bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of TNF-α Produced by Nonantigen-Specific Cells in a Fulminant Hepatitis Mouse Model
Authors: Ito Hiroyasu , Ando Kazuki , Ishikawa Tetsuya , Saito Kuniaki , Takemura Masao , Imawari Michio , Moriwaki Hisataka , Seishima Mitsuru 
Published: April 2014

Abstract
In previous studies, the mechanisms of acute liver injury and virus exclusion have been examined using a model wherein HBsAg-specific CTL are injected into HBsAg transgenic (Tg) mice. The importance of the role of TNF-α in virus exclusion was shown, but its role in liver injury was unclear. We crossed the TNF-α knockout mouse and HBsAg-Tg mouse to establish the HBsAg-Tg/TNF-α KO mouse, and examined the influence of TNF-α on liver injury. The severity of liver damage, as determined by serum alanine aminotransferase activity, was ∼100 times greater in HBsAg-Tg/TNF-α+/+ than in HBsAg-Tg/TNF-α−/− mice after i.v. administration of 5 × 106 CTLs. This liver damage reached the peak of its severity within 24–48 h, and was restored 7 days later. Histopathological examination showed hepatocellular necrosis and inflammatory cell infiltrate 24 h after the CTL injection in HBsAg-Tg/TNF-α+/+ mice but not in HBsAg-Tg/TNF-α−/− mice. The liver damage was fatal for all HBsAg-Tg/TNF-α+/+ mice that received 1.5 × 107 CTLs. In contrast, 1.5 × 107 CTLs could not kill the HBsAg-Tg/TNF-α−/− mice. The TNF-α production level was enhanced after the CTL injection in not only intrahepatic macrophages but also other types of mononuclear cells from non-HBsAg-Tg/TNF-α+/+ mice. An adoptive transfer examination revealed that severe liver damage occurred in HBsAg-Tg/TNF-α−/− mice that had received mononuclear cells from TNF-α+/+ mice. In conclusion, the present study provides evidence that TNF-α produced by intrahepatic non-Ag-specific inflammatory cells is critical in the development of lethal necroinflammatory liver disease.
Two Structurally Different Rituximab-Specific CD20 Mimotope Peptides Reveal That Rituximab Recognizes Two Different CD20-Associated Epitopes
Authors: Perosa Federico , Favoino Elvira , Vicenti Chiara , Guarnera Andrea , Racanelli Vito , De Pinto Vito , Dammacco Franco 
Published: April 2014

Abstract
Peptide mimotopes of the CD20 epitope recognized by rituximab are useful tools for studying this therapeutic mAb’s functional properties. We previously identified two structurally different peptides that are both effective mimotopes: a 7-mer cyclic peptide (Rp15-C) bearing the antigenic motif a/sNPS that matches 170ANPS173 of the extracellular loop of CD20, and a 12-mer linear peptide (Rp5-L) containing the antigenic motif WPxWLE lacking sequence homology to CD20. In this study, we investigated whether the different structures of Rp15-C and Rp5-L reflect the mimicry of the same or different CD20 epitopes recognized by rituximab. Using immunochemical methods, we found that, like Rp15-C, Rp5-L mimics the raft-associated form of CD20 (by inhibiting rituximab binding to CD20 in vitro). Rp5-L and Rp15-C elicit, in immunized mice, anti-CD20 Abs that stain CD20+ cells with a punctate pattern similar to that of rituximab. However, only anti-Rp5-L Abs recognize denatured CD20. When phage-display peptide libraries were panned with anti-Rp5-L, phage clones were enriched that expressed the consensus qWPxwL, similar to the antigenic motif WPxWLE, but not matching a/sNPS. Finally, WPxWLE and ANPS share some, but not all, contact sites within the rituximab Ag-combining site, indicating that WPxWLE is not an exact replica of Rp15-C (or CD20) ANPS. Altogether, these results indicate that the two structurally different peptides are also conformationally different, and suggest that rituximab recognizes two different CD20-associated epitopes.
Programmed Necrotic Cell Death Induced by Complement Involves a Bid-Dependent Pathway
Authors: Ziporen Lea , Donin Natalie , Shmushkovich Taisia , Gross Atan , Fishelson Zvi 
Published: April 2014

Abstract
The membrane attack complex (MAC) of the complement system induces a necrotic-type cell death. Earlier findings suggested that Bcl-2 protects cells from MAC-induced necrosis. Here we examined the involvement of Bid, a proapoptotic protein, in MAC-induced cytotoxicity. Bid knockout (Bid−/−) mouse embryonic fibroblasts (MEF) and primary fibroblasts were damaged by complement but to a significantly lower extent than wild-type (WT) fibroblasts. Bid silencing with small interfering RNA duplexes led to elevated resistance of mouse fibroblasts, human K562, and Jurkat cells to lysis by complement. Bid−/− MEF were also resistant to toxic doses of streptolysin O, melittin, and A23187. Analysis of complement protein deposition on fibroblasts demonstrated that less complement C3 and C9 bound to Bid−/− than to WT cells, even though expression of the membrane complement inhibitors Crry and CD59 was relatively reduced on Bid−/− cells. Bid was rapidly cleaved in WT MEF subjected to lytic doses of MAC. Pretreatment of the cells with the pan-caspase inhibitor z-Val-Ala-Asp(OMe)-fluoromethylketone reduced Bid cleavage and cell lysis. These results indicate that complement MAC activates two cell death pathways, one involving caspases and Bid and one that is Bid-independent.
Activated Vγ9Vδ2 T Cells Trigger Granulocyte Functions via MCP-2 Release
Authors: Agrati Chiara , Cimini Eleonora , Sacchi Alessandra , Bordoni Veronica , Gioia Cristiana , Casetti Rita , Turchi Federica , Tripodi Marco , Martini Federico 
Published: April 2014

Abstract
Vγ9Vδ2 T cells display a broad antimicrobial activity by directly killing infected cells and by inducing an effective adaptive immune response. The activation of Vγ9Vδ2 T cells by aminobisphosphonate drugs such as zoledronic acid (ZOL) results in a massive release of cytokines and chemokines that may induce a bystander activation of other immune cells. The aim of this work was to evaluate the ability of soluble factors released by ZOL-activated Vγ9Vδ2 T cells to induce granulocyte activation. We showed that soluble factors released by ZOL-stimulated Vγ9Vδ2 T cells activate granulocytes by inducing their chemotaxis, phagocytosis, and α-defensins release. Proteomic analysis allowed us to identify a number of cytokines and chemokines specifically released by activated Vγ9Vδ2 T cells. Moreover, MCP-2 depletion by neutralizing Ab revealed a critical role of this chemokine in induction of granulocyte α-defensins release. Altogether, these data show a Vγ9Vδ2-mediated activation of granulocytes through a bystander mechanism, and confirm the wide ability of Vγ9Vδ2 T-lymphocytes in orchestrating the immune response. In conclusion, an immune modulating strategy targeting Vγ9Vδ2 T cells may represent a key switch to induce an effective and well-coordinated immune response, and can be proposed as a way to strengthen the immune competence during infectious diseases.
Crosstalk between Prostaglandin E2 and Leukotriene B4 Regulates Phagocytosis in Alveolar Macrophages via Combinatorial Effects on Cyclic AMP
Authors: Lee Sang Pyo , Serezani Carlos H. , Medeiros Alexandra I. , Ballinger Megan N. , Peters-Golden Marc 
Published: April 2014

Abstract
Eicosanoid lipid mediators, including prostaglandin E2 (PGE2) and leukotrienes (LTs) B4 and D4, are produced in abundance in the infected lung. We have previously demonstrated that individually, PGE2 suppresses while both classes of LTs augment alveolar macrophage (AM) innate immune functions. In this study, we sought to more appropriately model the milieu at a site of infection by studying the in vitro effects of these lipid mediators on FcγR-mediated phagocytosis when they are present in combination. Consistent with their individual actions, both LTB4 and LTD4 opposed the suppressive effect of PGE2 on phagocytosis, but only LTB4 did so by mitigating the stimulatory effect of PGE2 on intracellular cAMP production. Unexpectedly, we observed that IgG-opsonized targets themselves elicited a dose-dependent reduction in intracellular cAMP in AMs, but this was not observed in peritoneal macrophages or elicited peritoneal neutrophils; this effect in AMs was completely abolished by treatment with the LT synthesis inhibitor AA861, the BLT receptor 1 antagonist CP 105,696, and the Gαi inhibitor pertussis toxin. Of two downstream cAMP effectors, protein kinase A and exchange protein activated by cAMP, the ability of PGE2 to activate the latter but not the former was abrogated by both LTs B4 and D4. Taken together, our results indicate that both classes of LTs oppose the immune suppressive actions of PGE2, with the stimulatory actions of LTB4 reflecting combinatorial modulation of intracellular cAMP and those of LTD4 being cAMP independent.
Interacting Neuroendocrine and Innate and Acquired Immune Pathways Regulate Neutrophil Mobilization from Bone Marrow following Hemorrhagic Shock
Authors: Liu Yujian , Yuan Youzhong , Li Yuehua , Zhang Jian , Xiao Guozhi , Vodovotz Yoram , Billiar Timothy R. , Wilson Mark A. , Fan Jie 
Published: April 2014

Abstract
Polymorphonuclear neutrophils (PMN) are critical innate immune effector cells that either protect the host or exacerbate organ dysfunction by migrating to injured or inflamed tissues. Resuscitated hemorrhagic shock following major trauma promotes the development of organ inflammation by priming PMN migration and activation in response to a second, often trivial, stimulus (a so-called “two hit” phenomenon). PMN mobilization from bone marrow supports a sustained, hemorrhagic shock/resuscitation (HS/R)-primed migration of PMN. We addressed the role and mechanism of HS/R in regulating PMN egress from bone marrow. We demonstrate that HS/R through the alarmin HMGB1 induces IL-23 secretion from macrophages in an autocrine and TLR4 signaling-dependent manner. In turn IL-23, through an IL-17 G-CSF-mediated mechanism, induces PMN egress from bone marrow. We also show that β-adrenergic receptor activation by catecholamine of macrophages mediates the HS/R-induced release of HMGB1. These data indicate that HS/R, a global ischemia/reperfusion stimulus, regulates PMN mobilization through a series of interacting pathways that include neuroendocrine and innate and acquired immune systems. Blocking this novel signaling axis may present a novel therapeutic target for posttrauma inflammation.
Adiponectin and Functional Adiponectin Receptor 1 Are Expressed by Airway Epithelial Cells in Chronic Obstructive Pulmonary Disease
Authors: Miller Marina , Cho Jae Youn , Pham Alexa , Ramsdell Joe , Broide David H. 
Published: April 2014

Abstract
We screened bronchoalveolar lavage (BAL) fluids from COPD-E (chronic obstructive pulmonary disease-Emphysema) and control subjects using a 120 Ab cytokine array and demonstrated that adiponectin was highly expressed in BAL in COPD-E. An adiponectin ELISA confirmed that adiponectin was highly expressed in BAL in COPD-E compared with smokers and healthy control subjects. Immunohistochemistry studies of lung sections from subjects with COPD-E demonstrated that airway epithelial cells expressed significant levels of adiponectin and adiponectin receptor (AdipoR) 1 but not AdipoR2. In vitro studies with purified populations of human lung A549 epithelial cells demonstrated that they expressed both adiponectin and AdipoR1 (but not AdipoR2) as assessed by RT-PCR, Western blot, and immunohistochemistry. Lung A549 epithelial AdipoR1were functional as incubation with adiponectin induced release of IL-8, which was inhibited by small interfering RNA to AdipoR1. Using a mouse model of COPD, tobacco smoke exposure induced both evidence of COPD as well as increased levels of adiponectin in BAL fluid and increased adiponectin expression by airway epithelial cells. As adiponectin expression in adipocytes is dependent upon NF-κB we determined levels of adiponectin in tobacco smoke exposed CC10-Cretg/IkkβΔ/Δ mice (deficient in the ability to activate NF-κB in airway epithelium). These studies demonstrated that CC10-Cretg/IkkβΔ/Δ and wild-type mice had similar levels of BAL adiponectin and airway epithelial adiponectin immunostaining. Overall, these studies demonstrate the novel observation that adiponectin and functional AdipoR1are expressed by lung epithelial cells, suggesting a potential autocrine and/or paracrine pathway for adiponectin to activate epithelial cells in COPD-E.
Fulminant Lymphocytic Choriomeningitis Virus-Induced Inflammation of the CNS Involves a Cytokine-Chemokine-Cytokine-Chemokine Cascade
Authors: Christensen Jeanette E. , Simonsen Stine , Fenger Christina , Sørensen Maria R. , Moos Torben , Christensen Jan P. , Finsen Bente , Thomsen Allan R. 
Published: April 2014

Abstract
Intracerebral inoculation of immunocompetent mice with lymphocytic choriomeningitis virus (LCMV) normally results in fatal CD8+ T cell mediated meningoencephalitis. However, in CXCL10-deficient mice, the virus-induced CD8+ T cell accumulation in the neural parenchyma is impaired, and only 30–50% of the mice succumb to the infection. Similar results are obtained in mice deficient in the matching chemokine receptor, CXCR3. Together, these findings point to a key role for CXCL10 in regulating the severity of the LCMV-induced inflammatory process. For this reason, we now address the mechanisms regulating the expression of CXCL10 in the CNS of LCMV-infected mice. Using mice deficient in type I IFN receptor, type II IFN receptor, or type II IFN, as well as bone marrow chimeras expressing CXCL10 only in resident cells or only in bone marrow-derived cells, we analyzed the up-stream regulation as well as the cellular source of CXCL10. We found that expression of CXCL10 initially depends on signaling through the type I IFN receptor, while late expression and up-regulation requires type II IFN produced by the recruited CD8+ T cells. Throughout the infection, the producers of CXCL10 are exclusively resident cells of the CNS, and astrocytes are the dominant expressors in the neural parenchyma, not microglial cells or recruited bone marrow-derived cell types. These results are consistent with a model suggesting a bidirectional interplay between resident cells of the CNS and the recruited virus-specific T cells with astrocytes as active participants in the local antiviral host response.
IL-10 Dampens TNF/Inducible Nitric Oxide Synthase-Producing Dendritic Cell-Mediated Pathogenicity during Parasitic Infection
Authors: Guilliams Martin , Movahedi Kiavash , Bosschaerts Tom , VandenDriessche Thierry , Chuah Marinee Khim , Hérin Michel , Acosta-Sanchez Abel , Ma Ling , Moser Muriel , Van Ginderachter Jo A. , Brys Lea , De Baetselier Patrick , Beschin Alain 
Published: April 2014

Abstract
Antiparasite responses are associated with the recruitment of monocytes that differentiate to macrophages and dendritic cells at the site of infection. Although classically activated monocytic cells are assumed to be the major source of TNF and NO during Trypanosoma brucei brucei infection, their cellular origin remains unclear. In this study, we show that bone marrow-derived monocytes accumulate and differentiate to TNF/inducible NO synthase-producing dendritic cells (TIP-DCs) in the spleen, liver, and lymph nodes of T. brucei brucei-infected mice. Although TIP-DCs have been shown to play a beneficial role in the elimination of several intracellular pathogens, we report that TIP-DCs, as a major source of TNF and NO in inflamed organs, could contribute actively to tissue damage during the chronic stage of T. brucei brucei infection. In addition, the absence of IL-10 leads to enhanced differentiation of monocytes to TIP-DCs, resulting in exacerbated pathogenicity and early death of the host. Finally, we demonstrate that sustained production of IL-10 following IL-10 gene delivery treatment with an adeno-associated viral vector to chronically infected mice limits the differentiation of monocytes to TIP-DCs and protects the host from tissue damage.
IL-12-Dependent Inducible Expression of the CD94/NKG2A Inhibitory Receptor Regulates CD94/NKG2C+ NK Cell Function
Authors: Sáez-Borderías Andrea , Romo Neus , Magri Giuliana , Gumá Mónica , Angulo Ana , López-Botet Miguel 
Published: April 2014

Abstract
The inhibitory CD94/NKG2A and activating CD94/NKG2C killer lectin-like receptors specific for HLA-E have been reported to be selectively expressed by discrete NK and T cell subsets. In the present study, minor proportions of NK and T cells coexpressing both CD94/NKG2A and CD94/NKG2C were found in fresh peripheral blood from adult blood donors. Moreover, CD94/NKG2A surface expression was transiently detected upon in vitro stimulation of CD94/NKG2C+ NK cells in the presence of irradiated allogeneic PBMC or rIL-12. A similar effect was observed upon coculture of NKG2C+ NK clones with human CMV-infected autologous dendritic cell cultures, and it was prevented by an anti-IL-12 mAb. NKG2A inhibited the cytolytic activity of NKG2C+ NK clones upon engagement either by a specific mAb or upon interaction with a transfectant of the HLA class I-deficient 721.221 cell line expressing HLA-E. These data indicate that beyond its constitutive expression by an NK cell subset, NKG2A may be also transiently displayed by CD94/NKG2C+ NK cells under the influence of IL-12, providing a potential negative regulatory feedback mechanism.
Epicutaneous Immunization with Protein Antigen in the Presence of TLR4 Ligand Induces TCRαβ+CD4+ T Contrasuppressor Cells That Reverse Skin-Induced Suppression of Th1-Mediated Contact Sensitivity
Authors: Ptak Włodzimierz , Majewska Monika , Bryniarski Krzysztof , Ptak Maria , Lobo Francis M. , Zając Katarzyna , Askenase Philip W. , Szczepanik Marian 
Published: April 2014

Abstract
Our previous work showed that epicutaneous (EC) immunization of mice with different protein Ags applied on the skin in the form of a patch induces a state of subsequent Ag-nonspecific unresponsiveness due to suppressor CD4+8+ T cells (Ts) that inhibit Th1-mediated contact sensitivity (CS) reactions via released TGF-β. In the present work we show that EC immunization with Ag together with the TLR4 ligand LPS induced cells that could prevent suppression by the Ag-nonspecific Ts. These up-regulatory cells, called contrasuppressor T cells (Tcs), belong to a population of Ag-specific TCRαβ CD4+ lymphocytes and are different from Th1 CD4+ cells that mediate the CS reaction. Experiments using knockout mice showed that EC induced contrasuppression is MyD88, INF-γ, and IL-12 dependent, whereas IL-6 is not involved in this phenomenon. Additional experiments with anti-IFN-γ mAb showed that IFN-γ is required for induction of Tcs cells but does not play a crucial role in the effector phase of contrasuppression. Additionally, treatment of CS effector cells with rIL-12 makes them resistant to EC induced suppression without affecting Ts cells, whereas IL-12 neutralization in vitro abrogates contrasuppression. These data show that IL-12 is indeed involved in the effector phase of EC induced contrasuppression and that this cytokine does not act directly on Ts cells. The mechanism of action of Tcs protects Th1 effector cells mediating CS from the nonspecific Ts, leaving suppression to other Ags intact. Ts and Tcs cells do not influence each other and can be induced simultaneously in the same animal.
Generation of a Novel System for Studying Spleen Tyrosine Kinase Function in Macrophages and B Cells
Authors: Miller Allison L. , Zhang Chao , Shokat Kevan M. , Lowell Clifford A. 
Published: April 2014

Abstract
Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that is expressed primarily in hematopoietic cells. Because this protein has been implicated in processes such as Fc-mediated phagocytosis, BCR signaling, oxidative burst, degranulation, cytokine secretion, and integrin-mediated outside-in signaling, it is hypothesized that Syk may be a viable target in the treatment of a variety of autoimmune and inflammatory diseases. Because efforts to design a small-molecule therapeutic that specifically inhibits Syk have been largely unsuccessful, and genetic studies of Syk have been hampered by the fact that syk−/− mice die in utero, we have taken a chemical genetic approach to study the function of Syk. Specifically, we have created a mutant form of Syk that retains its wild-type function, but is susceptible to inhibition by enlarged derivatives of the tyrosine kinase inhibitor, PP1. We report in this study that Syk M442A S505A reconstituted wild-type function when introduced into murine syk−/− bone marrow-derived macrophages and syk−/− DT40 chicken B cells, as determined by functional and biochemical assays. Furthermore, after screening a series of PP1 derivatives, we identified one compound, namely 2,3-DMB-PP1, that specifically inhibited Syk M442A S505A, but not wild-type Syk. This system provides us with the power to characterize immune functions that are Syk specific, and furthermore, it provides us with a tool to assess how inhibition of Syk may alter an immune response and influence disease pathogenesis and/or progression.
Memory Alloreactive B Cells and Alloantibodies Prevent Anti-CD154-Mediated Allograft Acceptance
Authors: Burns Audrea M. , Ma Lianli , Li Yijin , Yin Dengping , Shen JiKun , Xu Jing , Chong Anita S. 
Published: April 2014

Abstract
The impact of memory B cells and alloantibodies on the ability to induce transplantation tolerance has not been elucidated. We have developed a murine heart transplant model that isolates the contributions of functional memory B cells from memory T cells in allograft rejection. Memory 3-83 B cells with dual specificity for H-2Kk and H-2Kb were generated in 3-83 Igi BCR knockin (BALB/c background) mice by the transplantation of C3H (H-2Kk) hearts in the absence of immunosuppression. To test the effect of functional memory 3-83 B cells, C3H-primed 3-83 Igi recipients were challenged with C57BL/6 hearts (H-2Kb) at 60–90 days post-C3H heart transplant and treated with anti-CD154 mAbs. Despite immunosuppression, the C57BL/6 hearts were acutely rejected within 10–13 days and graft rejection was associated with increased frequencies of C57BL/6-specific IFN-γ-producing T cells. Histology revealed significant numbers of infiltrating T cells, consistent with acute T cell-mediated rejection. The resistance to tolerance induction was dependent on the synergistic effects of memory 3-83 B cells and alloantibodies, whereas memory T cells are not necessary. We conclude that the combined effects of functional memory B cells and alloantibodies prevent anti-CD154-mediated graft acceptance by facilitating the CD40-CD154-independent activation of alloreactive T cells. This study provides insight into the potential ability of memory B cells and alloantibodies to prevent anti-CD154-mediated graft acceptance.