European Journal of Immunology (Eur J Immunol )

Publisher: European Federation of Immunological Societies, John Wiley and Sons

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

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

John Wiley and Sons

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author can archive a post-print version
  • Conditions
    • See Wiley-Blackwell entry for articles after February 2007
    • On personal web site or secure external website at authors institution
    • Deposit in institutional repositories is not allowed
    • JASIST authors may deposit in an institutional repository
    • Non-commercial
    • Pre-print must be accompanied with set phrase (see individual journal copyright transfer agreements)
    • Published source must be acknowledged with set phrase (see individual journal copyright transfer agreements)
    • Publisher's version/PDF cannot be used
    • Articles in some journals can be made Open Access on payment of additional charge
    • 'John Wiley and Sons' is an imprint of 'Wiley'
  • Classification
    ​ green

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Cerebral malaria, a severe complication of Plasmodium falciparum infection, can be modeled in murine Plasmodium berghei ANKA (PbA)-infection. PbA-induced experimental cerebral malaria (ECM) is CD8(+) T-cell mediated, and influenced by TH 1/TH 2 balance. Here, we show that IL-33 expression is increased in brain undergoing ECM and we address the role of the IL-33/ST2 pathway in ECM development. ST2-deficient mice were resistant to PbA-induced neuropathology. They survived >20 days with no ECM neurological sign and a preserved cerebral microcirculation, while wild-type mice succumbed within 10 days with ECM, brain vascular leakage, distinct microvascular pathology obstruction and hemorrhages. Parasitemia and brain parasite load were similar in ST2-deficient and wild-type mice. Protection was accompanied by reduced brain sequestration of activated CD4(+) T cells and perforin(+) CD8(+) T cells. While IFN-γ and T-cell-attracting chemokines CXCL9 and CXCL10 were not affected in the absence of functional ST2 pathway, the local expression of ICAM-1, CXCR3 and LT-α, crucial for ECM development, was strongly reduced, and this may explain the diminished pathogenic T-cell recruitment and resistance to ECM. Therefore, IL-33 is induced in PbA sporozoite infection, and the pathogenic T-cell responses with local microvascular pathology are dependent on IL-33/ST2 signaling, identifying IL-33 as a new actor in ECM development. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 02/2015;
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    ABSTRACT: The deubiquitinating enzyme CYLD is an important tumor suppressor and inhibitor of immune responses. In contrast to full-length CYLD (FL-CYLD), the immunological function of the naturally occuring short splice variant of CYLD (sCYLD) is insufficiently described. Previously, we showed that dendritic cells (DCs), which lack FL-CYLD but express sCYLD, exhibit augmented NF-κB and DC activation. To explore the function of sCYLD in infection, we investigated whether DC-specific sCYLD regulates the pathogenesis of listeriosis. Upon Listeria monocytogenes infection of CD11c-Cre Cyld(ex7/8 fl/fl) mice, infection of CD8α(+) DCs, which are crucial for the establishment of listeriosis in the spleen, was not affected. However, NF-κB activity of CD11c-Cre Cyld(ex7/8 fl/fl) DCs was increased, while activation of ERK and p38 was normal. In addition, CD11c-Cre Cyld(ex7/8 fl/fl) DCs produced more TNF, IL-10 and IL-12 upon infection, which led to enhanced stimulation of IFN-γ-producing NK cells. In addition CD11c-Cre Cyld(ex7/8 fl/fl) DCs presented Listeria antigen more efficiently to CD8(+) T cells resulting in a stronger pathogen-specific CD8(+) T-cell proliferation and more IFN-γ production. Collectively, the improved innate and adaptive immunity and survival during listeriosis identify the DC-specific FL-/sCYLD balance as a potential target to modulate NK-cell and antigen-specific CD8(+) T-cell responses. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 02/2015;
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    ABSTRACT: Before B cells differentiate into long-lived antibody-secreting plasma cells (PCs), they undergo affinity maturation and class switch recombination of their immunoglobulin receptors during a germinal center (GC) reaction. Transcription factors such as Bach2 and Mitf are essential during this process, as they delay premature differentiation of GC B cells by repressing Blimp-1 and IRF4, two transcription factors required for terminal PC differentiation. Therefore, Bach2 and Mitf expression must be attenuated in activated B cells to allow terminal PC differentiation, but the precise mechanism remains enigmatic. Here, we provide evidence that miR-148a, a small non-coding microRNA, fosters PC differentiation and survival. Next-generation sequencing revealed that miR-148a is the most abundant microRNA in primary human and murine PCs, and its expression is upregulated in activated murine B cells and coincides with Blimp-1 synthesis. miR-148a targets Bach2, Mitf and proapoptotic factors such as PTEN and Bim. When prematurely expressed, miR-148a promotes the differentiation and survival of plasmablasts and reduces frequencies of IgG1+ cells in primary B-cell cultures. In summary, we propose that miR-148a is a new player in the regulatory network controlling terminal PC differentiation and could, therefore, be a therapeutic target for interfering with PC differentiation and survival.
    European Journal of Immunology 02/2015;
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    ABSTRACT: Secretion of type I interferon (IFN) is the first cellular reaction to invading pathogens. Despite the protective function of these cytokines, an excessive response to their action can contribute to serious pathologies, such as autoimmune diseases. Transcripts of most cytokines contain adenylate-uridylate (A/U)-rich elements (AREs) which make them highly unstable. RNA binding proteins (RBPs) are mediators of the regulatory mechanisms that determine the fate of mRNAs containing AREs. Here, we applied an affinity proteomic approach and identified lethal, abnormal vision, Drosophila-like 1 (ELAVL1)/Hu antigen R (HuR) as the predominant RBP of the IFN-β mRNA ARE. Reduced expression or chemical inhibition of HuR severely hampered the type I IFN response in various cell lines and fibroblast-like synoviocytes isolated from joints of rheumatoid arthritis patients. These results define a role for HuR as a potent modulator of the type I IFN response. Taken together, HuR could be used as therapeutic target for diseases where type I IFN production is exaggerated. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 02/2015;
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    ABSTRACT: Among human peripheral blood (PB) monocyte (Mo) subsets, the classical CD14(++) CD16(-) (cMo) and intermediate CD14(++) CD16(+) (iMo) Mo are known to activate pathogenic Th17 responses, whereas the impact of nonclassical CD14(+) CD16(++) Mo (nMo) on T-cell activation has been largely neglected. The aim of this study was to obtain new mechanistic insights on the capacity of Mo subsets from healthy donors (HD) to activate IL-17(+) T-cell responses in vitro, and assess whether this function was maintained or lost in states of chronic inflammation. When co-cultured with autologous CD4(+) T-cells in the absence of TLR-2/NOD2 agonists, PB nMo from HD were more efficient stimulators of IL-17-producing T-cells, as compared to cMo. These results could not be explained by differences in Mo lifespan and cytokine profiles. Notably, however, the blocking of LFA-1/ICAM-1 interaction resulted in a significant increase in the percentage of IL-17(+) T-cells expanded in nMo/T-cell co-cultures. As compared to HD, PB Mo subsets of patients with Rheumatoid Arthritis (RA) were hampered in their T-cell stimulatory capacity. Our new insights highlight the role of Mo subsets in modulating inflammatory T-cell responses and suggest that nMo could become a critical therapeutic target against IL-17-mediated inflammatory diseases. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 02/2015;
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    ABSTRACT: The role of mast cells (MCs) in autoimmunity is the matter of an intensive scientific debate. Based on observations in different MC-deficient mouse strains, MCs are considered as fundamental players in autoimmune diseases. However, most recent data suggest that the outcome of such diseases is strongly affected by the individual mouse strain used. By the use of two c-Kit mutant mast cell-deficient mouse strains and one c-Kit-independent strain, we here investigated the role of MCs in a systemic antibody transfer model of epidermolysis bullosa acquisita (EBA), a subepidermal autoimmune blistering skin disease characterized by autoantibodies against type VII collagen. While C57BL/6J-Kit(W-sh/W-sh) mice developed an unexpected increased blistering phenotype, no significant differences to wildtype controls were seen in WBB6F1 -Kit(W/W-v) or the novel Mcpt5-Cre iDTR animals. Interestingly, in a local antibody transfer model, which induces a localized disease, we showed that application of high concentrations of anti-COL7 antibodies induced MC activation and MC-dependent edema formation which did, however, not contribute to blister induction. Our results indicate that in the autoimmune disorder EBA MCs do not contribute to the immune-mediated tissue injury. Modern c-Kit mutant-independent MC-deficient mouse strains will help to further redefine the role of MCs in autoimmunity. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 02/2015;
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    ABSTRACT: The role of Th17 cells in the pathogenesis of autoantibody-mediated diseases is unclear. Here, we assessed the contribution of Th17 cells to the pathogenesis of experimental autoimmune myasthenia gravis (EAMG), which is induced by repetitive immunizations with Torpedo californica acetylcholine receptor (tAChR). We show that a significant fraction of tAChR-specific CD4(+) T cells is producing IL-17. IL-17(ko) mice developed fewer or no EAMG symptoms, although the frequencies of tAChR-specific CD4(+) T cells secreting IL-2, IFN-γ or IL-21, and the percentage of FoxP3(+) Treg cells were similar to WT mice. Even though the total anti-tAChR antibody levels were equal, the complement fixating IgG2b subtype was reduced in IL-17(ko) as compared to WT mice. Most importantly, pathogenic anti-murine AChR antibodies were significantly lower in IL-17(ko) mice. Furthermore, we confirmed the role of Th17 cells in EAMG pathogenesis by the reconstitution of TCR β/δ(ko) mice with WT or IL-17(ko) CD4(+) T cells. In conclusion we show that levels of IgG2b isotypes and loss of B-cell tolerance, which results in pathogenic anti-murine AChR specific antibodies, are dependent on IL-17 production by CD4(+) T cells. Thus, we describe here for the first time how Th17 cells are involved in the induction of classical antibody-mediated autoimmunity. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 02/2015;
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    ABSTRACT: CD4(+) regulatory T cells expressing the transcription factor Foxp3 can be generated in the thymus (tTreg cells), but the cellular and molecular pathways driving their development remain incompletely understood. Transforming growth factor-beta (TGF-β) is essential for the generation of Foxp3(+) Treg cells converted from peripheral naïve CD4(+) T cells (pTreg cells), yet a role for TGF-β in tTreg-cell development was initially refuted. Nevertheless, recent studies have unmasked a requirement for TGF-β in the generation of tTreg cells. Experimental evidence reveals that TGF-β in the context of TCR stimulation induces Foxp3 gene transcription in thymic Treg precursors, CD4(+) CD8(-) CD25(-) semi-mature and mature single-positive (SP) thymocytes. Intriguingly, thymic apoptosis was found to be intrinsically linked to the generation of tTreg cells, as apoptosis induced expression of TGF-β intra-thymically. In this short review, we will highlight key data, discuss the experimental evidence and propose a modified model of tTreg-cell development involving TGF-β. We will also outline the remaining unresolved questions concerning generation of thymic Foxp3(+) Treg cells and provide our personal perspectives on the mechanisms controlling tTreg-cell development. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 02/2015;
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    ABSTRACT: Immune enhancement is desirable in situations where decreased immunity results in increased morbidity. We investigated whether blocking the surface inhibitory receptor PD-1 and/or p38 MAP kinase could enhance the proliferation of the effector memory CD8(+) T-cell subset that re-expresses CD45RA (EMRA) and exhibits characteristics of senescence, which include decreased proliferation and telomerase activity but increased expression of the DNA damage response-related protein γH2AX. Blocking of both PD-1 and p38 MAPK signalling in these cells enhanced proliferation and the increase was additive when both pathways were inhibited simultaneously in both young and old human subjects. In contrast, telomerase activity in EMRA CD8(+) T cells was only enhanced by blocking the p38 but not the PD-1 signalling pathway, further indicating that non-overlapping signalling pathways were involved. Although blocking p38 MAPK inhibits TNF-α secretion in the EMRA population, this decrease was counteracted by the simultaneous inhibition of PD-1 signalling in these cells. Therefore, end-stage characteristics of EMRA CD8(+) T cells are stringently controlled by distinct and reversible cell signalling events. In addition, the inhibition of PD-1 and p38 signalling pathways together may enable the enhancement of proliferation of EMRA CD8(+) T cells without compromising their capacity for cytokine secretion. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 02/2015;
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    ABSTRACT: The participation of B-1 cells in a murine model of spontaneous diabetes has been recently reported. Here, we describe the role of B-1 cells in streptozotocin- (STZ)-induced diabetes in mice. We demonstrated that Xid (B-1 cell-deficient) mice are more susceptible to STZ treatment than WT mice, as evidenced by their higher blood glucose level (BGL) in response to STZ. Unexpectedly, the Xid mice that were intraperitoneally transferred with purified B-1 cells, either before or after the STZ treatment, did not develop diabetes. These cell transfers provided long-lasting protection for the Xid mice against STZ-induced diabetes, suggesting that B-1 cells play an important role in the experimental diabetes pathobiology. We also showed that B-1 cell culture supernatants were able to regulate the BGL of the diabetic Xid mice, and we identified insulin-producer cells when B-1 cells were differentiated in B-1 cell-derived phagocyte (B-1CDP) in vitro. These findings provide a novel role for B-1 cells in metabolic processes, presenting a new mechanism to explain the pathogenesis of diabetes and a possible therapeutical target. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 02/2015;
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    ABSTRACT: NFATc1 is a member of the nuclear factor of activated T cells (NFAT) family of transcription factors. NFAT are activated upon T-cell receptor activation followed by intra-cytoplasmatic calcium influx where calmodulin, a calcium sensor protein, activates the phosphatase calcineurin which dephosphorylates NFAT proteins and results in NFAT nuclear import. Here, we show the analysis of conditional NFATc1-deficient mice bearing a deletion of NFATc1 in CD4(+) and CD8(+) T cells. NFATc1-deficient CD4(+) T cells polarized under Th17 conditions express reduced levels of the Th17-associated transcription factor RORγT as well as the Th17-associated cytokines IL-17A, IL-17F, IL-21 and IL-10. In the murine model of experimental autoimmune encephalomyelitis (EAE), we found a strong reduction of the disease outcome in conditional NFATc1-deficient mice, as compared with control littermates. This was accompanied by a diminished inflammation in the brain and spinal cord and reduced IL-17A and IFN-γ expression by MOG-specific spleen, spinal cord and brain cells. Altogether, these results reveal an important role of NFATc1 in inducing Th17-cell responses and IFN-γ, both being relevant for the EAE development. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 02/2015;
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    ABSTRACT: Clinical studies suggest that triple negative breast cancer (TNBC) patients with epidermal growth factor receptor (EGFR)-expressing tumors could benefit from therapy with Cetuximab, which targets EGFR. NK cells are the primary effectors of antibody (Ab)-dependent cell-mediated cytotoxicity (ADCC) and thus play a role in Ab-based therapies. We have previously described diminished levels of Cetuximab-mediated ADCC in vitro in patients with advanced breast cancer. Here, we investigated the potential causes of this NK-cell functional deficiency. We characterized NK-cell activating/inhibitory receptors in the peripheral blood of breast cancer patients and found CD85j inhibitory receptor overexpression. The capacity of NK cells to perform Cetuximab-triggered ADCC against TNBC cells correlated inversely with CD85j expression, even in the presence of the stimulatory cytokines IL-2 or IL-15. Hence, patients expressing high levels of CD85j had an impaired ability to lyse TNBC cells in the presence of Cetuximab. We also found that CD85j overexpression was associated with HLA-I and soluble HLA-G expression by tumors. A CD85j functional blockade with a CD85j antagonist Ab restored ADCC levels in breast cancer patients and reverted this negative effect. Our data suggest that strategies which overcome the hurdles of immune activation could improve Cetuximab clinical efficacy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 02/2015;
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    ABSTRACT: B cell lymphoma (Bcl)-3 is a non-classical member of the IκB protein family known to interact with transcriptionally inactive NF-κB1 and NF-κB2 homodimers to modulate gene expression. Besides its action as an oncoprotein, Bcl-3 has been shown to have both pro-inflammatory and anti-inflammatory functions depending on the cell-type affected. In this issue of the European Journal of Immunology, Siebenlist and colleagues [Eur J. Immunol. 2015. 45: XXXX-XXXX] report that Bcl-3 inhibits the production of the pro-inflammatory chemokines CXCL9 and CXCL10 in keratinocytes, thereby restricting the influx of CD8(+) effector T cells in a mouse model of allergic contact dermatitis. In addition, mice with a global deficiency of Bcl-3 show enhanced ear swelling responses in the late phase of contact hypersensitivity responses. Besides keratinocytes, other radioresistant cell types appear to also utilize Bcl-3 to dampen the inflammatory response. This Commentary will discuss the evidence supporting Bcl-3 as a critical player in limiting inflammation during the later stages of contact hypersensitivity. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 02/2015;
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    ABSTRACT: T-helper type 17 cytokines have been implicated in epithelial cancer progression at mucosal sites. In this issue of the European Journal of Immunology, Nardinocchi, et al. [Eur. J. Immunol. 2015. 45: XXXX-XXXX] show that the Th17 cytokines IL-17 and IL-22 can both signal to non-melanoma skin cancer cells, inducing both cellular proliferation and enhanced migration of human basal-cell carcinoma (BCC) and squamous cell carcinoma (SCC) cell lines in vitro. These cytokines were also shown to exacerbate tumor growth in mice injected with the SCC line, CAL27. Thus, IL-17 and IL-22 may be key factors in skin cancer progression and may provide novel prognostic markers in non-melanoma skin cancer.This article is protected by copyright. All rights reserved
    European Journal of Immunology 02/2015;
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    ABSTRACT: B-cell depletion therapy has emerged as a powerful strategy to intercept the progression of T-cell-mediated autoimmune diseases such as rheumatoid arthritis, type 1 diabetes, or relapsing remitting multiple sclerosis. However, its mode of action remains incompletely defined, reflecting our incomplete understanding of the pathogenic functions of B cells in such pathologies. B cells can contribute to immune responses through the production of antibodies, presentation of antigen to T cells, and production of cytokines. In this issue of the European Journal of Immunology [Eur. J. Immunol. 2015. 45: XXXX-XXXX] Olalekan et al. demonstrate that IFN-γ production by B cells is essential for the development of arthritis in mice. Lack of IFN-γ expression in B cells results in reduced autoimmune T-cell responses and autoantibody levels, impacting the arthritogenic reaction akin to that in B-cell depletion therapy. Together with other reports, the article by Olalekan et al. emphasizes the importance of cytokine-producing B cells in the pathogenesis of autoimmune diseases. In this commentary, we discuss how these findings shed new light on the roles of B cells as drivers of autoimmune pathogenesis, and how they more generally contribute to our understanding of the role of B cells in immunity. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 02/2015;
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    ABSTRACT: The human antimicrobial peptide LL-37 is known to have chemotactic and modulatory activity on various cells including monocytes, T cells, and epithelial cells. Given that LL-37 enhances chemotactic attraction and modulates the activity of dendritic cells, it is conceivable that it might play a role as an immune adjuvant by skewing the immune environment toward immunostimulatory conditions. In this study, we characterized the mucosal adjuvant activity of LL-37 using model and pathogenic antigens. When LL-37-conjugated antigen was administered orally to mice, a tolerogenic Peyer's patch environment was altered to cell populations containing IL-6-secreting CD11c+ cells, CD11c+CD70+ cells, and Th17 cells capable of evoking a subsequent LL-37-conjugated antigen-specific immune response in both systemic and mucosal immune compartments. In addition, we showed presentation of formyl peptide receptor, an LL-37 receptor, on M cells, which may aid the initiation of an LL-37-mediated enhanced immune response through targeting and transcytosis of the conjugated antigen. Based on our findings, we conclude that LL-37 has potential as an oral mucosal adjuvant, not only by enhancing the delivery of LL-37-conjugated antigen to M cells, but also by triggering T-cell mediated antigen-specific immune responses through modulation of the mucosal immune environment.This article is protected by copyright. All rights reserved
    European Journal of Immunology 02/2015;
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    ABSTRACT: The NADPH oxidase 2 (NOX2) complex is responsible for the production of reactive oxygen species (ROS) in phagocytic cells. Genetic defects in NOX2 lead to opportunistic infections and inflammatory manifestations such as granulomas in humans, also known as chronic granulomatous disease (CGD). This condition is mirrored in mice with defective ROS production and interestingly both species are predisposed to autoimmune diseases. An unresolved question is whether the hyper-inflammation and tendency to develop autoimmunity are secondary to the increased infections, or whether these are parallel phenomena. We generated germ free ROS deficient Ncf1 mutant mice that when reared in specific pathogen free condition, are highly susceptible to collagen induced arthritis (CIA) compared with wild type mice. Strikingly, arthritis incidence and severity was almost identical in germ free and specific pathogen free ROS deficient mice. In addition, partial reduction of the microbial flora by antibiotics treatment did not alter the disease course. Taken together, this shows that ROS has a clear immune regulatory function that is decoupled from its function in host defence. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 02/2015;
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    ABSTRACT: Systemic inflammatory response syndrome describes a heterogeneous group of cytokine storm disorders, with different immunogens and cytokines leading to variations in organ pathology. The severe inflammation generated by the cytokine storm results in widespread organ pathology including alterations in T-and B-lymphocyte counts. This study explores the roles of TLR9 and IFN-γR stimulation in decreasing T- and B-cell lymphopoiesis in a mouse model of hyperinflammation. We demonstrate that early B-cell lymphopoiesis is severely compromised during TLR9 and IFN-γ driven hyperinflammation from the Ly-6D(+) common lymphoid progenitor (CLP) stage onwards with different effects inhibiting development at multiple stages. We show that TLR9 signaling directly decreases in vitro B-cell yields while increasing T-cell yields. IFN-γ also directly inhibits B-cell and T-cell differentiation in vitro as well as when induced by TLR9 in vivo. Microarray and RT-PCR analysis of Ly-6D(-) CLPs point to HOXa9 and EBF-1 as transcription factors altered by TLR9 induced inflammation. Our work demonstrates both cellular and molecular targets that lead to diminished B-cell lymphopoiesis in sustained TLR9 and IFN-γ driven inflammation that may be relevant in a number of infectious and autoimmune/inflammatory settings. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 01/2015;
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    ABSTRACT: It is believed that memory CD8(+) T cells are maintained in secondary lymphoid tissues, peripheral tissues and bone marrow by homeostatic proliferation. Their survival has been shown to be dependent on interleukin-7 (IL-7), but it is unclear where they acquire it. Here we show that in murine bone marrow, memory CD8(+) T cells individually colocalize with IL-7(+) reticular stromal cells. The T cells are resting in terms of global transcription and do not express markers of activation, e.g. 4-1BB (CD137), interleukin-2 or interferon-γ, despite the expression of CD69 on about 30% of the cells. 95% of the memory CD8(+) T cells in bone marrow are in G0 phase of cell cycle and do not express Ki-67. Less than 1% is in S/M/G2 of cell cycle, according to propidium iodide staining. While previous publications have estimated the extent of proliferation of CD8(+) memory T cells on the basis of BrdU incorporation, we show here, that BrdU itself induces proliferation of CD8(+) memory T cells. Taken together, the present results suggest that CD8(+) memory T cells are maintained as resting cells in the bone marrow in dedicated niches with their survival conditional on IL-7 receptor signaling. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 01/2015;