Hyang Chung

    Allergic conjunctivitis is mediated by eosinophilic infiltration and Th2 type immune responses. This study aims to elucidate the role of rapamycin, mTOR inhibitor, on OVA-induced experimental allergic conjunctivitis (EAC). Rapamycin administration intraperitoneally markedly reduced clinical signs, total and OVA-specific IgE and IgG1/G2a ratio in serum, and conjunctival eosinophilic infiltration. Infiltrations of CD11c+ dendritic cells and CD4+ T cells, and the expressions of chemokines and adhesion molecules in the conjunctiva were attenuated in rapamycin-treated mice, as well as decreased Th1 and Th2 cytokines in the cervical lymph nodes compared to non-treated mice. The expression of mTOR signaling proteins was increased in EAC and reduced by rapamycin treatment. Topical application of rapamycin was also proved to show reduced clinical signs, eosinophil infiltration, and Th2 type immune responses comparable to those from intraperitoneal injection of rapamycin. These findings suggest the therapeutic implications of rapamycin in the attenuation of allergic conjunctivitis.

  • Mechanistic aspects of epigenetic dysregulation in SLE
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-06
    Christian Michael Hedrich

    Epigenetic events have been linked with disease expression in individuals genetically predisposed to the development of systemic lupus erythematosus (SLE), a severe systemic autoimmune/inflammatory disease. Altered DNA methylation and hydroxymethylation as well as histone modifications mediate changes in chromatin accessibility and gene expression in immune cells from SLE patients. Defective epigenetic control contributes to uncontrolled expression of inflammatory mediators, including cytokines and co-receptors, resulting in systemic inflammation and tissue damage. While the pathophysiological involvement of epigenetic changes in SLE has been accepted for some time, we only recently started to investigate and understand molecular events contributing to epigenetic dysregulation. Here, epigenetic alterations will be discussed with a focus on underling molecular events that may be target of preventative measures or future treatment strategies.

  • Diminished antibody response to influenza vaccination is characterized by expansion of an age-associated B-cell population with low PAX5
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-06
    Allison J. Nipper, Megan J. Smithey, Raj C. Shah, David H. Canaday, Alan L. Landay

    Individuals over the age of 65 comprise a substantial portion of the world population and become more susceptible to vaccine-preventable infections with age as vaccination response diminishes. The underlying reason for this impaired vaccine response in older individuals is not entirely clear. We evaluated potential differences in phenotypic and functional responses of B cells from healthy younger (22–45 years) and older (64–95 years) individuals that may associate with a diminished antibody response to influenza vaccination. We report that age is associated with expansion of atypical memory B cells (CD10−CD20+CD21−CD27−) and an age-associated B cell (ABC, CD21−T-bet+CD11c+) phenotype. Reduced expression of PAX5 was also seen in older individuals. Poor influenza-specific antibody production following vaccination was associated with low PAX5 expression and a distinct composition of the ABC compartment. Collectively, these findings demonstrate that the characteristics of the ABC populations of older individuals are associated with antibody production following influenza vaccination.

  • Epigenetic editing: How cutting-edge targeted epigenetic modification might provide novel avenues for autoimmune disease therapy ☆
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-06
    Matlock A. Jeffries

    Autoimmune diseases are enigmatic and complex, and most been associated with epigenetic changes. Epigenetics describes changes in gene expression related to environmental influences mediated by a variety of effectors that alter the three-dimensional structure of chromatin and facilitate transcription factor or repressor binding. Recent years have witnessed a dramatic change and acceleration in epigenetic editing approaches, spurred on by the discovery and later development of the CRISPR/Cas9 system as a highly modular and efficient site-specific DNA binding domain. The purpose of this article is to offer a review of epigenetic editing approaches to date, with a focus on alterations of DNA methylation, and to describe a few prominent published examples of epigenetic editing. We will also offer as an example work done by our laboratory demonstrating epigenetic editing of the FOXP3 gene in human T cells. Finally, we discuss briefly the future of epigenetic editing in autoimmune disease.

  • Impaired X-CGD T cell compartment is gp91phox-NADPH oxidase independent
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-03
    Maria Chiriaco, Fabio Casciano, Gigliola Di Matteo, Berhard Gentner, Alessia Claps, Nicola Cotugno, D'. Argenio Patrizia, Paolo Rossi, Alessandro Aiuti, Andrea Finocchi

    Chronic granulomatous disease (CGD) is a phagocytic disorder characterized by a defective production of reactive oxygen species (ROS). Although infections and granuloma formation are the most common manifestations in CGD patients, a significant number of patients experienced autoimmunity and inflammatory diseases suggesting that adaptive immune abnormalities might be involved. Here we investigated T-cell compartment and showed that CGD patients respect to healthy donor (HD), had a skewed TCRV-beta distribution in CD8+ T cells, particularly in older patients, and a reduced proliferative responses toward mitogens. Afterwards we studied the role of gp91phox protein in causing these alterations and demonstrated that human T cells do not express gp91phox and TCR-stimulated ROS generation is gp91phox-NADPH oxidase independent. Finally, we proved that the NADPH oxidase is not active in the T cell compartment even forcing gp91phox expression transducing T cells from X-CGD and HD with a SIN lentiviral vector (LVV) expressing the gp91phox cDNA.

  • Citrullinated fibrinogen impairs immunomodulatory function of bone marrow mesenchymal stem cells by triggering toll-like receptor
    Clin. Immunol. (IF 3.99) Pub Date : 2018-01-31
    Yue Sun, Wei Deng, Genhong Yao, Weiwei Chen, Xiaojun Tang, Xuebing Feng, Liwei Lu, Lingyun Sun

    Bone marrow mesenchymal stem cells (BMSC) have been shown to possess immunomodulatory activities, while its role in rheumatoid arthritis (RA) remains unknown. Citrullinated fibrinogen (cfb) has been considered as a specific autoantigen in RA pathogenesis. Our study aims to determine the role of cfb on immunomodulatory function of BMSC. We demonstrated the specific role of toll-like receptor 4 (TLR4)-NFκB pathway in the pro-inflammatory response of BMSC to cfb with increased production of interleukin (IL)-6, IL-8 and chemokine C single bond C motif ligand 2 (CCL2). Moreover, cfb impaired BMSC-mediated suppression of peripheral blood mononuclear cells (PBMC) proliferation and reduced the production of the key immunomodulatory molecule indoleamine 2,3-dioxygenase (IDO) in BMSC. We have uncovered a previously unrecognized role of cfb in interfering BMSC-mediated immunoregulation in RA. Cfb could act as a damage-associated molecule pattern (DAMP) for BMSC and thereby contribute to the propagation of inflammation in RA.

  • Thymopoiesis following HSCT; a retrospective review comparing interventions for aGVHD in a pediatric cohort
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-01
    A.M. Flinn, C.F. Roberts, M.A. Slatter, R. Skinner, H. Robson, J. Lawrence, J. Guest, A.R. Gennery

    Acute graft-versus-host disease (aGVHD) complicates allogeneic hematopoietic stem cell transplantation (HSCT), and is treated with topical and/or systemic corticosteroids. Systemic corticosteroids and aGVHD damage thymic tissue. We compared thymopoietic effect of topical steroid therapy, corticosteroids and extracorporeal photopheresis (ECP) in 102 pediatric allogeneic HSCT patients. We categorized patients into 4 groups: - no aGVHD, aGVHD treated with topical or systemic steroid, or ECP. Naïve CD4+ CD45RA+ CD27+ T-lymphocyte values at 3, 6, 9, 12 months post-HSCT were recorded: for ECP patients, values were recorded at 3, 6, 9, 12 months during ECP. Differences were compared using the Kruskal-Wallis test. 41 patients had no aGVHD, 23 had aGVHD treated topically or systemically (25), 13 received ECP. Rate of thymopoiesis was significantly different between all groups at all time-points post-transplant (p = 0.002, p < 0.001, p < 0.001, p = 0.001 respectively). Even mild aGVHD impairs thymopoiesis. Worst recovery was in ECP patients. Earlier institution of ECP may speed thymic recovery.

  • Cisplatin inhibits the progression of bladder cancer by selectively depleting G-MDSCs: A novel chemoimmunomodulating strategy
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-02
    Ke Wu, Ming-Yue Tan, Jun-Tao Jiang, Xing-Yu Mu, Jie-Ren Wang, Wen-Jie Zhou, Xiang Wang, Ming-qing Li, Yin-Yan He, Zhi-Hong Liu

    Bladder cancer (BC) is a disease arising from the malignant cells of the urinary bladder. Myeloid-derived suppressor cells (MDSCs) expand broadly and have strong immunosuppressive activities in the cancer microenvironment. Determining how to inhibit the negative effects of MDSCs requires immediate attention. In this study, we found that granulocytic-MDSCs (G-MDSCs), which constitute one of the two types of MDSCs, were significantly increased in BC tissues compared with those in the adjacent bladder tissues. There was a robust negative correlation between the G-MDSCs and the CD8+ T cells in the BC tissues. In this study, we attempted to identify pharmacological approaches to eliminate MDSCs and restore T cell anti-tumor activities. It is necessary to explore a method to eliminate the detrimental effects of MDSCs. Cisplatin, a chemotherapy medication used to treat BC, not only rapidly kills proliferating cancer cells but also affects the tumor immune microenvironment. However, the mechanism underlying this phenomenon is largely unknown. In this study, we found that Cisplatin directly inhibited the proliferation and induced the apoptosis of T24 cells (a BC cell line), as well as decreased the percentage of the G-MDSCs in the population of peripheral blood mononuclear cells (PBMCs), which restored the expansion of the CD8+ T cells. In the C3H/He mouse BC model, Cisplatin treatment inhibited the progression of BC and effectively decreased the proportion of G-MDSCs. These results suggest that Cisplatin treatment enhances the anti-tumor function of CD8+ T cells by decreasing G-MDSCs. This finding provides a new perspective for Cisplatin treatment to prevent the progression of BC, particularly in patients with abnormally high levels of G-MDSCs.

  • Plasmablast antibody repertoires in elderly influenza vaccine responders exhibit restricted diversity but increased breadth of binding across influenza strains
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-02
    Chia-Hsin Ju, Lisa K. Blum, Sarah Kongpachith, Nithya Lingampalli, Rong Mao, Petter Brodin, Cornelia L. Dekker, Mark M. Davis, William H. Robinson

    Seasonal influenza vaccines elicit antibody responses that can prevent infection, but their efficacy is reduced in the elderly. While a subset of elderly individuals can still mount sufficient vaccine-induced antibody responses, little is known about the properties of the vaccine-induced antibody repertoires in elderly as compared to young responders. To gain insights into the effects of aging on influenza vaccine-induced antibody responses, we used flow cytometry and a cell-barcoding method to sequence antibody heavy and light chain gene pairs expressed by individual blood plasmablasts generated in response to influenza vaccination in elderly (aged 70–89) and young (aged 20–29) responders. We found similar blood plasmablast levels in the elderly and young responders seven days post vaccination. Informatics analysis revealed increased clonality, but similar heavy chain V(D)J gene usage in the elderly as compared to young vaccine responders. Although the elderly responders exhibited decreased antibody sequence diversity and fewer consequential mutations relative to young responders, recombinant antibodies from elderly responders bound a broader range of influenza strain HAs. Thus elderly influenza vaccine responders mount plasmablast responses with restricted diversity but with an increased breadth of binding across influenza strains. Our results suggest that the ability to generate plasmablast responses encoding cross-strain binding antibodies likely represents a mechanism important to vaccine responses in the elderly.

  • Human CD4+ CD25+ CD127hi cells and the Th1/Th2 phenotype
    Clin. Immunol. (IF 3.99) Pub Date : 2018-01-10
    Aditi Narsale, Rosita Moya, Joanna Davida Davies

    CD4+ T cells that co-express CD25 and CD127 (CD25+ CD127+) make up around 20% of all circulating CD4+ memory T cells in healthy people. The clinical significance of these cells is that in children with type 1 diabetes their relative frequency at diagnosis is significantly and directly correlated with rate of disease progression. The purpose of this study was to further characterize the CD25+ CD127hi cells. We show that they are a mix of Th1 and Th2 cells however, they have a significantly higher relative frequency of pre-committed and committed Th2 cells, and secrete significantly higher levels of Th2-type cytokines than CD25− memory T cells. Further, these cells are neither exhausted nor senescent and proliferate to the same extent as CD25− memory cells. Thus, CD25+ CD127hi cells are a highly active subset of memory T cells that might play a role in controlling inflammation via anti-inflammatory Th2-type deviation.

  • Pediatric-onset Evans syndrome: Heterogeneous presentation and high frequency of monogenic disorders including LRBA and CTLA4 mutations
    Clin. Immunol. (IF 3.99) Pub Date : 2018-01-10
    Caroline Besnard, Eva Levy, Nathalie Aladjidi, Marie-Claude Stolzenberg, Aude Magerus-Chatinet, Olivier Alibeu, Patrick Nitschke, Stéphane Blanche, Olivier Hermine, Eric Jeziorski, Judith Landman-Parker, Guy Leverger, Nizar Mahlaoui, Gérard Michel, Isabelle Pellier, Felipe Suarez, Isabelle Thuret, Geneviève de Saint-Basile, Capucine Picard, Alain Fischer, Bénédicte Neven, Frédéric Rieux-Laucat, Pierre Quartier

    Evans syndrome (ES) is defined by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. Clinical presentation includes manifestations of immune dysregulation, found in primary immune deficiencies, autoimmune lymphoproliferative syndrome with FAS (ALPS-FAS), Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and Lipopolysaccharide-Responsive vesicle trafficking Beige-like and Anchor protein (LRBA) defects. We report the clinical history and genetic results of 18 children with ES after excluding ALPS-FAS. Thirteen had organomegaly, five lymphocytic infiltration of non-lymphoid organs, nine hypogammaglobulinemia and fifteen anomalies in lymphocyte phenotyping. Seven patients had genetic defects: three CTLA4 mutations (c.151C > T; c.109 + 1092_568-512del; c.110-2A > G) identified by Sanger sequencing and four revealed by Next Generation Sequencing: LRBA (c.2450 + 1C > T), STAT3 gain-of-function (c.2147C > T; c.2144C > T) and KRAS (c.37G > T). No feature emerged to distinguish patients with or without genetic diagnosis. Our data on pediatric-onset ES should prompt physicians to perform extensive screening for mutations in the growing pool of genes involved in primary immune deficiencies with autoimmunity.

  • A young girl with severe cerebral fungal infection due to card 9 deficiency
    Clin. Immunol. (IF 3.99) Pub Date : 2018-01-04
    Pinar Gur Cetinkaya, Deniz Cagdas Ayvaz, Betül Karaatmaca, Rahsan Gocmen, Figen Söylemezoğlu, Wayne Bainter, Janet Chou, Talal A. Chatila, Ilhan Tezcan

    Pattern recognition receptors (PRRs), receptors of the innate immune system, are important in interaction with pathogens. Caspase Recruitment Domain-containing protein 9 (CARD9), a member of PRRs, is an intracellular adaptor protein important in fungal defense. CARD9 deficiency causes a rare primary immunodeficiency (PID) characterized by superficial and deep fungal infections. We report a 17 year-old female with a homozygous nonsense mutation in CARD9, who presented with severe cerebral fungal infection of the central nervous system. She was also found to have an heterozygous NLRP12 mutation, which may have had add-on effect on the severity of the infection.

  • Study of an extended family with CTLA-4 deficiency suggests a CD28/CTLA-4 independent mechanism responsible for differences in disease manifestations and severity
    Clin. Immunol. (IF 3.99) Pub Date : 2018-01-03
    Tie Zheng Hou, Peter Olbrich, Jose Manuel Lucena Soto, Berta Sanchez, Paula Sanchez Moreno, Stephan Borte, Hans J. Stauss, Siobhan O. Burns, Lucy S.K. Walker, Qiang Pan-Hammarström, Lennart Hammarström, David M. Sansom, Olaf Neth

    The CTLA-4 checkpoint regulates the activation of T cells. Individuals with heterozygous mutations in CTLA-4 have a complex phenotype typically characterized by antibody deficiency alongside variable autoimmunity. Despite severe disease in some individuals, others remain largely unaffected with reasons for this variation unknown. We studied a large family carrying a single point mutation in CTLA-4 leading to an amino acid change R75W and compared both unaffected with affected individuals. We measured a variety of features pertaining to T cell and CTLA-4 biology and observed that at the cellular level there was complete penetrance of CTLA-4 mutations. Accordingly, unaffected individuals were indistinguishable from those with disease in terms of level of CTLA-4 expression, percentage of Treg, upregulation of CTLA-4 upon stimulation and proliferation of CD4 T cells. We conclude that the wide variation in disease phenotype is influenced by immune variation outside of CTLA-4 biology.

  • Investigation of autoantibodies to SP-1 in Chinese patients with primary Sjögren's syndrome
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-29
    Jingxiu Xuan, Ying Wang, Yinglin Xiong, Hongyan Qian, Yan He, Guixiu Shi

    In order to evaluate autoantibody to SP-1 as an early biomarker in pSS, we investigated autoantibody to SP-1 in Chinese patients with primary Sjögren's syndrome (pSS). Autoantibodies to SP-1 are significantly increased in pSS patients compared to RA patients, SLE patients, and healthy people without secondary SS. The presence of anti SP-1 antibodies was negatively correlated with the focus score (FS), RF, and salivary gland function. It was positively correlated with FS = 0, RF ≤ 20, and normal salivary gland function. In further studies, the autoantigen SP-1 was identified in ductal epithelia of salivary glands in il14α TG mice by IIF. SP-1 mRNAs expression increased with growing age in il14α TG mice. SP-1 mRNA was also identified in labial biopsies of patients with pSS. In conclusion, autoantibody to SP-1 is an early marker in pSS. It is useful to diagnose pSS patients who lack RF or antibodies to Ro/La.

  • A novel bivalent fusion vaccine induces broad immunoprotection against Staphylococcus aureus infection in different murine models
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-28
    Liuyang Yang, Heng Zhou, Ping Cheng, Yun Yang, Yanan Tong, Qianfei Zuo, Jiao Luo, Qiang Feng, Quanming Zou, Hao Zeng

    With more and more drug-resistant Staphylococcus aureus strains emerging in hospitals, there is an urgent need to develop an effective vaccine to combat S. aureus infection. In this study, we constructed a novel bivalent fusion vaccine, SpA-DKKAA-FnBPA37-507 (SF), based on the D domain of staphylococcal protein A (SpA) and the A domain of fibronectin-binding protein A (FnBPA). Immunisation with SF induced a more ideal protective effect compared with the single components alone in a sepsis model. It also showed broad immunoprotection against seven FnBPA isotypes. Vaccination with SF induced strong antibodies responses and Th1/Th17 polarized cellular responses. Further we demonstrated the protective effect of antibodies by the opsonophagocytic assay (OPA) and passive immunisation. Moreover, vaccination with SF showed protective efficacy in a murine pneumonia model and skin abscess model. These results suggest that SF can be regarded as a promising vaccine candidate for the prevention of S. aureus infections.

  • Effect of glucocorticoid treatment on BAFF and APRIL expression in patients with immune thrombocytopenia (ITP)
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-26
    Julian Kamhieh-Milz, Nuha Ghosoun, Viktor Sterzer, Abdulgabar Salama

    Immune thrombocytopenic purpura (ITP) is an idiopathic bleeding disorder. B cell activating factor (BAFF) and ‘A proliferation-inducing ligand’ (APRIL) have regulatory effects on B and T cells and may represent relevant factors in the pathogenesis of ITP. Serum levels and gene expression were investigated in ITP patients. Both BAFF and APRIL serum levels were significantly elevated in active ITP. However, gene expression analysis revealed both factors to have a tendency toward downregulation. Glucocorticoid treatment significantly reduced BAFF but not APRIL serum levels, which may be mediated by differences in transcription factor binding sites. The glucocorticoid receptor binding site is present in the BAFF promotor region, but not in the APRIL promotor region. Prednisolone in combination with vitamin D3 may be effective in reducing APRIL serum levels. In conclusion, glucocorticoid treatment exerts different regulatory effects on both BAFF and APRIL, whereas antioxidant supplementation may also be beneficial in reducing serum levels.

  • IL-21 dependent Granzyme B production of B-cells is decreased in patients with lupus nephritis
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-21
    Mariam Rabani, Benjamin Wilde, Katharina Hübbers, Shilei Xu, Andreas Kribben, Oliver Witzke, Sebastian Dolff

    Objectives B-cells play a crucial role in the pathogenesis of lupus nephritis. Recently, a separate subset has been discovered characterized by expression of Granzyme B. The aim of this study is to investigate this subset in patients with systemic lupus erythematosus (SLE). Methods Isolated PBMCs of SLE-patients (n = 30) and healthy controls (n = 21) were in vitro stimulated with CPG, IgG + IgM and IL-21. Patients were sub-grouped in patients with and without biopsy proven lupus nephritis. B-cells were analyzed for intracellular Granzyme B expression by flow cytometry. Results The strongest stimulus for Granzyme B secretion of B-cells was IgG + IgM in presence of IL-21. SLE-patients had a significant decreased percentage of Granzyme B+ B-cells in particular SLE-patients with active disease and with lupus nephritis. Conclusions The frequency of GrB + producing B-cells is reduced in SLE patients. This may contribute to an imbalanced B-cell regulation towards effector B-cells which might promote the development of lupus nephritis.

  • Extracellular ATP signaling and clinical relevance
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-20
    Lei Dou, Yi-Fa Chen, Peter J. Cowan, Xiao-ping Chen

    Since purinergic signaling was discovered in the early 1970s, it has been shown that extracellular nucleotides, and their derivative nucleosides, are released in a regulated or unregulated manner by cells in various challenging settings and then bind defined purinergic receptors to activate intricate signaling networks. Extracellular ATP plays a role based on different P2 receptor subtypes expressed on specific cell types. Sequential hydrolysis of extracellular ATP catalyzed by ectonucleotidases (e.g. CD39, CD73) is the main pathway for the generation of adenosine, which in turn activates P1 receptors. Many studies have demonstrated that extracellular ATP signaling functions as an important dynamic regulatory pathway to coordinate appropriate immune responses in various pathological processes, including intracellular infection, host-tumor interaction, pro-inflammation vascular injury, and transplant immunity. ATP receptors and CD39 also participate in related clinical settings. Here, we review the latest research in to the development of promising clinical treatment strategies.

  • Modulation the expression of natural killer cell activating receptor (NKp44) in the peripheral blood of diffuse large B-cell lymphoma patients and the correlation with clinic pathological features
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-13
    Enas Said Essa, Gehan Abd-Elfatah Tawfeek, Suzan Ahmed El Hassanin, Khloud Gamal Mohammed Emara

    NK cell activation is one strategy to improve the immunotherapy of non-Hodgkin's lymphoma. So, we aimed to investigate expression of Natural killer cell activating receptor NKp44 in patients with diffuse large B-cell lymphoma (DLBCL) and its correlation with clinic pathological data. In this study, 30 new cases with DLBCL in addition to 20 healthy control were involved. All were submitted to full history, clinical examination, histopathology, Routine laboratory investigations including CBC, LDH, β2microgloubine and bone marrow examination. Cell culture of peripheral blood mononuclear cells and expression of CD56 and NKp44 by flowcytometry was done. We demonstrated increased NK cell populations (CD 56 + ve NKp44 –ve, CD 56 –veNKp44 + ve, total CD 56 + ve) and NKp44 MFI after in-vitro activation in both healthy control and DLBCL cases except for CD 56 + ve NKp44 + ve which significantly increased in patients not in healthy control (p = 0.005, 0.601) respectively. No significant difference between the DLBCL and healthy control regarding all NK cell populations without PHA stimulation. However, the culture with PHA in DLBCL showed significant increase in NK cell populations than the healthy control (CD 56 + ve NKp44 + ve 12.37 ± 7.52vs 6.80 ± 4.07, p = 0.008), (Total CD 56 + ve 18.80 ± 8.74vs 12.66 ± 5.17, p = 0.017), (MFI of NKp44 10.95 ± 6.18vs 5.58 ± 1.70, p = 0.001). Regarding the association with clinic pathologic features, increased expression of NKp44 was associated with lower values of LDH and earlier stages of DLBCL (p < 0.05). So, activating receptor NKp44 can be modulated by in-vitro activation, hence improvement of its function as an approach of immunotherapy of DLBCL.

  • Altered natural killer cell cytokine profile in type 2 autoimmune hepatitis
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-09
    Dalila Mele, Grazia Bossi, Giuseppe Maggiore, Barbara Oliviero, Stefania Mantovani, Beatrice Bonelli, Mario U. Mondelli, Stefania Varchetta
  • GM-CSF producing autoreactive CD4+ T cells in type 1 diabetes
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-08
    Jan Knoop, Anita Gavrisan, Denise Kuehn, Julia Reinhardt, Melanie Heinrich, Markus Hippich, Anne Eugster, Christian Ockert, Anette-Gabriele Ziegler, Ezio Bonifacio

    The phenotype of autoreactive T cells in type 1 diabetes is described as Th1, Th17 and/or Th21, but is largely uncharacterized. We combined multi-parameter cytokine profiling and proliferation, and identified GM-CSF producing cells as a component of the response to beta cell autoantigens proinsulin and GAD65. Overall cytokine profiles of CD4 + T cell were not altered in type 1 diabetes. In contrast, patients with recent onset type 1 diabetes had increased frequencies of proinsulin-responsive CD4 + CD45RA- T cells producing GM-CSF (p = 0.002), IFNγ (p = 0.004), IL-17A (p = 0.008), IL-21 (p = 0.011), and IL-22 (p = 0.007), and GAD65-responsive CD4 + CD45RA- T cells producing IL-21 (p = 0.039). CD4 + T cells with a GM-CSF + IFNγ-IL-17A-IL-21-IL-22- phenotype were increased in patients for responses to both proinsulin (p = 0.006) and GAD65 (p = 0.037). GM-CSF producing T cells are a novel phenotype in the repertoire of T helper cells in type 1 diabetes and consolidate a Th1/Th17 pro-inflammatory pathogenesis in the disease.

  • Chronic Granulomatous Disease in children: a single center experience
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-07
    Alessandra Beghin, Marta Comini, Annarosa Soresina, Luisa Imberti, Michela Zucchi, Alessandro Plebani, Alessandro Montanelli, Fulvio Porta, Arnalda Lanfranchi

    Chronic Granulomatous Disease (CGD) is caused by the failure of the phagocytes to kill pathogens. We carried out a retrospective analysis of cellular, molecular and clinical features of 14 young patients (mean age at the onset of symptoms and diagnosis: 10 and 25 months, respectively), 7 with autosomal recessive and 7 X-linked form, referred to the Children's Hospital of Brescia between 1999 and 2016. Two new mutations were found, one localized in the CYBB and one in the NCF1 genes. Twelve patients were followed in our institution; the average length of their follow-up after diagnosis was 66 months in X-linked patients and 126 months in autosomal recessive inheritance. The overall survival was 67%, 40% in X-linked and 86% in autosomal recessive form. Eight patients were treated with HSCT. We did not find a clear correlation between the clinical symptoms and the type of mutation, but the fine characterization of the patients was mandatory for therapeutic option, genetic counseling and prenatal diagnosis.

  • STAT3-mediated epigenetic silencing of FOXP3 in LADA T cells is regulated through HDAC5 and DNMT1
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-06
    Can Hou, Yanjun Zhong, Zhen Wang, Zhao Ming, Gan Huang, Lin Ouyang, Yijun Li, Qianjin Lu, Zhiguang Zhou

    In LADA patients, Tregs are reduced and FOXP3 is downregulated in CD4+ T cells, but the etiology remains unclear. Our study included in 20 LADA patients and 20 healthy control patients. qRT-PCR results showed that STAT3, HDAC3, HDAC5, SIRT1, DNMT1 and DNMT3b mRNAs were significantly upregulated in LADA CD4+ T cells than controls, while FOXP3 mRNA significantly decreased. p-STAT3, STAT3, DNMT1 and DNMT3b expressions were increased demonstrated by western blot. ChIP-PCR suggested that p-STAT3 binds to the Foxp3 promoter, meanwhile, histone H3 acetylation at K9 and K14 of FOXP3 promoter were significantly lower than controls. Luciferase reporter assay showed that ectopic STAT3 expression significantly reduced FOXP3 promoter activities. The Foxp3 promoter was significantly hypermethylated in LADA than controls. LADA patients showed stronger binding of p-STAT3, HDAC5 and DNMT1 than controls using CHIP. These findings reveal a crucial role of STAT3 in regulating the epigenetic status of T cells in LADA.

  • Up-regulation of chemokine CXCL13 in systemic candidiasis
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-01
    Congya Li, Ju Cao, Lifang Wang, Xiaojiong Jia, Jianchun He, Liping Zhang

    Candida albicans is the leading cause of healthcare associated bloodstream infections. Chemokine CXCL13 is well-known involved in inflammation, but its role in candidemia has not been assessed. Our study firstly demonstrated that serum CXCL13 levels were significantly elevated in candidemic patients compared with bacteremic patients and control subjects by ELISA, and CXCL13 concentrations were positively and significantly correlated with clinical Sequential Organ Failure Assessment (SOFA) scores and several laboratory parameters in patients. Moreover, ROC curve analysis showed the diagnostic efficiency of CXCL13 was superior to CRP and PCT. To further study the role of CXCL13, a mouse model was established. Importantly, the data showed the dramatically elevated levels of CXCL13 in mice serum and infected kidney, were significantly correlated with renal fungal burden and pathology scores. In conclusion, our results indicated that CXCL13 had strong potential as a novel biomarker of diagnosis and prognosis for candidemia.

  • Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia
    Clin. Immunol. (IF 3.99) Pub Date : 2017-11-28
    Angelo Vacca, Carolina Marasco, Assunta Melaccio, Azzurra Sportelli, Ilaria Saltarella, Antonio Solimando, Franco Dammacco, Roberto Ria

    Multiple myeloma is commonly associated with a reduction of non-paraprotein immunoglobulins, resulting in a higher risk of infections that represent the leading cause of the patients' death. Therefore, immunoglobulin replacement therapy appears a logical approach. A total number of 46 myeloma patients were enrolled: 24 of them were assigned to receive subcutaneous immunoglobulins, and 22 were controls. The primary endpoint was the evaluation of the annual rate of severe infections in immunoglobulins-receiving patients as compared with those untreated. Subcutaneous immunoglobulins-treated patients showed a significantly lower number of severe infections per year. Adverse events were limited to the site of infusion and were easily manageable. Health-related quality of life was significantly better in subcutaneous immunoglobulins-receiving patients. By decreasing the rate of infections, the prophylactic administration of SCIg improves both adherence to chemotherapy and health-related quality of life, and is cost-effective by reducing the need of hospitalization and the use of antibiotics.

  • Circulating IL-17-producing mucosal-associated invariant T cells (MAIT) are associated with symptoms in children with asthma
    Clin. Immunol. (IF 3.99) Pub Date : 2017-11-28
    Guillaume Lezmi, Rola Abou Taam, Céline Dietrich, Lucienne Chatenoud, Jacques de Blic, Maria Leite-de-Moraes

    IL-17 and mucosal-associated invariant T (MAIT) cells have been involved in asthma pathogenesis. However, IL-17-producing MAIT cells (MAIT-17) were not evidenced. We aimed to determine whether circulating MAIT-17 were detectable in children with asthma, and whether they correlated with asthma symptoms or lung function. Children from the SPASM cohort of preschoolers with severe wheeze were reassessed for asthma at school age, and categorized as exacerbators (1 or more severe exacerbations in the previous 12 months) or non-exacerbators. Nineteen children (10.9 years) were included (9 non-exacerbators, 10 exacerbators). Circulating MAIT-17 were detected by flow cytometry. Their frequency was higher in exacerbators than in non-exacerbators (1.9 [1.01–3.55] vs 0.58 [0.46–1.15], p < 0.01). MAIT-17 correlated with the number of severe exacerbations (r = 0.68, p < 0.001), and correlated negatively with the ACT score (r = − 0.55, p = 0.01). In summary, MAIT-17 are present in children with asthma and associated with asthma symptoms.

  • An optimized whole blood assay measuring expression and activity of NLRP3, NLRC4 and AIM2 inflammasomes
    Clin. Immunol. (IF 3.99) Pub Date : 2017-11-26
    Lev Grinstein, Hella Luksch, Felix Schulze, Avril A.B. Robertson, Matthew A. Cooper, Angela Rösen-Wolff, Stefan Winkler

    The proinflammatory protease caspase-1 plays pivotal roles in central pathways of innate immunity, thereby contributing to pathogen clearance. Beside its physiological role, dysregulated activity of caspase-1 is known to contribute to an increasing number of diseases. In this study we optimized and validated a low-volume human whole blood assay facilitating the measurement of caspase-1 activation and inflammasome-related gene expression upon stimulation of the NLRP3, NLRC4 or AIM2 inflammasome. Using the NLRP3 inflammasome specific inhibitor MCC950 we were able to measure the activity of canonical or alternative NLRP3 pathways, AIM2 and NLRC4 inflammasomes in whole blood. Based on our data we assume a superposition of NLRP3 and NLRC4 inflammasome activities in human whole blood following stimulation with S. typhimurium. The optimized whole blood assay may be suitable for diagnostic and research purposes for pediatric patients who can only donate small amounts of blood.

  • The epidermal growth factor receptor inhibitor AG1478 inhibits eosinophilic inflammation in upper airways
    Clin. Immunol. (IF 3.99) Pub Date : 2017-11-26
    Shino Shimizu, Kumiko Takezawa-Yasuoka, Takao Ogawa, Ichiro Tojima, Hideaki Kouzaki, Takeshi Shimizu

    Mucus hypersecretion and eosinophil infiltration are important characteristics of eosinophilic inflammation in upper airways, such as allergic rhinitis and chronic rhinosinusitis with nasal polyp. EGFR transactivation induces mucus and inflammatory cytokine secretion from airway epithelial cells. However, the roles of EGFR in eosinophilic inflammation in upper airways are still unknown. The purpose of the study is to elucidate the effects of the EGFR inhibitor AG1478 on eosinophilic airway inflammation. AG1478 significantly inhibited thrombin-induced GM-CSF secretion from nasal epithelial cells and thrombin-induced secretion of eotaxin-1 and RANTES from nasal fibroblasts. Intranasal instillation of AG1478 inhibited OVA-induced goblet cell metaplasia, mucus production and eosinophil/neutrophil infiltration in rat nasal epithelium, as did intraperitoneal injection of AG1478. These results indicate that EGFR transactivation plays an important role in eosinophilic airway inflammation. Intranasal instillation of an EGFR inhibitor may be a new therapeutic approach for the treatment of intractable eosinophilic inflammation in upper airways.

  • A novel de novo activating mutation in STAT3 identified in a patient with common variable immunodeficiency (CVID)
    Clin. Immunol. (IF 3.99) Pub Date : 2017-11-24
    Mark A. Russell, Manuela Pigors, Maha E. Houssen, Ania Manson, David Kelsell, Hilary Longhurst, Noel G. Morgan

    Common variable immunodeficiency (CVID) is characterised by repeated infection associated with primary acquired hypogammaglobulinemia. CVID frequently has a complex aetiology but, in certain cases, it has a monogenic cause. Recently, variants within the gene encoding the transcription factor STAT3 were implicated in monogenic CVID. Here, we describe a patient presenting with symptoms synonymous with CVID, who displayed reduced levels of IgG and IgA, repeated viral infections and multiple additional co-morbidities. Whole-exome sequencing revealed a de novo novel missense mutation in the coiled-coil domain of STAT3 (c.870A > T; p.K290N). Accordingly, the K290N variant of STAT3 was generated, and a STAT3 responsive dual-luciferase reporter assay revealed that the variant strongly enhances STAT3 transcriptional activity both under basal and stimulated (with IL-6) conditions. Overall, these data complement earlier studies in which CVID-associated STAT3 mutations are predicted to enhance transcriptional activity, suggesting that such patients may respond favourably to IL-6 receptor antagonists (e.g. tocilizumab).

  • Novel anti-suprabasin antibodies may contribute to the pathogenesis of neuropsychiatric systemic lupus erythematosus
    Clin. Immunol. (IF 3.99) Pub Date : 2017-11-21
    Kunihiro Ichinose, Kaname Ohyama, Kaori Furukawa, Osamu Higuchi, Akihiro Mukaino, Katsuya Satoh, Shunya Nakane, Toshimasa Shimizu, Masataka Umeda, Shoichi Fukui, Ayako Nishino, Hideki Nakajima, Tomohiro Koga, Shin-ya Kawashiri, Naoki Iwamoto, Mami Tamai, Hideki Nakamura, Tomoki Origuchi, Atsushi Kawakami

    Neuropsychiatric systemic lupus erythematosus (NPSLE) is often difficult to diagnose and distinguish from other diseases, because no NPSLE-specific antibodies have been identified. We developed a novel proteomic strategy for identifying and profiling antigens in immune complexes in the cerebrospinal fluid (CSF), and applied this strategy to 26 NPSLE patients. As controls, we also included 25 SLE patients without neuropsychiatric manifestations (SLE), 15 with relapsing remitting multiple sclerosis (MS) and 10 with normal pressure hydrocephalus (NPH). We identified immune complexes of suprabasin (SBSN) in the CSF of the NPSLE group. The titer of anti-SBSN antibodies was significantly higher in the CSF of the NPSLE group compared to those of the SLE, MS and NPH groups. Microarray data showed that the senescence and autophagy pathways were significantly changed in astrocytes exposed to anti-SBSN antibodies. Our findings indicate that SBSN could be a novel autoantibody for the evaluation of suspected NPSLE.

  • mTOR inhibitor rapamycin induce polymorphonuclear myeloid-derived suppressor cells mobilization and function in protecting against acute graft-versus-host disease after bone marrow transplantation
    Clin. Immunol. (IF 3.99) Pub Date : 2017-11-10
    Yu Lin, Binsheng Wang, Wei Shan, Yamin Tan, Jingjing Feng, Lin Xu, Limengmeng Wang, Biqing Han, Mingming Zhang, Jian Yu, Xiaohong Yu, He Huang

    The mammalian target of rapamycin (mTOR) inhibitor rapamycin (RAPA) has been shown to be an effective immunosuppressor in the management of acute graft-versus-host disease (aGVHD) after bone marrow transplantation. Myeloid-derived suppressor cells (MDSCs) also have a protective effect in aGVHD regulation. However, the relationship between RAPA and MDSCs in aGVHD models is unclear. Meanwhile, the effect of RAPA on different subgroups of MDSCs is also less well described. In this study, we demonstrate that in vivo administration of RAPA results in the expansion and functional enhancement of polymorphonuclear MDSCs (PMN-MDSCs) in a murine model of aGVHD. RAPA treatment can enhance the suppressive function of PMN-MDSCs via up-regulation of arginase1 (Arg1) and induced nitric oxide synthase (iNOS) at later time points. Moreover, RAPA can also induce a strong immunosuppressive function in PMN-MDSCs from murine bone marrow in vitro, but has a contrary effect on monocytic MDSCs (M-MDSCs). We found that RAPA-treated PMN-MDSCs can restrain the differentiation of Th1/Th2 cells and promote induction of regulatory T cells in in vitro studies.

  • Treatment of chronic spontaneous urticaria: Immunomodulatory approaches
    Clin. Immunol. (IF 3.99) Pub Date : 2017-11-09
    de Montjoye Laurence, Herman Anne, Nicolas Jean-François, Baeck Marie

    This paper summarizes and reviews the mechanisms of action and data concerning efficacy of recommended treatments as well as other treatments that have been tested, independently of the outcomes, in the management of chronic spontaneous urticaria. Due to the central role of mast cells and histamine in the pathophysiology of this disease, H1-antihistamines remain the first-line treatment. However, current knowledge about this complex disease, also recognizes an important role for T lymphocytes, B lymphocytes, and autoantibodies. Implications of these others mediators thus provide further targets for treatment. Indeed, agents previously used to treat other autoimmune and inflammatory diseases, have demonstrated efficacy in chronic spontaneous urticaria and are therefore potential therapeutic alternatives for antihistamine unresponsive patients.

  • Enhanced activation of circulating plasmacytoid dendritic cells in patients with Chronic Obstructive Pulmonary Disease and experimental smoking-induced emphysema
    Clin. Immunol. (IF 3.99) Pub Date : 2017-11-08
    Shi-lin Qiu, Liang-jian Kuang, Qi-ya Tang, Min-chao Duan, Jing Bai, Zhi-yi He, Jian-quan Zhang, Mei-hua Li, Jing-min Deng, Guang-nan Liu, Xiao-ning Zhong

    Plasmacytoid dendritic cells (pDCs) are key cells bridging the innate with adaptive immunity. However, the phenotypic characteristics of circulating pDCs and its role in smoking related-Chronic Obstructive Pulmonary Disease (COPD) remain largely unknown. The aim of this study was analyzed the phenotype of circulating pDCs and the expression of IFN-γ producing CD8+ T cells and IL-17-producing CD8+ T cells in patients with COPD by using multi-colour flow cytometry. The cytokine profiles in peripheral blood from all subjects were measured by ELISA. The influence of cigarette smoke on pDCs was evaluated in an experimental mouse model of emphysema. Circulating pDCs in patients with COPD and in mice exposed to cigarette smoke expressed high levels of co-stimulatory molecules CD40 or CD86 accompanied by exaggerated IFN-γ producing CD8+ T cells and IL-17-producing CD8+ T cells. In vitro, cigarette smoke directly promoted pDCs maturation and release of IFN-α, IL-6 and IL-12, subsequently inducing differentiation of IFN-γ producing CD8+ T cells and IL-17-producing CD8+ T cells from mouse naïve CD8+ T cells. These data suggested that circulating pDCs display an enhanced activation phenotype in patients with COPD and in experimental smoking mouse model of emphysema, which might contribute to exaggerated IFN-γ producing CD8+ T and IL-17-producing CD8+ T cell-mediated immune responses.

  • Downregulation of BDH2 modulates iron homeostasis and promotes DNA demethylation in CD4+ T cells of systemic lupus erythematosus
    Clin. Immunol. (IF 3.99) Pub Date : 2017-11-04
    Ming Zhao, Meng-ying Li, Xiao-fei Gao, Su-jie Jia, Ke-qin Gao, Yin Zhou, Hui-hui Zhang, Yi Huang, Jing Wang, Hai-jing Wu, Qian-jin Lu

    DNA hypomethylation plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Here we investigated whether 3-hydroxy butyrate dehydrogenase 2 (BDH2), a modulator of intracellular iron homeostasis, was involved in regulating DNA hypomethylation and hyper-hydroxymethylation in lupus CD4+ T cells. Our results showed that BDH2 expression was decreased, intracellular iron was increased, global DNA hydroxymethylation level was elevated, while methylation level was reduced in lupus CD4+ T cells compared with healthy controls. The decreased BDH2 contributed to DNA hyper-hydroxymethylation and hypomethylation via increasing intracellular iron in CD4+ T cells, which led to overexpression of immune related genes. Moreover, we showed that BDH2 was the target gene of miR-21. miR-21 promoted DNA demethylation in CD4+ T cells through inhibiting BDH2 expression. Our data demonstrated that the dysregulation of iron homeostasis in CD4+ T cells induced by BDH2 deficiency contributes to DNA demethylation and self-reactive T cells in SLE.

  • HIV patients, healthy aging and transplant recipients can reveal the hidden footprints of CMV
    Clin. Immunol. (IF 3.99) Pub Date : 2017-11-03
    Shelley Waters, Emily Brook, Silvia Lee, Riwanti Estiasari, Ibnu Ariyanto, Patricia Price

    Cytomegalovirus (CMV) is a β-herpesvirus. Latent infections are common in all populations. However age-associated increases in levels of CMV-reactive antibody are testament to repeated reactivations and periods of viral replication. CMV has been associated with several diseases of aging, including vasculopathy and neurocognitive impairment. These conditions occur at a younger age in persons with particularly high burdens of CMV - transplant recipients and people living with HIV. Here we define the “clinical footprints” as immunopathologies triggered by CMV that develop over many years. A high burden of CMV also drives accumulation of multifunctional terminally-differentiated αβ T-cells, a novel population of Vδ2 − γδ T-cells, and a population of CD56lo NK cells lacking a key regulatory molecule. An understanding of these “immunological footprints” of CMV may reveal how they collectively promote the “clinical footprints” of the virus. This is explored here in transplant recipients, HIV patients and healthy aging.

  • SOCS-1 ameliorates smoke inhalation-induced acute lung injury through inhibition of ASK-1 activity and DISC formation
    Clin. Immunol. (IF 3.99) Pub Date : 2017-11-03
    Leifang Zhang, Kairei Zhu, Yating Ma, Chenming Xu, Qiwen Shi, Xiaoming Chen, Weike Su, Hang Zhao

    Smoke inhalation leads to acute lung injury (ALI), a devastating clinical problem associated with high mortality. Suppressor of cytokine signaling-1 (SOCS-1) is a negative regulator of apoptosis and pro-inflammatory cytokine signaling, two major contributors to the pathogenesis of ALI. We have found that SOCS-1 protects lung epithelial cells from smoke-induced apoptosis through two mechanisms. One is that SOCS-1 enhances degradation of ASK-1 and diminishes cleavage of pro-caspase-3 to repress smoke-triggered apoptosis in lung epithelial cells. The other is that SOCS-1 represses smoke-triggered DISC formation through altering TRADD-caspase-8 interaction rather than TNFR-1-TRADD interaction or TNFR-1-TRAF-2 interaction. In conclusion, SOCS-1 relieves smoke inhalation-induced lung injury by repressing ASK-1 and DISC-mediated epithelium apoptosis.

  • Recurrent allograft C3 glomerulonephritis and unsuccessful eculizumab treatment
    Clin. Immunol. (IF 3.99) Pub Date : 2017-10-31
    Kati Kaartinen, Leena Martola, Anne Räisänen-Sokolowski, Seppo Meri

    There is a great lack of efficient treatments for membranoproliferative glomerulonephritis (MPGN) and recently emerged complement therapies have been proposed to be useful. We report a patient with a complement-mediated MPGN having recurrencies in kidney allografts and an unsuccessful treatment with complement inhibitor, eculizumab (anti-C5 monoclonal antibody). Nephritic factor (C3Nef), an autoantibody against C3bBb, in the patient serum activated C3 but not C5 showing that major damage was mediated by C3 activation with clearly less involvement of C5 explaining unresponsiveness to eculizumab. Analyzing C3Nef-mediated C3 and C5 activation separately could help in choosing the right patients for eculizumab therapy.

  • Fingolimod induces BAFF and expands circulating transitional B cells without activating memory B cells and plasma cells in multiple sclerosis
    Clin. Immunol. (IF 3.99) Pub Date : 2017-10-25
    Yusei Miyazaki, Masaaki Niino, Eri Takahashi, Masako Suzuki, Masanori Mizuno, Shin Hisahara, Toshiyuki Fukazawa, Itaru Amino, Fumihito Nakano, Masakazu Nakamura, Sachiko Akimoto, Naoya Minami, Naoto Fujiki, Shizuki Doi, Shun Shimohama, Yasuo Terayama, Seiji Kikuchi

    Patients with multiple sclerosis (MS) who are treated with fingolimod have an increased proportion of transitional B cells in the circulation, but the underlying mechanism is not known. We hypothesized that B cell-activating factor of the tumor necrosis factor family (BAFF) is involved in the process. Compared with healthy controls and untreated MS patients, fingolimod-treated MS patients had significantly higher serum concentrations of BAFF, which positively correlated with the proportions and the absolute numbers of transitional B cells in blood. Despite the elevated concentrations of BAFF in fingolimod-treated MS patients, serum levels of soluble transmembrane activator and calcium-modulating cyclophilin ligand interactor, and B cell maturation antigen were not elevated. Our results show that fingolimod induces BAFF in the circulation and expands transitional B cells, but does not activate memory B cells or plasma cells in MS, which is favorable for the treatment of this disease.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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