bluuebunny/crossref_metadata_2025_split huggingface dataset:
A SerpinB1 Regulatory Mechanism Is Essential for Restricting Neutrophil Extracellular Trap Generation
Authors: Farley Kalamo , Stolley J. Michael , Zhao Picheng , Cooley Jessica , Remold-O’Donnell Eileen 
Published: September 2012

Abstract
NETosis (neutrophil extracellular trap [NET] generation), a programmed death pathway initiated in mature neutrophils by pathogens and inflammatory mediators, can be a protective process that sequesters microbes and prevents spread of infection, but it can also be a pathological process that causes inflammation and serious tissue injury. Little is known about the regulatory mechanism. Previously, we demonstrated that serpinb1-deficient mice are highly susceptible to pulmonary bacterial and viral infections due to inflammation and tissue injury associated with increased neutrophilic death. In this study, we used in vitro and in vivo approaches to investigate whether SerpinB1 regulates NETosis. We found that serpinb1-deficient bone marrow and lung neutrophils are hypersusceptible to NETosis induced by multiple mediators in both an NADPH-dependent and -independent manner, indicating a deeply rooted regulatory role in NETosis. This role is further supported by increased nuclear expansion (representing chromatin decondensation) of PMA-treated serpinb1-deficient neutrophils compared with wild-type, by migration of SerpinB1 from the cytoplasm to the nucleus of human neutrophils that is coincident with or preceding early conversion of lobulated (segmented) nuclei to delobulated (spherical) morphology, as well as by the finding that exogenous human recombinant SerpinB1 abrogates NET production. NETosis of serpinb1-deficient neutrophils is also increased in vivo during Pseudomonas aeruginosa lung infection. The findings identify a previously unrecognized regulatory mechanism involving SerpinB1 that restricts the production of NETs.
Adipocyte-Derived Soluble Factor(s) Inhibits Early Stages of B Lymphopoiesis
Authors: Bilwani Fareena A. , Knight Katherine L. 
Published: September 2012

AbstractB lymphopoiesis declines with age, and in rabbits this occurs by 8 wk of age. We found that CFU fibroblasts (CFU-Fs) in the bone marrow (BM) decrease 10-fold by a few weeks of age and that the CFU-Fs preferentially differentiate into adipocytes instead of osteoblasts. BM becomes filled with fat spaces during this time, making rabbit a unique model to study the effects of accelerated fat accumulation on B lymphopoiesis. We show that adipocytes of both rabbit and human secrete a soluble factor(s) that inhibits B lymphopoiesis, and we tested if this inhibition was due to effects on the BM stroma or hematopoietic progenitors. Pretreatment of BM mononuclear cells with adipocyte conditioned medium dramatically inhibited their differentiation into proB cells in cocultures with OP9 stromal cells. In contrast, pretreatment of OP9 stromal cells with adipocyte conditioned medium had no effect on B lymphopoiesis. Using human hematopoietic stem cells, we show that inhibition by the adipocyte-derived factor occurred at the common lymphoid progenitor to preproB cell stage. We propose that the age-related decline in B lymphopoiesis is due to a decrease in CFU-Fs, an increase in adipocytes, and an adipocyte-derived factor that blocks B lymphopoiesis at the common lymphoid progenitor to preproB cell stage.
Exposure to Ionizing Radiation Induces the Migration of Cutaneous Dendritic Cells by a CCR7-Dependent Mechanism
Authors: Cummings Ryan J. , Gerber Scott A. , Judge Jennifer L. , Ryan Julie L. , Pentland Alice P. , Lord Edith M. 
Published: September 2012

Abstract
In the event of a deliberate or accidental radiological emergency, the skin would likely receive substantial ionizing radiation (IR) poisoning, which could negatively impact cellular proliferation, communication, and immune regulation within the cutaneous microenvironment. Indeed, as we have previously shown, local IR exposure to the murine ear causes a reduction of two types of cutaneous dendritic cells (cDC), including interstitial dendritic cells of the dermis and Langerhans cells of the epidermis, in a dose- and time-dependent manner. These APCs are critical regulators of skin homeostasis, immunosurveillance, and the induction of T and B cell-mediated immunity, as previously demonstrated using conditional cDC knockout mice. To mimic a radiological emergency, we developed a murine model of sublethal total body irradiation (TBI). Our data would suggest that TBI results in the reduction of cDC from the murine ear that was not due to a systemic response to IR, as a loss was not observed in shielded ears. We further determined that this reduction was due, in part, to the upregulation of the chemoattractant CCL21 on lymphatic vessels as well as CCR7 expressed on cDC. Migration as a potential mechanism was confirmed using CCR7−/− mice in which cDC were not depleted following TBI. Finally, we demonstrated that the loss of cDC following TBI results in an impaired contact hypersensitivity response to hapten by using a modified contact hypersensitivity protocol. Taken together, these data suggest that IR exposure may result in diminished immunosurveillance in the skin, which could render the host more susceptible to pathogens.
Genetic Depletion of Complement Receptors CD21/35 Prevents Terminal Prion Disease in a Mouse Model of Chronic Wasting Disease
Authors: Michel Brady , Ferguson Adam , Johnson Theodore , Bender Heather , Meyerett-Reid Crystal , Pulford Bruce , von Teichman Adriana , Seelig Davis , Weis John H. , Telling Glenn C. , Aguzzi Adriano , Zabel Mark D. 
Published: September 2012

AbstractThe complement system has been shown to facilitate peripheral prion pathogenesis. Mice lacking complement receptors CD21/35 partially resist terminal prion disease when infected i.p. with mouse-adapted scrapie prions. Chronic wasting disease (CWD) is an emerging prion disease of captive and free-ranging cervid populations that, similar to scrapie, has been shown to involve the immune system, which probably contributes to their relatively facile horizontal and environmental transmission. In this study, we show that mice overexpressing the cervid prion protein and susceptible to CWD (Tg(cerPrP)5037 mice) but lack CD21/35 expression completely resist clinical CWD upon peripheral infection. CD21/35-deficient Tg5037 mice exhibit greatly impaired splenic prion accumulation and replication throughout disease, similar to CD21/35-deficient murine prion protein mice infected with mouse scrapie. TgA5037;CD21/35−/− mice exhibited little or no neuropathology and deposition of misfolded, protease-resistant prion protein associated with CWD. CD21/35 translocate to lipid rafts and mediates a strong germinal center response to prion infection that we propose provides the optimal environment for prion accumulation and replication. We further propose a potential role for CD21/35 in selecting prion quasi-species present in prion strains that may exhibit differential zoonotic potential compared with the parental strains.
CD40/CD154 Blockade Inhibits Dendritic Cell Expression of Inflammatory Cytokines but Not Costimulatory Molecules
Authors: Ferrer Ivana R. , Liu Danya , Pinelli David F. , Koehn Brent H. , Stempora Linda L. , Ford Mandy L. 
Published: September 2012

Abstract
Blockade of the CD40/CD154 pathway remains one of the most effective means of promoting graft survival following transplantation. However, the effects of CD40/CD154 antagonism on dendritic cell (DC) phenotype and functionality following transplantation remain incompletely understood. To dissect the effects of CD154/CD40 blockade on DC activation in vivo, we generated hematopoietic chimeras in mice that expressed a surrogate minor Ag (OVA). Adoptive transfer of OVA-specific CD4+ and CD8+ T cells led to chimerism rejection, which was inhibited by treatment with CD154 blockade. Surprisingly, CD154 antagonism did not alter the expression of MHC and costimulatory molecules on CD11c+ DCs compared with untreated controls. However, DCs isolated from anti-CD154–treated animals exhibited a significant reduction in inflammatory cytokine secretion. Combined blockade of inflammatory cytokines IL-6 and IL-12p40 attenuated the expansion of Ag-specific CD4+ and CD8+ T cells and transiently inhibited the rejection of OVA-expressing cells. These results suggest that a major effect of CD154 antagonism in vivo is an impairment in the provision of signal three during donor-reactive T cell programming, as opposed to an impact on the provision of signal two. We conclude that therapies designed to target inflammatory cytokines during donor-reactive T cell activation may be beneficial in attenuating these responses and prolonging graft survival.
Cysteinyl Leukotriene 2 Receptor on Dendritic Cells Negatively Regulates Ligand-Dependent Allergic Pulmonary Inflammation
Authors: Barrett Nora A. , Fernandez James M. , Maekawa Akiko , Xing Wei , Li Li , Parsons Matthew W. , Austen K. Frank , Kanaoka Yoshihide 
Published: September 2012

Abstract
Cysteinyl leukotrienes (cys-LTs) can mediate Th2 immunity to the house dust mite, Dermatophagoides farinae, via the type 1 receptor CysLT1R on dendritic cells (DCs). However, the role of the homologous type 2 receptor CysLT2R in Th2 immunity is unknown. D. farinae sensitization and challenge of CysLT2R-deficient mice showed a marked augmentation of eosinophilic pulmonary inflammation, serum IgE, and Th2 cytokines. Wild-type (WT) mice sensitized by adoptive transfer of D. farinae-pulsed CysLT2R-deficient bone marrow-derived DCs (BMDCs) also had a marked increase in D. farinae-elicited eosinophilic lung inflammation and Th2 cytokines in restimulated hilar nodes. This response was absent in mice sensitized with D. farinae-pulsed BMDCs lacking leukotriene C4 synthase (LTC4S), CysLT1R, or both CysLT2R/LTC4S, suggesting that CysLT2R negatively regulates LTC4S- and CysLT1R-dependent DC-mediated sensitization. CysLT2R-deficient BMDCs had increased CysLT1R-dependent LTD4-induced ERK phosphorylation, whereas N-methyl LTC4 activation of CysLT2R on WT BMDCs reduced such signaling. Activation of endogenously expressed CysLT1R and CysLT2R occurred over an equimolar range of LTD4 and N-methyl LTC4, respectively. Although the baseline expression of cell surface CysLT1R was not increased on CysLT2R-deficient BMDCs, it was upregulated at 24 h by a pulse of D. farinae, compared with WT or CysLT2R/LTC4S-deficient BMDCs. Importantly, treatment with N-methyl LTC4 reduced D. farinae-induced CysLT1R expression on WT BMDCs. Thus, CysLT2R negatively regulates the development of cys-LT–dependent Th2 pulmonary inflammation by inhibiting both CysLT1R signaling and D. farinae-induced LTC4S-dependent cell surface expression of CysLT1R on DCs. Furthermore, these studies highlight how the biologic activity of cys-LTs can be tightly regulated by competition between these endogenously expressed receptors.
Ancient Manioc Agriculture South of the Ceren Village, El Salvador
Authors: Sheets Payson , Lentz David , Piperno Dolores , Jones John , Dixon Christine , Maloof George , Hood Angela 
Published: September 2012

AbstractThe role of seed crops in the Maya diet is well understood. The role of root crops in the ancient Maya diet has been controversial, with some scholars suggesting they were staples, and others arguing they were not cultivated at all. Research in the 1990s found occasional manioc plants in kitchen gardens within the Classic period Cerén village, leading to the interpretation that manioc did contribute to the diet, but was not a staple. Recent research outside the village encountered sophisticated raised-bed monocropping of manioc over an extensive area. This area was harvested essentially all at once, about a week prior to the eruption. An estimated ten tons of tubers were harvested. The various uses of manioc include consumption as food, exchange with other settlements, fermentation, drying and storage as a powder, and as an adhesive. It is possible that many or all these alternatives were being followed. At Cerén manioc was a staple, not just an occasional adjunct to the diet. Because Cerén is toward the wet end of the ideal range for manioc cultivation, other areas of the Neotropics that receive less than 1,700 mm of precipitation may be more suitable for manioc cultivation than Cerén.
Development and Validation of a New Disease Activity Index as a Numerical Sum of Four Variables in Patients With Early Arthritis
Authors: Castrejón Isabel , Carmona Loreto , Ortiz Ana M. , Belmonte Miguel A. , Martínez‐López Juan A. , González‐Álvaro Isidoro 
Published: September 2012

AbstractObjectiveTo describe the development and validation of a disease activity index in early arthritis that can be easily applied in daily practice and clinical research.MethodsThe Hospital Universitario La Princesa Index (HUPI) was developed after analysis of data from an early arthritis cohort (202 patients with 756 visits). It is the sum of 4 variables (graded 0–3): tender joint count, swollen joint count, patient global assessment, and acute‐phase reactants (erythrocyte sedimentation rate [ESR] and/or C‐reactive protein [CRP] level, depending on availability at the moment of evaluation). The score for each variable was based on its quartile distribution in the cohort. The HUPI was validated using the following properties: feasibility, internal consistency (Cronbach's alpha), convergent validity (Pearson's r coefficients with other activity measures), criterion validity (area under the receiver operating characteristic curve [AUC ROC] to detect minimal disease activity [MDA]), and sensitivity to change (AUC ROC) to detect change with the physician's and patient's assessment of disease activity.ResultsInternal consistency is reasonable (α = 0.63). The HUPI correlates well with activity measures such as the Disease Activity Score in 28 joints (DAS28; r = 0.89) and the Simplified Disease Activity Index (SDAI; r = 0.70), and correlates slightly worse with the functional index of the Health Assessment Questionnaire (r = 0.69). It discriminates MDA correctly (AUC 0.95), and its sensitivity to change is slightly superior (AUC 0.902) to that of the DAS28‐ESR (AUC 0.864), the DAS28‐CRP (AUC 0.889), and the SDAI (AUC 0.791).ConclusionThe HUPI has face validity, is easy to calculate, is sensitive, and is a valid composite index for the assessment of disease activity in patients with early arthritis, both in clinical research and in routine care.
Interleukin‐13–producing CD8+ T cells mediate dermal fibrosis in patients with systemic sclerosis
Authors: Fuschiotti Patrizia , Larregina Adriana T. , Ho Johnan , Feghali‐Bostwick Carol , Medsger Thomas A. 
Published: September 2012

AbstractObjectiveFibrosis is a major contributor to morbidity and mortality in systemic sclerosis (SSc). T cells are the predominant inflammatory infiltrate in affected tissue and are thought to produce cytokines that drive the synthesis of extracellular matrix (ECM) proteins by fibroblasts, resulting in excessive fibrosis. We have previously shown that aberrant interleukin‐13 (IL‐13) production by peripheral blood effector CD8+ T cells from SSc patients correlates with the extent of skin fibrosis. The present study was undertaken to investigate the role of IL‐13 production by CD8+ T cells in dermal fibrosis, an early and specific manifestation of SSc.MethodsECM protein production by normal dermal fibroblasts cocultured with SSc CD8+ T cell supernatants was determined by quantitative polymerase chain reaction and Western blotting. Skin‐homing receptor expression and IL‐13 production by CD8+ T cells in the peripheral blood of SSc patients were measured by flow cytometry. IL‐13+ and CD8+ cells in sclerotic skin were identified by immunohistochemistry.ResultsIL‐13–producing circulating CD8+ T cells from patients with SSc expressed skin‐homing receptors and induced a profibrotic phenotype in normal dermal fibroblasts, which was inhibited by an anti–IL‐13 antibody. High numbers of CD8+ T cells and IL‐13+ cells were found in the skin lesions of SSc patients, particularly during the early inflammatory phase of the disease.ConclusionThese findings show that IL‐13–producing CD8+ T cells are directly involved in modulating dermal fibrosis in SSc. The demonstration that CD8+ T cells homing to the skin early in the course of SSc are associated with accumulation of IL‐13 is an important mechanistic contribution to the understanding of the pathogenesis of dermal fibrosis in SSc and may represent a potential target for therapeutic intervention.
The TTTT B lymphocyte stimulator promoter haplotype is associated with good response to rituximab therapy in seropositive rheumatoid arthritis resistant to tumor necrosis factor blockers
Authors: Fabris Martina , Quartuccio Luca , Vital Ed , Pontarini Elena , Salvin Sara , Fabro Cinzia , Zabotti Alen , Benucci Maurizio , Manfredi Mariangela , Ravagnani Viviana , Biasi Domenico , Atzeni Fabiola , Sarzi‐Puttini Piercarlo , Morassi Pia , Fischetti Fabio , Bazzicchi Laura , Saracco Marta , Pellerito Raffaele , Cimmino Marco , Carraro Valeria , Semeraro Angelo , Schiavon Franco , Caporali Roberto , Bortolotti Roberto , Govoni Marcello , Fogolari Federico , Tonutti Elio , Bombardieri Stefano , Emery Paul , De Vita Salvatore 
Published: September 2012

AbstractObjectiveTo investigate the polymorphisms in the promoter region of the B lymphocyte stimulator (BLyS) gene as markers of response to rituximab (RTX) in rheumatoid arthritis (RA).MethodsThe study was first conducted in 152 Italian RA patients and then replicated in an additional 117 RA patients (73 Italian, 44 British). The European League Against Rheumatism response criteria were used to evaluate the response rate at months 4 and 6 after the first cycle of RTX, by means of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate; patients were classified according to the best response shown between months 4 and 6. BLyS promoter polymorphisms were analyzed by polymerase chain reaction followed by the analysis of the restriction fragments, BLyS promoter haplotypes were analyzed using the expectation‐maximization algorithm, and BLyS serum levels were analyzed using enzyme‐linked immunosorbent assay. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs).ResultsThe TTTT BLyS promoter haplotype appeared to be significantly associated with response to RTX only in the subset of seropositive patients (those positive for rheumatoid factor and/or anti–cyclic citrullinated peptide). The replication study confirmed that this association was limited to seropositive RA patients in whom treatment with anti–tumor necrosis factor (anti‐TNF) agents had previously failed. In the whole series of seropositive patients in whom anti‐TNF agents had previously failed, patients carrying the TTTT BLyS promoter haplotype were more prevalent in good responders (18 of 43 [41.9%]) than in moderate responders (20 of 83 [24.1%]) or in nonresponders (1 of 21 [4.8%]) (for good responders versus nonresponders, OR 14.4 [95% CI 1.77–117.39], P = 0.0028). Furthermore, multivariate analysis selected the TTTT BLyS promoter haplotype as an independent marker of good response to RTX (for good responders versus nonresponders, OR 16.2 [95% CI 1.7–152.5], P = 0.01; for good responders versus moderate responders and nonresponders combined, OR 3.1 [95% CI 1.2–7.8], P = 0.02). The relationship between BLyS polymorphisms and BLyS serum levels remained unclear.ConclusionBLyS promoter genotyping may be suitable for identifying seropositive RA patients who may have a good response to RTX after anti‐TNF agents have failed.
Identification of a susceptibility locus in STAT4 for Behçet's disease in Han Chinese in a genome‐wide association study
Authors: Hou Shengping , Yang Zhenglin , Du Liping , Jiang Zhengxuan , Shu Qinmeng , Chen Yuanyuan , Li Fuzhen , Zhou Qingyun , Ohno Shigeaki , Chen Rui , Kijlstra Aize , Rosenbaum James T. , Yang Peizeng 
Published: September 2012

AbstractObjectiveTo identify susceptibility loci for Behçet's disease (BD) and elucidate their functional role.MethodsA genome‐wide association study (GWAS) and functional studies were conducted. A total of 149 patients and 951 controls were enrolled in the initial GWAS, and 554 patients and 1,159 controls were enrolled in the replication study. Real‐time polymerase chain reaction, luciferase reporter assay, and enzyme‐linked immunosorbent assay were performed.ResultsOur GWAS and replication studies identified a susceptibility locus around STAT4 (single‐nucleotide polymorphisms [SNPs] rs7574070, rs7572482, and rs897200; P = 3.36 × 10−7 to 6.20 × 10−9). Increased expression of STAT4 was observed in individuals carrying the rs897200 risk genotype AA. Consistent with the idea that STAT4 regulates the production of interleukin‐17 (IL‐17) and interferon‐γ, IL17 messenger RNA and protein levels were increased in individuals carrying the rs897200 risk genotype AA. Interestingly, the risk allele A of rs897200 creates a putative transcription factor binding site. To test whether it directly affects STAT4 transcription, an in vitro luciferase reporter gene assay was performed. Higher transcription activity was observed in individuals carrying the risk allele A, suggesting that rs897200 is likely to directly affect STAT4 expression. Additionally, 2 SNPs, rs7574070 and rs7572482, which are tightly linked with rs897200, were cis‐expression quantitative trait loci (eQTL) SNPs, suggesting that SNP rs897200 is an eQTL SNP. Most importantly, the clinical disease severity score was higher in individuals with the rs897200 risk genotype AA.ConclusionThese findings strongly suggest that STAT4 is a novel locus underlying BD. We propose a model in which up‐regulation of STAT4 expression and subsequent STAT4‐driven production of inflammatory cytokines, such as IL‐17, constitute a potential pathway leading to BD.
Efficacy of B cell depletion therapy for murine joint arthritis flare is associated with increased lymphatic flow
Authors: Li Jie , Ju Yawen , Bouta Echoe M. , Xing Lianping , Wood Ronald W. , Kuzin Igor , Bottaro Andrea , Ritchlin Christopher T. , Schwarz Edward M. 
Published: September 2012

AbstractObjectiveB cell depletion therapy ameliorates rheumatoid arthritis by mechanisms that are incompletely understood. Arthritis flare in tumor necrosis factor (TNF)–transgenic mice is associated with efferent lymph node (LN) “collapse,” triggered by B cell translocation into lymphatic spaces and decreased lymphatic drainage. The aim of this study was to examine whether the efficacy of B cell depletion therapy is associated with restoration of lymphatic drainage due to removal of obstructing nodal B cells.MethodsWe used contrast‐enhanced magnetic resonance imaging, indocyanine green near‐infrared imaging, and intravital immunofluorescence imaging to longitudinally assess synovitis, lymphatic flow, and cell migration in lymphatic vessels in TNF‐transgenic mice. We conducted tests to determine whether the efficacy of B cell depletion therapy is associated with restoration of lymphatic draining and cell egress from arthritic joints.ResultsUnlike active lymphatics to normal and prearthritic knees, afferent lymphatic vessels to collapsed LNs in inflamed knees do not pulse. Intravital immunofluorescence imaging demonstrated that CD11b+ monocyte/macrophages in lymphatic vessels afferent to expanding LNs travel at high velocity (mean ± SD 186 ± 37 μm/second), while these cells are stationary in lymphatic vessels afferent to collapsed popliteal LNs. B cell depletion therapy for arthritis flares in TNF‐transgenic mice significantly decreased knee synovium volume (by 50% from the baseline level) and significantly increased lymphatic clearance compared with placebo (P < 0.05). This increased lymphatic drainage restored macrophage egress from inflamed joints without recovery of the lymphatic pulse.ConclusionThese results support a novel mechanism in which B cell depletion therapy for joint arthritis flares lessens inflammation by increasing lymphatic drainage and subsequent migration of cells and cytokines from the synovial space.