bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complement Activation on B Lymphocytes Opsonized with Rituximab or Ofatumumab Produces Substantial Changes in Membrane Structure Preceding Cell Lysis
Authors: Beum Paul V. , Lindorfer Margaret A. , Beurskens Frank , Stukenberg P. Todd , Lokhorst Henk M. , Pawluczkowycz Andrew W. , Parren Paul W. H. I. , van de Winkel Jan G. J. , Taylor Ronald P. 
Published: April 2014

AbstractBinding of the CD20 mAb rituximab (RTX) to B lymphocytes in normal human serum (NHS) activates complement (C) and promotes C3b deposition on or in close proximity to cell-bound RTX. Based on spinning disk confocal microscopy analyses, we report the first real-time visualization of C3b deposition and C-mediated killing of RTX-opsonized B cells. C activation by RTX-opsonized Daudi B cells induces rapid membrane blebbing and generation of long, thin structures protruding from cell surfaces, which we call streamers. Ofatumumab, a unique mAb that targets a distinct binding site (the small loop epitope) of the CD20 Ag, induces more rapid killing and streaming on Daudi cells than RTX. In contrast to RTX, ofatumumab promotes streamer formation and killing of ARH77 cells and primary B cells from patients with chronic lymphocytic leukemia. Generation of streamers requires C activation; no streaming occurs in media, NHS-EDTA, or in sera depleted of C5 or C9. Streamers can be visualized in bright field by phase imaging, and fluorescence-staining patterns indicate they contain membrane lipids and polymerized actin. Streaming also occurs if cells are reacted in medium with bee venom melittin, which penetrates cells and forms membrane pores in a manner similar to the membrane-attack complex of C. Structures similar to streamers are demonstrable when Ab-opsonized sheep erythrocytes (non-nucleated cells) are reacted with NHS. Taken together, our findings indicate that the membrane-attack complex is a key mediator of streaming. Streamer formation may, thus, represent a membrane structural change that can occur shortly before complement-induced cell death.
Mechanisms of Immunity in Hydatid Disease: Implications for Vaccine Development
Authors: Zhang Wenbao , Ross Allen G. , McManus Donald P. 
Published: April 2014

Abstract
The Echinococcus organisms, the cause of echinococcosis (hydatid disease), are parasitic helminths with life cycles involving a carnivorous definitive host (usually dog or fox) and an intermediate host (human, ungulate, or rodent). They are complex multicellular pathogens that, despite being under constant barrage by the immune system, are able to modulate antiparasite immune responses and persist and flourish in their mammalian hosts. Understanding how the immune system deals with these parasites is a major challenge. Recent application of modern molecular and immunological approaches has revealed insights on the nature of immune responses generated during the course of hydatid infection, although many aspects of the Echinococcus-host interplay remain unexplored. This review summarizes current understanding of the immunology of echinococcosis, indicates areas where information is lacking, and shows how knowledge of host protective immunity has been translated into the design and development of anti-Echinococcus vaccines for application in intermediate hosts.
Cutting Edge: Helminth Infection Induces IgE in the Absence of μ- or δ-Chain Expression
Authors: Perona-Wright Georgia , Mohrs Katja , Taylor Justin , Zaph Colby , Artis David , Pearce Edward J. , Mohrs Markus 
Published: April 2014

Abstract
Infections with helminth parasites are associated with an IgE isotype switch and high serum IgE concentrations. IgE is rapidly bound by the high affinity IgE receptor (FcεRI), thereby sensitizing FcεRI-bearing basophils and mast cells for IgE-inducible effector functions such as IL-4 production. The development of Ab-secreting B cells is dependent on IgM and consequently, μMT mice, which lack surface IgM, are considered devoid of Abs. In this study we report the unexpected finding that C57BL/6 μMT mice generate robust IgE responses upon infection with three distinct helminth parasites, Heligmosomoides polygyrus, Trichuris muris, and Schistosoma mansoni. IgE is produced despite an apparent block in B cell development and licenses basophils for IgE-induced IL-4 production. Our findings reveal the existence of an evolutionarily conserved, IgM-independent pathway for the production of IgE upon infection with helminth parasites.
Interaction of Monocytes with NK Cells upon Toll-Like Receptor-Induced Expression of the NKG2D Ligand MICA
Authors: Kloss Mercedes , Decker Patrice , Baltz Katrin M. , Baessler Tina , Jung Gundram , Rammensee Hans-Georg , Steinle Alexander , Krusch Matthias , Salih Helmut R. 
Published: April 2014

AbstractReciprocal interactions between NK cells and dendritic cells have been shown to influence activation of NK cells, maturation, or lysis of dendritic cells and subsequent adaptive immune responses. However, little is known about the crosstalk between monocytes and NK cells and the receptors involved in this interaction. We report in this study that human monocytes, upon TLR triggering, up-regulate MHC class I-Related Chain (MIC) A, but not other ligands for the activating immunoreceptor NKG2D like MICB or UL-16 binding proteins 1–3. MICA expression was associated with CD80, MHC class I and MHC class II up-regulation, secretion of proinflammatory cytokines, and apoptosis inhibition, but was not accompanied by release of MIC molecules in soluble form. TLR-induced MICA on the monocyte cell surface was detected by autologous NK cells as revealed by NKG2D down-regulation. Although MICA expression did not render monocytes susceptible for NK cell cytotoxicity, LPS-treated monocytes stimulated IFN-γ production of activated NK cells which was substantially dependent on MICA-NKG2D interaction. No enhanced NK cell proliferation or cytotoxicity against third-party target cells was observed after stimulation of NK cells with LPS-activated monocytes. Our data indicate that MICA-NKG2D interaction constitutes a mechanism by which monocytes and NK cells as an early source of IFN-γ may communicate directly during an innate immune response to infections in humans.
Lipopolysaccharide-Induced Expression of NAD(P)H:Quinone Oxidoreductase 1 and Heme Oxygenase-1 Protects against Excessive Inflammatory Responses in Human Monocytes
Authors: Rushworth Stuart A. , MacEwan David J. , O'Connell Maria A. 
Published: April 2014

Abstract
Monocytes play a central role in the immunopathological effects of sepsis. This role is mediated by production of the cytokines TNF-α and IL-1β. The transcription factor NF-E2-related factor 2 (Nrf2) regulates innate immune responses in various experimental disease models. Presently, the role of Nrf2-regulated genes in LPS-treated human monocytes is not well defined. Herein we show that Nrf2 mediates a significant regulation of LPS-induced inflammatory responses. Analysis of Nrf2-regulated gene expression in human monocytes showed that LPS induced the expression of the phase II detoxification gene NAD(P)H:quinone oxidoreductase 1 (NQO1). Furthermore, NQO1 mRNA or protein expression in response to LPS was regulated by Nrf2. Silencing Nrf2 expression in human monocytes inhibited LPS-induced NQO1 expression; however, in contrast, it significantly increased TNF and IL-1β production. Silencing expression of NQO1 alone, or in combination with heme oxygenase-1 (HO-1) silencing, markedly increased LPS-induced TNF and IL-1β expression. Additionally, overexpression of NQO1 and/or HO-1 inhibited LPS-induced TNF and IL-1β expression. These results show for the first time that LPS induces NQO1 and HO-1 expression in human monocytes via Nrf2 to modulate their inflammatory responsiveness, thus providing novel potential therapeutic strategies for the treatment of sepsis.
The Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Induce the Expression of Programmed Death-1 and Its Ligands
Authors: Kinter Audrey L. , Godbout Emily J. , McNally Jonathan P. , Sereti Irini , Roby Gregg A. , O'Shea Marie A. , Fauci Anthony S. 
Published: April 2014

Abstract
The programmed death (PD)-1 molecule and its ligands (PD-L1 and PD-L2), negative regulatory members of the B7 family, play an important role in peripheral tolerance. Previous studies have demonstrated that PD-1 is up-regulated on T cells following TCR-mediated activation; however, little is known regarding PD-1 and Ag-independent, cytokine-induced T cell activation. The common γ-chain (γc) cytokines IL-2, IL-7, IL-15, and IL-21, which play an important role in peripheral T cell expansion and survival, were found to up-regulate PD-1 and, with the exception of IL-21, PD-L1 on purified T cells in vitro. This effect was most prominent on memory T cells. Furthermore, these cytokines induced, indirectly, the expression of PD-L1 and PD-L2 on monocytes/macrophages in PBMC. The in vivo correlate of these observations was confirmed on PBMC isolated from HIV-infected individuals receiving IL-2 immunotherapy. Exposure of γc cytokine pretreated T cells to PD-1 ligand-IgG had no effect on STAT5 activation, T cell proliferation, or survival driven by γc cytokines. However, PD-1 ligand-IgG dramatically inhibited anti-CD3/CD28-driven proliferation and Lck activation. Furthermore, following restimulation with anti-CD3/CD28, cytokine secretion by both γc cytokine and anti-CD3/CD28 pretreated T cells was suppressed. These data suggest that γc cytokine-induced PD-1 does not interfere with cytokine-driven peripheral T cell expansion/survival, but may act to suppress certain effector functions of cytokine-stimulated cells upon TCR engagement, thereby minimizing immune-mediated damage to the host.
Aging Impairs IFN Regulatory Factor 7 Up-Regulation in Plasmacytoid Dendritic Cells during TLR9 Activation
Authors: Stout-Delgado Heather W. , Yang Xin , Walker Wendy E. , Tesar Bethany M. , Goldstein Daniel R. 
Published: April 2014

Abstract
Plasmacytoid dendritic cells (pDCs) are innate sensors that produce IFN-α in response to viral infections. Determining how aging alters the cellular and molecular function of these cells may provide an explanation of increased susceptibility of older people to viral infections. Hence, we examined whether aging critically impairs pDC function during infection with HSV-2, a viral pathogen that activates TLR9. We found that impaired IFN-α production by aged murine pDCs led to impaired viral clearance with aging. Upon TLR9 activation, aged pDCs displayed defective up-regulation of IFN-regulatory factor 7, a key adaptor in the type I IFN pathway, as compared with younger counterparts. Aged pDCs had more oxidative stress, and reducing oxidative stress in aged pDCs partly recovered the age-induced IFN-α defect during TLR9 activation. In sum, aging impairs the type I IFN pathway in pDCs, and this alteration may contribute to the increased susceptibility of older people to certain viral infections.
Regulatory Roles for NKT Cell Ligands in Environmentally Induced Autoimmunity
Authors: Vas Jaya , Mattner Jochen , Richardson Stewart , Ndonye Rachel , Gaughan John P. , Howell Amy , Monestier Marc 
Published: April 2014

Abstract
The development of autoimmune diseases is frequently linked to exposure to environmental factors such as chemicals, drugs, or infections. In the experimental model of metal-induced autoimmunity, administration of subtoxic doses of mercury (a common environmental pollutant) to genetically susceptible mice induces an autoimmune syndrome with rapid anti-nucleolar Ab production and immune system activation. Regulatory components of the innate immune system such as NKT cells and TLRs can also modulate the autoimmune process. We examined the interplay among environmental chemicals and NKT cells in the regulation of autoimmunity. Additionally, we studied NKT and TLR ligands in a tolerance model in which preadministration of a low dose of mercury in the steady state renders animals tolerant to metal-induced autoimmunity. We also studied the effect of Sphingomonas capsulata, a bacterial strain that carries both NKT cell and TLR ligands, on metal-induced autoimmunity. Overall, NKT cell activation by synthetic ligands enhanced the manifestations of metal-induced autoimmunity. Exposure to S. capsulata exacerbated autoimmunity elicited by mercury. Although the synthetic NKT cell ligands that we used are reportedly similar in their ability to activate NKT cells, they displayed pronounced differences when coinjected with environmental agents or TLR ligands. Individual NKT ligands differed in their ability to prevent or break tolerance induced by low-dose mercury treatment. Likewise, different NKT ligands either dramatically potentiated or inhibited the ability of TLR9 agonistic oligonucleotides to disrupt tolerance to mercury. Our data suggest that these differences could be mediated by the modification of cytokine profiles and regulatory T cell numbers.
Enhanced Early Expansion and Maturation of Semi-Invariant NK T Cells Inhibited Autoimmune Pathogenesis in Congenic Nonobese Diabetic Mice
Authors: Ueno Aito , Wang Jianxiong , Cheng Lu , Im Jin S. , Shi Yan , Porcelli Steven A. , Yang Yang 
Published: April 2014

Abstract
Semi-invariant NK T cell (iNKT) deficiency has long been associated with the pathogenesis of type 1 diabetes (T1D), but the linkage between this the deficiency and T1D susceptibility gene(s) remains unclear. We analyzed NOD mice subcongenic for resistant alleles of Idd9 locus in search for protective mechanisms against T1D, and found that iNKT cell development was significantly enhanced with a more advanced mature phenotype and function in mice containing Idd9.1 sublocus of B10 origin. The enhanced iNKT cell development and function suppressed effector function of diabetogenic T cells. Elimination of iNKT cells by CD1d deficiency almost abolished T1D protection in these mice. Interestingly, although the iNKT cells were responsible for a Th2 orientated cytokine profile that is often regarded as a mechanism of T1D prevention, our data suggests that the Th2 bias played little if any role for the protection. In addition, dendritic cells from the congenic NOD mice showed increased abilities to engage and potentiate iNKT cells, suggesting that a mechanism mediated by dendritic cells or other APCs may be critical for the enhanced development and maturation of iNKT cells. The products of T1D susceptibility gene(s) in Idd9.1 locus may be a key factor for this mechanism.
Caspase 6 Regulates B Cell Activation and Differentiation into Plasma Cells
Authors: Watanabe Chie , Shu Geraldine L. , Zheng Timothy S. , Flavell Richard A. , Clark Edward A. 
Published: April 2014

Abstract
Caspase (Casp) family proteases regulate not only lymphocyte apoptosis but also lymphocyte activation and development. In this study, we show that Casp6 regulates B cell activation and differentiation into plasma cells by modifying cell cycle entry. B cells from Casp6 knockout (Casp6 KO) mice examined ex vivo have more cells in G1 than wild-type B cells, and mitogen-induced G1 entry of Casp6 KO B cells is much faster than that of wild-type B cells. Even so, S phase entry and proliferation are not increased in Casp6 KO B cells. Rather than proliferating, activated Casp6 KO B cells preferentially differentiate into syndecan-1+ plasma cells and produce Abs. In Casp6 KO mice compared with WT mice, serum levels of IgG1, IgG2a, and IgG2b are increased and Ag-specific Ab responses are also enhanced along with increased percentages of syndecan-1+ plasma cells. Casp6 may regulate both B cell activation and differentiation by modifying requirements for G0 B cells to enter G1.
Experimental Antibody Therapy of Liver Metastases Reveals Functional Redundancy between FcγRI and FcγRIV
Authors: Otten Marielle A. , van der Bij Gerben J. , Verbeek Sjef J. , Nimmerjahn Falk , Ravetch Jeffrey V. , Beelen Robert H. J. , van de Winkel Jan G. J. , van Egmond Marjolein 
Published: April 2014

Abstract
Many patients with colorectal cancer will develop liver metastases, even after successful surgical removal of the primary tumor at a time at which no visible metastases are present. We previously demonstrated that surgery—although mandatory—paradoxically enhances the risk of developing liver metastases. Because Ab therapy has been acknowledged as a successful strategy to treat malignancies, we studied the potential of postoperative adjuvant Ab therapy to prevent outgrowth of liver metastases. Treatment with murine anti-gp75 (TA99) mAb completely prevented outgrowth of B16F10 liver metastases in over 90% of mice. Therapeutic efficacy was maintained in either C1q- or complement receptor 3-deficient mice but was completely abrogated in FcR γ-chain knockout mice. This indicates that the classical complement pathway was not essential, but interaction with activatory FcγR was necessary for successful therapy. TA99-treatment was still effective in FcγRI−/−, FcγRIII−/−, FcγRI/III−/−, and FcγRI/II/III−/− mice, suggesting an important role for FcγRIV. However, wild-type mice that were treated with TA99 Abs and an FcγRIV blocking Ab (mAb 9E9) were protected against development of liver metastases as well. Only when both FcγRI and FcγRIV functions were simultaneously inhibited, TA99-mediated curative Ab treatment was abrogated, indicating functional redundancy between both IgG receptors in the liver. Furthermore, depletion of liver macrophages (Kupffer cells) reduced the efficacy of Ab therapy, supporting that Kupffer cells are involved as effector cells. Importantly, since Ab treatment almost completely prevented development of liver metastases, postoperative adjuvant Ab therapy may help to improve patient prognosis.
IL-21 Stimulates Human Myeloma Cell Growth through an Autocrine IGF-1 Loop
Authors: Ménoret Emmanuelle , Maïga Sophie , Descamps Géraldine , Pellat-Deceunynck Catherine , Fraslon Caroline , Cappellano Melania , Moreau Philippe , Bataille Régis , Amiot Martine 
Published: April 2014

Abstract
IL-21 is a member of the type I cytokine family related most closely to IL-2 and IL-15. IL-21 is a pleiotropic cytokine, produced by T, NKT, and dendritic cells, which modulates lymphoid and myeloid cell functions. Besides its activities on normal lymphoid cells, it has been shown that IL-21 is a growth factor for myeloma cells. In the present study, we demonstrate that IL-21 generated myeloma colonies from 9 of 24 human myeloma cell lines (HMCL) in a collagen-based assay. Of major interest, the capacity of IL-21 to stimulate clonogenicity was restricted to CD45− HMCL. We found that IL-21 induced tyrosine phosphorylation of STAT-3, STAT-1, and Erk1/2. Interestingly, an Akt activation was observed lately after 30 min to 1 h of IL-21 stimulation, indicating that this Akt phosphorylation could be due to an IGF-1 autocrine loop. This hypothesis was sustained both by the fact that IL-21 treatment induced an IGF-1 mRNA synthesis and that an antagonistic anti-IGF-1 receptor mAb (AVE1642) strongly inhibits the IL-21-induced clonogenicity. Thus, we demonstrated by quantitative PCR that IL-21 induced clonogenicity through an autocrine IGF-1 secretion in HMCL and primary myeloma cells. Because we have previously demonstrated that CD45 phosphatase inhibits the IGF-1 signaling, this inhibitory effect of CD45 explains why the IL-21-induced clonogenicity was restricted to CD45− HMCL. These results support that therapy against IGF-1R, which are presently under investigation in multiple myeloma, could be beneficial, not only to suppress IGF-1-mediated myeloma cell growth, but also IL-21-mediated myeloma cell growth.
Neuropeptide Y Is Expressed by Rat Mononuclear Blood Leukocytes and Strongly Down-Regulated during Inflammation
Authors: Holler Julia , Zakrzewicz Anna , Kaufmann Andreas , Wilhelm Jochen , Fuchs-Moll Gabriele , Dietrich Hartmut , Padberg Winfried , Kuncová Jitka , Kummer Wolfgang , Grau Veronika 
Published: April 2014

Abstract
Neuropeptide Y (NPY), a classical sympathetic comediator, regulates immunological functions including T cell activation and migration of blood leukocytes. A NPY-mediated neuroimmune cross-talk is well conceivable in sympathetically innervated tissues. In denervated, e.g., transplanted organs, however, leukocyte function is not fundamentally disturbed. Thus, we hypothesized that NPY is expressed by blood leukocytes themselves and regulated during inflammation. NPY mRNA and peptide expression were analyzed in mononuclear leukocytes isolated from the blood vessels of healthy rat kidneys, as well as from the blood vessels of isogeneic and allogeneic renal grafts transplanted in the Dark Agouti to Lewis or in the Fischer 344 to Lewis rat strain combination. Depending on the donor strain, acute allograft rejection is either fatal or reversible but both experimental models are characterized by massive accumulation of intravascular leukocytes. Leukocytes, predominantly monocytes, isolated from the blood vessels of untreated kidneys and isografts expressed high amounts of NPY mRNA and peptide, similar to expression levels in sympathetic ganglia. During acute allograft rejection, leukocytic NPY expression drastically dropped to ∼1% of control levels in both rat strain combinations. In conclusion, NPY is an abundantly produced and tightly regulated cytokine of mononuclear blood leukocytes.
IFN-γ-Dependent Regulatory Circuits in Immune Inflammation Highlighted in Diabetes
Authors: Calderon Boris , Suri Anish , Pan Xiaoou O. , Mills Jason C. , Unanue Emil R. 
Published: April 2014

AbstractWe demonstrate diverse roles of IFN-γ in the induction and regulation of immune-mediated inflammation using a transfer model of autoimmune diabetes. The diabetogenic CD4+BDC2.5 (BDC) T cell clone upon transfer into NOD.scid mice induced destruction of islets of Langerhans leading to diabetes. Administration of a neutralizing Ab to IFN-γ (H22) resulted in long-term protection (LTP) from diabetes, with inflammation but persistence of a significant, albeit decreased, number of β cells. BDC T cells were a mixture of cells expressing high, intermediate, and low levels of the TCR. Clonotypelow BDC T cells were required for LTP. Furthermore, islet-infiltrating leukocytes in the LTP mice contained Foxp3+CD4 T cells. Islet inflammation in both diabetic and LTP mice was characterized by heavy infiltration of macrophages. Gene expression profiles indicated that macrophages in diabetic mice were M1 type, while LTP mice contained M2 differentiated. The LTP was abolished if mice were treated with either Ab-depleting CD4 T cells or a neutralizing Ab to CTLA-4, in this case, only at a late stage. Neutralization of IL-10, TGF-β, glucocorticoid-induced TNF receptor (GITR), or CD25 had no effect. Transfer of only clonotypehigh- expressing BDC T cells induced diabetes; in contrast, H22 Abs did not inhibit diabetes. While clonotypehigh T cells induced diabetes even when IFN-γ was neutralized, paradoxically there was reduced inflammation and no diabetes if host myeloid cells lacked IFN-γ receptor. Hence, using monoclonal CD4 T cells, IFN-γ can have a wide diversity of roles, depending on the setting of the immune process.
Dynamin 2 Regulates Granule Exocytosis during NK Cell-Mediated Cytotoxicity
Authors: Arneson Laura N. , Segovis Colin M. , Gomez Timothy S. , Schoon Renee A. , Dick Christopher J. , Lou Zhenkun , Billadeau Daniel D. , Leibson Paul J. 
Published: April 2014

Abstract
NK cells are innate immune cells that can eliminate their targets through granule release. In this study, we describe a specialized role for the large GTPase Dynamin 2 (Dyn2) in the regulation of these secretory events leading to cell-mediated cytotoxicity. By modulating the expression of Dyn2 using small interfering RNA or by inhibiting its activity using a pharmacological agent, we determined that Dyn2 does not regulate conjugate formation, proximal signaling, or granule polarization. In contrast, during cell-mediated killing, Dyn2 localizes with lytic granules and polarizes to the NK cell–target interface where it regulates the final fusion of lytic granules with the plasma membrane. These findings identify a novel role for Dyn2 in the exocytic events required for effective NK cell-mediated cytotoxicity.