bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Influence of Sex on Patients with Rheumatoid Arthritis in a Large Observational Cohort
Authors: IIKUNI NORIKO , SATO ERI , HOSHI MASAYA , INOUE EISUKE , TANIGUCHI ATSUO , HARA MASAKO , TOMATSU TAISUKE , KAMATANI NAOYUKI , YAMANAKA HISASHI 
Published: October 2009

Objective.To compare the sex differences of various components of rheumatoid arthritis (RA).Methods.Data of 4823 patients from a large observational cohort study were analyzed. Remarkable differences were noted between the sexes, and overall, women had significantly higher disease activity.Results.When variables were adjusted using sex, age, and duration, Health Assessment Questionnaire, rather than Disease Activity Score, contributed most to sex difference. Further analysis showed evidence that progression of disability was approximately 3 times more rapid in female patients compared to male patients.Conclusion.Women overall have higher RA disease activity and are prone to greater and faster progression of disability over time.
Prednisone, Lupus Activity, and Permanent Organ Damage
Authors: THAMER MAE , HERNÁN MIGUEL A. , ZHANG YI , COTTER DENNIS , PETRI MICHELLE 
Published: October 2009

Objective.To estimate the effect of corticosteroids (prednisone dose) on permanent organ damage among persons with systemic lupus erythematosus (SLE).Methods.We identified 525 patients with incident SLE in the Hopkins Lupus Cohort. At each visit, clinical activity indices, laboratory data, and treatment were recorded. The study population was followed from the month after the first visit until June 29, 2006, or attainment of irreversible organ damage, death, loss to follow-up, or receipt of pulse methylprednisolone therapy. We estimated the effect of cumulative average dose of prednisone on organ damage using a marginal structural model to adjust for time-dependent confounding by indication due to SLE disease activity.Results.Compared with non-prednisone use, the hazard ratio of organ damage for prednisone was 1.16 (95% CI 0.54, 2.50) for cumulative average doses > 0–180 mg/month, 1.50 (95% CI 0.58, 3.88) for > 180–360 mg/month, 1.64 (95% CI 0.58, 4.69) for > 360–540 mg/month, and 2.51 (95% CI 0.87, 7.27) for > 540 mg/month. In contrast, standard Cox regression models estimated higher hazard ratios at all dose levels.Conclusion.Our results suggest that low doses of prednisone do not result in a substantially increased risk of irreversible organ damage.
Antibody Reactivity to α-Enolase in Mothers of Children with Congenital Heart Block
Authors: LLANOS CAROLINA , CHAN EDWARD K.L. , LI SONGQING , ABADAL GRANT X. , IZMIRLY PETER , BYRNE CAROLINE , CLANCY ROBERT M. , BUYON JILL P. 
Published: October 2009

Objective.To evaluate the frequency of anti-α-enolase antibodies in the sera of mothers whose children have congenital heart block (CHB), given provocative results in which α-enolase, a membrane protein, was recognized by monoclonal antibodies reactive with the peptide p200 of 52 kDa Ro/SSA in a neonatal rat heart library.Methods.An ELISA using a recombinant α-enolase protein was developed. Sera from 100 anti-Ro52+ CHB mothers in the Research Registry for Neonatal Lupus, 50 patients with systemic lupus erythematosus (SLE; 7 anti-Ro52+), and 48 healthy controls were tested for anti-α-enolase reactivity.Results.There were no significant differences in the median values obtained from CHB mothers, patients with SLE, or controls at each of the dilutions tested. Only 7 (7%) at 1:100 dilution and 2 (2%) at 1:1000 dilution of 100 CHB sera were 3 standard deviations above the mean value obtained for controls. Preincubation with recombinant Ro52 did not inhibit anti-α-enolase reactivity.Conclusion.The low frequency of anti-α-enolase antibodies in the sera of CHB mothers and the absence of apparent cross-reactivity with Ro52 suggest that antibodies to Ro52 are not likely to mediate CHB via binding to α-enolase.
Common γ-Chain-Dependent Signals Confer Selective Survival of Eosinophils in the Murine Small Intestine
Authors: Carlens Julia , Wahl Benjamin , Ballmaier Matthias , Bulfone-Paus Silvia , Förster Reinhold , Pabst Oliver 
Published: October 2009

Abstract
Eosinophils are potent effector cells that are recruited to sites of inflammation. However, in some tissues, in particular in the gastrointestinal tract, eosinophils constitute an abundant leukocyte population also under homeostatic conditions. The lack of suitable isolation protocols restricted the analysis of these cells to histological assessment of cell numbers while important aspects of their phenotype, turnover, and functions remain unresolved. In this study, we report a protocol that allows the quantitative isolation of intestinal eosinophils. We characterized small intestinal eosinophils by flow cytometry as SSChighCD11b+CD11c+CCR3+Siglec-F+ cells. Intestinal eosinophils resembled eosinophils isolated from thymus and uterus but differed from eosinophils isolated from lung or blood. Eosinophils in intestine, thymus, and uterus showed in vivo a markedly higher life time compared with eosinophils present in lung and blood measured by incorporation of BrdU. This indicates that under steady-state conditions homeostasis of eosinophils is controlled by regulation of cell survival. Intestinal eosinophils are severely reduced in the intestines of Rag-2/common γ-chain double-deficient mice but not Rag-2-deficient mice, correlating with differential expression of GM-CSF and CCL11 in both mouse strains. Moreover, under steady-state conditions, intestinal eosinophils constitutively express high levels of the common γ-chain transcripts compared with lung eosinophils as well as eosinophils present under inflammatory conditions. These observations reveal a hitherto unrecognized diversity in phenotypic and functional properties of eosinophils and suggest that tissue-specific common γ-chain-dependent signals might profoundly affect eosinophil function and homeostasis.
Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus
Authors: Lartigue Aurelia , Colliou Natacha , Calbo Sébastien , François Arnault , Jacquot Serge , Arnoult Christophe , Tron Francois , Gilbert Daniele , Musette Philippe 
Published: October 2009

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathogenic autoantibodies directed against nuclear Ags and immune complex deposits in damaged organs. Environmental factors have been thought to play a role in the onset of the disease. The recognition of these factors is mediated by TLRs, in particular TLR2 and TLR4 which bind pathogen-associated molecular patterns of Gram+ and Gram− bacteria, respectively. We attempted to determine the role of these TLRs in SLE by creating TLR2- or TLR4-deficient C57BL/6lpr/lpr mice. These mice developed a less severe disease and fewer immunological alterations. Indeed, in C57BL/6lpr/lpr-TLR2 or -TLR4-deficient mice, glomerular IgG deposits and mesangial cell proliferation were dramatically decreased and antinuclear, anti-dsDNA, and anti-cardiolipin autoantibody titers were significantly reduced. However, the response against nucleosome remained unaffected, indicating a role of TLR2 and TLR4 in the production of Abs directed against only certain categories of SLE-related autoantigens. Analysis of B cell phenotype showed a significant reduction of marginal zone B cells, particularly in C57BL/6lpr/lpr-TLR4-deficient mice, suggesting an important role of TLR4 in the sustained activation of these cells likely involved in autoantibody production. Interestingly, the lack of TLR4 also affected the production of cytokines involved in the development of lupus disease.
FROUNT Is a Common Regulator of CCR2 and CCR5 Signaling to Control Directional Migration
Authors: Toda Etsuko , Terashima Yuya , Sato Tsuyoshi , Hirose Kenzo , Kanegasaki Shiro , Matsushima Kouji 
Published: October 2009

Abstract
FROUNT is a known CCR2-binding protein that facilitates monocyte/macrophage infiltration. Here we report that FROUNT also binds to the C-terminal region of CCR5 and enhances CCR5-mediated cellular chemotaxis. We show that FROUNT overexpression enhances the directionality of chemotaxis, while FROUNT suppression results in impaired responsiveness. Furthermore, we found an increase in consolidated pseudopodium formation in FROUNT-overexpressing cells (FNT cells) on uniform stimulation with CCL4 (MIP1-β), a specific ligand of CCR5. In most FNT cells, one to two pseudopodia directed toward higher chemokine concentration were found, whereas most FNT-suppressed cells had multiple pseudopodia. The data indicate that FROUNT is involved in sensing and amplifying a shallow extracellular chemokine gradient that leads to a limited number of accurate pseudopodia directed toward the chemokine concentration. In addition to its separate roles in CCR2- and CCR5-mediated chemotaxis, FROUNT, as a common regulator of these receptors, possibly plays a crucial role in the recruitment of immune cells expressing these receptors.
TNFR2-Deficient Memory CD8 T Cells Provide Superior Protection against Tumor Cell Growth
Authors: Kim Edward Y. , Teh Soo-Jeet , Yang Jocelyn , Chow Michael T. , Teh Hung-Sia 
Published: October 2009

Abstract
TNF receptor-2 (TNFR2) plays a critical role in promoting the activation and survival of naive T cells during the primary response. Interestingly, anti-CD3 plus IL-2 activated TNFR2−/− CD8 T cells are highly resistant to activation-induced cell death (AICD), which correlates with high expression levels of prosurvival molecules such as Bcl-2, survivin, and CD127 (IL-7Rα). We determined whether the resistance of activated TNFR2−/− CD8 T cells to AICD contributes to more effective protection against tumor cell growth. We found that during a primary tumor challenge, despite initial inferiority in controlling tumor cell growth, TNFR2−/− mice were able to more effectively control tumor burden over time compared with wild-type (WT) mice. Furthermore, vaccination of TNFR2−/− mice with recombinant Listeria monocytogenes that express OVA confers better protection against the growth of OVA-expressing E.G7 tumor cells relative to similarly vaccinated WT mice. The enhanced protection against tumor cell growth was not due to more effective activation of OVA-specific memory CD8 T cells in vaccinated TNFR2−/− mice. In vitro studies indicate that optimally activated OVA-specific TNFR2−/− CD8 T cells proliferated to the same extent and possess similar cytotoxicity against E.G7 tumor cells as WT CD8 T cells. However, relative to WT cells, activated OVA-specific TNFR2−/− CD8 T cells were highly resistant to AICD. Thus, the enhanced protection against E.G7 in TNFR2−/− mice is likely due to the recruitment and activation of OVA-specific memory TNFR2−/− CD8 T cells and their prolonged survival at the tumor site.
CCR7-Dependent Stimulation of Survival in Dendritic Cells Involves Inhibition of GSK3β
Authors: Escribano Cristina , Delgado-Martín Cristina , Rodríguez-Fernández José Luis 
Published: October 2009

Abstract
Chemokine receptor CCR7 regulates chemotaxis and survival in mature dendritic cells (DCs). We studied the role of glycogen synthase kinase-3β (GSK3β) in the regulation of CCR7-dependent survival. We show that GSK3β behaves as a proapoptotic regulator in cultured monocyte-derived human DCs and murine splenic DCs in vitro, and in lymph node DCs in vivo. In keeping with its prosurvival role, stimulation of CCR7 induced phosphorylation/inhibition of GSK3β, which was mediated by the prosurvival regulator Akt1, but it was independent of ERK1/2, a key regulator of chemotaxis. Stimulation of CCR7 also induced translocation of two transcription-factor targets of Akt, prosurvival NF-κB and proapoptotic FOXO1, to the nucleus and cytosol, respectively, resulting in DCs with a phenotype more resistant to apoptotic stimuli. We analyzed if GSK3β was able to modulate the mobilizations of these transcription factors. Using pharmacological inhibitors, small interfering RNA, and a construct encoding constitutively active GSK3β, we show that active GSK3β fosters and hampers the translocations to the nucleus of FOXO and NF-κB, respectively. Inhibition of GSK3β resulted in the degradation of the NF-κB inhibitor IκB, indicating a mechanism whereby GSK3 can control the translocation of NF-κB to the nucleus. GSK3β and FOXO interacted in vivo, suggesting that this transcription factor could be a substrate of GSK3. The results provide a novel mechanism whereby active GSK3β contributes to regulate apoptosis in DCs. They also suggest that upon stimulation of CCR7, Akt-mediated phosphorylation/inhibition of GSK3β may be required to allow complete translocations of FOXO and NF-κB that confer DCs an extended survival.
Constitutive Expression of IDO by Dendritic Cells of Mesenteric Lymph Nodes: Functional Involvement of the CTLA-4/B7 and CCL22/CCR4 Interactions
Authors: Onodera Toshiharu , Jang Myoung Ho , Guo Zijin , Yamasaki Mikako , Hirata Takako , Bai Zhongbin , Tsuji Noriko M. , Nagakubo Daisuke , Yoshie Osamu , Sakaguchi Shimon , Takikawa Osamu , Miyasaka Masayuki 
Published: October 2009

Abstract
Dendritic cells (DCs) express the immunoregulatory enzyme IDO in response to certain inflammatory stimuli, but it is unclear whether DCs express this enzyme under steady-state conditions in vivo. In this study, we report that the DCs in mesenteric lymph nodes (MLNs) constitutively express functional IDO, which metabolizes tryptophan to kynurenine. In line with a previous report that regulatory T cells (Tregs) can induce IDO in DCs via the CTLA-4/B7 interaction, a substantial proportion of the MLN DCs were located in juxtaposition to Tregs, whereas this tendency was not observed for splenic DCs, which do not express IDO constitutively. When CTLA-4 was selectively deleted in Tregs, the frequency of IDO-expressing DCs in MLNs decreased significantly, confirming CTLA-4’s role in IDO expression by MLN DCs. We also found that the MLN DCs produced CCL22, which can attract Tregs via CCR4, and that the phagocytosis of autologous apoptotic cells induced CCL22 expression in CCL22 mRNA-negative DCs. Mice genetically deficient in the receptor for CCL22, CCR4, showed markedly reduced IDO expression in MLN-DCs, supporting the involvement of the CCL22/CCR4 axis in IDO induction. Together with our previous observation that MLN DCs contain much intracytoplasmic cellular debris in vivo, these results indicate that reciprocal interactions between the DCs and Tregs via both B7/CTLA-4 and CCL22/CCR4 lead to IDO induction in MLN DCs, which may be initiated and/or augmented by the phagocytosis of autologous apoptotic cells by intestinal DCs. Such a mechanism may help induce the specific milieu in MLNs that is required for the induction of oral tolerance.
Mouse Mast Cell Protease 4 Is the Major Chymase in Murine Airways and Has a Protective Role in Allergic Airway Inflammation
Authors: Waern Ida , Jonasson Sofia , Hjoberg Josephine , Bucht Anders , Åbrink Magnus , Pejler Gunnar , Wernersson Sara 
Published: October 2009

Abstract
It is widely established that mast cells (MCs) have a harmful role in asthma, for example by secreting various proinflammatory substances stored within their secretory granule. However, in this study, we show that one of the substances stored within MC granule, chymase, in fact has a protective role in allergic airway inflammation, indicating that MCs may possess both harmful and protective activities in connection with this type of disease. Wild-type (WT) mice and mice lacking mouse MC protease 4 (mMCP-4), a chymase that is functionally homologous to human chymase, were sensitized and challenged with OVA, followed by the assessment of airway physiology and inflammatory parameters. Our results show that the airway hyperresponsiveness was significantly higher in mMCP-4−/− as compared with WT mice. Moreover, the degree of lung tissue inflammation was markedly higher in mice lacking mMCP-4 than in WT controls. Histological analysis revealed that OVA sensitization/challenge resulted in a marked increased in the thickness of the smooth muscle cell (SMC) layer and, notably, that the degree of SMC layer thickening was more pronounced in mMCP-4−/− animals than in WT controls, thus indicating that chymase may have an effect on airway SMCs. In support of this, mMCP-4-positive MCs were located in the close vicinity of the SMC layer, mainly in the upper airways, and mMCP-4 was shown to be the major chymase expressed in these MCs. Taken together, our results indicate that chymase present in the upper airways protects against allergic airway responses, possibly by regulating SMCs.
Epidermal Langerhans Cells Are Not Required for UV-Induced Immunosuppression
Authors: Wang Liangchun , Jameson Stephen C. , Hogquist Kristin A. 
Published: October 2009

Abstract
UV light can be highly beneficial in the treatment of skin disorders such as psoriasis. It is thought to cause immunosuppression by depleting or altering the function of epidermal Langerhans cells (LC). Our previous studies identified a novel langerin+ dendritic cell in the dermis, distinct from LC in phenotype, circulation, and function. In this study, we determined the role of LC and dermal langerin+ cells in UV suppression. UV light suppressed the CD8 T cell response to both contact hypersensitivity and epicutaneous protein immunization, and resulted in a dramatically altered phenotype of LC. UV light did not alter early CD8 T cell activation in the lymph nodes, but rather reduced CD8 T cell expansion at later time points. We found that dermal langerin+ cells, but not LC, were essential for the CD8 T cell response. Furthermore, in the selective absence of LC, UV light still caused suppression of both CD8 T cell expansion and contact hypersensitivity.
Phosphoinositide 3-Kinase p110δ Regulates Natural Antibody Production, Marginal Zone and B-1 B Cell Function, and Autoantibody Responses
Authors: Durand Caylib A. , Hartvigsen Karsten , Fogelstrand Linda , Kim Shin , Iritani Sally , Vanhaesebroeck Bart , Witztum Joseph L. , Puri Kamal D. , Gold Michael R. 
Published: October 2009

Abstract
B-1 and marginal zone (MZ) B cells produce natural Abs, make Ab responses to microbial pathogens, and contribute to autoimmunity. Although the δ isoform of the PI3K p110 catalytic subunit is essential for development of these innate-like B cells, its role in the localization, activation, and function of normal B-1 and MZ B cells is not known. Using IC87114, a highly selective inhibitor of p110δ enzymatic activity, we show that p110δ is important for murine B-1 and MZ B cells to respond to BCR clustering, the TLR ligands LPS and CpG DNA, and the chemoattractants CXCL13 and sphingosine 1-phosphate. In these innate-like B cells, p110δ activity mediates BCR-, TLR- and chemoattractant-induced activation of the Akt prosurvival kinase, chemoattractant-induced migration, and TLR-induced proliferation. Moreover, we found that TLR-stimulated Ab responses by B-1 and MZ B cells, as well as the localization of MZ B cells in the spleen, depend on p110δ activity. Finally, we show that the in vivo production of natural Abs requires p110δ and that p110δ inhibitors can reduce in vivo autoantibody responses. Thus, targeting p110δ may be a novel approach for regulating innate-like B cells and for treating Ab-mediated autoimmune diseases.
A Herceptin-Based Chimeric Antigen Receptor with Modified Signaling Domains Leads to Enhanced Survival of Transduced T Lymphocytes and Antitumor Activity
Authors: Zhao Yangbing , Wang Qiong J. , Yang Shicheng , Kochenderfer James N. , Zheng Zhili , Zhong Xiaosong , Sadelain Michel , Eshhar Zelig , Rosenberg Steven A. , Morgan Richard A. 
Published: October 2009

Abstract
To generate chimeric Ag receptors (CARs) for the adoptive immunotherapy of cancer patients with ErbB2-expressing tumors, a single-chain Ab derived from the humanized mAb 4D5 Herceptin (trastuzumab) was initially linked to T cell signaling domains derived from CD28 and the CD3ζ to generate a CAR against ErbB2. Human PBLs expressing the 4D5 CAR demonstrated Ag-specific activities against ErbB2+ tumors. However, a gradual loss of transgene expression was noted for PBLs transduced with this 4D5 CAR. When the CD3ζ signaling domain of the CAR was truncated or mutated, loss of CAR expression was not observed, suggesting that the CD3ζ signaling caused the transgene decrease, which was supported by the finding that T cells expressing 4D5 CARs with CD3ζ ITAM mutations were less prone to apoptosis. By adding 4-1BB cytoplasmic domains to the CD28-CD3ζ signaling moieties, we found increased transgene persistence in 4D5 CAR-transduced PBLs. Furthermore, constructs with 4-1BB sequences demonstrated increased cytokine secretion and lytic activity in 4D5 CAR-transduced T cells. More importantly, PBLs expressing this new version of the 4D5 CAR could not only efficiently lyse the autologous fresh tumor digests, but they could strongly suppress tumor growth in a xenogenic mouse model.
Thalidomide Inhibits Activation of Caspase-1
Authors: Keller Martin , Sollberger Gabriel , Beer Hans-Dietmar 
Published: October 2009

Abstract
Thalidomide is an efficient anti-inflammatory and anti-angiogenic drug, but its therapeutic use is problematic due to a strong teratogenic activity. Nevertheless, thalidomide was approved for the treatment of inflammatory skin diseases and certain types of cancer, and it is extensively tested for several other indications. Recently, we demonstrated that active caspase-1, whose activation is dependent on inflammasome complexes, is required for unconventional protein secretion of proinflammatory cytokines such as IL-1 and of the proangiogenic fibroblast growth factor 2. In this study, we show that pharmacological doses of thalidomide strongly reduced the secretion of both proteins. Thalidomide-treated cells also released less of other leaderless proteins, which require caspase-1 activity for their secretion. In line with these findings, the drug inhibited activation and activity of caspase-1 in cultured cells but not in vitro. The latter finding suggests that the pharmacological activity is exerted by a metabolite of the drug. The anti-inflammatory activity of thalidomide was also mediated via caspase-1 in mice. These findings represent a novel mechanism by which thalidomide exerts its pharmacological activity and suggest that inhibition of the activity of IL-1 might represent a novel strategy to substitute thalidomide.