bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endogenously Produced IL-4 Nonredundantly Stimulates CD8+ T Cell Proliferation
Authors: Morris Suzanne C. , Heidorn Stephanie M. , Herbert De'Broski R. , Perkins Charles , Hildeman David A. , Khodoun Marat V. , Finkelman Fred D. 
Published: April 2014

Abstract
T cell proliferation and survival are regulated by the cytokine receptor common γ-chain-associated cytokines IL-2, IL-7, and IL-15, while IL-4, another γ-chain-associated cytokine, is thought to primarily affect T cell quality rather than quantity. In contrast, our experiments reveal that endogenously produced IL-4 is a direct, nonredundant, and potent stimulator of CD8+ T cell proliferation in Ag- and pathogen-induced CD8+ T cell responses. These stimulatory effects of IL-4 are observed in both BALB/c and C57BL/6 mice and activate both naive and memory/activated phenotype CD8+ T cells, although the former are stimulated less than are the latter. IL-4 effects are IL-7- and IL-15-independent, but MHC class I-dependent stimulation appears to be required for the mitogenic effect of IL-4 on naive phenotype CD8+ T cells. Thus, endogenously produced IL-4 is an important regulator of quantitative as well as qualitative aspects of T cell immunity.
B and T Lymphocyte Attenuator Regulates B Cell Receptor Signaling by Targeting Syk and BLNK
Authors: Vendel Andrew C. , Calemine-Fenaux Jill , Izrael-Tomasevic Anita , Chauhan Vandana , Arnott David , Eaton Dan L. 
Published: April 2014

Abstract
B and T lymphocyte attenuator (BTLA) functions as a negative regulator of T cell activation and proliferation. Although the role of BTLA in regulating T cell responses has been characterized, a thorough investigation into the precise molecular mechanisms involved in BTLA-mediated lymphocyte attenuation and, more specifically, its role in regulating B cell activation has not been presented. In this study, we have begun to elucidate the biochemical mechanisms by which BTLA functions to inhibit B cell activation. We describe the cell surface expression of BTLA on various human B cell subsets and confirm its ability to attenuate B cell proliferation upon associating with its known ligand, herpesvirus entry mediator (HVEM). BTLA associates with the BCR and, upon binding to HVEM, recruits the tyrosine phosphatase Src homology 2 domain-containing phosphatase 1 and reduces activation of signaling molecules downstream of the BCR. This is exemplified by a quantifiable decrease in tyrosine phosphorylation of the protein tyrosine kinase Syk, as measured by absolute quantification mass spectrometry. Furthermore, effector molecules downstream of BCR signaling, including the B cell linker protein, phospholipase Cγ2, and NF-κB, display decreased activation and nuclear translocation, respectively, after BTLA activation by HVEM. These results begin to provide insight into the mechanism by which BTLA negatively regulates B cell activation and indicates that BTLA is an inhibitory coreceptor of the BCR signaling pathway and attenuates B cell activation by targeting the downstream signaling molecules Syk and B cell linker protein.
Complement Inhibitor C4b-Binding Protein Interacts Directly with Small Glycoproteins of the Extracellular Matrix
Authors: Happonen Kaisa E. , Sjöberg Andreas P. , Mörgelin Matthias , Heinegård Dick , Blom Anna M. 
Published: April 2014

AbstractComponents derived from cartilage have been suggested to maintain the inflammation in joints in arthritis. Small leucine-rich repeat proteins (SLRPs) are structural components of cartilage important in organizing the meshwork of extracellular matrix components. It has recently been shown that the SLRP fibromodulin interacts with complement initiator C1q, leading to complement activation. The complement response is limited since fibromodulin also interacts with the complement inhibitor factor H. We have now found that osteoadherin, chondroadherin, fibromodulin, and proline arginine-rich end leucine-rich repeat protein bind to the complement inhibitor C4b-binding protein (C4BP). Using direct binding assays with C4BP fragments and C4BP mutants lacking individual domains in combination with electron microscopy, we have demonstrated that mainly the central core of C4BP mediated binding to SLRPs. Binding of SLRPs to C4BP did not affect its ability to inhibit complement. Osteoadherin, fibromodulin, and chondroadherin, which bind C1q and activate complement, were found to cause significantly higher C9 deposition in C4BP-depleted serum compared with Igs, indicating that the level of complement activation initiated by SLRPs is regulated by simultaneous binding to C4BP. A similar dual binding of C1q and complement inhibitors was observed previously for other endogenous ligands (amyloid, prions, C-reactive protein, and apoptotic cells) but not for exogenous activators (bacteria-bound Igs). These interactions can be significant during inflammatory joint diseases, such as rheumatoid arthritis, where cartilage is degraded, and cartilage components are released into synovial fluid, where they can interact with factors of the complement system.
A Comparative Study of HLA Binding Affinity and Ligand Diversity: Implications for Generating Immunodominant CD8+ T Cell Responses
Authors: Rao Xiangyu , Fontaine Costa Ana Isabel C. A. , van Baarle Debbie , Keşmir Can 
Published: April 2014

Abstract
Conventional CD8+ T cell responses against intracellular infectious agents are initiated upon recognition of pathogen-derived peptides presented at the cell surface of infected cells in the context of MHC class I molecules. Among the major MHC class I loci, HLA-B is the swiftest evolving and the most polymorphic locus. Additionally, responses restricted by HLA-B molecules tend to be dominant, and most associations with susceptibility or protection against infectious diseases have been assigned to HLA-B alleles. To assess whether the differences in responses mediated via two major HLA class I loci, HLA-B and HLA-A, may already begin at the Ag presentation level, we have analyzed the diversity and binding affinity of their peptide repertoire by making use of curated pathogen-derived epitope data retrieved from the Immune Epitope Database and Analysis Resource, as well as in silico predicted epitopes. In contrast to our expectations, HLA-B alleles were found to have a less diverse peptide repertoire, which points toward a more restricted binding motif, and the respective average peptide binding affinity was shown to be lower than that of HLA-A-restricted epitopes. This unexpected observation gives rise to new hypotheses concerning the mechanisms underlying immunodominance of CD8+ T cell responses.
Soluble IL-2RA Levels in Multiple Sclerosis Subjects and the Effect of Soluble IL-2RA on Immune Responses
Authors: Maier Lisa M. , Anderson David E. , Severson Christopher A. , Baecher-Allan Clare , Healy Brian , Liu David V. , Wittrup K. Dane , De Jager Philip L. , Hafler David A. 
Published: April 2014

Abstract
Multiple sclerosis (MS) is an organ-specific autoimmune disorder that is in part genetically determined. The gene encoding the α-chain of the IL-2 receptor, IL2RA, harbors alleles associated with risk to MS and other autoimmune diseases. In addition, IL2RA genetic variants correlate with the levels of a soluble form of the IL-2 receptor in subjects with type 1 diabetes and multiple sclerosis. Here, we show that the IL2RA genotypes differentially affects soluble IL-2RA (sIL-2RA) levels in MS cases vs healthy controls; the two variants associated with MS (rs12722489 and rs2104286) account for 15 and 18% of the total variance in log10-transformed sIL-2RA concentration in control subjects but less so in subjects with MS (2 and 5%), suggesting that perturbations associated with disease or treatment may influence sIL-2RA levels in subjects with MS. Whereas analyses demonstrate that sIL-2RA serum concentrations are a remarkably stable phenotype in both healthy controls and untreated MS subjects, a difference is observed between benign and malignant MS. These data indicate that, in addition to specific allelic variants at IL2RA, immunological perturbations associated with aggressive forms of the disease can influence sIL-2RA levels in serum of MS subjects. We also demonstrate, functionally, that sIL-2RA can inhibit IL-2 signaling, yet enhance T cell proliferation and expansion. In summary, we propose that before disease onset, strong genetic factors associated with disease risk dictate sIL-2RA levels that may be further modulated with onset of chronic systemic inflammation associated with MS.
Cytomegalovirus-Infected Human Endothelial Cells Can Stimulate Allogeneic CD4+ Memory T Cells by Releasing Antigenic Exosomes
Authors: Walker Jason D. , Maier Cheryl L. , Pober Jordan S. 
Published: April 2014

Abstract
Human CMV infection is controlled by T cell-mediated immunity and in immunosuppressed transplant patients it is associated with acute allograft rejection as well as chronic allograft vasculopathy. CMV infects endothelial cells (EC) and it is thought that CMV-specific host immune responses to infected allograft EC contribute to rejection. In vitro, CD4+ T cells from CMV-positive donors (but not CMV-negative donors) are readily activated by CMV-infected allogeneic EC, although it is unclear how allogeneic CMV-infected EC activate self-class II MHC-restricted memory CD4+ T cells. In this study, we confirm that purified CD4+ T cells from CMV+ donors are activated by allogeneic CMV-infected EC, but find that the response is dependent upon copurified APC expressing class II MHC that are autologous to the T cells. The transfer of CMV Ags from infected EC to APC can be mediated by EC-derived exosome-like particles. These results provide a mechanism by which CMV can exacerbate allograft rejection and suggest a novel function of EC-derived exosomes that could contribute in a more general manner to immune surveillance.
Acute Alcohol Intoxication Inhibits the Lineage−c-kit+Sca-1+ Cell Response to Escherichia coli Bacteremia
Authors: Zhang Ping , Welsh David A. , Siggins Robert W. , Bagby Gregory J. , Raasch Caroline E. , Happel Kyle I. , Nelson Steve 
Published: April 2014

Abstract
Alcohol abuse predisposes the host to bacterial infections. In response to bacterial infection, the bone marrow hematopoietic activity shifts toward granulocyte production, which is critical for enhancing host defense. This study investigated the hematopoietic precursor cell response to bacteremia and how alcohol affects this response. Acute alcohol intoxication was induced in BALB/c mice 30 min before initiation of Escherichia coli bacteremia. Bacteremia caused a significant increase in the number of bone marrow lineage (lin−)-c-kit+Sca-1+ cells. Marrow lin−c-kit+Sca-1+ cells isolated from bacteremic mice showed an increase in CFU-granulocyte/macrophage activity compared with controls. In addition to enhanced proliferation of lin−c-kit+Sca-1+ cells as reflected by BrdU incorporation, phenotypic inversion of lin−c-kit+Sca-1+Sca-1− cells primarily accounted for the rapid increase in marrow lin−c-kit+Sca-1+ cells following bacteremia. Bacteremia increased plasma concentration of TNF-α. Culture of marrow lin−c-kit+Sca-1+Sca-1− cells with murine rTNF-α for 24 h caused a dose-dependent increase in conversion of these cells to lin−c-kit+Sca-1+ cells. Sca-1 mRNA expression by the cultured cells was also up-regulated following TNF-α stimulation. Acute alcohol intoxication inhibited the increase in the number of lin−c-kit+Sca-1+ cells in the bone marrow after E. coli infection. Alcohol impeded the increase in BrdU incorporation into marrow lin−c-kit+Sca-1+ cells in response to bacteremia. Alcohol also suppressed the plasma TNF-α response to bacteremia and inhibited TNF-α-induced phenotypic inversion of lin−c-kit+Sca-1+Sca-1− cells in vitro. These data show that alcohol inhibits the hematopoietic precursor cell response to bacteremia, which may serve as one mechanism underlying the impaired host defense in alcohol abusers with severe bacterial infections.
Eosinophil Deficiency Compromises Parasite Survival in Chronic Nematode Infection
Authors: Fabre Valeria , Beiting Daniel P. , Bliss Susan K. , Gebreselassie Nebiat G. , Gagliardo Lucille F. , Lee Nancy A. , Lee James J. , Appleton Judith A. 
Published: April 2014

Abstract
Immune responses elicited by parasitic worms share many features with those of chronic allergy. Eosinophils contribute to the inflammation that occurs in both types of disease, and helminths can be damaged or killed by toxic products released by eosinophils in vitro. Such observations inform the widely held view that eosinophils protect the host against parasitic worms. The mouse is a natural host for Trichinella spiralis, a worm that establishes chronic infection in skeletal muscle. We tested the influence of eosinophils on T. spiralis infection in two mouse strains in which the eosinophil lineage is ablated. Eosinophils were prominent in infiltrates surrounding infected muscle cells of wild-type mice; however, in the absence of eosinophils T. spiralis muscle larvae died in large numbers. Parasite death correlated with enhanced IFN-γ and decreased IL-4 production. Larval survival improved when mice were treated with inhibitors of inducible NO synthase, implicating the NO pathway in parasite clearance. Thus, the long-standing paradigm of eosinophil toxicity in nematode infection requires reevaluation, as our results suggest that eosinophils may influence the immune response in a manner that would sustain chronic infection and insure worm survival in the host population. Such a mechanism may be deployed by other parasitic worms that depend upon chronic infection for survival.
Is Porphyromonas gingivalis Cell Invasion Required for Atherogenesis? Pharmacotherapeutic Implications
Authors: Amar Salomon , Wu Shou-chieh , Madan Monika 
Published: April 2014

Abstract
Various studies have demonstrated an association between chronic bacterial infections and atherosclerotic cardiovascular disease. Porphyromonas gingivalis, which can invade endothelial cells, is one pathogen that may link these disorders. If so, antibiotics that block its invasiveness may ameliorate atherosclerotic plaque progression. To explore the role of invasion of P. gingivalis in inflammation- and infection-associated atherosclerosis, 10-wk-old ApoE+/− mice were fed either a high fat diet or a regular chow diet. All mice were inoculated i.v., once per week for 24 consecutive wk, with either 50 μl of live P. gingivalis (strain 381) (107 CFU); a fimbria-deficient P. gingivalis; or metronidazole before P. gingivalis. Mice were euthanized and evaluated 24 wk after the first inoculation. ApoE+/− mice injected with DPG3 or metronidazole showed significantly fewer atheromatous lesions in the proximal aorta and the aortic tree compared with ApoE+/− mice injected with wild-type P. gingivalis for either diet condition. Serum amyloid A levels were significantly lower in ApoE+/− mice that received either DPG3 or metronidazole before P. gingivalis than from ApoE+/− mice that received P. gingivalis alone. Serum cytokine analysis revealed decreased levels of proinflammatory cytokines in both DPG3-injected and metronidazole/P. gingivalis-treated ApoE+/− mice compared with mice receiving only P. gingivalis, irrespective of diet. P. gingivalis invasion is a critical phenomenon in the progression of atherosclerosis. The present data offer new insights into the pathophysiological pathways involved in atherosclerosis and pave the way for new pharmacological interventions aimed at reducing atherosclerosis.
Novel Chlamydia muridarum T Cell Antigens Induce Protective Immunity against Lung and Genital Tract Infection in Murine Models
Authors: Yu Hong , Jiang Xiaozhou , Shen Caixia , Karunakaran Karuna P. , Brunham Robert C. 
Published: April 2014

Abstract
Using a combination of affinity chromatography and tandem mass spectrometry, we recently identified 8 MHC class II (I-Ab) -bound Chlamydia peptides eluted from dendritic cells (DCs) infected with Chlamydia muridarum. In this study we cloned and purified the source proteins that contained each of these peptides and determined that three of the eight peptide/protein Ags were immunodominant (PmpG-1, RplF, and PmpE/F-2) as identified by IFN-γ ELISPOT assay using splenocytes from C57BL/6 mice recovered from C. muridarum infection. To evaluate whether the three immunodominant Chlamydia protein Ags were also able to protect mice against Chlamydia infection in vivo, we adoptively transferred LPS-matured DCs transfected ex vivo with the cationic liposome DOTAP (N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate) and individual PmpG-1(25–500aa), RplF, or PmpE/F-2 (25–575 aa) proteins. The results showed that the transfected Chlamydia proteins were efficiently delivered intracellularly into DCs. Mice vaccinated with DCs transfected with individual Chlamydia protein PmpG-125–500, RplF, or PmpE/F-225–575 exhibited significant resistance to challenge infection as indicated by reduction in the median Chlamydia inclusion forming units in both the lung and genital tract models. The major outer membrane protein was used as a reference Ag but conferred significant protection only in the genital tract model. Overall, vaccination with DCs transfected with PmpG-125–500 exhibited the greatest degree of protective immunity among the four Chlamydia Ags tested. This study demonstrates that T cell peptide Ags identified by immunoproteomics can be successfully exploited as T cell protein-based subunit vaccines and that PmpG-125–500 protein may be a suitable vaccine candidate for further evaluation.
TSLP Conditions the Lung Immune Environment for the Generation of Pathogenic Innate and Antigen-Specific Adaptive Immune Responses
Authors: Headley Mark B. , Zhou Baohua , Shih Weihui X. , Aye Theingi , Comeau Michael R. , Ziegler Steven F. 
Published: April 2014

Abstract
Thymic stromal lymphopoietin (TSLP) is crucial for the development of atopic diseases in humans and mice. Mice that express a lung-specific TSLP transgene (surfactant protein C promoter (SPC)-TSLP) develop a spontaneous and progressive asthma-like disease, suggesting that TSLP expression alone was sufficient for disease development. In this study, we show that, in fact, TSLP alone only causes a weak innate response that is insufficient for development of full airway inflammatory disease. Complete disease development requires both TSLP and antigenic stimulation. These data suggest that the spontaneous lung inflammation observed in SPC-TSLP mice reflects a TSLP-driven predisposition toward the development of aberrant responses against innocuous environmental Ags. This provides evidence that TSLP may act directly to induce susceptibility to the inappropriate allergic responses that characterize atopy and asthma. We additionally show that disease development requires CD4 T cells but not B cells. Further, we reveal a TSLP-driven innate response involving mucus overproduction and goblet cell metaplasia. Taken together, these data suggest a multifaceted model of TSLP-mediated airway inflammation, with an initial activation of resident innate immune cells, followed by activation of the adaptive immune system and full disease development. This study provides new insight into the unique features of the asthma pathology contributed by the innate and adaptive immune responses in response to TSLP stimulation.
IL-17 Signaling for mRNA Stabilization Does Not Require TNF Receptor-Associated Factor 6
Authors: Hartupee Justin , Liu Caini , Novotny Michael , Sun Dongxu , Li Xiaoxia , Hamilton Thomas A. 
Published: April 2014

AbstractIL-17 alone is a relatively weak inducer of gene expression, but cooperates with other cytokines, including TNF-α, to generate a strong response in part via prolongation of mRNA t1/2. Because TNFR-associated factor 6 (TRAF6) has been reported to be essential for signaling by IL-17, we examined its involvement in IL-17-mediated mRNA stabilization. Although overexpression of TRAF6 in HeLa cells activates NF-κB, it does not stabilize transfected KC mRNA. Furthermore, a dominant-negative TRAF6 abrogates NF-κB activation, but does not block IL-17-induced chemokine mRNA stabilization. IL-17 can stabilize KC and MIP-2 mRNAs comparably in TNF-α-treated mouse embryo fibroblasts from TRAF6+/+ and TRAF6−/− mice. TRAF6 is known to couple upstream signals with activation of p38 MAPK and mitogen activated protein kinase activated protein kinase 2, both of which have been shown to be important for Toll/IL-1R-mediated mRNA stabilization in various cell types. Inhibition of p38 MAPK, however, does not block IL-17-induced KC mRNA stabilization, and IL-17 can stabilize KC mRNA equally in mouse embryo fibroblasts from both wild-type and mitogen activated protein kinase activated protein kinase 2/3 doubly-deficient mice. Finally, IL-17 can amplify the levels of multiple TNF-α-stimulated mRNAs in wild-type and TRAF6-deficient cells, but not in cells from Act1−/− mice. Collectively, these findings demonstrate the existence of a TRAF6/p38 MAPK-independent pathway that couples the IL-17R with enhanced mRNA stability. Because the most potent effects of IL-17 on gene expression are obtained in cooperation with other cytokines such as TNF-α, these findings suggest that this pathway is a major contributing mechanism for response to IL-17.
Novel Autoantibodies against the Activated Coagulation Factor IX (FIXa) in the Antiphospholipid Syndrome That Interpose the FIXa Regulation by Antithrombin
Authors: Yang Yao-Hsu , Chien Daniel , Wu Meifang , FitzGerald John , Grossman Jennifer M. , Hahn Bevra H. , Hwang Kwan-Ki , Chen Pojen P. 
Published: April 2014

Abstract
We previously reported that some human antiphospholipid Abs (aPL) in patients with the antiphospholipid syndrome (APS) bind to the homologous enzymatic domains of thrombin and the activated coagulation factor X (FXa). Moreover, some of the reactive Abs are prothrombotic and interfere with inactivation of thrombin and FXa by antithrombin (AT). Considering the enzymatic domain of activated coagulation factor IX (FIXa) is homologous to those of thrombin and FXa, we hypothesized that some aPLs in APS bind to FIXa and hinder AT inactivation of FIXa. To test this hypothesis, we searched for IgG anti-FIXa Abs in APS patients. Once the concerned Abs were found, we studied the effects of the Ab on FIXa inactivation by AT. We found that 10 of 12 patient-derived monoclonal IgG aPLs bound to FIXa and that IgG anti-FIXa Abs in APS patients were significantly higher than those in normal controls (p &lt; 0.0001). Using the mean + 3 SD of 30 normal controls as the cutoff, the IgG anti-FIXa Abs were present in 11 of 38 (28.9%) APS patients. Importantly, 4 of 10 FIXa-reactive monoclonal aPLs (including the B2 mAb generated against β2-glycoprotein I significantly hindered AT inactivation of FIXa. More importantly, IgG from two positive plasma samples were found to interfere with AT inactivation of FIXa. In conclusion, IgG anti-FIXa Ab occurred in ∼30% of APS patients and could interfere with AT inactivation of FIXa. Because FIXa is an upstream procoagulant factor, impaired AT regulation of FIXa might contribute more toward thrombosis than the dysregulation of the downstream FXa and thrombin.