bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does the Frequency and Avidity Spectrum of the Neuroantigen-Specific T Cells in the Blood Mirror the Autoimmune Process in the Central Nervous System of Mice Undergoing Experimental Allergic Encephalomyelitis?
Authors: Hofstetter Harald H. , Targoni Oleg S. , Karulin Alexey Y. , Forsthuber Thomas G. , Tary-Lehmann Magdalena , Lehmann Paul V. 
Published: April 2014

AbstractIn humans, studies of autoreactive T cells that mediate multiple sclerosis have been largely confined to testing peripheral blood lymphocytes. Little is known how such measurements reflect the disease-mediating autoreactive T cells in the CNS. This information is also not available for murine experimental allergic encephalomyelitis (EAE); the low number of T cells that can be obtained from the blood or the brain of mice prevented such comparisons. We used single-cell resolution IFN-γ ELISPOT assays to measure the frequencies and functional avidities of myelin basic protein (MBP:87–99)-specific CD4 cells in SJL mice immunized with this peptide. Functional MBP:87–99-specific IFN-γ-producing cells were present in the CNS during clinical signs of EAE, but not during phases of recovery. In contrast, MBP:87–99-specific T cells persisted in the blood during all stages of the disease, and were also present in mice that did not develop EAE. Therefore, the increased frequency of MBP:87–99-reactive T cells in the blood reliably reflected the primed state, but not the inflammatory activity of these cells in the brain. The functional avidity of the MBP:87–99-reactive T cells was identical in the brain and blood and did not change over 2 mo as the mice progressed from acute to chronic EAE. Therefore, high-affinity T cells did not become selectively enriched in the target organ, and avidity maturation of the MBP:87–99-specific T cell repertoire did not occur in the observation period. The data may help the interpretation of measurements made with peripheral blood lymphocytes of multiple sclerosis patients.
Rac2 Regulates Neutrophil Chemotaxis, Superoxide Production, and Myeloid Colony Formation through Multiple Distinct Effector Pathways
Authors: Carstanjen Dirk , Yamauchi Akira , Koornneef Annemart , Zang Heesuk , Filippi Marie-Dominique , Harris Chad , Towe Jason , Atkinson Simon , Zheng Yi , Dinauer Mary C. , Williams David A. 
Published: April 2014

Abstract
Polymorphonuclear neutrophils (PMN) are an important component of the innate immune system. We have shown previously that migration and superoxide (O⨪2) production, as well as some kinase signaling pathways are compromised in mice deficient in the Ras-related Rho GTPase Rac2. In this study, we demonstrate that Rac2 controls chemotaxis and superoxide production via distinct pathways and is critical for development of myeloid colonies in vitro. The Rac2 mutants V36A, F37A, and N39A all bind to both Pak1 and p67phox, yet are unable to rescue superoxide production and chemotaxis when expressed in Rac2−/− PMN. In contrast, the N43A mutant, which binds to Por1 (Arfaptin 2), p67phox, and Pak1, is able to rescue superoxide production but not chemotaxis. The F37A mutant, demonstrated to have reduced binding to Por1, shows reduced rescue of fMLP-induced chemotaxis. Finally, the Rac2Y40C mutant that is defective in binding to all three potential downstream effectors (Pak1, p67phox, and Por1) is unable to rescue chemotaxis, motility, or superoxide production, but is able to rescue defective growth of myeloid colonies in vitro. These findings suggest that binding to any single effector is not sufficient to rescue the distinct cellular phenotypes of Rac2−/− PMN, implicating multiple, distinct, and potentially parallel effector pathways.
Suppressive Effect of IL-4 on IL-13-Induced Genes in Mouse Lung
Authors: Finkelman Fred D. , Yang Mingyan , Perkins Charles , Schleifer Kathleen , Sproles Alyssa , Santeliz JoAnna , Bernstein Jonathan A. , Rothenberg Marc E. , Morris Suzanne C. , Wills-Karp Marsha 
Published: April 2014

AbstractAlthough IL-4 signals through two receptors, IL-4Rα/common γ-chain (γc) and IL-4Rα/IL-13Rα1, and only the latter is also activated by IL-13, IL-13 contributes more than IL-4 to goblet cell hyperplasia and airway hyperresponsiveness in murine asthma. To determine whether unique gene induction by IL-13 might contribute to its greater proasthmatic effects, mice were inoculated intratracheally with IL-4 or IL-13, and pulmonary gene induction was compared by gene microarray and real-time PCR. Only the collagen α2 type VI (Ca2T6) gene and three small proline-rich protein (SPRR) genes were reproducibly induced &gt;4-fold more by IL-13 than by IL-4. Preferential IL-13 gene induction was not attributable to B cells, T cells, or differences in cytokine potency. IL-4 signaling through IL-4Rα/γc suppresses Ca2T6 and SPRR gene expression in normal mice and induces these genes in RAG2/γc-deficient mice. Although IL-4, but not IL-13, induces IL-12 and IFN-γ, which suppress many effects of IL-4, IL-12 suppresses only the Ca2T6 gene, and IL-4-induced IFN-γ production does not suppress the Ca2T6 or SPRR genes. Thus, IL-4 induces genes in addition to IL-12 that suppress STAT6-mediated SPRR gene induction. These results provide a potential explanation for the dominant role of IL-13 in induction of goblet cell hyperplasia and airway hyperresponsiveness in asthma.
Tumor Vaccine Based on Cell Surface Expression of DcR3/TR6
Authors: Shi Guixiu , Mao Jianning , Yu Guang , Zhang Jun , Wu Jiangping 
Published: April 2014

AbstractDcR3/TR6, a secreted protein belonging to the TNF receptor superfamily, interacts with lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entrance mediator (LIGHT), Fas ligand (FasL), and TL1A, all members of the TNF superfamily. Solid-phase TR6 can trigger reverse signaling of LIGHT and FasL expressed on T cells, and lead to T cell costimulation. In this study, we engineered tumor cells to express cell surface TR6 and used these cells as a tumor vaccine. We demonstrated that mastocytoma P815 cells expressing surface TR6 (TR6-P815) effectively augmented the T cells response in vitro and ex vivo in terms of proliferation, as well as IL-2 and IFN-γ secretion. TR6-P815 cells had reduced tumorigenicity compared with parental P815 cells. When inactivated TR6-P815 cells were employed as a vaccine, they protected the mice from challenge with live parental P815 cells, and eliminated established P815 tumors. The cell surface TR6-based tumor vaccine was also effective against low antigenicity tumors, such as B16 melanoma; co-administration of bacillus Calmette-Guérin further enhanced the vaccine’s efficacy. Thus, cell surface TR6 expression is a useful addition to our tumor vaccine arsenal.
Surfactant Protein-D Regulates Soluble CD14 through Matrix Metalloproteinase-12
Authors: Senft Albert P. , Korfhagen Thomas R. , Whitsett Jeffrey A. , Shapiro Steven D. , LeVine Ann Marie 
Published: April 2014

AbstractSurfactant protein D (SP-D) and CD14 are important innate immune defense molecules that mediate clearance of pathogens and apoptotic cells from the lung. To test whether CD14 expression and function were influenced by SP-D, the surface expression of CD14 was assessed on alveolar macrophages from SP-D−/− mice. CD14 was reduced on alveolar macrophages from SP-D−/− mice and was associated with reduced uptake of LPS and decreased production of TNF-α after LPS stimulation. CD14 is proteolytically cleaved from the cell surface to form a soluble peptide. Soluble CD14 (sCD14) was increased in the bronchoalveolar lavage fluid from SP-D−/− mice. Because matrix metalloproteinase (MMP)-9 and -12 activities were increased in the lungs of SP-D−/− mice, the role of these metalloproteases in the production of sCD14 was assessed. sCD14 was decreased in both MMP9−/−/SP-D−/− and MMP12−/−/SP-D−/− mice demonstrating MMP-9 and MMP-12 contribute to proteolytic shedding of CD14. The increased sCD14 seen in SP-D−/− mice was dependent upon the activation of MMP-12 via an MMP-9-dependent mechanism. Supporting this observation, MMP-12 caused the release of sCD14 from RAW 264.7 cells in vitro. In conclusion, SP-D influences innate host defense, in part, by regulating sCD14 in a process mediated by MMP-9 and MMP-12.
Early Establishment of γ-Herpesvirus Latency: Implications for Immune Control
Authors: Flaño Emilio , Jia Qingmei , Moore John , Woodland David L. , Sun Ren , Blackman Marcia A. 
Published: April 2014

Abstract
The human γ-herpesviruses, EBV and Kaposi’s sarcoma-associated herpesvirus, infect &gt;90% of the population worldwide, and latent infection is associated with numerous malignancies. Rational vaccination and therapeutic strategies require an understanding of virus-host interactions during the initial asymptomatic infection. Primary EBV infection is associated with virus replication at epithelial sites and entry into the circulating B lymphocyte pool. The virus exploits the life cycle of the B cell and latency is maintained long term in resting memory B cells. In this study, using a murine γ-herpesvirus model, we demonstrate an early dominance of latent virus at the site of infection, with lung B cells harboring virus almost immediately after infection. These data reinforce the central role of the B cell not only in the later phase of infection, but early in the initial infection. Early inhibition of lytic replication does not impact the progression of the latent infection, and latency is established in lymphoid tissues following infection with a replication-deficient mutant virus. These data demonstrate that lytic viral replication is not a requirement for γ-herpesvirus latency in vivo and suggest that viral latency can be disseminated by cellular proliferation. These observations emphasize that prophylactic vaccination strategies must target latent γ-herpesvirus at the site of infection.
Leukotriene B4 Receptor-1 Is Essential for Allergen-Mediated Recruitment of CD8+ T Cells and Airway Hyperresponsiveness
Authors: Miyahara Nobuaki , Takeda Katsuyuki , Miyahara Satoko , Taube Christian , Joetham Anthony , Koya Toshiyuki , Matsubara Shigeki , Dakhama Azzeddine , Tager Andrew M. , Luster Andrew D. , Gelfand Erwin W. 
Published: April 2014

AbstractRecent studies in both human and rodents have indicated that in addition to CD4+ T cells, CD8+ T cells play an important role in allergic inflammation. We previously demonstrated that allergen-sensitized and -challenged CD8-deficient (CD8−/−) mice develop significantly lower airway hyperresponsiveness (AHR), eosinophilic inflammation, and IL-13 levels in bronchoalveolar lavage fluid compared with wild-type mice, and that all these responses were restored by adoptive transfer of in vivo-primed CD8+ T cells or in vitro-generated effector CD8+ T cells (TEFF). Recently, leukotriene B4 and its high affinity receptor, BLT1, have been shown to mediate in vitro-generated TEFF recruitment into inflamed tissues. In this study we investigated whether BLT1 is essential for the development of CD8+ T cell-mediated allergic AHR and inflammation. Adoptive transfer of in vivo-primed BLT1+/+, but not BLT1−/−, CD8+ T cells into sensitized and challenged CD8−/− mice restored AHR, eosinophilic inflammation, and IL-13 levels. Moreover, when adoptively transferred into sensitized CD8−/− mice, in vitro-generated BLT1+/+, but not BLT1−/−, TEFF accumulated in the lung and mediated these altered airway responses to allergen challenge. These data are the first to show both a functional and an essential role for BLT1 in allergen-mediated CD8+ TEFF recruitment into the lung and development of AHR and airway inflammation.
Composition of the Lectin Pathway of Complement inGallus gallus: Absence of Mannan-Binding Lectin-Associated Serine Protease-1 in Birds
Authors: Lynch Nicholas J. , Khan Saeed-ul-Hassan , Stover Cordula M. , Sandrini Sara M. , Marston Denise , Presanis Julia S. , Schwaeble Wilhelm J. 
Published: April 2014

AbstractThe lectin pathway of complement is activated by multimolecular complexes that recognize and bind to microbial polysaccharides. These complexes comprise a multimeric carbohydrate recognition subunit (either mannan-binding lectin (MBL) or a ficolin), three MBL-associated serine proteases (MASP-1, -2, and -3), and MAp19 (a truncated product of the MASP-2 gene). In this study we report the cloning of chicken MASP-2, MASP-3, and MAp19 and the organization of their genes and those for chicken MBL and a novel ficolin. Mammals usually possess two MBL genes and two or three ficolin genes, but chickens have only one of each, both of which represent the undiversified ancestors of the mammalian genes. The primary structure of chicken MASP-2 is 54% identical with those of the human and mouse MASP-2, and the organization of its gene is the same as in mammals. MASP-3 is even more conserved; chicken MASP-3 shares ∼75% of its residues with human and Xenopus MASP-3. It is more widely expressed than other lectin pathway components, suggesting a possible function of MASP-3 different from those of the other components. In mammals, MASP-1 and MASP-3 are alternatively spliced products of a single structural gene. We demonstrate the absence of MASP-1 in birds, possibly caused by the loss of MASP-1-specific exons during phylogeny. Despite the lack of MASP-1-like enzymatic activity in sera of chicken and other birds, avian lectin pathway complexes efficiently activate C4.
Autoimmune Alterations Induced by the New Zealand BlackLbw2Locus in BWF1 Mice
Authors: Haraldsson Maria K. , dela Paz Nathanial G. , Kuan Jason G. , Gilkeson Gary S. , Theofilopoulos Argyrios N. , Kono Dwight H. 
Published: April 2014

AbstractThe New Zealand Black (NZB) Lbw2 locus (lupus NZB × New Zealand White (NZW) 2 locus) was previously linked to mortality and glomerulonephritis, but not to IgG autoantibodies, suggesting that it played a role in a later disease stage. To define its contribution, (NZB × NZW)F1 hybrids (BWF1) containing two, one, or no copies of this locus were generated. Lack of the NZB Lbw2 indeed reduced mortality and glomerulonephritis, but not serum levels of total and anti-DNA IgG Abs. There were, however, significant reductions in the B cell response to LPS, total and anti-DNA IgM and IgG Ab-forming cells, IgM Ab levels, and glomerular Ig deposits. Furthermore, although serum IgG autoantibody levels correlated poorly with kidney IgG deposits, the number of spontaneous IgG Ab-forming cells had a significant correlation. Genome-wide mapping of IgM anti-chromatin levels identified only Lbw2, and analysis of subinterval congenics tentatively reduced Lbw2 to ∼5 Mb. Because no known genes associated with B cell activation and lupus are in this interval, Lbw2 probably represents a novel B cell activation gene. These findings establish the importance of Lbw2 in the BWF1 hybrid and indicate that Lbw2, by enhancing B cell hyperactivity, promotes the early polyclonal activation of B cells and subsequent production of autoantibodies.
Bone Marrow Clonogenic Capability, Cytokine Production, and Thymic Output in Patients with Common Variable Immunodeficiency
Authors: Isgrò Antonella , Marziali Marco , Mezzaroma Ivano , Luzi Giuseppe , Mazzone Anna Maria , Guazzi Vanessa , Andolfi Grazia , Cassani Barbara , Aiuti Alessandro , Aiuti Fernando 
Published: April 2014

AbstractIn patients with primary Ab deficiencies, hematological and immunological abnormalities are frequently observed. A regenerative failure of hemopoietic stem/progenitor cells has been hypothesized. We evaluated in the bone marrow (BM) of 11 patients with common variable immunodeficiency, the phenotype of BM progenitors and their in vitro growth by colony-forming cell (CFC) and long-term culture (LTC) assays. A significant decrease in erythroid and mixed CFC and, to a greater extent, in primitive LTC-CFC progenitors was observed in patients compared with healthy controls. The frequency of BM pre-B and pro-B cells correlated directly with the absolute number of CD19+ lymphocytes. BM cells cultured in vitro produced spontaneously lower amounts of IL-2 and elevated levels of TNF-α compared with controls, indicating a skewing toward a proapoptotic cytokine pattern. In addition, stromal cells generated after BM LTC secreted less IL-7 and displayed by immunohistochemistry an altered phenotype. These findings were associated with a significant decrease in naive Th cells coexpressing CD31 in the peripheral blood. These results indicate an impaired growth and differentiation capacity of progenitor cells in patients with common variable immunodeficiency.
CCL1-CCR8 Interactions: An Axis Mediating the Recruitment of T Cells and Langerhans-Type Dendritic Cells to Sites of Atopic Skin Inflammation
Authors: Gombert Michael , Dieu-Nosjean Marie-Caroline , Winterberg Franziska , Bünemann Erich , Kubitza Robert C. , Da Cunha Ludivine , Haahtela Anna , Lehtimäki Sari , Müller Anja , Rieker Juliane , Meller Stephan , Pivarcsi Andor , Koreck Andrea , Fridman Wolf-Herman , Zentgraf Hans-Walter , Pavenstädt Hermann , Amara Ali , Caux Christophe , Kemeny Lajos , Alenius Harri , Lauerma Antti , Ruzicka Thomas , Zlotnik Albert , Homey Bernhard 
Published: April 2014

AbstractAtopic dermatitis represents a chronically relapsing skin disease with a steadily increasing prevalence of 10–20% in children. Skin-infiltrating T cells, dendritic cells (DC), and mast cells are thought to play a crucial role in its pathogenesis. We report that the expression of the CC chemokine CCL1 (I-309) is significantly and selectively up-regulated in atopic dermatitis in comparison to psoriasis, cutaneous lupus erythematosus, or normal skin. CCL1 serum levels of atopic dermatitis patients are significantly higher than levels in healthy individuals. DC, mast cells, and dermal endothelial cells are abundant sources of CCL1 during atopic skin inflammation and allergen challenge, and Staphylococcus aureus-derived products induce its production. In vitro, binding and cross-linking of IgE on mast cells resulted in a significant up-regulation of this inflammatory chemokine. Its specific receptor, CCR8, is expressed on a small subset of circulating T cells and is abundantly expressed on interstitial DC, Langerhans cells generated in vitro, and their monocytic precursors. Although DC maintain their CCR8+ status during maturation, brief activation of circulating T cells recruits CCR8 from intracytoplamic stores to the cell surface. Moreover, the inflammatory and atopy-associated chemokine CCL1 synergizes with the homeostatic chemokine CXCL12 (SDF-1α) resulting in the recruitment of T cell and Langerhans cell-like DC. Taken together, these findings suggest that the axis CCL1-CCR8 links adaptive and innate immune functions that play a role in the initiation and amplification of atopic skin inflammation.
CD8α+ Dendritic Cells Selectively Present MHC Class I-Restricted Noncytolytic Viral and Intracellular Bacterial Antigens In Vivo
Authors: Belz Gabrielle T. , Shortman Ken , Bevan Michael J. , Heath William R. 
Published: April 2014

Abstract
CD8α+ dendritic cells (DCs) have been shown to be the principal DC subset involved in priming MHC class I-restricted CTL immunity to a variety of cytolytic viruses, including HSV type 1, influenza, and vaccinia virus. Whether priming of CTLs by CD8α+ DCs is limited to cytolytic viruses, which may provide dead cellular material for this DC subset, or whether these DCs selectively present intracellular Ags, is unknown. To address this question, we examined Ag presentation to a noncytolytic virus, lymphocytic choriomeningitis virus, and to an intracellular bacterium, Listeria monocytogenes. We show that regardless of the type of intracellular infection, CD8α+ DCs are the principal DC subset that initiate CD8+ T cell immunity.
Cutting Edge: B-1 Cells Are Deficient in Lck: Defective B Cell Receptor Signal Transduction in B-1 Cells Occurs in the Absence of Elevated Lck Expression
Authors: Francés Rubén , Tumang Joseph R. , Rothstein Thomas L. 
Published: April 2014

Abstract
B-1 cells constitute a unique B cell subset that is primarily responsible for producing nonimmune Ig. This natural Ig acts as a principal line of defense against infection. A key feature of B-1 cells is the failure of BCR-triggered signal transduction. Recently, defective BCR signaling in B-1 cells has been attributed to elevated expression of the canonical T cell src kinase, Lck. In the present study, we re-examined Lck expression in normal B-1 cells. We found that B-1 cells expressed less Lck at both the protein and RNA levels than did B-2 cells. The same B-1 cells manifested defective BCR-mediated induction of IKKβ phosphorylation, IκBα degradation, and intracellular Ca2+ mobilization. Thus, the failure of BCR signaling in B-1 cells does not relate to subset-specific elevation of Lck.
The CD3ε Proline-Rich Sequence, and Its Interaction with Nck, Is Not Required for T Cell Development and Function
Authors: Szymczak Andrea L. , Workman Creg J. , Gil Diana , Dilioglou Smaroula , Vignali Kate M. , Palmer Ed , Vignali Dario A. A. 
Published: April 2014

Abstract
The CD3ε proline-rich sequence (PRS) binds to the cytosolic adaptor molecule Nck after TCR ligation. It has been proposed that this interaction is essential for immunological synapse formation and T cell activation. To assess the physiological importance of the CD3ε PRS, we have generated mice that lack this motif (CD3ε.PRSM). Pull-down experiments demonstrated the inability of Nck to bind to the CD3ε PRS in thymocytes from mutant mice after TCR ligation. Surprisingly, no differences were observed in the number and percentage of T cell subsets in the thymus and spleen, and there was no apparent defect in positive or negative selection. Furthermore, the proliferative response of CD3ε.PRSM T cells to staphylococcal enterotoxin B and anti-CD3 Ab was normal. TCR surface expression, constitutive internalization, and Ag-induced down-modulation were also normal. These data suggest that the interaction between the CD3ε PRS and Nck, or any other Src homology 3 domain-containing molecule, is not essential for T cell development and function.
The Unique Region of Surrogate Light Chain Component λ5 Is a Heavy Chain-Specific Regulator of Precursor B Cell Receptor Signaling
Authors: Guloglu F. Betul , Bajor Ewa , Smith Brendan P. , Roman Christopher A. J. 
Published: April 2014

AbstractSignals transduced by precursor-BCRs (pre-BCRs) composed of Ig μ heavy chains (HCs) and the surrogate L chain components λ5 and VpreB are critical for B cell development. A conserved unique region (UR) of λ5 was shown to activate pre-BCR complexes in transformed cells and to engage putative ligands, but its contribution to pre-B cell development is not known. It is also not clear why the λ-like sequences in λ5 are used to select HCs that will associate mainly with κ L chains. In this study, we show that, in transformed and primary mouse B cell progenitors, receptors containing full-length HCs and lacking the λ5UR were expressed at higher surface levels, but exhibited reduced activity compared with normal pre-BCRs in supporting developmental changes that accompany the progenitor to pre-B cell transition in primary cell culture systems and in the bone marrow in vivo. In contrast, deletion of the λ5UR did not change net signaling output by the Dμ-pre-BCR, a developmentally defective receptor that exhibited impaired activity in the primary cell culture system. Moreover, the λ-like sequences in λ5 were more accommodating than κ in supporting surface expression and signaling by the different HCs. These results show that the λ5UR is important, although not essential, for surrogate L chain-dependent receptor signaling in primary cells, and furthermore may help allow discrimination of signaling competency between normal and Dμ-pre-BCRs. That the λ-like portion of λ5 in the absence of the UR was nondiscriminatory suggests that the λ5UR focuses pre-BCR-dependent selection on the HC V region.