bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lymph Node Resident Rather Than Skin-Derived Dendritic Cells Initiate Specific T Cell Responses after Leishmania major Infection
Authors: Iezzi Giandomenica , Fröhlich Anja , Ernst Bettina , Ampenberger Franziska , Saeland Sem , Glaichenhaus Nicolas , Kopf Manfred 
Published: April 2014

Abstract
Langerhans cells have been thought to play a major role as APCs for induction of specific immune responses to Leishmania major. Although their requirement for control of infection has been challenged recently, it remains unclear whether they can transport Ag to lymph nodes and promote initiation of T cell responses. Moreover, the role of dermal dendritic cells (DCs), another population of skin DCs, has so far not been addressed. We have investigated the origin and characterized the cell population responsible for initial activation of L. major-specific T cells in susceptible and resistant mice. We found that Ag presentation in draining lymph nodes peaks as early as 24 h after infection and is mainly mediated by a population of CD11chighCD11bhighGr-1−CD8−langerin− DCs residing in lymph nodes and acquiring soluble Ags possibly drained through the conduit network. In contrast, skin-derived DCs, including Langerhans cells and dermal DCs, migrated poorly to lymph nodes and played a minor role in early T cell activation. Furthermore, prevention of migration through early removal of the infection site did not affect Ag presentation by CD11chigh CD11bhigh DCs and activation of Leishmania major-specific naive CD4+ T cells in vivo.
Pathogenic Consequences in Semen Quality of an Autoimmune Response against the Prostate Gland: From Animal Models to Human Disease
Authors: Motrich Ruben D. , Maccioni Mariana , Ponce Andres A. , Gatti Gerardo A. , Oberti Juan P. Mackern , Rivero Virginia E. 
Published: April 2014

Abstract
We have recently proposed an autoimmune etiology in ∼35% of chronic nonbacterial prostatitis patients, the most frequent form of prostatitis observed, because they exhibit IFN-γ-secreting lymphocytes specific to prostate Ags. Interestingly, this particular group of patients, but not the rest of chronic nonbacterial prostatitis patients, also presented striking abnormalities in their semen quality.
In this work, we use an experimental animal model of autoimmune prostatitis on Wistar rats developed in our laboratory to investigate when, where, and how sperm cells from autoimmune prostatitis individuals are being damaged. As in patients, a marked reduction in sperm concentration, almost null sperm motility and viability, and an increased percentage of apoptotic spermatozoa were detected in samples from animals with the disease. Prostate-specific autoantibodies as well as elevated levels of NO, TNF-α, and IFN-γ were also detected in their seminal plasma. In contrast, epididymal spermatozoa remain intact, indicating that sperm damage occurs at the moment of joining of prostate secretion to sperm cells during ejaculation. These results were further supported by experiments in which mixture of normal sperm cells with autoimmune seminal plasma were performed.
We hypothesize that sperm damage in experimental autoimmune prostatitis can be the consequence of an inflammatory milieu, originally produced by an autoimmune response in the prostate; a diminished prostate functionality, evidenced by reduced levels of citric acid in semen or by both mechanisms simultaneously. Once more, we suggest that autoimmunity to prostate may have consequences on fertility.
Role of Immunoproteasomes in Cross-Presentation
Authors: Palmowski Michael J. , Gileadi Uzi , Salio Mariolina , Gallimore Awen , Millrain Maggie , James Edward , Addey Caroline , Scott Diane , Dyson Julian , Simpson Elizabeth , Cerundolo Vincenzo 
Published: April 2014

AbstractThe evidence that proteasomes are involved in the processing of cross-presented proteins is indirect and based on the in vitro use of proteasome inhibitors. It remains, therefore, unclear whether cross-presentation of MHC class I peptide epitopes can occur entirely within phagolysosomes or whether it requires proteasome degradation. To address this question, we studied in vivo cross-presentation of an immunoproteasome-dependent epitope. First, we demonstrated that generation of the immunodominant HY Uty246–254 epitope is LMP7 dependent, resulting in the lack of rejection of male LMP7-deficient (LMP7−/−) skin grafts by female LMP7−/− mice. Second, we ruled out an altered Uty246–254-specific T cell repertoire in LMP7−/− female mice and demonstrated efficient Uty246–254 presentation by re-expressing LMP7 in male LMP7−/− cells. Finally, we observed that LMP7 expression significantly enhanced cross-priming of Uty246–254-specific T cells in vivo. The observations that male skin grafts are not rejected by LMP7−/− female mice and that presentation of a proteasome-dependent peptide is not efficiently rescued by alternative cross-presentation pathways provide strong evidence that proteasomes play an important role in cross-priming events.
Cutting Edge: Inhibition of TLR and FcR Responses in Macrophages by Triggering Receptor Expressed on Myeloid Cells (TREM)-2 and DAP12
Authors: Hamerman Jessica A. , Jarjoura Jessica R. , Humphrey Mary Beth , Nakamura Mary C. , Seaman William E. , Lanier Lewis L. 
Published: April 2014

Abstract
DAP12 is an ITAM-containing adapter that associates with receptors in myeloid and NK cells. DAP12-associated receptors can give activation signals leading to cytokine production; however, in some situations, DAP12 inhibits cytokine production stimulated through TLRs and FcRs. Here we show that Triggering Receptor Expressed on Myeloid cells (TREM)-2 is responsible for the DAP12-mediated inhibition in mouse macrophages. A chimeric receptor composed of the extracellular domain of TREM-2 and the cytoplasmic domain of DAP12 inhibited the TLR- and FcR-induced TNF production of DAP12-deficient macrophages, whereas a TREM-1 chimera did not. In wild-type macrophages, TREM-2 knockdown increased TLR-induced TNF production. A TREM-2 Fc fusion protein bound to macrophages, indicating that macrophages express a TREM-2 ligand. Thus, the interaction of TREM-2 and its ligand results in an inhibitory signal that can reduce the inflammatory response.
Modulation of Monocyte Function by Activated Protein C, a Natural Anticoagulant
Authors: Stephenson Daniel A. , Toltl Lisa J. , Beaudin Suzanne , Liaw Patricia C. 
Published: April 2014

AbstractActivated protein C is the first effective biological therapy for the treatment of severe sepsis. Although activated protein C is well established as a physiological anticoagulant, emerging data suggest that it also exerts anti-inflammatory and antiapoptotic effects. In this study, we investigated the ability of activated protein C to modulate monocyte apoptosis, inflammation, phagocytosis, and adhesion. Using the immortalized human monocytic cell line THP-1, we demonstrated that activated protein C inhibited camptothecin-induced apoptosis in a dose-dependent manner. The antiapoptotic effect of activated protein C requires its serine protease domain and is dependent on the endothelial cell protein C receptor and protease-activated receptor-1. In primary blood monocytes from healthy individuals, activated protein C inhibited spontaneous apoptosis. With respect to inflammation, activated protein C inhibited the production of TNF, IL-1β, IL-6, and IL-8 by LPS-stimulated THP-1 cells. Activated protein C did not influence the phagocytic internalization of Gram-negative and Gram-positive bioparticles by THP-1 cells or by primary blood monocytes. Activated protein C also did not affect the expression of adhesion molecules by LPS-stimulated blood monocytes nor the ability of monocytes to adhere to LPS-stimulated endothelial cells. We hypothesize that the protective effect of activated protein C in sepsis reflects, in part, its ability to prolong monocyte survival in a manner that selectively inhibits inflammatory cytokine production while maintaining phagocytosis and adherence capabilities, thereby promoting antimicrobial properties while limiting tissue damage.
Regulatory and Effector T Cell Activation Levels Are Prime Determinants of In Vivo Immune Regulation
Authors: Billiard Fabienne , Litvinova Elena , Saadoun David , Djelti Fathia , Klatzmann David , Cohen José L. , Marodon Gilles , Salomon Benoı̂t L. 
Published: April 2014

AbstractLittle is known about the in vivo conditions in which CD4+CD25+ regulatory T cells (Treg) exert their suppressive effect in nonlymphopenic mice. To this end, we analyzed Treg-mediated suppression of expansion and cytokine production at different levels of Ag-specific CD4+CD25− T cell activation. Using Ab-mediated depletion of endogenous Treg, we show that basal immunosuppression is dependent on effector T cell activation. These polyclonal Treg, which were poorly activated in our immunization conditions, were effective in weak but not high T cell activation context. In contrast, the same immunization conditions led to proliferation of cotransferred Ag-specific Treg. Those efficiently inhibited T cell proliferation and cytokine production even in strong T cell activation context. Interestingly, Treg selectively suppressed expansion or cytokine production depending on the experimental approach. The importance of the immune context for efficient suppression is further supported by the observation that Treg depletion exacerbated diabetes of NOD mice only at the early stage of the disease. Overall, our study suggests that Treg-mediated suppression depends on the relative activation of Treg and effector T cells in vivo. This balance may be a critical factor in the regulation of immune responses.
Toxoplasma gondiiGenotype Determines MyD88-Dependent Signaling in Infected Macrophages
Authors: Kim Leesun , Butcher Barbara A. , Lee Chiang W. , Uematsu Satoshi , Akira Shizuo , Denkers Eric Y. 
Published: April 2014

AbstractInfection of mouse macrophages with Toxoplasma gondii elicits MAPK activation and IL-12 production, but host cell signaling pathways have not been clearly delineated. Here, we compared macrophage signaling in response to high virulence type I (RH) vs low virulence type II (ME49) strain infection. Tachyzoites of both strains induced p38 MAPK-dependent macrophage IL-12 release, although ME49 elicited 2- to 3-fold more cytokine than RH. IL-12 production was largely restricted to infected cells in each case. RH-induced IL-12 release did not require MyD88, whereas ME49-triggered IL-12 production was substantially dependent on this TLR/IL-1R adaptor molecule. MyD88 was also not required for RH-stimulated p38 MAPK activation, which occurred in the absence of detectable upstream p38 MAPK kinase activity. In contrast, ME49-driven p38 MAPK activation displayed an MyD88-dependent component. This parasite strain also induced MyD88-dependent activation of MKK4, an upstream activator of p38 MAPK. The results suggest that RH triggers MAPK activation and IL-12 production using MyD88-independent signaling, whereas ME49 uses these pathways as well as MyD88-dependent signaling cascades. Differences in host signaling pathways triggered by RH vs ME49 may contribute to the high and low virulence characteristics displayed by these parasite strains.
Inflammation-Responsive Transcription Factor SAF-1 Activity Is Linked to the Development of Amyloid A Amyloidosis
Authors: Ray Alpana , Shakya Arvind , Kumar Deepak , Benson Merrill D. , Ray Bimal K. 
Published: April 2014

AbstractAbundantly expressed serum amyloid A (SAA) protein under chronic inflammatory conditions gives rise to insoluble aggregates of SAA derivatives in multiple organs resulting in reactive amyloid A (AA) amyloidosis, a consequence of rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, familial Mediterranean fever, and Castleman’s disease. An inflammation-responsive transcription factor, SAF (for SAA activating factor), has been implicated in the sustained expression of amyloidogenic SAA under chronic inflammatory conditions. However, its role in the pathogenesis of AA amyloidosis has thus far remained obscure. In this paper we have shown that SAF-1, a major member of the SAF family, is abundantly present in human AA amyloidosis patients. To assess whether SAF-1 is directly linked to the pathogenesis of AA amyloidosis, we have developed a SAF-1 transgenic mouse model. SAF-1-overexpressing mice spontaneously developed AA amyloidosis at the age of 14 mo or older. Immunohistochemical analysis confirmed the nature of the amyloid deposits as an AA type derived from amyloidogenic SAA1. Furthermore, SAF-1 transgenic mice rapidly developed severe AA amyloidosis in response to azocasein injection, indicating increased susceptibility to inflammation. Also, during inflammation SAF-1 transgenic mice exhibited a prolonged acute phase response, leading to an extended period of SAA synthesis. Together, these results provide direct evidence that SAF-1 plays a key role in the development of AA amyloidosis, a consequence of chronic inflammation.
Prostaglandin D2 Plays an Essential Role in Chronic Allergic Inflammation of the Skin via CRTH2 Receptor
Authors: Satoh Takahiro , Moroi Rie , Aritake Kosuke , Urade Yoshihiro , Kanai Yasumasa , Sumi Koji , Yokozeki Hiroo , Hirai Hiroyuki , Nagata Kinya , Hara Toshifumi , Utsuyama Masanori , Hirokawa Katsuiku , Sugamura Kazuo , Nishioka Kiyoshi , Nakamura Masataka 
Published: April 2014

AbstractPGD2 plays roles in allergic inflammation via specific receptors, the PGD receptor designated DP and CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells). We generated mutant mice carrying a targeted disruption of the CRTH2 gene to investigate the functional roles of CRTH2 in cutaneous inflammatory responses. CRTH2-deficent mice were fertile and grew normally. Ear-swelling responses induced by hapten-specific IgE were less pronounced in mutant mice, giving 35–55% of the responses of normal mice. Similar results were seen in mice treated with a hemopoietic PGD synthase inhibitor, HQL-79, or a CRTH2 antagonist, ramatroban. The reduction in cutaneous responses was associated with decreased infiltration of lymphocytes, eosinophils, and basophils and decreased production of macrophage-derived chemokine and RANTES at inflammatory sites. In models of chronic contact hypersensitivity induced by repeated hapten application, CRTH2 deficiency resulted in a reduction by approximately half of skin responses and low levels (63% of control) of serum IgE production, although in vivo migration of Langerhans cells and dendritic cells to regional lymph nodes was not impaired in CRTH2-deficient mice. In contrast, delayed-type hypersensitivity to SRBC and irritation dermatitis in mutant mice were the same as in wild-type mice. These findings indicate that the PGD2-CRTH2 system plays a significant role in chronic allergic skin inflammation. CRTH2 may represent a novel therapeutic target for treatment of human allergic disorders, including atopic dermatitis.
Increased Levels of Soluble CD40L in African Tick Bite Fever: Possible Involvement of TLRs in the Pathogenic Interaction betweenRickettsia africae, Endothelial Cells, and Platelets
Authors: Damås Jan K. , Jensenius Mogens , Ueland Thor , Otterdal Kari , Yndestad Arne , Frøland Stig S. , Rolain Jean-Marc , Myrvang Bjørn , Raoult Didier , Aukrust Pål 
Published: April 2014

AbstractThe pathophysiological hallmark of spotted fever group rickettsioses comprises infection of endothelial cells with subsequent infiltration of inflammatory cells. Based on its ability to promote inflammation and endothelial cell activation, we investigated the role of CD40L in African tick bite fever (ATBF), caused by Rickettsia africae, using different experimental approaches. Several significant findings were revealed. 1) Patients with ATBF (n = 15) had increased serum levels of soluble CD40 ligand (sCD40L), which decreased during follow-up. 2) These enhanced sCD40L levels seem to reflect both direct and indirect (through endothelial cell activation involving CX3CL1-related mechanisms) effects of R. africae on platelets. 3) In combination with sCD40L, R. africae promoted a procoagulant state in endothelial cells by up-regulating tissue factor and down-regulating thrombomodulin expression. 4) Although the R. africae-mediated activation of platelets involved TLR2, the combined procoagulant effects of R. africae and sCD40L on endothelial cells involved TLR4. 5) Doxycycline counteracted the combined procoagulant effects of R. africae and sCD40L on endothelial cells. Our findings suggest an inflammatory interaction between platelets and endothelial cells in ATBF, involving TLR-related mechanisms. This interaction, which includes additive effects between sCD40L and R. africae, may contribute to endothelial inflammation and hypercoagulation in this disorder.
Double-Negative T Regulatory Cells Can Develop Outside the Thymus and Do Not Mature from CD8+ T Cell Precursors
Authors: Ford Megan S. , Zhang Zhu-Xu , Chen Wenhao , Zhang Li 
Published: April 2014

AbstractRecent studies have demonstrated that activated peripheral αβTCR+CD3+CD4−CD8−NK1.1− (double-negative, DN) regulatory T cells (Tregs) from both mice and humans are able to down-regulate immune responses in vitro and in vivo. However, the origin and developmental requirements of functional DN Tregs remain unclear. In this study, we investigated the requirement for CD8 expression as well as the presence of a thymus for the development of functional DN Tregs. We demonstrate that DN Tregs exist in CD8-deficient mice and that stimulation of CD8+ T cells in vivo with TCR-specific Ag does not convert CD8+ T cells into DN Tregs. In addition, we found that DN T cells are present in the spleens and lymph nodes of thymectomized mice that are irradiated and reconstituted with T cell-depleted bone marrow cells. Interestingly, DN Tregs that develop in thymectomized mice can suppress syngeneic CD8+ T cells more effectively than those that develop in sham-thymectomized mice. Taken together, our data suggest that DN Tregs are not derived from CD8+ T cell precursors and that functional DN Tregs may preferentially develop outside of the thymus. These data suggest that DN Tregs may represent a developmentally and functionally unique cell population.
Phosphatidylinositol Mannoside fromMycobacterium tuberculosisBinds α5β1 Integrin (VLA-5) on CD4+ T Cells and Induces Adhesion to Fibronectin
Authors: Rojas Roxana E. , Thomas Jeremy J. , Gehring Adam J. , Hill Preston J. , Belisle John T. , Harding Clifford V. , Boom W. Henry 
Published: April 2014

AbstractThe pathological hallmark of the host response to Mycobacterium tuberculosis is the granuloma where T cells and macrophages interact with the extracellular matrix (ECM) to control the infection. Recruitment and retention of T cells within inflamed tissues depend on adhesion to the ECM. T cells use integrins to adhere to the ECM, and fibronectin (FN) is one of its major components. We have found that the major M. tuberculosis cell wall glycolipid, phosphatidylinositol mannoside (PIM), induces homotypic adhesion of human CD4+ T cells and T cell adhesion to immobilized FN. Treatment with EDTA and cytochalasin D prevented PIM-induced T cell adhesion. PIM-induced T cell adhesion to FN was blocked with mAbs against α5 integrin chain and with RGD-containing peptides. α5β1 (VLA-5) is one of two major FN receptors on T cells. PIM was found to bind directly to purified human VLA-5. Thus, PIM interacts directly with VLA-5 on CD4+ T lymphocytes, inducing activation of the integrin, and promoting adhesion to the ECM glycoprotein, FN. This is the first report of direct binding of a M. tuberculosis molecule to a receptor on human T cells resulting in a change in CD4+ T cell function.
Factor I-Mediated Processing of Complement Fragments on HIV Immune Complexes Targets HIV to CR2-Expressing B Cells and Facilitates B Cell-Mediated Transmission of Opsonized HIV to T Cells
Authors: Bánki Zoltán , Wilflingseder Doris , Ammann Christoph G. , Pruenster Monika , Müllauer Brigitte , Holländer Karoline , Meyer Martina , Sprinzl Georg M. , van Lunzen Jan , Stellbrink Hans-Jürgen , Dierich Manfred P. , Stoiber Heribert 
Published: April 2014

Abstract
Our study demonstrates that binding of complement-opsonized HIV to complement receptor type 1 on human erythrocytes (E) via C3b fragments is followed by a rapid normal human serum-mediated detachment of HIV from E. The release was dependent on the presence of factor I indicating a conversion of C3b fragments to iC3b and C3d on the viral surface. This in turn resulted in an efficient binding of opsonized HIV to CR2-expressing B cells, thus facilitating B cell-mediated transmission of HIV to T cells. These data provide a new dynamic view of complement opsonization of HIV, suggesting that association of virus with E might be a transient phenomenon and the factor I-mediated processing of C3b to iC3b and C3d on HIV targets the virus to complement receptor type 2-expressing cells. Thus, factor I in concert with CR1 on E and factor H in serum due to their cofactor activity are likely to be important contributors for the generation of C3d-opsonized infectious HIV reservoirs on follicular dendritic cells and/or B cells in HIV-infected individuals.
Cutting Edge: TLR9 and TLR2 Signaling Together Account for MyD88-Dependent Control of Parasitemia in Trypanosoma cruzi Infection
Authors: Bafica Andre , Santiago Helton Costa , Goldszmid Romina , Ropert Catherine , Gazzinelli Ricardo T. , Sher Alan 
Published: April 2014

Abstract
Activation of innate immune cells by Trypanosoma cruzi-derived molecules such as GPI anchors and DNA induces proinflammatory cytokine production and host defense mechanisms. In this study, we demonstrate that DNA from T. cruzi stimulates cytokine production by APCs in a TLR9-dependent manner and synergizes with parasite-derived GPI anchor, a TLR2 agonist, in the induction of cytokines by macrophages. Compared with wild-type animals, T. cruzi-infected Tlr9−/− mice displayed elevated parasitemia and decreased survival. Strikingly, infected Tlr2−/−Tlr9−/− mice developed a parasitemia equivalent to animals lacking MyD88, an essential signaling molecule for most TLR, but did not show the acute mortality displayed by MyD88−/− animals. The enhanced susceptibility of Tlr9−/− and Tlr2−/−Tlr9−/− mice was associated with decreased in vivo IL-12/IFN-γ responses. Our results reveal that TLR2 and TLR9 cooperate in the control of parasite replication and that TLR9 has a primary role in the MyD88-dependent induction of IL-12/IFN-γ synthesis during infection with T. cruzi.
Cutting Edge: TREM-2 Attenuates Macrophage Activation
Authors: Turnbull Isaiah R. , Gilfillan Susan , Cella Marina , Aoshi Taiki , Miller Mark , Piccio Laura , Hernandez Maristela , Colonna Marco 
Published: April 2014

Abstract
The triggering receptor expressed on myeloid cells 2 (TREM-2) delivers intracellular signals through the adaptor DAP12 to regulate myeloid cell function both within and outside the immune system. The role of TREM-2 in immunity has been obscured by the failure to detect expression of the TREM-2 protein in vivo. In this study, we show that TREM-2 is expressed on macrophages infiltrating the tissues from the circulation and that alternative activation with IL-4 can induce TREM-2. TREM-2 expression is abrogated by macrophage maturation with LPS of IFN-γ. Using TREM-2−/− mice, we find that TREM-2 functions to inhibit cytokine production by macrophages in response to the TLR ligands LPS, zymosan, and CpG. Furthermore, we find that TREM-2 completely accounts for the increased cytokine production previously reported by DAP12−/− macrophages. Taken together, these data show that TREM-2 is expressed on newly differentiated and alternatively activated macrophages and functions to restrain macrophage activation.