bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rai Acts as a Negative Regulator of Autoimmunity by Inhibiting Antigen Receptor Signaling and Lymphocyte Activation
Authors: Savino Maria Teresa , Ortensi Barbara , Ferro Micol , Ulivieri Cristina , Fanigliulo Daniela , Paccagnini Eugenio , Lazzi Stefano , Osti Daniela , Pelicci Giuliana , Baldari Cosima T. 
Published: April 2014

AbstractRai (ShcC) belongs to the family of Shc adaptor proteins and is expressed in neuronal cells, where it acts as a survival factor activating the PI3K/Akt survival pathway. In vivo, Rai protects the brain from ischemic damage. In this study, we show that Rai is expressed in T and B lymphocytes. Based on the finding that Rai−/− mice consistently develop splenomegaly, the role of Rai in lymphocyte homeostasis and proliferation was addressed. Surprisingly, as opposed to neurons, Rai was found to impair lymphocyte survival. Furthermore, Rai deficiency results in a reduction in the frequency of peripheral T cells with a concomitant increase in the frequency of B cells. Rai−/− lymphocytes display enhanced proliferative responses to Ag receptor engagement in vitro, which correlates with enhanced signaling by the TCR and BCR, and more robust responses to allergen sensitization in vivo. A high proportion of Rai−/− mice develop a lupus-like autoimmune syndrome characterized by splenomegaly, spontaneous peripheral T and B cell activation, autoantibody production, and deposition of immune complexes in the kidney glomeruli, resulting in autoimmune glomerulonephritis. The data identify Rai as a negative regulator of lymphocyte survival and activation and show that loss of this protein results in breaking of immunological tolerance and development of systemic autoimmunity.
Btk Regulates B Cell Receptor-Mediated Antigen Processing and Presentation by Controlling Actin Cytoskeleton Dynamics in B Cells
Authors: Sharma Shruti , Orlowski Gregory , Song Wenxia 
Published: April 2014

Abstract
The high efficiency of Ag processing and presentation by B cells requires Ag-induced BCR signaling and actin cytoskeleton reorganization, although the underlying mechanism for such requirements remains elusive. In this study, we identify Bruton’s tyrosine kinase (Btk) as a linker connecting BCR signaling to actin dynamics and the Ag transport pathway. Using xid mice and a Btk inhibitor, we show that BCR engagement increases actin polymerization and Wiskott-Aldrich syndrome protein activation in a Btk-dependent manner. Concurrently, we observe Btk-dependent increases in the levels of phosphatidylinositide-4,5-bisphosphate and phosphorylated Vav upon BCR engagement. The rate of BCR internalization, its movement to late endosomes, and efficiency of BCR-mediated Ag processing and presentation are significantly reduced in both xid and Btk inhibitor-treated B cells. Thus, Btk regulates actin dynamics and Ag transport by activating Wiskott-Aldrich syndrome protein via Vav and phosphatidylinositides. This represents a novel mechanism by which BCR-mediated signaling regulates BCR-mediated Ag processing and presentation.
Cutting Edge: Autoimmune Disease Risk Variant of STAT4 Confers Increased Sensitivity to IFN-α in Lupus Patients In Vivo
Authors: Kariuki Silvia N. , Kirou Kyriakos A. , MacDermott Emma J. , Barillas-Arias Lilliana , Crow Mary K. , Niewold Timothy B. 
Published: April 2014

Abstract
Increased IFN-α signaling is a primary pathogenic factor in systemic lupus erythematosus (SLE). STAT4 is a transcription factor that is activated by IFN-α signaling, and genetic variation of STAT4 has been associated with risk of SLE and rheumatoid arthritis. We measured serum IFN-α activity and simultaneous IFN-α-induced gene expression in PBMC in a large SLE cohort. The risk variant of STAT4 (T allele; rs7574865) was simultaneously associated with both lower serum IFN-α activity and greater IFN-α-induced gene expression in PBMC in SLE patients in vivo. Regression analyses confirmed that the risk allele of STAT4 was associated with increased sensitivity to IFN-α signaling. The IFN regulatory factor 5 SLE risk genotype was associated with higher serum IFN-α activity; however, STAT4 showed dominant influence on the sensitivity of PBMC to serum IFN-α. These data provide biologic relevance for the risk variant of STAT4 in the IFN-α pathway in vivo.
The Peroxisome Proliferator-Activated Receptor γ Agonist Rosiglitazone Ameliorates Murine Lupus by Induction of Adiponectin
Authors: Aprahamian Tamar , Bonegio Ramon G. , Richez Christophe , Yasuda Kei , Chiang Lo-Ku , Sato Kaori , Walsh Kenneth , Rifkin Ian R. 
Published: April 2014

AbstractSystemic lupus erythematosus (SLE) is an inflammatory autoimmune disease for which current therapy is suboptimal. SLE is characterized by autoantibody production, with renal disease and premature atherosclerosis being common and severe manifestations causing appreciable morbidity and mortality. Peroxisome proliferator-activated receptor γ (PPARγ) agonists are widely used in the treatment of diabetes mellitus for their insulin-sensitizing properties, but also have immunomodulatory effects. In this report, we show that the PPARγ agonist rosiglitazone reduces autoantibody production, renal disease, and atherosclerosis in mouse models of SLE. The beneficial effect of rosiglitazone on SLE manifestations depends on the induction of adiponectin, because rosiglitazone has no effect on autoantibody production or renal disease in lupus mice that lack adiponectin. In addition, lupus mice that lack adiponectin develop more severe disease than adiponectin-sufficient lupus mice, indicating that endogenous adiponectin is involved in regulating disease activity. Furthermore, administration of exogenous adiponectin ameliorates disease. These experiments suggest that PPARγ agonists may be useful agents for the treatment of SLE. They also demonstrate that induction of adiponectin is a major mechanism underlying the immunomodulatory effects of PPARγ agonists.
IL-3 Inhibits TNF-α-Induced Bone Resorption and Prevents Inflammatory Arthritis
Authors: Yogesha S. D. , Khapli Shruti M. , Srivastava Rupesh K. , Mangashetti Latha S. , Pote Satish T. , Mishra Gyan C. , Wani Mohan R. 
Published: April 2014

Abstract
IL-3, a cytokine secreted by activated T cells is well known to regulate the proliferation, differentiation, and survival of pluripotent hematopoietic stem cells. IL-3 functions as a link between the immune and the hematopoietic system. In this study, we suggest an important new role of IL-3 in inhibition of TNF-α-induced bone resorption in vitro and prevention of inflammatory arthritis in mice. We show here that IL-3 potently and irreversibly inhibits TNF-α-induced bone resorption in hematopoietic precursors of monocyte/macrophage lineage. IL-3 showed an inhibitory effect on TNF-α-induced bone resorption even in the presence of proinflammatory cytokines such as IL-1α, TGF-β1, TGF-β3, IL-6, and PGE2. We found that IL-3 prevented TNF-α-induced c-fos nuclear translocation and AP-1 DNA-binding activity. Interestingly, IL-3 pretreatment prevented the development of inflammatory arthritis in mice induced by a mixture of anti-type II collagen mAbs and LPS. Furthermore, IL-3 prevented cartilage and bone loss in the joints indirectly through inhibition of inflammation. Thus, we provide the first evidence that IL-3, a strong regulator of hematopoiesis, also plays an important role in inhibition of TNF-α-induced bone resorption and prevention of inflammatory arthritis in mice.
OX40 Costimulation Prevents Allograft Acceptance Induced by CD40-CD40L Blockade
Authors: Burrell Bryna E. , Lu Guanyi , Li Xian C. , Bishop D. Keith 
Published: April 2014

AbstractDisrupting the CD40-CD40L costimulation pathway promotes allograft acceptance in many settings. Herein, we demonstrate that stimulating OX40 overrides cardiac allograft acceptance induced by disrupting CD40-CD40L interactions. This effect of OX40 stimulation was dependent on CD4+ T cells, which in turn provided help for CD8+ T cells and B cells. Allograft rejection was associated with donor-reactive Th1 and Th2 responses and an unconventional granulocytic infiltrate and thrombosis of the arteries. Interestingly, OX40 stimulation induced a donor-reactive IgG class switch in the absence of CD40-CD40L interactions, and the timing of OX40 stimulation relative to transplantation affected the isotype of donor-reactive Ab produced. Inductive OX40 stimulation induced acute graft rejection, which correlated with both IgG1 and IgG2a deposition within the graft. Once graft acceptance was established following CD40-CD40L blockade, delayed OX40 stimulation did not induce acute allograft rejection despite priming of graft-reactive Th1 and Th2. Rather, chronic rejection was induced, which was characterized by IgG1 but not IgG2a deposition within the graft. These studies reveal both redundancy and key differences in function among costimulatory molecules that manifest in distinct pathologies of allograft rejection. These findings may help guide development of therapeutics aimed at promoting graft acceptance in transplant recipients.
Toxoplasma gondii Prevents Chromatin Remodeling Initiated by TLR-Triggered Macrophage Activation
Authors: Leng Jin , Butcher Barbara A. , Egan Charlotte E. , Abi Abdallah Delbert S. , Denkers Eric Y. 
Published: April 2014

Abstract
Macrophages infected with the opportunistic protozoan Toxoplasma gondii are unable to up-regulate many proinflammatory cytokine genes, including TNF (TNF-α), upon stimulation with LPS and other TLR ligands. In this study, we examined the influence of T. gondii on transcription factors associated with TNF-α transcription, as well as phosphorylation and acetylation of histone H3 at distal and proximal regions of the TNF-α promoter. During LPS stimulation, we found that Toxoplasma blocks nuclear accumulation of transcription factor c-Jun, but not that of cAMP response element-binding protein or NF-κB. However, chromatin immunoprecipitation studies revealed that binding of all of these transcription factors to the TNF promoter was decreased by T. gondii infection. Furthermore, the parasite blocked LPS-induced Ser10 phosphorylation and Lys9/Lys14 acetylation of histone H3 molecules associated with distal and proximal regions of the TNF-α promoter. Our results show that Toxoplasma inhibits TNF-α transcription by interfering with chromatin remodeling events required for transcriptional activation at the TNF promoter, revealing a new mechanism by which a eukaryotic pathogen incapacitates proinflammatory cytokine production during infection.
Potent and Broad-Spectrum Antimicrobial Activity of CXCL14 Suggests an Immediate Role in Skin Infections
Authors: Maerki Christa , Meuter Simone , Liebi Mark , Mühlemann Kathrin , Frederick Mitchell J. , Yawalkar Nikhil , Moser Bernhard , Wolf Marlene 
Published: April 2014

Abstract
The skin is constantly exposed to commensal microflora and pathogenic microbes. The stratum corneum of the outermost skin layer employs distinct tools such as harsh growth conditions and numerous antimicrobial peptides (AMPs) to discriminate between beneficial cutaneous microflora and harmful bacteria. How the skin deals with microbes that have gained access to the live part of the skin as a result of microinjuries is ill defined. In this study, we report that the chemokine CXCL14 is a broad-spectrum AMP with killing activity for cutaneous Gram-positive bacteria and Candida albicans as well as the Gram-negative enterobacterium Escherichia coli. Based on two separate bacteria-killing assays, CXCL14 compares favorably with other tested AMPs, including human β-defensin and the chemokine CCL20. Increased salt concentrations and skin-typical pH conditions did not abrogate its AMP function. This novel AMP is highly abundant in the epidermis and dermis of healthy human skin but is down-modulated under conditions of inflammation and disease. We propose that CXCL14 fights bacteria at the earliest stage of infection, well before the establishment of inflammation, and thus fulfills a unique role in antimicrobial immunity.
Toll-Like Receptor-Mediated Production of IL-1Ra Is Negatively Regulated by GSK3 via the MAPK ERK1/2
Authors: Rehani Kunal , Wang Huizhi , Garcia Carlos A. , Kinane Denis F. , Martin Michael 
Published: April 2014

Abstract
IL-1 receptor antagonist (IL-1Ra), a natural inhibitor of IL-1β, has been shown to regulate the progression of a variety of inflammatory diseases. Although experimental studies and clinical trials have demonstrated the importance of IL-1Ra in chronic inflammatory diseases, the cellular mechanisms responsible for regulating the endogenous production of IL-1Ra by innate immune cells are currently unresolved. In the present study, we identify that glycogen-synthase kinase 3 (GSK3) regulates the production of the anti-inflammatory cytokine IL-1Ra via its ability to regulate the MAPK ERK1/2 in TLR-stimulated cells. Elucidation of the cell-signaling pathway by which GSK3 controlled ERK activity demonstrated that GSK3 inhibition resulted in an abrogation in the levels of the inhibitory residue serine 71 on Rac1 and increased the ability of Rac1 to interact with and activate p21-activated protein kinase. siRNA-mediated knockdown of Rac1 attenuated the ability of GSK3 inhibition to augment phopsho-ERK1/2 levels in LPS-stimulated immune cells. Moreover, inhibiting the ability of GSK3 to augment ERK1/2 activity abrogated enhanced IL-1Ra production by GSK3-inhibited cells. Our findings identify that GSK3 negatively regulates the levels of IL-1Ra produced by LPS-stimulated innate immune cells.
Inflammatory Cytokine Production by Human Neutrophils Involves C/EBP Transcription Factors
Authors: Cloutier Alexandre , Guindi Chantal , Larivée Pierre , Dubois Claire M. , Amrani Abdelaziz , McDonald Patrick P. 
Published: April 2014

Abstract
A growing number of neutrophil-derived cytokines have proven to be crucial to various inflammatory and immune processes in vivo. Whereas C/EBP (CCAAT/enhancer-binding protein) transcription factors are important for neutrophil differentiation from myeloid precursors, we report herein that they also regulate cytokine production in mature neutrophils. All known C/EBP proteins but C/EBPγ are expressed in neutrophils; most isoforms localize to the nucleus, except for C/EBPα, which is cytoplasmic. Neutrophil stimulation does not alter the overall levels, cellular distribution, or turnover of C/EBP proteins; it also does not further induce the constitutive DNA-binding activity detected in nuclear extracts, consisting of C/EBPβ and C/EBPε. However, nuclear C/EBPβ is rapidly phosphorylated upon cell stimulation, suggesting that it can activate cytokine promoters. Indeed, the transactivation of an IL-8 promoter-luciferase construct in a human neutrophil-like cell line was impaired when its C/EBP or NF-κB sites were mutated. Overexpression of a C/EBP repressor also impeded IL-8 promoter transactivation, as well as the generation of IL-8, Mip-1α, and Mip-1β in this cellular model, whereas TNF-α generation was mostly unaffected. Finally, overexpression of a C/EBPβ mutant (T235A) as well as chromatin immunoprecipitation assays unveiled an important role for this residue in cytokine induction. This is the first demonstration that C/EBP factors are important regulators of cytokine expression in human neutrophils.
IL-10 Enhances MD-2 and CD14 Expression in Monocytes and the Proteins Are Increased and Correlated in HIV-Infected Patients
Authors: Sandanger Øystein , Ryan Liv , Bohnhorst Janne , Iversen Ann-Charlotte , Husebye Harald , Halaas Øyvind , Landrø Linn , Aukrust Pål , Frøland Stig S. , Elson Greg , Visintin Alberto , Øktedalen Olav , Damås Jan Kristian , Sundan Anders , Golenbock Douglas , Espevik Terje 
Published: April 2014

AbstractSoluble proteins that bind LPS, like myeloid differentiation-2 (MD-2) and CD14, have essential roles in regulating LPS signaling through TLR4. During a Gram-negative bacterial infection, the host may control the response by adjusting the levels of soluble MD-2 and CD14. To address the surface expression of MD-2 on human leukocytes, we developed a mAb, IIC1, that recognized MD-2 both free and when bound to TLR4. MD-2 was found on the surface of freshly isolated monocytes, on a subpopulation of CD19+ B-cells and on CD15+ neutrophils. LPS transiently reduced the MD-2 levels on monocytes, which is most likely due to endocytosis of the LPS receptor complex since MD-2 colocalized with TLR4 in early endosomes after LPS stimulation. In the absence of LPS, MD-2 partly colocalized with TLR4 in Golgi trans and medial compartments. Cultivating monocytes for 18–20 h resulted in loss of MD-2 expression on the surface, which was reversed either by LPS or IL-10. Furthermore, addition of IL-10, but not LPS, resulted in a considerable increase in mRNA for both MD-2 and CD14. Using ELISA, we demonstrated that IL-10 had a profound dose- and time-related effect on the release of soluble MD-2 and soluble CD14 from monocytes. In HIV-infected patients, the amounts of MD-2, CD14, and IL-10 increased significantly in the patient group with AIDS. Of interest, we found that IL-10, CD14, and MD-2 levels were positively correlated, suggesting that IL-10 may be a driving force for increased release of MD-2 and CD14 during systemic inflammation.
Identification and Characterization of a Transmembrane Isoform of CD160 (CD160-TM), a Unique Activating Receptor Selectively Expressed upon Human NK Cell Activation
Authors: Giustiniani Jérôme , Bensussan Armand , Marie-Cardine Anne 
Published: April 2014

Abstract
CD160 has been initially identified as a GPI-anchored MHC-class I activating receptor mainly expressed on peripheral blood NK cells. Herein, we report the identification of three additional CD160-related mRNAs generated through alternative splicings of the CD160 gene, among which one encoded a putative CD160 transmembrane isoform (CD160-TM). We first establish that CD160-TM surface expression is highly restricted to NK cells and is activation-dependent. Additionally, we provide evidence that CD160-TM represents a novel activating receptor, as assessed by the increased CD107a NK cell surface mobilization observed upon its engagement. Finally, we demonstrate that the CD160-TM cytoplasmic tail is by itself sufficient to mediate the recruitment of Erk1/2 signaling pathway, and that the initiation of this activation process is dependent on the Src-family kinase p56lck. The identification of CD160-TM therefore provides new possibilities regarding the role of CD160 isoforms in the regulation of NK cell functions.
Involvement of the Apoptotic Mechanism in Pemphigus Foliaceus Autoimmune Injury of the Skin
Authors: Li Ning , Zhao Minglang , Wang Jinzhao , Liu Zhi , Diaz Luis A. 
Published: April 2014

Abstract
Pemphigus foliaceus (PF) is an organ-specific autoimmune skin disease characterized by subcorneal epidermal cell detachment (acantholysis) and pathogenic autoantibodies against desmoglein 1. The mechanism responsible for pemphigus autoantibody-induced epidermal injury is not fully understood. In this study, we used the IgG passive transfer mouse model of PF to investigate the relevance of the apoptotic mechanism in pemphigus pathogenesis. TUNEL-positive epidermal cells and increased oligonucleosomes in the epidermal cytosolic fractions were detected in the diseased mice. Time course study reveals that TUNEL-positive epidermal cells appear before intraepidermal blisters. Moreover, the proapoptotic factor Bax was up-regulated at the earlier time points (2 and 4 h), whereas the antiapoptotic factor Bcl-xL was down-regulated at the later time points (6, 8, and 20 h) post-PF IgG injection by Western blot analysis. The active forms of caspase-3 and -6 were detected at the later time period (6, 8, and 20 h). Administration of Ac-DEVD-cmk, a peptide-based caspase-3/7 inhibitor, protected mice from developing intraepidermal blisters and clinical disease induced by PF IgG. The same protective effect was also observed using a broad-spectrum caspase inhibitor, Bok-D-fmk. Collectively, these findings show that biochemical events of apoptosis are provoked in the epidermis of mice injected with PF autoantibodies. Caspase activation may contribute to acantholytic blister formation in PF.
The CD70/CD27 Pathway Is Critical for Stimulation of an Effective Cytotoxic T Cell Response against B Cell Precursor Acute Lymphoblastic Leukemia
Authors: Glouchkova Ludmila , Ackermann Birgit , Zibert Andree , Meisel Roland , Siepermann Meinolf , Janka-Schaub Gritta E. , Goebel Ulrich , Troeger Anja , Dilloo Dagmar 
Published: April 2014

Abstract
For effective immunotherapy, maintaining the frequency and cytotoxic potential of effector cells is critical. In this context costimulation via the CD70/CD27 pathway has been proven essential. CD70 has been reported to be expressed to varying degrees on malignant B cells. However, in B cell precursor acute lymphboblastic leukemia, the most common childhood malignancy, the role of CD70 in stimulation of antileukemic T cell responses has so far not been delineated. Herein we demonstrate that in B cell precursor acute lymphboblastic leukemia expression of CD70 is low but can be induced upon blast activation via CD40. Both CD70 and CD80/CD86 up-regulated on CD40-stimulated blasts contribute to primary stimulation of T cell proliferation and cytokine production in an additive manner. These two signals also cooperate in the prevention of T cell anergy. In contrast to blockade of CD70 during the effector phase, inhibition of CD70-mediated costimulation during generation of antileukemic T cells prevents effector cell proliferation and reduces their cytotoxic capacity. Modulation of the CD70/CD27 pathway may thus represent a novel therapeutic approach for augmenting magnitude and quality of the antileukemic response in B cell precursor acute lymphboblastic leukemia.
Functional Analysis of Killer Ig-Like Receptor-Expressing Cytomegalovirus-Specific CD8+ T Cells
Authors: van der Veken Lars T. , Diez Campelo Maria , van der Hoorn Menno A. W. G. , Hagedoorn Renate S. , van Egmond H. M. Esther , van Bergen Jeroen , Willemze Roel , Falkenburg J. H. Frederik , Heemskerk Mirjam H. M. 
Published: April 2014

Abstract
Killer Ig-like receptors (KIR) are expressed by human NK cells and T cells. Although Ag-specific cytolytic activity and cytokine production of KIR+ T cells can be inhibited by KIR ligation, the effect of KIR on proliferation is unclear. KIR+ T cells have been reported to have a general proliferative defect. To investigate whether KIR+ T cells represent end-stage dysfunctional T cells, we characterized KIR+ CMV-specific T cells in allogeneic stem cell transplantation patients and healthy donors. In both patients and healthy donors, a significant percentage KIR+ T cells was detected at various time points. All stem cell transplantation patients studied showed KIR expression on CMV-specific T cells, while not all donors had KIR-expressing CMV-specific T cells. From two of the patients and one donor KIR+ CMV-specific T clones were isolated and analyzed functionally. T cells were detected that expressed KIR that could not encounter their corresponding KIR ligands in vivo, illustrating that KIR expression by these T cells was not based on functional selection but a random process. Our data demonstrate that KIR+ T cells are fully functional T cells that are only restricted in effector functions and proliferation upon KIR ligation. The level of KIR-mediated inhibition of the effector functions and proliferation depended on the strength of TCR stimulation. We observed no diminished general proliferative capacity and therefore we conclude that these T cells do not represent end-stage dysfunctional T cells.