European Journal of Immunology Impact Factor & Information

Publisher: European Federation of Immunological Societies, Wiley-VCH Verlag

Journal description

The European Journal of Immunology is an international journal focusing on the various aspects of immunological research. One of the world's leading journals of immunology it reports on the latest breakthroughs in the area. The European Journal of Immunology is a well-respected high-impact publication with the best Executive Committee in the field. Top authors have submitted their best papers to the journal for many years therefore building a high quality immunology journal. An ever-increasing amount of papers is being published from top authors from all over the world. The European Journal of Immunology is committed to publishing excellence with a focus on originality topicality and speed of publication. Well balanced coverage of immunology! The European Journal of Immunology provides a monthly forum for top-quality papers on the various aspects of immunological research. Original papers and short communications report the progress being made in the following fields of immunology: immunobiology experimental/human immunology molecular immunology immunopathology immunogenetics clinical immunology The Executive Committee and the international Editorial Board ensure the publication of high quality papers and an international and broad subject coverage. Kurztext Diese Zeitschrift zählt zur Weltspitze der wissenschaftlichen Immunologie-Journale. In ihr erscheinen Originalbeiträge und Kurzmitteilungen aus einem außerordentlich weiten Themengebiet. Hierzu gehören Aspekte der molekularen Immunologie der Immunogenetik der Cytokine der Immunochemie sowie der zellulären und klinischen Immunologie. Es werden außerdem Beiträge zu neuen Entwicklungen experimenteller Methoden und Techniken veröffentlicht. Society Affiliation European Federation of Immunological Societies (EFIS) Readers Immunologists biochemists molecular biologists cell biologists

Current impact factor: 4.52

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2013 / 2014 Impact Factor 4.518
2012 Impact Factor 4.97
2011 Impact Factor 5.103
2010 Impact Factor 4.942
2009 Impact Factor 5.179
2008 Impact Factor 4.865
2007 Impact Factor 4.662
2006 Impact Factor 4.772
2005 Impact Factor 4.876
2004 Impact Factor 5.005
2003 Impact Factor 4.536
2002 Impact Factor 4.832
2001 Impact Factor 4.99
2000 Impact Factor 5.24
1999 Impact Factor 5.635
1998 Impact Factor 5.438
1997 Impact Factor 5.256
1996 Impact Factor 5.701
1995 Impact Factor 6.015
1994 Impact Factor 5.664
1993 Impact Factor 5.577
1992 Impact Factor 4.934

Impact factor over time

Impact factor
Year

Additional details

5-year impact 4.77
Cited half-life 8.10
Immediacy index 0.74
Eigenfactor 0.06
Article influence 1.98
Website European Journal of Immunology website
Other titles European journal of immunology (Online), European Journal of Immunology, EJI
ISSN 1521-4141
OCLC 41614778
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Wiley-VCH Verlag

  • Pre-print
    • Author cannot archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • Upon funder agreement with publisher
  • Conditions
    • Pre-print may be deposited on personal intranet or institutional intranet repository, but not on a public repository
    • Pre-print must not updates with future versions
    • Published source must be acknowledged with set phrases (See policy)
    • Must link to publisher's site: http://www.interscience.wiley.com/
    • Publisher's version/PDF cannot be used
    • Some journal exceptions-check individual homepages
  • Classification
    ​ white

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Intra-macrophage protozoan parasite Leishmania donovani, causative agent of visceral leishmaniasis, escapes TLR-dependent early host immune response by inducing the de-ubiquitinating enzyme A20, which is sustained up to 6 h post-infection only. Therefore, Leishmania must apply other means to deactivate late host responses. Here we elucidated the role of IRAK-M, a negative regulator of TLR signaling, in down regulating macrophage proinflammatory response during late hours of in vitro infection. Our data reveal a sharp decline in IRAK1 and IRAK4 phosphorylation at 24 h post-infection along with markedly reduced association of IRAK1-TRAF6, which is mandatory for TLR activation. In contrast, IRAK-M was induced after A20 levels decreased and reached a maximum at 24 h post-infection. IRAK-M induction coincided with increased stimulation of TGF-β, a hallmark cytokine of visceral infection. TGF-β-dependent signaling mediated induction of SMAD family of proteins, 2, 3 and 4 play important roles in transcriptional up-regulation of IRAK-M. In infected macrophages, siRNA mediated silencing of IRAK-M displayed enhanced IRAK1 and IRAK4 phosphorylation with a concomitant increase in downstream NF-κB activity and reduced parasite survival. Taken together, the results suggest that IRAK-M may be targeted by L. donovani to inhibit TLR-mediated pro-inflammatory response late during in vitro infection. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 07/2015; DOI:10.1002/eji.201445336
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    ABSTRACT: Natural killer (NK) cells are a subset of cytotoxic lymphocytes that recognize and kill tumor- and virus-infected cells without prior stimulation. Killing of target cells is a multi-step process including adhesion to target cells, formation of an immunological synapse, polarization and release of cytolytic granules. The role of distinct potassium channels in this orchestrated process is still poorly understood. The current study reveals that in addition to the voltage-gated KV 1.3 and the calcium-activated KCa 3.1 channels, human NK cells also express the two-pore domain K2 P channel TASK2. Expression of Task2 varies among NK-cell subsets and depends on their differentiation and activation state. Despite its different expression in TASK2(high) CD56(bright) CD16(-) and TASK2(low) CD56(dim) CD16(+) NK cells, TASK2 is involved in cytokine-induced proliferation and cytolytic function of both subsets. TASK2 is crucial for leukocyte functional antigen (LFA-1) mediated adhesion of both resting and cytokine-activated NK cells to target cells, an early step in killing of target cells. With regard to the following mechanism, TASK2 plays a role in release of cytotoxic granules by resting, but not IL-15-induced NK cells. Taken together our data exhibit two-pore potassium channels as important players in NK-cell activation and effector function. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 07/2015; DOI:10.1002/eji.201445208
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    ABSTRACT: While binding of IgG antibodies (IgG1, IgG2a, b or c, and IgG3 in the murine system) to Fc gamma receptors (FcγR) via their Fc part is crucial for the activity of therapeutic antibodies in vivo, it is a well-known cause of erroneous results in immunological assays, such as flow cytometric analysis. Thus, blocking of the IgG binding sites of FcγRs has been established as a preventive procedure. In mice, four different FcγRs are expressed on a wide variety of immune cells. These include FcγRI (CD64), an activating receptor with high affinity to IgG which is able to bind monomeric IgG molecules, and the lower affinity receptors FcγRIIb (CD32b; inhibitory), FcγRIII (CD16; activating) and FcγRIV, which bind immune-complexes rather than monomeric IgG [1, 2]. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 07/2015; DOI:10.1002/eji.201545463
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    ABSTRACT: Dendritic cells (DCs) are professional antigen-presenting cells playing a crucial role in the initiation of T-cell responses to combat infection. However, systemic bacterial infection with various pathogens leads to DC-depletion in humans and mice. The mechanisms of pathogen-induced DC-depletion remain poorly understood. Previously, we showed that mice infected with Yersinia enterocolitica (Ye) had impaired de novo DC-development, one reason for DC-depletion. Here, we extend these studies to gain insight into the molecular mechanisms of DC-depletion and the impact of different bacteria on DC-development. We show that the number of BM hematopoietic progenitors committed to the DC lineage is reduced following systemic infection with different Gram-positive and Gram-negative bacteria. This is associated with a TLR4- and IFN-γ-signaling dependent increase of committed monocyte progenitors in the BM and mature monocytes in the spleen upon Ye-infection. Adoptive transfer experiments revealed that infection-induced monopoiesis occurs at the expense of DC-development. Our data provide evidence for a general response of hematopoietic progenitors upon systemic bacterial infections to enhance monocyte production, thereby increasing the availability of innate immune cells for pathogen control, whereas impaired DC-development leads to DC-depletion, possibly driving transient immunosuppression in bacterial sepsis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 07/2015; DOI:10.1002/eji.201545530
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    ABSTRACT: Chromoblastomycosis is a chronic skin infection caused by the pigmented saprophytic mould Fonsecaea pedrosoi. Chronicity of infection can be broken by a coordinated innate recognition of the spores by pattern recognition receptors (PRRs). While Mincle signaling via the Syk/Card9 pathway is required for fungal recognition by host cells, it is not sufficient for host control. Exogenously applied TLR agonists are necessary to promote the induction of proinflammatory cytokines and clearance of infection in vivo. Here, we investigated whether co-stimulation by TLR agonists fosters the development of adaptive immune responses, by examining the development of fungus-specific T cells. Subcutaneous infection of mice with F. pedrosoi spores induced the activation, expansion and differentiation of Ag-specific CD4(+) T cells but TLR co-stimulation did not further augment these T-cell responses. The Dectin-2/FcRγ/Card9 signaling pathway promoted the differentiation of fungus-specific CD4(+) T cells into Th17 cells, whereas Mincle inhibited the development of this T helper subset in infected mice. These results indicate differential roles for Dectin-2 and Mincle in the generation of adaptive immune responses to F. pedrosoi infection. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 07/2015; DOI:10.1002/eji.201545591
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    ABSTRACT: Passive immunotherapy with polyclonal or hyperimmune serum immunoglobulin G (IgG) preparations provides an efficient means of protecting immunocompromised patients from microbial infections. More recently, the use of passive immunotherapy to prevent or to treat established infections with the human immunodeficiency virus (HIV) has gained much attention, due to promising pre-clinical data obtained in monkey and humanized mouse in vivo model systems demonstrating that the transfer of HIV specific antibodies can not only prevent HIV infection but also diminish virus load during chronic infection. Furthermore, an array of broadly neutralizing HIV-specific antibodies has become available and the importance of the IgG constant region as a critical modulator of broadly neutralizing activity has been demonstrated. The aim of this review is to summarize the most recent findings with regard to the molecular and cellular mechanisms responsible for antibody mediated clearance of HIV infection, and to discuss how this may help to improve HIV therapy via optimizing Fcγ-receptor dependent activities of HIV-specific antibodies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 07/2015; DOI:10.1002/eji.201445386
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    ABSTRACT: Helminth parasites suppress immune responses to prolong their survival within the mammalian host. Thereby not only helminth-specific but also non-helminth-specific bystander immune responses are suppressed. Here we use the murine model of Litomosoides sigmodontis infection to elucidate the underlying mechanisms leading to this bystander T-cell suppression. When OT-II T cells specific for the third-party antigen ovalbumin are transferred into helminth-infected mice, these cells respond to antigen-specific stimulation with reduced proliferation compared to activation within non-infected mice. Thus, the presence of parasitic worms in the thoracic cavity translates to suppression of T cells with a different specificity at a different site. By eliminating regulatory receptors, cytokines and cell populations from this system, we provide evidence for a two-staged process. Parasite products first engage the TGF-β receptor on host-derived T cells that are central to suppression. In a second step, host-derived T cells produce IL-10 and subsequently suppress the adoptively transferred OT-II T cells. Terminal suppression was IL-10-dependant but independent of intrinsic TGF-β receptor- or PD-1-mediated signaling in the suppressed OT-II T cells. Blockade of the same key suppression mediators, i.e. TGF-β- and IL-10 receptor, also ameliorated the suppression of IgG response to bystander antigen vaccination in L. sigmodontis-infected mice. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 07/2015; DOI:10.1002/eji.201545503
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    ABSTRACT: Tuberculosis (TB), a chronic bacterial infectious disease caused by Mycobacterium tuberculosis (Mtb), typically affects the lung and causes profound morbidity and mortality rates worldwide. Recent advances in cellular immunology emphasize the complexity of myeloid cell subsets controlling TB inflammation. The specialization of myeloid cell subsets for particular immune processes has tailored their roles in protection and pathology. Among myeloid cells, dendritic cells (DCs) are essential for the induction of adaptive immunity, macrophages predominantly harbor Mtb within TB granulomas and polymorphonuclear neutrophils (PMNs) orchestrate lung damage. However, within each myeloid cell population, diverse phenotypes with unique functions are currently recognized, differentially influencing TB pneumonia and granuloma functionality. More recently, myeloid-derived suppressor cells (MDSCs) have been identified at the site of Mtb infection. Along with PMNs, MDSCs accumulate within the inflamed lung, interact with granuloma-residing cells and contribute to exuberant inflammation. In this review, we discuss the contribution of different myeloid cell subsets to inflammation in TB by highlighting their interactions with Mtb and their role in lung pathology. Uncovering the manifold nature of myeloid cells in TB pathogenesis will inform the development of future immune therapies aimed at tipping the inflammation balance to the benefit of the host. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 07/2015; DOI:10.1002/eji.201545493
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    ABSTRACT: Single cell immunoglobulin (Ig) gene amplification and sequencing has been widely used for the molecular and functional assessment of human antibody repertoires and has led to the identification of recombinant monoclonal antibodies with therapeutic potential against diverse pathogens (1-3). Due to the high reagent and Sanger sequencing costs, these antibody-cloning strategies are limited to the analysis of relatively small B-cell numbers and do not allow in-depth repertoire measurements to assess the clonality and clonal evolution of B-cell responses. A major goal in the field has been the development of platforms that allow the high-throughput analysis of antibody repertoires at low costs (4). Next generation sequencing (NGS) of Ig heavy and light chain genes facilitates the high-throughput analysis of antibody repertoires. So far only one platform preserves natural Ig gene associations at single-cell level through linkage of Ig heavy and light chain amplicons before sequencing (5). However, due to the short NGS read-lengths full length Ig genes are not readily available for cloning and recombinant monoclonal antibody production. Here we describe a platform for the high-throughput analysis of human antibody repertoires at single cell level that is fully compatible with direct Ig gene cloning and expression. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 07/2015; DOI:10.1002/eji.201545526
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    ABSTRACT: Macrophages have important functions in tissue homeostasis, but the exact mechanisms regarding wide spectrum of macrophage phenotype remain unresolved. In this study, we report that mouse bone marrow derived naïve macrophages produce prostaglandin E2 (PGE2 ) endogenously, resulting in anti-inflammatory gene expression upon differentiation induced by macrophage colony stimulating factor (M-CSF). Cyclooxygenase (COX) inhibition by indomethacin reduced endogenous PGE2 production of macrophages and subsequently reduced arg1, IL10 and Mrc1, YmI and FizzI gene expressions. Of note, PGE2 phosphorylates CREB via EP2 and EP4 receptor ligation, thereby transcriptionally increasing C/EBPβ expression in BALB/c bone marrow derived macrophages (BMDM). Activated CREB directly binds to the CREB-responsive element of the C/EBPβ promoter, such that PGE2 ultimately reinforces arg1, IL10 and Mrc1 gene expression. Cyclic AMP activator forskolin also phosphorylated CREB and induced the C/EBPβ cascade, but this was completely blocked by the PKA inhibitor, H89. Consequently, M-CSF grown macrophages inhibited T-cell proliferation but the inhibition ability was reduced when the COX is inhibited by indomethacin or macrophage C/EBPβ expression was decreased by siRNA transduction. Our results collectively describe the molecular basis for homeostatic macrophage differentiation by endogenous PGE2 . This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 06/2015; DOI:10.1002/eji.201545471
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    ABSTRACT: Delta-like protein 1 (DLK1) is a non-canonical ligand that inhibits NOTCH1 receptor activity and regulates multiple differentiation processes. In macrophages, NOTCH signaling increases TLR-induced expression of key pro-inflammatory mediators. We have investigated the role of DLK1 in macrophage activation and inflammation using Dlk1-deficient mice and Raw 264.7 cells overexpressing Dlk1. In the absence of Dlk1, NOTCH1 expression is increased and the activation of macrophages with TLR3 or TLR4 agonists leads to higher production of IFN-β and other pro-inflammatory cytokines, including TNF-α, IL-12 and IL-23. The expression of key proteins involved in IFN-β signaling, such as IRF3, IRF7, IRF1 or STAT1, as well as cRel, or RelB, which are responsible for the generation of IL-12 and IL-23, is enhanced in Dlk1 KO macrophages. Consistently, Dlk1 KO mice are more sensitive to LPS-induced endotoxic shock. These effects seem to be mediated through the modulation of NOTCH1 signaling. TLR4 activation reduces DLK1 expression, whereas increases NOTCH1 levels. In addition, DLK1 expression diminishes during differentiation of human U937 cells to macrophages. Overall, these results reveal a novel role for DLK1 as a regulator of NOTCH-mediated, pro-inflammatory macrophage activation, which could help to ensure a baseline level preventing constant tissue inflammation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 06/2015; DOI:10.1002/eji.201545514
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    ABSTRACT: The strong link between T-cell metabolism and effector functions is well characterized in the murine system but hardly investigated in human T cells. Therefore, we analyzed glycolytic and mitochondrial activity in correlation to function in activated human CD4 and CD8 T cells. Glycolysis was barely detectable upon stimulation but accelerated beyond 24h, whereas mitochondrial activity was elevated immediately in both T-cell populations. Glucose deprivation or mitochondrial restriction reduced proliferation, had only a transient impact on "on-blast formation" and no impact on viability, IFN-γ, IL-2, IL-4 and IL-10 production, whereas TNF was reduced. Similar results were obtained in bulk T cells and T-cell subsets. Elevated respiration under glucose restriction demonstrated metabolic flexibility. Administration of the glycolytic inhibitor 2-deoxy-glucose suppressed both glycolysis and respiration and exerted a strong impact on cytokine production that persisted for IFN-γ after removal of 2-deoxy-glucose. Taken together, glycolytic or mitochondrial restriction alone compromised proliferation of human T cells, but barely affected their effector functions. In contrast, effector functions were severely affected by 2-deoxy-glucose treatment. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 06/2015; DOI:10.1002/eji.201545473
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    ABSTRACT: The thymus is an anatomically compartmentalized primary lymphoid organ that fosters the production of self-tolerant T cells. The thymic cortex provides a specialized microenvironment in which cortical thymic epithelial cells (cTECs) support the positive selection and further differentiation of self-MHC-restricted thymocytes. Following their migration into the medulla, positively selected thymocytes are further screened for self-reactivity, which involves both negative selection and Foxp3(+) regulatory T-cell generation via interactions with medullary thymic epithelial cells (mTECs). Given the importance of both cortical and medullary microenvironments for T-cell development, studies that address the developmental origins of cTECs and mTECs are important in understanding the processes that shape the developing T-cell receptor repertoire, and reduce the frequency of self-reactive T cells that initiate autoimmune disease. In this issue of the European Journal of Immunology, Onder et al. [Eur. J. Immunol. 2015.45: XXXX-XXXX] identify a subset of podoplanin(+) mTECs in mice that reside at the cortico-medullary junction, and show that their development is important to establish self-tolerance, and require the presence of self-reactive T cells. Collectively, their findings highlight the cortico-medullary junction as a potential repository for precursors of the mTEC lineage, and provide a better understanding of thymus medulla formation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 06/2015; DOI:10.1002/eji.201545829
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    ABSTRACT: Cellular inhibitor of apoptosis proteins (c-IAP) 1 and 2 are widely expressed ubiquitin protein ligases that regulate a variety of cellular functions, including the sensitivity of T cells to co-stimulation. 4-1BB is a TNFR family member that signals via a complex that includes TRAF family members and the c-IAPs to upregulate NF-κB and ERK, and has been implicated in memory T-cell survival. Here we show that effector and memory T cells from mice expressing a dominant negative E3-inactive c-IAP2 (c-IAP2(H570A) ) have impaired signaling downstream of 4-1BB. When infected with LCMV, unlike mice in which c-IAPs were acutely downregulated by c-IAP antagonists, the primary response of c-IAP2(H570A) mice was normal. However, the number of antigen-specific CD8(+) but not CD4(+) T cells declined more rapidly and to a greater extent in c-IAP2(H570A) mice than in wild type (WT) controls. Studies with T-cell adoptive transfer demonstrated that the enhanced decay of memory cells was T-cell-intrinsic. Thus, c-IAP E3 activity is required for 4-1BB co-receptor signaling and maintenance of CD8(+) T-cell memory. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 06/2015; DOI:10.1002/eji.201445342
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    ABSTRACT: Chronic skin inflammation resulting from a defective epidermal barrier is a hallmark of Atopic Dermatitis (AD). We previously demonstrated that mice lacking fibroblast growth factor (FGF) receptors 1 and 2 in keratinocytes (K5-R1/R2 mice) develop an AD-like chronic dermatitis as a result of an impaired epidermal barrier. Here we show that γδ T cells, which rapidly respond to various insults, accumulate in the epidermis of K5-R1/R2 mice before the development of histological abnormalities. Their number and activation further increase as the phenotype progresses, most likely as a consequence of increased expression of Il-2 and Il-7 and the stress-induced proteins Rae-1, H60c, Mult1, PlexinB2 and Skint1. To determine the role of γδ T cells in the skin phenotype, we generated quadruple mutant K5-R1/R2 mice lacking γδ T cells. Surprisingly, loss of γδ T cells did not or only marginally affect keratinocyte proliferation, epidermal thickness, epidermal barrier function and accumulation and activation of different immune cells in the skin of K5-R1/R2 mice, possibly due to partial compensation by αβ T cells. These results demonstrate that γδ T cells do not contribute to the development or maintenance of chronic inflammation in response to a defect in the epidermal barrier. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 06/2015; DOI:10.1002/eji.201545675
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    ABSTRACT: The innate immune system has been shown to play an important pathologic role in systemic lupus erythematosus (SLE). Toll-like receptor 2 (TLR2), a pattern recognition receptor, recognizes exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs), and has been implicated in the initiation and maintenance of the perpetuated inflammatory reactions in autoimmune diseases. Here, we report increased expression of TLR2 in CD4(+) and CD8(+) T cells, CD19(+) B cells and CD14(+) monocytes from SLE patients. Conventional treatment, such as hydroxychloroquine and corticosteroids, showed no effect on TLR2 expression in CD4(+) T cells from SLE patients. In vitro stimulation of TLR2 in CD4(+) T cells from SLE patients increased CD40L and CD70 expression, as well as secretion of IL-6, IL-17A, IL-17F, and TNF-α, while Foxp3 transcription decreased. This effect was be reversed by TLR2 siRNA. Moreover, TLR2 activation up-regulated H3K4 tri-methylation and H4 acetylation levels while down-regulated H3K9 tri-methylation level in the IL-17A promoter region. In addition, it also increased H4 acetylation levels and decreased H3K9 tri -methylation levels in the IL-17F promoter region. In summary, our findings demonstrate that increased expression of TLR2 contributes to immune reactivity and promotes IL-17A and IL-17F expression through histone modifications in SLE. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 06/2015; DOI:10.1002/eji.201445219
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    ABSTRACT: Regulatory Tcells (Tregs) limit contact between Dendritic cells (DCs) and conventional T cells (Tcons), decreasing the formation of aggregates as well as down-modulating the expression of co-stimulatory molecules by DCs, thus decreasing DC immunogenicity and abrogating T-cell activation. Despite the importance of this Treg-cell function, the capacity of Tregs from term and preterm neonates to suppress DCs, and the suppressive mechanisms they use, are still undefined. We found that, relative to adult Tregs, activated Tregs from human neonates expressed lower FOXP3 and CTLA-4, but contained higher levels of cAMP. We developed an in vitro model in which Treg function was measured at a physiological ratio of 1 Treg for 10 Tcon and 1 monocyte-derived DC, as Treg target. Term and preterm Tregs failed to suppress the formation of DC-Tcon aggregates, in contrast to naïve and memory Tregs from adults. However, neonatal Tregs diminished DC and Tcon activation as well as actin polymerization at the immunological synapses. In addition, CTLA-4 and cAMP were the main suppressive molecules used by neonatal Treg. Altogether, both preterm and term neonatal Tregs appear less functional than adult Tregs, and this defect is consistent with the general impairment of CD4 cell function in newborns. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 06/2015; DOI:10.1002/eji.201445371
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    ABSTRACT: Mucosal associated invariant T (MAIT) cells are characterized by an invariant TCRVα7.2 chain recognizing microbial vitamin B metabolites presented by the MHC-Ib molecule MR1. They are mainly detectable in the CD8(+) and CD8(-) CD4(-) "double negative" T-cell compartments of mammals and exhibit both Th1- and Th17-associated features. As MAIT-cells show a tissue-homing phenotype and operate at mucosal surfaces with myriads of pathogenic encounters, we wondered how IL-15, a multifaceted cytokine being part of the intestinal mucosal barrier, impacts on their functions. We demonstrate that in the absence of TCR crosslinking, human MAIT- cells secrete IFN-γ, increase perforin expression and switch on granzyme B production in response to IL-15. As this mechanism was dependent on the presence of CD14(+) cells and sensitive to IL-18 blockade, we identified IL-15 induced IL-18 production by monocytes as an inflammatory, STAT5-dependent feedback mechanism predominantly activating the MAIT-cell population. IL-15 equally affects TCR-mediated MAIT-cell functions since it dramatically amplifies bacteria-induced IFN-γ secretion, granzyme production and cytolytic activity at early time points, an effect being most pronounced under suboptimal TCR stimulation conditions. Our data reveal a new quality of IL-15 as player in an inflammatory cytokine network impacting on multiple MAIT-cell functions. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 06/2015; DOI:10.1002/eji.201445313
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    ABSTRACT: Orally administrated iron is suspected to increase susceptibility to enteric infections among children in infection endemic regions. Here we investigated the effect of dietary iron on the pathology and local immune responses in intestinal infection models. Mice were held on iron-deficient, normal-iron, or high-iron diets and after two weeks they were orally challenged with the pathogen Citrobacter rodentium. Microbiome analysis by pyrosequencing revealed profound iron- and infection-induced shifts in microbiota composition. Fecal levels of the innate defensive molecules and markers of inflammation lipocalin-2 and calprotectin were not influenced by dietary iron intervention alone, but were markedly lower in mice on the iron-deficient diet after infection. Next, mice on the iron-deficient diet tended to gain more weight and to have a lower grade of colon pathology. Furthermore, survival of the nematode Caenorhabditis elegans infected with Salmonella enterica serovar Typhimurium was prolonged after iron-deprivation. Together, these data show that iron limitation restricts disease pathology upon bacterial infection. However, our data also showed decreased intestinal inflammatory responses of mice fed on high-iron diets. Thus additionally, our study indicates that the effects of iron on processes at the intestinal host-pathogen interface may highly depend on host iron status, immune status and gut microbiota composition. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 06/2015; DOI:10.1002/eji.201545642