bluuebunny/crossref_metadata_2025_split huggingface dataset:
DC-SIGN, a C-type lectin on dendritic cells that unveils many aspects of dendritic cell biology
Authors: Geijtenbeek Teunis B H , Engering Anneke , van Kooyk Yvette 
Published: September 2022

AbstractDendritic cells (DC) are present in essentially every tissue where they operate at the interface of innate and acquired immunity by recognizing pathogens and presenting pathogen-derived peptides to T cells. It is becoming clear that not all C-type lectins on DC serve as antigen receptors recognizing pathogens through carbohydrate structures. The C-type lectin DC-SIGN is unique in that it regulates adhesion processes, such as DC trafficking and T-cell synapse formation, as well as antigen capture. Moreover, even though several C-type lectins have been shown to bind HIV-1, DC-SIGN does not only capture HIV-1 but also protects it in early endosomes allowing HIV-1 transport by DC to lymphoid tissues, where it enhances trans infection of T cells. Here we discuss the carbohydrate/protein recognition profile and other features of DC-SIGN that contribute to the potency of DC to control immunity.
Selective up-regulation of phospholipase C-β2 during granulocytic differentiation of normal and leukemic hematopoietic progenitors
Authors: Bertagnolo Valeria , Marchisio Marco , Pierpaoli Sabina , Colamussi Maria Luisa , Brugnoli Federica , Visani Giuseppe , Zauli Giorgio , Capitani Silvano 
Published: September 2022

AbstractIn this study, we have investigated the expression of phospholipase C-β2 during the course of granulocytic differentiation of normal and malignant progenitors. As a model system, we used the NB4 cell line, a reliable in vitro model for the study of acute promyelocytic leukemia (APL), a variety of acute myeloid leukemia (AML) that responds to pharmacological doses of all trans-retinoic acid (ATRA) by differentiating in a neutrophil-like manner. We found that PLC-β2, virtually absent in untreated NB4 cells, was strongly up-regulated after ATRA-induced granulocytic differentiation. Remarkably, using primary blasts purified from bone marrow of patients affected by APL successfully induced to remission by treatment with ATRA, we showed a striking correlation between the amount of PLC-β2 expression and the responsiveness of APL blasts to the differentiative activity of ATRA. An increase of PLC-β2 expression also characterized the cytokine-induced granulocytic differentiation of CD34+ normal hematopoietic progenitors. Taken together, these data show that PLC-β2 represents a sensitive and reliable marker of neutrophil maturation of normal and malignant myeloid progenitors. Moreover, PLC-β2 levels can predict the in vivo responsiveness to ATRA of APL patients.
Compound exocytosis of granules in human neutrophils
Authors: Lollike Karsten , Lindau Manfred , Calafat Jero , Borregaard Niels 
Published: September 2022

AbstractHuman neutrophils are of prime importance for the immune defense. Recent data from eosinophils and pancreatic beta cells have indicated that granules, upon exocytosis, occasionally fuse with each other in the cytosol prior to their subsequent fusion with the plasma membrane. This is termed compound exocytosis. We therefore studied exocytosis of single granules from human neutrophils by the high-resolution cell-attached patch-clamp capacitance technique. We found that 1.5% of the capacitance steps was greater than 5 fF, i.e., significantly larger than steps expected for exocytosis of single granules. The mean step size of these events was 20.5 fF, corresponding to compounds formed by at least five granules. The capacitance input from compound steps contributed more than 20% of the total capacitance increase. Electron microscopy captured morphological manifestations of transient exocytic events, confirming the functional results obtained by capacitance measurements. Compound exocytosis may be a mechanism for efficient targeting of release during exocytosis.
Wegener's granulomatosis: antiproteinase 3 antibodies induce monocyte cytokine and prostanoid release—role of autocrine cell activation
Authors: Hattar Katja , Bickenbach Annette , Csernok Elena , Rosseau Simone , Grandel Ulrich , Seeger Werner , Grimminger Friedrich , Sibelius Ulf 
Published: September 2022

AbstractAntineutrophil cytoplasmic antibodies (ANCA) targeting proteinase 3 [PR3; cytoplasmic ANCA (c-ANCA)], a leukocyte serine protease, are highly specific for Wegener's Granulomatosis (WG). A pathogenetic role for c-ANCA has been proposed as a result of their ability of activating neutrophils, whereas their interaction with monocytes is less well characterized. We investigated the influence of monoclonal anti-PR3 antibodies (anti-PR3) and c-ANCA from WG sera on monocyte cytokine and prostanoid release. We found that PR3 was expressed on the surface of isolated monocytes. Anti-PR3 challenge provoked a pronounced release of cytokines with early appearance of tumor necrosis factor α (TNF-α) and interleukin (IL)-1β and delayed release of IL-6, IL-8, and thromboxane A2 (TxA2). The secretory response was reproduced by c-ANCA but not by human and murine control IgG and anti-CD14 antibodies. Because F(ab)2 fragments of anti-PR3 were ineffective, coligation of Fc gamma receptors (FcγR) was apparently mandatory for monocyte activation. Using soluble receptors for TNF-α and IL-1β and a Tx receptor antagonist, we noted that the “early” cytokines functioned as inducers of TxA2, which then activated IL-8 release. In contrast, IL-6 formation was an independent event. We concluded that anti-PR3 antibodies are potent inducers of monocyte cytokine and prostanoid release, and TNF-α, IL-1β, and TxA2 function as facilitators of the secretory response. These mechanisms may contribute to inflammatory tissue injury in WG.
Systemic immunoregulatory and pathogenic functions of homeostatic chemokine receptors
Authors: Müller Gerd , Höpken Uta E , Stein Harald , Lipp Martin 
Published: September 2022

AbstractThe adoptive immune response relies on a precise temporal and spatial positioning of lymphocytes within lymphoid and nonlymphoid tissues. Chemokines, constitutively expressed or induced during inflammation provide a flexible navigation system directing lymphocytes into specific microcompartments. Precision and specificity in this process are achieved by varying patterns of chemokine receptors expressed on the cell surface of lymphocytes in the course of cell differentiation. The chemokine receptors CXCR5 and CCR7 are principal regulators for targeting T cells, B cells, and dendritic cells into secondary lymphoid organs. The analyses of knockout mice have been instrumental in exploring the crucial role of these receptors for the compartmentalization of secondary lymphoid organs into functionally separated T and B cell zones. Aside from the homeostatic recirculation of lymphocytes and inflammatory processes, chemokine receptors are also involved in malignancies such as lymphoproliferative diseases and cancer metastasis. Recent results from our laboratory present evidence for the involvement of CCR7 in the dissemination of neoplastic cells in classic Hodgkin disease. There is also accumulating evidence for the involvement of CXCR5 in the formation of ectopic follicles as observed in lymphomas or autoimmune diseases. In addition, CCR7 and CXCR5 have been identified as useful markers in the classification of functionally distinct subsets of T-helper cells, which will lead to a better understanding of T cell memory and T cell effector function in lymphoid system homeostasis and disease.
Viral chemokine-binding proteins
Authors: Seet Bruce T , McFadden Grant 
Published: September 2022

AbstractThe chemokines are a large family of small signaling proteins that bind to G-protein-coupled receptors (GPCRs) on target cells and mediate the directional migration of immune cells into sites of infection or inflammation. The large DNA viruses, particularly the poxviruses and herpesviruses, have evolved several mechanisms to corrupt the normal functioning of the chemokine network. Two strategies rely on mimicking chemokines or chemokine receptors. A third strategy involves the production of secreted chemokine-binding proteins (CKBPs) that exhibit no sequence similarity to any known host proteins, yet function to competitively bind and inhibit the interactions of chemokines with cognate receptors. Each strategy has provided unique insights into the elusively complex world of the chemokines. Here, we focus on recent advances made in the understanding of secreted CKBPs encoded by poxviruses and herpesviruses. A better understanding of how viral CKBPs function to manipulate the immune response may provide further clues as to how to develop specific therapeutic agents to abrogate chemokine-mediated disease conditions.
Transient expression of Ym1, a heparin-binding lectin, during developmental hematopoiesis and inflammation
Authors: Hung Shuen-Iu , Chang Alice Chien , Kato Ikunoshin , Chang Nan-Chi A 
Published: September 2022

AbstractYm1, a secretory protein transiently produced by activated peritoneal macrophages elicited by parasitic infections, has been identified as a novel heparin-binding lectin. X-ray crystallography study revealed that Ym1 has a β/α barrel structure with a carbohydrate-binding cleft similar to that of triose-phosphate isomerases. To further delineate the physiological significance of Ym1, we examined its expression patterns during mouse embryonic development and inflammation states elicited by agents other than parasitic infections in the peritoneal cavity and brain. This is the first report revealing prominent expression of Ym1 in early myeloid precursor cells of hematopoietic tissues—initially in the yolk sac and subsequently in fetal liver, spleen, and bone marrow. In nonhematopoietic systems, Ym1 was not detected in most of the tissues examined, with the exception of lung. Although no expression was detected up to gestation day 16.5 (E16.5), an increasing level of Ym1 expression in lung was detected from E18.5 on and persisted through adulthood. While most resident macrophages in various tissues examined are Ym1-negative, transient expression of Ym1 may be induced in their activated counterparts during inflammation in response to different stimuli in vivo, ranging from various chemical agents to brain injuries. The temporal and spatial expression in myeloid precursors and its transient induction in activated macrophages support the notion that Ym1 may be involved in hematopoiesis and inflammation. In addition, its putative functional association with heparin/heparan sulfate is discussed.
H1° histone and differentiation of dendritic cells. A molecular target for tumor-derived factors
Authors: Gabrilovich Dmitry I , Cheng Pingyan , Fan Yuhong , Yu Bin , Nikitina Ekaterina , Sirotkin Allen , Shurin Michael , Oyama Tsunehiro , Adachi Yasushi , Nadaf Sorena , Carbone David P , Skoultchi Arthur I 
Published: September 2022

AbstractDendritic cells (DC) play a central role in antitumor immune responses. Abnormal differentiation of DC and their inability to stimulate T cells are important factors in tumor escape from immune-system control. However, the mechanisms of this process remain elusive. Here, we have described one possible molecular mechanism that involves replacement linker histone H1°. A close association between expression of H1° and DC differentiation in vitro has been found. DC production in H1°-deficient mice was decreased significantly, whereas generation and function of macrophages, granulocytes, and lymphocytes appear to be normal. However, these mice had a significantly reduced response to vaccination with antigens. Tumor-derived factors considerably reduced h1° expression in hematopoietic progenitor cells. We have demonstrated that transcription factor NF-κB is involved actively in regulation of h1°. Thus, H1° histone may be an important factor in normal DC differentiation. Tumor-derived factors may inhibit DC differentiation by affecting H1° expression.
Cytokine responses of bovine dendritic cells and T cells following exposure to live or inactivated bovine respiratory syncytial virus
Authors: Werling Dirk , Collins Robert A , Taylor Geraldine , Howard Chris J 
Published: September 2022

AbstractWe compared the effects of live or inactivated bovine respiratory syncytial virus (BRSV) on cytokine production by bovine monocyte-derived dendritic cells (MoDC). We also investigated the response of resting memory CD4+ T cells to MoDC exposed to both viral preparations. Although BRSV did not appear to replicate in MoDC or to affect expression of major histocompatibility complex (MHC) class I, MHC class II, or CD80/86, a higher percentage of cells exposed to live virus appeared to undergo apoptosis/necrosis. To investigate how the interaction of BRSV with MoDC affects the immune response, a multiplex, real-time, polymerase chain reaction was established to analyze transcription of bovine cytokines. Exposure of MoDC to live BRSV induced more interleukin (IL)-10 mRNA and markedly less IL-12p40 and IL-15 mRNA than did heat-inactivated virus. To determine whether these differences might influence the T cell response, CD4+ memory T cells primed in vivo were restimulated in vitro by MoDC pulsed with heat-inactivated or live BRSV. Stimulation of CD4+ T cells induced similar levels of IL-2-and IL-4-like activity and interferon-γ. These observations suggest that while IL-10, produced by MoDC as a result of exposure to live BRSV, may affect IL-12 and IL-15 synthesis by MoDC, it does not appear to affect the cytokine response of BRSV-specific memory CD4+ T cells. It is possible, however, that differences in the pattern of cytokines produced by MoDC exposed to live or inactivated virus may influence the development of the primary CD4+ T cell response in vivo.
Human dendritic cell mediated cytotoxicity against breast carcinoma cells in vitro
Authors: Manna Partha P , Mohanakumar T 
Published: September 2022

AbstractDendritic cells (DC) are an important subset of antigen-presenting cells characterized by their potent capacity to activate immunologically naïve T cells. However, their role in effector function in tumor resistance is less well characterized. We report here that activated human peripheral blood DC acquire a potent antitumor effect against breast cancer cell lines in vitro, leading to growth inhibition and apoptosis of the tumor cell. The antitumor effect of DC was augmented by proinflammatory stimuli induced by lipopolysaccharide (LPS) treatment. Tumor necrosis factor α (TNF-α) produced after DC activation was responsible for the antitumor activity of DC. Interferon-γ, interleukin-15, or LPS treatment of DC markedly augmented the effector function of DC against most of the breast cells, indicating heterogeneity of the tumor and its susceptibility to cytokine-mediated damage. Treatment of LPS-activated DC or cell-free supernatant with anti-human TNF-α significantly reduces the antitumor effect against the tumor cells tested. These results suggest that in addition to their predominant role as immune regulatory cells, DC could serve as innate effector cells in tumor immunity.
Nitric oxide reduces bacterial superantigen-immune cell activation and consequent epithelial abnormalities
Authors: Rachlis Alisa , Watson James L , Lu Jun , McKay Derek M 
Published: September 2022

AbstractInhibition of the inducible form of nitric oxide (NO) synthase prolonged the murine enteropathy evoked by the bacterial superantigen, Staphylococcus aureus enterotoxin B (SEB). We examined the ability of NO to alleviate SEB-induced epithelial dysfunction and immune cell activation. Human peripheral blood mononuclear cells (PBMC) were activated by SEB for 24 h ± the NO donors, S-nitroso-N-acetylpenicillamine and spermine-NONOate. The conditioned medium (CM) was collected and applied to T84 epithelial monolayers, and permeability [i.e., transepithelial resistance (TER)] and stimulated ion transport (i.e., short-circuit current responses to carbachol and forskolin) were assessed 24 h later. Exposure to CM led to an ∼40% drop in TER and hyporesponsiveness to both secretagogues. CM made in the presence of NO donors (10−4 M) had no significant effect on epithelial barrier or ion transport parameters. NO donors alone had no effect on naive epithelia, and addition of the NO donors to previously made CM did not affect the ability of this CM to alter epithelial function. Moreover, the NO donors dose-dependently reduced SEB-evoked PBMC proliferation and cytokine production (i.e., interferon-γ, tumor necrosis factor α) but did not affect viability. These findings suggest a beneficial role for NO in inflammation by reducing immune cell activation and thus ameliorating consequent physiological abnormalities, in this instance, perturbed epithelial permeability and active ion transport.
Physiological levels of interleukin-18 stimulate multiple neutrophil functions through p38 MAP kinase activation
Authors: Wyman Travis H , Dinarello Charles A , Banerjee Anirban , Gamboni-Robertson Fabia , Hiester Andrew A , England Kelly M , Kelher Marguerite , Silliman Christopher C 
Published: September 2022

AbstractPatients with sepsis and acute lung injury have increased interleukin (IL)-18 levels systemically. We hypothesize that IL-18 stimulates neutrophils (PMNs) at physiologic concentrations. IL-18 primed the oxidase at 15 min (10–100 ng/ml), 30 min (0.1–100 ng/ml), and 60 min (100 ng/ml; P&lt;0.05) and caused translocation of p47phox to the membrane similar to lipopolysaccharides. CD11b surface expression was increased by IL-18 in a time- and concentration-dependent manner. IL-18 caused up-regulation of the formyl-Met-Leu-Phe receptor, changes in PMN size, and elastase release. Investigation of signaling demonstrated IL-18-mediated activation of p38 mitogen-activated protein (MAP) kinase in a concentration (0.1–100 ng/ml)-, time (5–15 min)-, and Ca2+-dependent manner. IL-18 directly increased cytosolic Ca2+ concentration. IL-18 activation of PMNs was blocked by inhibition of p38 MAP kinase activity (SB203580) or by inhibition of p38 MAP kinase activation by chelation of cytosolic Ca2+. We conclude that IL-18, at physiologic concentrations, is an effective PMN priming agent that requires p38 MAP kinase activity.
Orphan nuclear receptors in T lymphocyte development
Authors: He You-Wen 
Published: September 2022

AbstractLymphocyte development is initiated from hematopoietic stem cells and can be divided into multiple phenotypically distinct stages. Transcription factors play important roles in programming the developmental process of lymphocytes. Recent studies have identified key roles of several orphan nuclear receptors in T lymphocyte development. The orphan nuclear receptor RORγ has been shown to promote thymocyte survival by activating the expression of antiapoptotic protein Bcl-xL. RORγ is also required for the development of lymph nodes and Peyer's patches. The orphan receptors Nur77 and Nor1 are involved in TCR-mediated cell death and thymocyte-negative selection. These studies provide novel insights into the molecular mechanisms of T lymphocyte development.
Interleukin-10 inhibits proinflammatory activation of endothelium in response toBorrelia burgdorferior lipopolysaccharide but not interleukin-1β or tumor necrosis factor α
Authors: Lisinski Tracy J , Furie Martha B 
Published: September 2022

AbstractInterleukin (IL)-10 is generally regarded as an anti-inflammatory cytokine, since it acts on a variety of cell types to suppress production of proinflammatory mediators. In inflammation, endothelial cells (EC) play a crucial role in recruiting leukocytes to sites of injury or infection. In this study, the actions of IL-10 on human umbilical vein EC were investigated. IL-10 reduced migration of monocytes and T lymphocytes across endothelium stimulated by lipopolysaccharide and decreased endothelial production of chemokines in response to lipopolysaccharide and Borrelia burgdorferi, the agent of Lyme disease. However, IL-10 did not affect these responses when EC were activated by the host proinflammatory cytokines IL-lβ or tumor necrosis factor α. Moreover, IL-10 did not prevent up-regulation of the adhesion molecules E-selectin and intercellular adhesion molecule-1 by EC exposed to any of these activating agents. IL-10 therefore inhibits proinflammatory activation of EC in a manner that is selective with respect to stimulus and effector response.
Human pregnancy-specific glycoprotein 1a (PSG1a) induces alternative activation in human and mouse monocytes and suppresses the accessory cell-dependent T cell proliferation
Authors: Motrán Claudia Cristina , Díaz Fernando López , Gruppi Adriana , Slavin Daniela , Chatton Bruno , Bocco José Luis 
Published: September 2022

AbstractIt has been proposed that pregnancy-specific factors induce the suppression of a specific arm of the maternal response accompanied by activation of the nonspecific, innate immune system. The aim of this study was to determine whether pregnancy-specific glycoprotein 1a (PSG1a), the major variant of PSG polypeptides, is able to modulate the monocyte/macrophage (Mo) metabolism to rgulate T cell activation and proliferation. Using the recombinant form of this glycoprotein (rec-PSG1a), expressed in mammalian cells with a vaccinia-based expression vector, we have demonstrated that human PSG1a induces arginase activity in peripheral blood human Mo and human and murine Mo cell lines. In addition, rec-PSG1a is able to induce alternative activation because it up-regulates the arginase activity and inhibits the nitric oxide production in Mo activated by lipopolysaccharides. We also observed that rec-PSG1a is an important accessory cells-dependent T cell suppressor factor that causes partial growth arrest at the S/G2/M phase of the cell cycle. Additionally, an impaired T cell proliferative response induced by mitogens and specific antigen was observed in BALB/c mice upon in vivo expression of PSG1a. Our results suggest that PSG1a function contributes to the immunomodulation during pregnancy, having opposite effects on maternal innate and adaptative systems.
In vitro and in vivo activities of OX40 (CD134)-IgG fusion protein isoforms with different levels of immune-effector functions
Authors: Taylor Liz , Bachler Marcus , Duncan Imogen , Keen Simon , Fallon Rosie , Mair Catherine , McDonald Thomas T , Schwarz Herbert 
Published: September 2022

AbstractRecombinant fusion proteins consisting of the extracellular domain of immunoregulatory proteins and the constant domain of immunoglobulin G (IgG) are a novel class of human therapeutics. IgG isofors exert different levels of immune effector functions, such as complement lysis and antibody-dependent cell cytotoxicity (ADCC). Several OX40-Ig fusion proteins were generated and compared in their potency to inhibit immune reactions. OX40-IgG fusion proteins act as decoys and inhibit T cell costimulation and extravasation induced by OX40 ligand-expressing antigen-presenting cells (APC) and vascular endothelial cells, respectively. In addition, OX40-IgG1 protein induces ADCC and complement lysis in OX40 ligand-expressing cells. Replacement of the IgG1 by the IgG4 domain (OX40-IgG4) eliminated complement lysis and reduced ADCC by half. Mutation of Leu235 to Glu in IgG4 eliminated the remaining ADCC activity and generated a protein devoid of immune effector functions (OX40-IgG4mut). In vitro, OX40-IgG1 was more potent in inhibiting proliferation and cytokine release by peripheral blood mononuclear cells than OX40-IgG4mut, as OX40-IgG1 induced cell death in APC. However, both proteins reduced T cell-mediated colitis in mice to the same extent, indicating that in vivo neutralization of OX40L is sufficient. This study also demonstrates that effector functions of antibodies are retained and can be rationally designed in receptor-IgG fusion proteins.