bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclophilin B Attenuates the Expression of TNF-α in Lipopolysaccharide-Stimulated Macrophages through the Induction of B Cell Lymphoma-3
Authors: Marcant Adeline , Denys Agnès , Melchior Aurélie , Martinez Pierre , Deligny Audrey , Carpentier Mathieu , Allain Fabrice 
Published: July 2012

Abstract
Extracellular cyclophilin A (CyPA) and CyPB have been well described as chemotactic factors for various leukocyte subsets, suggesting their contribution to inflammatory responses. Unlike CyPA, CyPB accumulates in extracellular matrixes, from which it is released by inflammatory proteases. Hence, we hypothesized that it could participate in tissue inflammation by regulating the activity of macrophages. In the current study, we confirmed that CyPB initiated in vitro migration of macrophages, but it did not induce production of proinflammatory cytokines. In contrast, pretreatment of macrophages with CyPB attenuated the expression of inflammatory mediators induced by LPS stimulation. The expression of TNF-α mRNA was strongly reduced after exposure to CyPB, but it was not accompanied by significant modification in LPS-induced activation of MAPK and NF-κB pathways. LPS activation of a reporter gene under the control of TNF-α gene promoter was also markedly decreased in cells treated with CyPB, suggesting a transcriptional mechanism of inhibition. Consistent with this hypothesis, we found that CyPB induced the expression of B cell lymphoma-3 (Bcl-3), which was accompanied by a decrease in the binding of NF-κB p65 to the TNF-α promoter. As expected, interfering with the expression of Bcl-3 restored cell responsiveness to LPS, thus confirming that CyPB acted by inhibiting initiation of TNF-α gene transcription. Finally, we found that CyPA was not efficient in attenuating the production of TNF-α from LPS-stimulated macrophages, which seemed to be due to a modest induction of Bcl-3 expression. Collectively, these findings suggest an unexpected role for CyPB in attenuation of the responses of proinflammatory macrophages.
Genetic Interdependence of Lyn and Negative Regulators of B Cell Receptor Signaling in Autoimmune Disease Development
Authors: Tsantikos Evelyn , Maxwell Mhairi J. , Kountouri Nicole , Harder Kenneth W. , Tarlinton David M. , Hibbs Margaret L. 
Published: July 2012

Abstract
Ab-mediated autoimmune disease is multifaceted and may involve many susceptibility loci. The majority of autoimmune patients are thought to have polymorphisms in a number of genes that interact in different combinations to contribute to disease pathogenesis. Studies in mice and humans have implicated the Lyn protein tyrosine kinase as a regulator of Ab-mediated autoimmune disease. To examine whether haploinsufficiency of Lyn gives rise to cellular and clinical manifestations of autoimmune disease, we evaluated the phenotype of Lyn+/− mice. We find that their B cell compartment is significantly perturbed, with reduced numbers of marginal zone and transitional stage 2 B cells, expansion of plasma cells, downregulation of surface IgM, and upregulation of costimulatory molecules. Biochemical studies show that Lyn+/− B cells have defects in negative regulation of signaling, whereas Lyn+/− mice develop IgG autoantibodies and glomerulonephritis with age. Because Lyn has a pivotal role in the activation of inhibitory phosphatases, we generated mice harboring double heterozygous loss-of-function mutations in Lyn and SHP-1 or Lyn and SHIP-1. Partial inactivation of SHP-1 or SHIP-1 amplifies the consequence of Lyn haploinsufficiency, leading to an accelerated development of autoantibodies and disease. Our data also reveal that the BALB/c background is protective against autoimmune-mediated glomerulonephritis, even in the face of high titer autoantibodies, whereas the C57BL/6 background is susceptible. This study demonstrates that Lyn is a haploinsufficient gene in autoimmune disease and importantly shows that quantitative genetic variation in Lyn-regulated pathways can mirror the complete loss of a single critical inhibitory molecule.
CD4+ T Cells Disarm or Delete Cytotoxic T Lymphocytes under IL-17–Polarizing Conditions
Authors: Tsai Jy-Ping , Lee Meng-Hua , Hsu Shu-Ching , Chen Mei-Yu , Liu Shih-Jen , Chang Joseph T. , Liao Chun-Ta , Cheng Ann-Joy , Chong Pele , Chu Ching-Liang , Shen Chia-Rui , Chen Hsin-Wei 
Published: July 2012

Abstract
Previous studies have shown that TGF-β acts cooperatively with IL-6 to elicit a high frequency of IL-17–secreting CD4+ T cells (termed Th17) and an elevated CD8+IL-17+ T cell population (termed Tc17). These CD8+ cells fail to behave like most cytotoxic T lymphocytes that express IFN-γ and granzyme B, but they exhibit a noncytotoxic phenotype. Although a significant increase in the number of these Tc17 cells was found in tumors, their role and interaction with other cell types remain unclear. In this study, we demonstrate that the presence of CD4+CD25− T cells, but not the CD4+CD25+ (regulatory T [Treg]) cell population, significantly reduced the elicitation of Tc17 cells, possibly as a result of the induction of apoptotic signals. Importantly, these signals may be derived from soluble mediators, and the addition of anti–IL-2 restored the reduction of Tc17 cells in the presence of CD4+CD25− T cells. Finally, the elicited Tc17 and Treg cells exhibited a close association in patients with head and neck cancer, indicating that the surrounding Treg cells might maintain the survival of the Tc17 cells. Taken together, these results reveal an intriguing mechanism in which Tc17 cells are controlled by a finely tuned collaboration between the different types of CD4+ T cells in distinct tumor microenvironments.
Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis
Authors: Tajiri Kazuko , Imanaka-Yoshida Kyoko , Matsubara Akihiro , Tsujimura Yusuke , Hiroe Michiaki , Naka Tetsuji , Shimojo Nobutake , Sakai Satoshi , Aonuma Kazutaka , Yasutomi Yasuhiro 
Published: July 2012

Abstract
Myocarditis and subsequent dilated cardiomyopathy are major causes of heart failure in young adults. Myocarditis in humans is highly heterogeneous in etiology. Recent studies have indicated that a subgroup of myocarditis patients may benefit from immune-targeted therapies, because autoimmunity plays an important role in myocarditis as well as contributing to the progression to cardiomyopathy and heart failure. Suppressor of cytokine signaling (SOCS) 1 plays a key role in the negative regulation of both TLR- and cytokine receptor-mediated signaling, which is involved in innate immunity and subsequent adaptive immunity. In this study, we investigated the therapeutic effect of SOCS1 DNA administration on experimental autoimmune myocarditis (EAM) in mice. EAM was induced by s.c. immunization with cardiac-specific peptides derived from α myosin H chain in BALB/c mice. In contrast to control myocarditis mice, SOCS1 DNA-injected mice were protected from development of EAM and heart failure. SOCS1 DNA administration was effective for reducing the activation of autoreactive CD4+ T cells by inhibition of the function of Ag-presenting dendritic cells. Our findings suggest that SOCS1 DNA administration has considerable therapeutic potential in individuals with autoimmune myocarditis and dilated cardiomyopathy.
IL-6 Amplifier, NF-κB–Triggered Positive Feedback for IL-6 Signaling, in Grafts Is Involved in Allogeneic Rejection Responses
Authors: Lee Jihye , Nakagiri Tomoyuki , Oto Takahiro , Harada Masaya , Morii Eiichi , Shintani Yasushi , Inoue Masayoshi , Iwakura Yoichiro , Miyoshi Shinichiro , Okumura Meinoshin , Hirano Toshio , Murakami Masaaki 
Published: July 2012

Abstract
The IL-6-amplifier first was discovered as a synergistic activation mechanism for NF-κB/STAT3 in type 1 collagen+ cells. This process is marked by the hyperinduction of chemokines and subsequent local inflammation that leads to autoimmune diseases. In this study, we show that IL-6 amplifier activation in grafts plays important roles in allogeneic graft rejection by using a tracheal heterotopic transplantation model that includes bronchiolitis obliterans, a pathological marker for chronic rejection. IL-6, epidermal growth factor, and IFN-γ all stimulate IL-6 amplifier activation, whereas CCL2, a chemotactic factor for Th1 cells, was one of the amplifier’s main targets. Interestingly, IFN-γ hyperinduced CCL2 in type 1 collagen+ cells via the IL-6 amplifier at least in vitro. In addition, we detected IL-6, CCL2, phospho-STAT3, and phospho-NF-κB in epithelial type 1 collagen+ cells of allogeneic tracheal grafts. These results show that IL-6 amplifier activation in grafts plays a critical role for graft rejection responses after allogeneic transplantation, including chronic rejection. From these results, we consider whether the IL-6 amplifier in grafts might be a valuable therapeutic target for the prevention of transplant rejection, including chronic rejection.
Enhanced Th17 Differentiation and Aggravated Arthritis in IEX-1–Deficient Mice by Mitochondrial Reactive Oxygen Species-Mediated Signaling
Authors: Zhi Liang , Ustyugova Irina V. , Chen Xinyuan , Zhang Qi , Wu Mei X. 
Published: July 2012

Abstract
CD4+ Th1 and Th17 cells both can cause autoimmune diseases, either alone or collaboratively, if left unchecked. However, what determines the dominant Th effector phenotype in a specific autoimmune disease remains poorly understood. Our present investigation shows that null mutation of IEX-1 promotes differentiation of Th17 cells but compromises the survival of Th1 cells. The differential effect gave rise to a greater number of Th17 cells, a higher level of IL-17 production, and more severe arthritis in IEX-1 knockout mice than in wild-type mice after immunizations with collagen. IEX-1 deficiency-facilitated Th17 cell differentiation was mediated by the increased formation of reactive oxygen species (ROS) at mitochondria following T cell activation, as suggested by marked inhibition of Th17 induction with ROS scavenger N-acetylcysteine or mitoquinone, a specific inhibitor for mitochondrial ROS production. Mitochondrial ROS augmented the expression of B cell-activating transcription factor, which may contribute to increased IL-17 production in the absence of IEX-1, in light of its importance in IL-17 transcription. The results demonstrate that mitochondrial ROS contribute significantly to the dominant Th effector phenotype in autoimmunity in addition to the cytokine milieu.
Abrogation of Src Homology Region 2 Domain-Containing Phosphatase 1 in Tumor-Specific T Cells Improves Efficacy of Adoptive Immunotherapy by Enhancing the Effector Function and Accumulation of Short-Lived Effector T Cells In Vivo
Authors: Stromnes Ingunn M. , Fowler Carla , Casamina Chanel C. , Georgopolos Christina M. , McAfee Megan S. , Schmitt Thomas M. , Tan Xiaoxia , Kim Tae-Don , Choi Inpyo , Blattman Joseph N. , Greenberg Philip D. 
Published: July 2012

Abstract
T cell expression of inhibitory proteins can be a critical component for the regulation of immunopathology owing to self-reactivity or potentially exuberant responses to pathogens, but it may also limit T cell responses to some malignancies, particularly if the tumor Ag being targeted is a self-protein. We found that the abrogation of Src homology region 2 domain-containing phosphatase-1 (SHP-1) in tumor-reactive CD8+ T cells improves the therapeutic outcome of adoptive immunotherapy in a mouse model of disseminated leukemia, with benefit observed in therapy employing transfer of CD8+ T cells alone or in the context of also providing supplemental IL-2. SHP-1−/− and SHP-1+/+ effector T cells were expanded in vitro for immunotherapy. Following transfer in vivo, the SHP-1−/− effector T cells exhibited enhanced short-term accumulation, followed by greater contraction, and they ultimately formed similar numbers of long-lived, functional memory cells. The increased therapeutic effectiveness of SHP-1−/− effector cells was also observed in recipients that expressed the tumor Ag as a self-antigen in the liver, without evidence of inducing autoimmune toxicity. SHP-1−/− effector CD8+ T cells expressed higher levels of eomesodermin, which correlated with enhanced lysis of tumor cells. Furthermore, reduction of SHP-1 expression in tumor-reactive effector T cells by retroviral transduction with vectors that express SHP-1–specific small interfering RNA, a translatable strategy, also exhibited enhanced antitumor activity in vivo. These studies suggest that abrogating SHP-1 in effector T cells may improve the efficacy of tumor elimination by T cell therapy without affecting the ability of the effector cells to persist and provide a long-term response.
Phospholipase C Activator m-3M3FBS Protects against Morbidity and Mortality Associated with Sepsis
Authors: Kim Sang Doo , Kim Hak Jung , Shim Jae Woong , Lee Ha Young , Lee Sung Kyun , Kwon Soonil , Jung Young Su , Baek Suk-Hwan , Park Joon Seong , Zabel Brian A. , Bae Yoe-Sik 
Published: July 2012

Abstract
Although phospholipase C (PLC) is a crucial enzyme required for effective signal transduction and leukocyte activation, the role of PLC in polymicrobial sepsis remains unclear. In this study, we show that the direct PLC activator m-3M3FBS treatment significantly attenuates vital organ inflammation, widespread immune cell apoptosis, and mortality in a mouse sepsis model induced by lethal cecal ligation and puncture challenge. Mechanistically, m-3M3FBS–dependent protection was largely abolished by pretreatment of mice with the PLC-selective inhibitor U-73122, thus confirming PLC agonism by m-3M3FBS in vivo. PLC activation enhanced the bactericidal activity and hydrogen peroxide production of mouse neutrophils, and it also enhanced the production of IFN-γ and IL-12 while inhibiting proseptic TNF-α and IL-1β production in cecal ligation and puncture mice. In a second model of sepsis, PLC activation also inhibited the production of TNF-α and IL-1β following systemic LPS challenge. In conclusion, we show that agonizing the central signal transducing enzyme PLC by m-3M3FBS can reverse the progression of toxic shock by triggering multiple protective downstream signaling pathways to maintain organ function, leukocyte survival, and to enhance microbial killing.
Cutting Edge: Brazilian Pemphigus Foliaceus Anti-Desmoglein 1 Autoantibodies Cross-React with Sand Fly Salivary LJM11 Antigen
Authors: Qian Ye , Jeong Joseph S. , Maldonado Mike , Valenzuela Jesus G. , Gomes Regis , Teixeira Clarissa , Evangelista Flor , Qaqish Bahjat , Aoki Valeria , Hans Gunter , Rivitti Evandro A. , Eaton Donald , Diaz Luis A. 
Published: July 2012

Abstract
The environmental factors that contribute to the development of autoimmune diseases are largely unknown. Endemic pemphigus foliaceus in humans, known as Fogo Selvagem (FS) in Brazil, is mediated by pathogenic IgG4 autoantibodies against desmoglein 1 (Dsg1). Clusters of FS overlap with those of leishmaniasis, a disease transmitted by sand fly (Lutzomyia longipalpis) bites. In this study, we show that salivary Ags from the sand fly, and specifically the LJM11 salivary protein, are recognized by FS Abs. Anti-Dsg1 monoclonal autoantibodies derived from FS patients also cross-react with LJM11. Mice immunized with LJM11 generate anti-Dsg1 Abs. Thus, insect bites may deliver salivary Ags that initiate a cross-reactive IgG4 Ab response in genetically susceptible individuals and lead to subsequent FS. Our findings establish a clear relationship between an environmental, noninfectious Ag and the development of potentially pathogenic autoantibodies in an autoimmune disease.
Chronic Exposure to Staphylococcal Superantigen Elicits a Systemic Inflammatory Disease Mimicking Lupus
Authors: Chowdhary Vaidehi R. , Tilahun Ashenafi Y. , Clark Chad R. , Grande Joseph P. , Rajagopalan Govindarajan 
Published: July 2012

Abstract
Chronic nasal and skin colonization with superantigen (SAg)-producing Staphylococcus aureus is well documented in humans. Given that trans-mucosal and trans-cutaneous absorption of SAgs can occur, we determined whether chronic exposure to small amounts of SAg per se could activate autoreactive CD4+ and CD8+ T cells and precipitate any autoimmune disease without further external autoantigenic stimulation. Because HLA class II molecules present SAg more efficiently than do mouse MHC class II molecules, HLA-DQ8 transgenic mice were implanted s.c. with mini-osmotic pumps capable of continuously delivering the SAg, staphylococcal enterotoxin B (total of 10 μg/mouse), or PBS over 4 wk. Chronic exposure to staphylococcal enterotoxin B resulted in a multisystem autoimmune inflammatory disease with features similar to systemic lupus erythematosus. The disease was characterized by mononuclear cell infiltration of lungs, liver, and kidneys, accompanied by the production of anti-nuclear Abs and deposition of immune complexes in the renal glomeruli. The inflammatory infiltrates in various organs predominantly consisted of CD4+ T cells bearing TCR Vβ8. The extent of immunopathology was markedly reduced in mice lacking CD4+ T cells and CD28, indicating that the disease is CD4+ T cell mediated and CD28 dependent. The absence of disease in STAT4-deficient, as well as IFN-γ–deficient, HLA-DQ8 mice suggested the pathogenic role of Th1-type cytokines, IL-12 and IFN-γ. In conclusion, our study suggests that chronic exposure to extremely small amounts of bacterial SAg could be an etiological factor for systemic lupus erythematosus.
Dynamics of Human Prothymocytes and Xenogeneic Thymopoiesis in Hematopoietic Stem Cell-Engrafted Nonobese Diabetic-SCID/IL-2rγnull Mice
Authors: Parietti Véronique , Nelson Elisabeth , Telliam Gladys , Le Noir Sandrine , Pla Marika , Delord Marc , Vanneaux Valérie , Mohtashami Mahmood , Macintyre Elizabeth A. , Gluckman Jean Claude , Asnafi Vahid , Zúñiga-Pflücker Juan-Carlos , Larghero Jérôme , Canque Bruno 
Published: July 2012

Abstract
To model the developmental pattern of human prothymocytes and thymopoiesis, we used NOD-scid/γc−/− mice grafted with human umbilical cord blood CD34+ hematopoietic progenitor cells (HPCs). Human prothymocytes developed in the murine bone marrow (BM) from multipotent CD34++CD38lolineage− HPCs to CD34++CD7+CD2- pro-T1 cells that progressed in a Notch-dependent manner to CD34+CD7++CD2+ pro-T2 cells, which migrated to the thymus. BM prothymocyte numbers peaked 1 mo after graft, dropped at mo 2, and persisted at low levels thereafter, with only a few CD34+CD7lo prothymocytes with limited T potential being detected by mo 5. As a consequence, thymopoiesis in this xenogeneic setting began by weeks 4–6, peaked at mo 3, and decreased thenceforth. Analyzing mice grafted at 2, 4 or 8, mo of age showed that in an “older” BM, prothymocyte differentiation was perturbed and resulted in CD34+CD7lo prothymocytes with limited T potential. Whereas the early drop in BM thymopoietic activity was related to a Notch-independent loss of T potential by CD34++CD38lolineage− HPCs, the later age-dependent production decline of prothymocytes was linked to a more complex mix of cell-intrinsic and microenvironmental defects. Accordingly, and contrasting with what was observed with umbilical cord blood HPCs, CD34+ HPCs from human adult BM displayed only marginal thymopoietic activity when grafted into young 2-mo-old NOD-scid/γc−/− mice. These data demonstrate that the developmental pattern of BM prothymocytes during human late fetal and early postnatal life can be reproduced in humanized mice, and they suggest that onset of human thymus involution relates to decreased colonization by prothymocytes.
Differential Requirement for CD70 and CD80/CD86 in Dendritic Cell-Mediated Activation of Tumor-Tolerized CD8 T Cells
Authors: Bak S. Peter , Barnkob Mike Stein , Bai Ailin , Higham Eileen M. , Wittrup K. Dane , Chen Jianzhu 
Published: July 2012

Abstract
A major obstacle to efficacious T cell-based cancer immunotherapy is the tolerizing-tumor microenvironment that rapidly inactivates tumor-infiltrating lymphocytes. In an autochthonous model of prostate cancer, we have previously shown that intratumoral injection of Ag-loaded dendritic cells (DCs) delays T cell tolerance induction as well as refunctionalizes already tolerized T cells in the tumor tissue. In this study, we have defined molecular interactions that mediate the effects of DCs. We show that pretreating Ag-loaded DCs with anti-CD70 Ab abolishes the ability of DCs to delay tumor-mediated T cell tolerance induction, whereas interfering with 4-1BBL, CD80, CD86, or both CD80 and CD86 had no significant effect. In contrast, CD80−/− or CD80−/−CD86−/− DCs failed to reactivate already tolerized T cells in the tumor tissue, whereas interfering with CD70 and 4-1BBL had no effect. Furthermore, despite a high level of programmed death 1 expression by tumor-infiltrating T cells and programmed death ligand 1 expression in the prostate, disrupting programmed death 1/programmed death ligand 1 interaction did not enhance T cell function in this model. These findings reveal dynamic requirements for costimulatory signals to overcome tumor-induced tolerance and have significant implications for developing more effective cancer immunotherapies.
Quality of Trauma Surgery Podcasts in Credibility, Content, and Design
Authors: Merchant Asma Altaf Hussain , Shah Shayan Ali , Khursheed Asfia Arham , Ali Madeeha , Najam Sohaib , Farooq Rimsha , Bakhshi Saqib Kamran , Afzal Noreen , Rahim Komal Abdul , Shaikh Namra Qadeer , Haider Adil H. 
Published: June 2024

ImportanceThere has been an emerging trend of podcast use in medical education over the past decade. With the increasing number of podcasts and learners’ interest in trauma surgery, it is vital to validate the quality of these podcasts.ObjectiveTo determine the quantity and quality of podcast episodes on trauma surgery.Design, Setting, and ParticipantsThis cross-sectional study identified trauma surgery podcasts published globally on the Google, Apple, and Spotify platforms as of May 31, 2023. An initial screening excluded podcasts not fulfilling the inclusion criteria (published as of May 31, 2023, and covering clinical knowledge or mentorship on general trauma surgery). A 10-item checklist developed from a modified Delphi consensus method was created to assess the podcasts’ credibility, content, and design as indicators of quality. Data extracted from each podcast episode included the duration, setting, host and guest credentials, and fulfillment of quality indicators. Data were analyzed on August 13, 2023.Main Outcomes and MeasuresThe quality of each podcast was assessed using the 10-question checklist. A score of at least 80% in credibility (4 of 5 points), 75% in content (3 of 4 points), and 100% in design (1 of 1 point) was required to classify a podcast episode as having good quality.ResultsThe initial search identified 204 podcasts on trauma surgery, of which 55 podcasts met the inclusion criteria. All 55 podcasts were published after 2014, with the majority hosted by males (85% [61 of 72 hosts]), based in the US (91% [50 of 55 podcasts]), and focused on clinical knowledge (80% [44 of 55 podcasts]). Podcast hosts and guests predominantly held a Doctor of Medicine degree (83% [113 of 136]), with 72% [46 of 64] of guests identifying as practicing trauma surgeons. While all 55 podcasts had excellent quality in terms of content and design, 20% (11 of 55) of podcasts were rated poorly on credibility. Credibility was further reduced for 60% (33 of 55) of podcasts because of nondisclosure of conflicts of interest.Conclusions and RelevanceIn this cross-sectional study of trauma surgery podcasts, most had good-quality content and design, but there was a lack of explicit conflict of interest disclosure. Content producers need to disclose their conflicts of interest appropriately to ensure credibility and improve the quality of their podcasts.