bluuebunny/crossref_metadata_2025_split huggingface dataset:
Artiodactyl IgD: The Missing Link
Authors: Zhao Yaofeng , Kacskovics Imre , Pan Qiang , Liberles David A. , Geli Janos , Davis Scott K. , Rabbani Hodjattallah , Hammarstrom Lennart 
Published: April 2014

AbstractIgD has been suggested to be a recently developed Ig class, only present in rodents and primates. However, in this paper the cow, sheep, and pig Ig δ genes have been identified and shown to be transcriptionally active. The deduced amino acid sequences from their cDNAs show that artiodactyl IgD H chains are structurally similar to human IgD, where the cow, sheep, and pig IgD H chain constant regions all contain three domains and a hinge region, sharing homologies of 43.6, 44, and 46.8% with their human counterpart, respectively. According to a phylogenetic analysis, the Cδ gene appears to have been duplicated from the Cμ gene &gt;300 million yr ago. The ruminant μCH1 exon and its upstream region was again duplicated before the speciation of the cow and sheep, ∼20 million yr ago, inserted upstream of the δ gene hinge regions, and later modified by gene conversion. A short Sδ (switch δ) sequence resulting from the second duplication, is located immediately upstream of the bovine Cδ gene and directs regular μ-δ class switch recombination in the cow. The presence of Cδ genes in artiodactyls, possibly in most mammals, suggests that IgD may have some as yet unknown biological properties, distinct from those of IgM, conferring a survival advantage.
FcγR-Mediated Phagocytosis Stimulates Localized Pinocytosis in Human Neutrophils
Authors: Botelho Roberto J. , Tapper Hans , Furuya Wendy , Mojdami Donna , Grinstein Sergio 
Published: April 2014

Abstract
Engulfment of IgG-coated particles by neutrophils and macrophages is an essential component of the innate immune response. This process, known as phagocytosis, is triggered by clustering of FcγR at sites where leukocytes make contact with the opsonized particles. We found that phagocytosis is accompanied by a burst of fluid phase pinocytosis, which is largely restricted to the immediate vicinity of the phagosomal cup. FcγR-induced pinocytosis preceded and appeared to be independent of phagosomal sealing. Accordingly, fluid phase uptake was accentuated by actin depolymerization, which precludes phagocytosis. Stimulation of pinocytosis required phosphatidylinositol 3-kinase activity and was eliminated when changes in the cytosolic free Ca2+ concentration were prevented. Because stimulation of FcγR also induces secretion, which is similarly calcium and phosphatidylinositol 3-kinase dependent, we studied the possible relationship between these events. Neutrophil fragments devoid of secretory granules (cytoplasts) were prepared by sedimentation through Ficoll gradients. Cytoplasts could perform FcγR-mediated phagocytosis, which was not accompanied by activation of pinocytosis. This observation suggests that granule exocytosis is required for stimulation of pinocytosis. Analysis of the cytosolic Ca2+ dependence of secretion and pinocytosis suggests that primary (lysosomal) granule exocytosis is the main determinant of pinocytosis during FcγR stimulation. Importantly, primary granules are secreted in a polarized fashion near forming phagosomes. Focal pinocytosis during particle engulfment may contribute to Ag processing and presentation and/or to retrieval of components of the secretory machinery. Alternatively, it may represent an early event in the remodeling of the phagosomal membrane, leading to phagosomal maturation.
IFN-γ Production from Liver Mononuclear Cells of Mice in Burn Injury As Well As in Postburn Bacterial Infection Models and the Therapeutic Effect of IL-18
Authors: Ami Katsunori , Kinoshita Manabu , Yamauchi Akira , Nishikage Tetsuro , Habu Yoshiko , Shinomiya Nariyoshi , Iwai Takehisa , Hiraide Hoshio , Seki Shuhji 
Published: April 2014

Abstract
Hosts after severe burn injury are known to have a defect in the Th1 immune response and are susceptible to bacterial infections. We herein show that liver NK cells are potent IFN-γ producers early after burn injury. However, when mice were injected with LPS 24 h after burn injury, IFN-γ production from liver mononuclear cells (MNC; which we previously showed to be NK cells) was suppressed, and the serum IFN-γ concentration did not increase, while serum IL-10 conversely increased compared with control mice. Interestingly, a single injection of IL-18 simultaneously with LPS greatly restored the serum IFN-γ concentration in mice with burn injury and also increased IFN-γ production from liver MNC. Nevertheless, a single IL-18 injection into mice simultaneously with LPS was no longer effective in the restoration of serum IFN-γ and IFN-γ production from the liver MNC at 7 days after burn injury, when mice were considered to be the most immunocompromised. However, IL-18 injections into mice on alternate days beginning 1 day after burn injury strongly up-regulated LPS-induced serum IFN-γ levels and IFN-γ production from liver and spleen MNC of mice 7 days after burn injury and down-regulated serum IL-10. Furthermore, similar IL-18 therapy up-regulated serum IFN-γ levels in mice with experimental bacterial peritonitis 7 days after burn injury and greatly decreased mouse mortality. Thus, IL-18 therapy restores the Th1 response and may decrease the susceptibility to bacterial infection in mice with burn injury.
Retroviral Interference on STAT Activation in Individuals Coinfected with Human T Cell Leukemia Virus Type 2 and HIV-1
Authors: Bovolenta Chiara , Pilotti Elisabetta , Mauri Massimiliano , Panzeri Barbara , Sassi Monica , Dall’Aglio PierPaolo , Bertazzoni Umberto , Poli Guido , Casoli Claudio 
Published: April 2014

AbstractHuman T cell leukemia virus (HTLV) type-2 is a human retrovirus whose infection has not been tightly linked to human diseases. However, the fairly high prevalence of this infection among HIV-1-positive individuals indicates the importance of better understanding the potential interference of HTLV-2 infection on HIV-1 infection and AIDS. We previously demonstrated that one signature of PBMC freshly derived from HIV-1-infected individuals is the constitutive activation of a C-terminal truncated STAT5 (STAT5Δ). Therefore, we analyzed the potential activation of STATs in HTLV-2 monoinfected and HTLV-2/HIV-1 dually infected individuals. We observed that PBMC of HTLV-2-infected individuals do not show STAT activation unless they are cultivated ex vivo, in the absence of any mitogenic stimuli, for at least 8 h. The emergence of STAT activation, namely of STAT1, in culture was mostly related to the secretion of IFN-γ. Of note, this phenomenon is not only a characteristic feature of HTLV-2-infected individuals but also occurred with PBMC of HIV-1+ individuals. Surprisingly, HTLV-2/HIV-1 coinfection resulted in low/absent STAT activation in vivo that paralleled a diminished secretion of IFN-γ after ex vivo cultivation. Our findings indicate that both HTLV-2 and HIV-1 infection prime T lymphocytes for STAT1 activation, but they also highlight an interference exerted by HTLV-2 on HIV-1-induced STAT1 activation. Although the nature of such a phenomenon is unclear at the present, these findings support the hypothesis that HTLV-2 may interfere with HIV-1 infection at multiple levels.
The Innate Immune Response Differs in Primary and SecondarySalmonellaInfection
Authors: Kirby Alun C. , Yrlid Ulf , Wick Mary Jo 
Published: April 2014

AbstractThis study examines innate immunity to oral Salmonella during primary infection and after secondary challenge of immune mice. Splenic NK and NKT cells plummeted early after primary infection, while neutrophils and macrophages (Mφ) increased 10- and 3-fold, respectively. In contrast, immune animals had only a modest reduction in NK cells, no loss of NKT cells, and a slight increase in phagocytes following secondary challenge. During primary infection, the dominant sources of IFN-γ were, unexpectedly, neutrophils and Mφ, the former having intracellular stores of IFN-γ that were released during infection. IFN-γ-producing phagocytes greatly outnumbered IFN-γ-producing NK cells, NKT cells, and T cells during the primary response. TNF-α production was also dominated by neutrophils and Mφ, which vastly outnumbered NKT cells producing this cytokine. Neither T cells nor NK cells produced TNF-α early during primary infection. The TNF-α response was reduced in a secondary response, but remained dominated by neutrophils and Mφ. Moreover, no significant IFN-γ production by Mφ was associated with the secondary response. Indeed, only NK1.1+ cells and T cells produced IFN-γ in these mice. These studies provide a coherent view of innate immunity to oral Salmonella infection, reveal novel sources of IFN-γ, and demonstrate that immune status influences the nature of the innate response.
Synergistic Engagement of an Ineffective Endogenous Anti-Tumor Immune Response and Induction of IFN-γ and Fas-Ligand-Dependent Tumor Eradication by Combined Administration of IL-18 and IL-2
Authors: Wigginton Jon M. , Lee Jong-Keuk , Wiltrout Theresa A. , Alvord W. Gregory , Hixon Julie A. , Subleski Jeffrey , Back Timothy C. , Wiltrout Robert H. 
Published: April 2014

AbstractIFN-γ is a critical component of the endogenous and many cytokine-induced antitumor immune responses. In this study we have shown that the combination of IL-18 and IL-2 (IL-18/IL-2) synergistically enhances IFN-γ production both in vitro and in vivo, and synergizes in vivo to induce complete durable regression of well-established 3LL tumors in &gt;80% of treated mice. We have observed a nascent, but ineffective, host immune response against 3LL that depends on endogenous IFN-γ and IL-12 production and the Fas/Fas ligand (Fas-L) pathway. The combined administration of IL-18/IL-2 engages this endogenous response to induce tumor regression via a mechanism that is independent of NK and NKT cells or IL-12, but is critically dependent on CD8+ T cells, IFN-γ, and the Fas/Fas-L pathway. These studies demonstrate the importance of IFN-γ as well as the Fas/Fas-L pathway in both endogenous and cytokine-driven antitumor immune responses engaged by IL-18/IL-2 and provide preclinical impetus for clinical investigation of this potent anti-tumor combination.
Differential Requirement for NF-κB Family Members in Control of Helminth Infection and Intestinal Inflammation
Authors: Artis David , Shapira Sagi , Mason Nicola , Speirs Kendra M. , Goldschmidt Michael , Caamaño Jorge , Liou Hsiou-Chi , Hunter Christopher A. , Scott Phillip 
Published: April 2014

Abstract
The NF-κB family of transcription factors is critical in controlling the expression of a wide range of immune response genes. However, whether individual family members perform specific roles in regulating immunity and inflammation remains unclear. Here we investigated the requirement for NF-κB1, NF-κB2, and c-Rel in the expression of Th2 cytokine responses, development of host protective immunity, and regulation of intestinal inflammation following infection with the gut-dwelling helminth parasite Trichuris muris. While mice deficient in c-Rel mounted sufficient Th2 responses to expel infection, NF-κB1 knockout (KO) and NF-κB2 KO mice developed chronic infections associated with elevated production of Ag-specific IFN-γ. However, only infected NF-κB1 KO mice exhibited polarized IFN-γ responses associated with the loss of intestinal goblet cells and the development of destructive colitis-like pathology. Furthermore, blockade of IL-12 (previously shown to confer resistance in susceptible strains) recovered Ag-specific IL-13 responses and resistance to infection in NF-κB2 KO, but not NF-κB1 KO mice. Therefore, unique infection, immunological, and pathological outcomes were observed in different NF-κB KO strains. Taken together, these results provide direct evidence of nonoverlapping functions for NF-κB family members in the development of Th2 cytokine-mediated resistance to T. muris and the control of infection-induced intestinal inflammation.
The Mouse Model of Amebic Colitis Reveals Mouse Strain Susceptibility to Infection and Exacerbation of Disease by CD4+ T Cells
Authors: Houpt Eric R. , Glembocki David J. , Obrig Tom G. , Moskaluk Christopher A. , Lockhart Lauren A. , Wright Rhonda L. , Seaner Regina M. , Keepers Tiffany R. , Wilkins Tracy D. , Petri William A. 
Published: April 2014

Abstract
Amebic colitis is an important worldwide parasitic disease for which there is not a well-established animal model. In this work we show that intracecal inoculation of Entamoeba histolytica trophozoites led to established infection in 60% of C3H mice, while C57BL/6 or BALB/c mice were resistant, including mice genetically deficient for IL-12, IFN-γ, or inducible NO synthase. Infection was a chronic and nonhealing cecitis that pathologically mirrored human disease. Characterization of the inflammation by gene chip analysis revealed abundant mast cell activity. Parasite-specific Ab and cellular proliferative responses were robust and marked by IL-4 and IL-13 production. Depletion of CD4+ cells significantly diminished both parasite burden and inflammation and correlated with decreased IL-4 and IL-13 production and loss of mast cell infiltration. This model reveals important immune factors that influence susceptibility to infection and demonstrates for the first time the pathologic contribution of the host immune response in amebiasis.
Differences Between T Cell Epitopes Recognized After Immunization and After Infection
Authors: Vogel Thorsten U. , Horton Helen , Fuller Deborah H. , Carter Donald K. , Vielhuber Kathy , O’Connor David H. , Shipley Tim , Fuller Jim , Sutter Gerd , Erfle Volker , Wilson Nancy , Picker Louis J. , Watkins David I. 
Published: April 2014

AbstractEvidence suggests that cellular immune responses play a crucial role in the control of HIV and SIV replication in infected individuals. Several vaccine strategies have therefore targeted these CD8+ and CD4+ responses. Whether vaccination induces the same repertoire of responses seen after infection is, however, a key unanswered question in HIV vaccine development. We therefore compared the epitope specificity induced by vaccination to that present postchallenge in the peripheral blood. Intracellular cytokine staining of PBMC stimulated with overlapping 15/20-mer peptides spanning the proteins of SIV were measured after DNA/modified vaccinia Ankara vaccination of eight rhesus macaques. Lymphocytes from 8 animals recognized a total of 39 CD8 epitopes and 41 CD4 epitopes encoded by the vaccine. T cell responses were again monitored after challenge with SIVmac239 to investigate the evolution of these responses. Only 57% of all CD8+ T cell responses and 19% of all CD4+ T cell responses present after vaccination were recalled after infection as measured in the peripheral blood. Interestingly, 29 new CD8 epitopes and 5 new CD4 epitopes were recognized by PBMC in the acute phase. These new epitopes were not detected after vaccination, and only some of them were maintained in the chronic phase (33% of CD8 and no CD4 responses). Additionally, 24 new CD8 epitopes and 7 new CD4 epitopes were recognized by PBMC in the chronic phase of infection. The repertoire of the immune response detected in the peripheral blood after immunization substantially differed from the immune response detected in the peripheral blood after infection.
Pseudomonas aeruginosaActivates Human Mast Cells to Induce Neutrophil Transendothelial Migration Via Mast Cell-Derived IL-1α and β
Authors: Lin Tong-Jun , Garduno Rafael , Boudreau Robert T. M. , Issekutz Andrew C. 
Published: April 2014

AbstractThe mechanisms of neutrophil (PMN) recruitment to Pseudomonas aeruginosa infection remain incompletely defined. Mast cells (MC) involvement in this process has not been studied previously. In this study, we demonstrate that human cord blood-derived MC phagocytose P. aeruginosa and release mediators that activate HUVEC monolayers for supporting PMN transmigration. Pretreatment of supernatants from P. aeruginosa-MC cocultures with neutralizing anti-IL-1α plus anti-IL-1β Abs, or IL-1R antagonist before addition to HUVEC for stimulation completely abrogated MC-induced PMN transmigration, while anti-TNF-α treatment had no effect. The expression of E-selectin and ICAM-1 on HUVEC, the latter a ligand for PMN CD11/CD18, was significantly up-regulated by P. aeruginosa-induced MC mediators. Pretreatment of human PMN with anti-CD18 mAb or pretreatment of HUVEC with a combination of three mAbs (against ICAM-1, ICAM-2, and E-selectin) inhibited by 85% the MC-dependent PMN transmigration. Moreover, P. aeruginosa-induced production of IL-1α and IL-1β was down-regulated by IL-10 and dexamethasone. This study demonstrates for the first time that MC may mediate P. aeruginosa-induced PMN recruitment via production of IL-1α and β. These findings have important implications for diseases involving P. aeruginosa infection and suggest novel targets for modulating P. aeruginosa-induced inflammation.
Leukocyte Rolling Velocities and Migration Are Optimized by Cooperative L-Selectin and Intercellular Adhesion Molecule-1 Functions
Authors: Kadono Takafumi , Venturi Guglielmo M. , Steeber Douglas A. , Tedder Thomas F. 
Published: April 2014

AbstractSelectin family members largely mediate initial tethering and rolling of leukocytes on vascular endothelium, whereas integrin and Ig family members are essential for leukocyte firm adhesion. To quantify functional synergy between L-selectin and Ig family members during leukocyte rolling, the EA.hy926 human vascular endothelial line was transfected with either fucosyltransferase VII (926-FtVII) cDNA to generate L-selectin ligands alone or together with ICAM-1 cDNA (926-FtVII/ICAM-1). The ability of transfected 926 cells to support human leukocyte interactions was assessed in vitro using parallel plate flow chamber assays. Lymphocyte rolling on 926-FtVII cells was increased by ∼70% when ICAM-1 was expressed at physiological levels. Although initial tether formation was similar for both cell types, lymphocyte rolling was 26% slower on 926-FtVII/ICAM-1 cells. Pretreatment of lymphocytes with an anti-CD18 mAb eliminated the increase in rolling, and all rolling was blocked by anti-L-selectin mAb. In addition, rolling velocities of lymphocytes from CD18-hypomorphic mice were 48% faster on 926-FtVII/ICAM-1 cells, with a similar reduction in rolling frequency relative to wild-type lymphocytes. CD18-hypomorphic lymphocytes also showed an ∼40% decrease in migration to peripheral and mesenteric lymph nodes during in vivo migration assays compared with wild-type lymphocytes. Likewise, wild-type lymphocyte migration to peripheral lymph nodes was reduced by ∼50% in ICAM-1−/− recipient mice. Similar to human lymphocytes, human neutrophils showed enhanced rolling interactions on 926-FtVII/ICAM-1 cells, but also firmly adhered. Thus, in addition to mediating leukocyte firm adhesion, CD18 integrin/ICAM-1 interactions regulate leukocyte rolling velocities and thereby optimize L-selectin-mediated leukocyte rolling.
HIV-1 Envelope gp41 Peptides Promote Migration of Human FcεRI+ Cells and Inhibit IL-13 Synthesis Through Interaction with Formyl Peptide Receptors
Authors: de Paulis Amato , Florio Giovanni , Prevete Nella , Triggiani Massimo , Fiorentino Isabella , Genovese Arturo , Marone Gianni 
Published: April 2014

AbstractWe evaluated the effects of synthetic peptides (2017, 2019, 2020, 2021, 2023, 2027, 2029, 2030, 2031, and 2035) encompassing the structure of HIV-1MN envelope gp41 on both chemotaxis of human basophils and the release of preformed mediators (histamine) and of cytokines (IL-13). Peptides 2019 and 2021 were potent basophil chemoattractants, whereas the other peptides examined were ineffective. Preincubation of basophils with FMLP or gp41 2019 resulted in complete desensitization to a subsequent challenge with homologous stimulus. Incubation of basophils with low concentration (5 × 10−7 M) of FMLP, which binds with high affinity to N-formyl peptide receptor (FPR), but not to FPR-like 1, did not affect the chemotactic response to a heterologous stimulus (gp41 2019). In contrast, a high concentration (10−4 M) of FMLP, which binds also to FPR-like 1, significantly reduced the chemotactic response to gp41 2019. The FPR antagonist cyclosporin H inhibited chemotaxis induced by FMLP, but not by gp41 2019. None of these peptides singly induced the release of histamine or cytokines (IL-4 and IL-13) from basophils. However, low concentrations of peptides 2019 and 2021 (10−8–10−6 M) inhibited histamine release from basophils challenged with FMLP but not the secretion caused by anti-IgE and gp120. Preincubation of basophils with peptides 2019 and 2021 inhibited the expression of both IL-13 mRNA, and the FMLP-induced release of IL-13 from basophils. These data highlight the complexity of the interactions between viral and bacterial peptides with FPR subtypes on human basophils.
Receptors and Signaling Mechanisms Required for Prostaglandin E2-Mediated Regulation of Mast Cell Degranulation and IL-6 Production
Authors: Nguyen MyTrang , Solle Michael , Audoly Laurent P. , Tilley Stephen L. , Stock Jeffrey L. , McNeish John D. , Coffman Thomas M. , Dombrowicz David , Koller Beverly H. 
Published: April 2014

Abstract
Mast cells are implicated in the pathogenesis of a broad spectrum of immunological disorders. These cells release inflammatory mediators in response to a number of stimuli, including IgE-Ag complexes. The degranulation of mast cells is modified by PGs. To begin to delineate the pathway(s) used by PGs to regulate mast cell function, we examined bone marrow-derived mast cells (BMMC) cultured from mice deficient in the EP1, EP2, EP3, and EP4 receptors for PGE2. Although BMMCs express all four of these PGE2 receptors, potentiation of Ag-stimulated degranulation and IL-6 cytokine production by PGE2 is dependent on the EP3 receptor. Consistent with the coupling of this receptor to Gαi, PGE2 activation of the EP3 receptor leads to both inhibition of adenylate cyclase and increased intracellular Ca2+. The magnitude of increase in intracellular Ca2+ induced by EP3 activation is similar to that observed after activation of cells with IgE and Ag. Although PGE alone is not sufficient to initiate BMMC degranulation, stimulation of cells with PGE along with PMA induces degranulation. These actions are mediated by the EP3 receptor through signals involving Ca2+ mobilization and/or decreased cAMP levels. Accordingly, these studies identify PGE2/EP3 as a proinflammatory signaling pathway that promotes mast cell activation.