bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proinflammatory Proteases Liberate a Discrete High-Affinity Functional FPRL1 (CCR12) Ligand from CCL23
Authors: Miao Zhenhua , Premack Brett A. , Wei Zheng , Wang Yu , Gerard Craig , Showell Henry , Howard Maureen , Schall Thomas J. , Berahovich Robert 
Published: April 2014

AbstractMost chemokines have been found to bind to and signal through single or highly related chemokine receptors. However, a single chemokine protein, a processed form of the alternatively spliced CCL23 (CKβ8/MPIF-1) gene product, potently engages both the “classical” chemokine receptor CCR1, as well as FPRL1, a type of pattern recognition receptor on innate immune cells. However, the mechanism by which the alternative form of CCL23 is processed is unknown. In this study, we show that proteases associated with inflammation cleave CCL23 immediately N-terminal to the 18-residue domain encoded by the alternatively spliced nucleotides, resulting in potent CCR1 and FPRL1 activity. The proteases also cleave CCL23 immediately C-terminal to the inserted domain, producing a typical CC chemokine “body” containing even further-increased CCR1 potency and a released ∼18-aa peptide with full FPRL1 activity but no activity for CCR1. This peptide, which we term SHAAGtide, is by itself an attractant of monocytes and neutrophils in vitro, recruits leukocytes in vivo, and is 50- to 100-fold more potent than all other natural agents posited to act on FPRL1. The appearance of SHAAGtide appears to be transient, however, as the proinflammatory proteases subsequently cleave within the peptide, abolishing its activity for FPRL1. The sequential activation of a transient FPRL1 ligand and a longer-lived CCR1 ligand within a single chemokine may have important consequences for the development of inflammation or the link between innate and adaptive immunity.
Tubulin Is a Neuronal Target of Autoantibodies in Sydenham’s Chorea
Authors: Kirvan Christine A. , Cox Carol J. , Swedo Susan E. , Cunningham Madeleine W. 
Published: April 2014

AbstractSydenham’s chorea is a CNS disorder and sequela of group A streptococcal infection where deposition of Abs in brain may result in movement and neuropsychiatric abnormalities. We studied human mAbs 24.3.1, 31.1.1, and 37.2.1 derived from chorea and selected for cross-reactivity with group A streptococci and brain Ags. Our novel findings reveal that Sydenham’s chorea mAbs target a 55-kDa brain protein with an N-terminal amino acid sequence of MREIVHLQ corresponding to β-tubulin. Chorea mAb specificity for purified brain tubulin was confirmed in ELISA and Western immunoblot, and significant levels of anti-tubulin IgG were found in acute chorea sera and cerebrospinal fluid. Lysoganglioside GM1 inhibited binding of chorea mAbs to tubulin and mAb reactivity with human caudate and putamen brain sections was blocked by anti-tubulin mAb. The chorea mAbs labeled both intra- and extracellular Ags of a neuronal cell line providing evidence suggesting mimicry between intracellular brain protein tubulin and extracellular lysoganglioside. In addition, chorea mAb 24.3.1 and acute chorea sera induced calcium/calmodulin-dependent protein kinase II activity in human neuronal cells. Nucleotide sequence analysis of the chorea mAb VH genes revealed that mAb 24.3.1 VH gene was encoded by the VH1 germline gene family which encodes other anti-ganglioside VH genes associated with motor neuropathies. mAb recognition of tubulin and the neuronal cell surface with initiation of cell signaling and dopamine release supports an emerging theme in autoimmunity whereby cross-reactive or polyreactive autoantibodies against intracellular Ags recognize cell surface epitopes potentially leading to disease.
Abrogation of Lupus Nephritis in Activation-Induced Deaminase-Deficient MRL/lpr Mice
Authors: Jiang Chuancang , Foley Julie , Clayton Natasha , Kissling Grace , Jokinen Micheal , Herbert Ronald , Diaz Marilyn 
Published: April 2014

AbstractWe generated MRL/lpr mice deficient in activation-induced deaminase (AID). Because AID is required for Ig hypermutation and class switch recombination, these mice lack hypermutated IgG Abs. Unlike their AID wild-type littermates, AID-deficient MRL/lpr mice not only lacked autoreactive IgG Abs but also experienced a dramatic increase in the levels of autoreactive IgM. This phenotype in AID-deficient mice translated into a significant reduction in glomerulonephritis, minimal mononuclear cell infiltration in the kidney, and a dramatic increase in survival to levels comparable to those previously reported for MRL/lpr mice completely lacking B cells and well below those of mice lacking secreted Abs. Therefore, this study wherein littermates with either high levels of autoreactive IgM or autoreactive IgG were directly examined proves that autoreactive IgM Abs alone are not sufficient to promote kidney disease in MRL/lpr mice. In addition, the substantial decrease in mortality combined with a dramatic increase in autoreactive IgM Abs in AID-deficient MRL/lpr mice suggest that autoreactive IgM Abs might not only fail to promote nephritis but may also provide a protective role in MRL/lpr mice. This novel mouse model containing high levels of autoreactive, unmutated IgM Abs will help delineate the contribution of autoreactive IgM to autoimmunity.
Immunization of HLA Class I Transgenic Mice Identifies Autoantigenic Epitopes Eliciting Dominant Responses in Type 1 Diabetes Patients
Authors: Blancou Philippe , Mallone Roberto , Martinuzzi Emanuela , Sévère Sabine , Pogu Sylvie , Novelli Giulia , Bruno Graziella , Charbonnel Bernard , Dolz Manuel , Chaillous Lucy , van Endert Peter , Bach Jean-Marie 
Published: April 2014

Abstract
Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic β cells. CD8+ T cells have recently been assigned a major role in β cell injury. Consequently, the identification of autoreactive CD8+ T cells in humans remains essential for development of therapeutic strategies and of assays to identify aggressive cells. However, this identification is laborious and limited by quantities of human blood samples available. We propose a rapid and reliable method to identify autoantigen-derived epitopes recognized by human CD8+ T lymphocytes in T1D patients. Human histocompatibility leukocyte Ags-A*0201 (HLA-A*0201) transgenic mice were immunized with plasmids encoding the T1D-associated autoantigens: 65 kDa glutamic acid decarboxylase (GAD) or insulinoma-associated protein 2 (IA-2). Candidate epitopes for T1D were selected from peptide libraries by testing the CD8+ reactivity of vaccinated mice. All of the nine-candidate epitopes (five for GAD and four for IA-2) identified by our experimental approach were specifically recognized by CD8+ T cells from newly diagnosed T1D patients (n = 19) but not from CD8+ T cells of healthy controls (n = 20). Among these, GAD114–123, GAD536–545 and IA-2805–813 were recognized by 53%, 25%, and 42% of T1D patients, respectively.
Comparing ELISA and Surface Plasmon Resonance for Assessing Clinical Immunogenicity of Panitumumab
Authors: Lofgren James A. , Dhandapani Sripriya , Pennucci Jason J. , Abbott Christina M. , Mytych Daniel T. , Kaliyaperumal Arunan , Swanson Steven J. , Mullenix Michael C. 
Published: April 2014

Abstract
Evaluation of the immunogenicity of panitumumab, a fully human anti-epidermal growth factor receptor mAb approved for use in colorectal cancer patients, led to the development of two separate immunoassays for the detection of anti-panitumumab Abs. The first immunoassay used a bridging ELISA capable of detecting 10 ng/ml positive control anti-panitumumab Ab. The ELISA incorporated an acid dissociation step to reduce drug interference and tolerated the presence of ∼100-fold molar excess of drug. During eight clinical trials, the ELISA detected developing Ab responses in 2 of 612 (0.3%) subjects. In one of the ELISA positive subjects, neutralizing Abs were detected using an epidermal growth factor receptor phosphorylation bioassay. The second immunoassay used a Biacore biosensor immunoassay format capable of detecting 1 μg/ml positive control Ab while tolerating the presence of equal molar amounts of drug. Although less sensitive and less tolerant to competing drug in the assay, the Biacore assay detected developing Ab responses in 25 of the 604 (4.1%) subjects. Additionally, the Biacore assay identified eight subjects who developed neutralizing Abs. Mouse mAbs with affinities ranging from 1.1 × 10−6 to 8.4 × 10−10 M were used to characterize both assay types. The ELISA was more sensitive for the detection of higher affinity mAbs and detected high-affinity mAbs in the presence of higher molar ratio of drug to mAb. The Biacore assay was more sensitive for detection of lower affinity mAbs and detected low affinity Abs in the presence of higher molar ratios of drug to mAb.
Enhanced Immune Reconstitution by Sex Steroid Ablation following Allogeneic Hemopoietic Stem Cell Transplantation
Authors: Goldberg Gabrielle L. , Alpdogan Önder , Muriglan Stephanie J. , Hammett Maree V. , Milton Morag K. , Eng Jeffrey M. , Hubbard Vanessa M. , Kochman Adam , Willis Lucy M. , Greenberg Andrew S. , Tjoe Kartono H. , Sutherland Jayne S. , Chidgey Ann , van den Brink Marcel R. M. , Boyd Richard L. 
Published: April 2014

AbstractDelayed immune reconstitution in adult recipients of allogeneic hemopoietic stem cell transplantations (HSCT) is related to age-induced thymic atrophy. Overcoming this paucity of T cell function is a major goal of clinical research but in the context of allogeneic transplants, any strategy must not exacerbate graft-vs-host disease (GVHD) yet ideally retain graft-vs-tumor (GVT) effects. We have shown sex steroid ablation reverses thymic atrophy and enhances T cell recovery in aged animals and in congenic bone marrow (BM) transplant but the latter does not have the complications of allogeneic T cell reactivity. We have examined whether sex steroid ablation promoted hemopoietic and T cell recovery following allogeneic HSCT and whether this benefit was negated by enhanced GVHD. BM and thymic cell numbers were significantly increased at 14 and 28 days after HSCT in castrated mice compared with sham-castrated controls. In the thymus, the numbers of donor-derived thymocytes and dendritic cells were significantly increased after HSCT and castration; donor-derived BM precursors and developing B cells were also significantly increased. Importantly, despite restoring T cell function, sex steroid inhibition did not exacerbate the development of GVHD or ameliorate GVT activity. Finally, IL-7 treatment in combination with castration had an additive effect on thymic cellularity following HSCT. These results indicate that sex steroid ablation can profoundly enhance thymic and hemopoietic recovery following allogeneic HSCT without increasing GVHD and maintaining GVT.
Cutting Edge: Essential Role of Hypoxia Inducible Factor-1α in Development of Lipopolysaccharide-Induced Sepsis
Authors: Peyssonnaux Carole , Cejudo-Martin Pilar , Doedens Andrew , Zinkernagel Annelies S. , Johnson Randall S. , Nizet Victor 
Published: April 2014

Abstract
Sepsis, the leading cause of death in intensive care units, reflects a detrimental host response to infection in which bacteria or LPS act as potent activators of immune cells, including monocytes and macrophages. In this report, we show that LPS raises the level of the transcriptional regulator hypoxia-inducible factor-1α (HIF-1α) in macrophages, increasing HIF-1α and decreasing prolyl hydroxylase mRNA production in a TLR4-dependent fashion. Using murine conditional gene targeting of HIF-1α in the myeloid lineage, we demonstrate that HIF-1α is a critical determinant of the sepsis phenotype. HIF-1α promotes the production of inflammatory cytokines, including TNF-α, IL-1, IL-4, IL-6, and IL-12, that reach harmful levels in the host during early sepsis. HIF-1α deletion in macrophages is protective against LPS-induced mortality and blocks the development of clinical markers including hypotension and hypothermia. Inhibition of HIF-1α activity may thus represent a novel therapeutic target for LPS-induced sepsis.
Cutting Edge: Human Th17 Cells Are Identified as Bearing CCR2+CCR5− Phenotype
Authors: Sato Wakiro , Aranami Toshimasa , Yamamura Takashi 
Published: April 2014

Abstract
Recent reports have shown that IL-17-producing CD4+ T cells (Th17 cells) belong to a distinct helper T cell lineage and are critically involved in the pathogenesis of autoimmune diseases and allergies. However, the chemokine receptor profile of Th17 cells remains to be clarified. In this study, we report that human Th17 cells are identified as CCR2+CCR5− memory CD4+ T cells. Analysis of PBMC from healthy donors showed that CCR2+ cells produce much larger amounts of IL-17 than CCR2− cells, indicating the preferential expression of CCR2 on Th17 cells. Notably, CCR2+CCR5− memory CD4+ T cells produced a large amount of IL-17 and little IFN-γ, whereas CCR2+CCR5+ cells reciprocally produced an enormous amount of IFN-γ but little IL-17. Moreover, a higher expression of T-bet was seen in the CCR5+ memory T cells. These results indicate that absence of CCR5 distinguishes human Th17 cells from Th1 cells.
Type I IFN Contributes to NK Cell Homeostasis, Activation, and Antitumor Function
Authors: Swann Jeremy B. , Hayakawa Yoshihiro , Zerafa Nadeen , Sheehan Kathleen C. F. , Scott Bernadette , Schreiber Robert D. , Hertzog Paul , Smyth Mark J. 
Published: April 2014

Abstract
This study demonstrates that type I IFNs are an early and critical regulator of NK cell numbers, activation, and antitumor activity. Using both IFNAR1- and IFNAR2-deficient mice, as well as an IFNAR1-blocking Ab, we demonstrate that endogenous type I IFN is critical for controlling NK cell-mediated antitumor responses in many experimental tumor models, including protection from methylcholanthrene-induced sarcomas, resistance to the NK cell-sensitive RMA-S tumor and cytokine immunotherapy of lung metastases. Protection from RMA-S afforded by endogenous type I IFN is more potent than that of other effector molecules such as IFN-γ, IL-12, IL-18, and perforin. Furthermore, cytokine immunotherapy using IL-12, IL-18, or IL-21 was effective in the absence of endogenous type I IFN, however the antimetastatic activity of IL-2 was abrogated in IFNAR-deficient mice, primarily due to a defect in IL-2-induced cytotoxic activity. This study demonstrates that endogenous type I IFN is a central mediator of NK cell antitumor responses.
Agonist-Driven Development of CD4+CD25+Foxp3+ Regulatory T Cells Requires a Second Signal Mediated by Stat6
Authors: Sanchez-Guajardo Vanesa , Tanchot Corinne , O’Malley John T. , Kaplan Mark H. , Garcia Sylvie , Freitas Antonio A. 
Published: April 2014

Abstract
The factors that induce Foxp3 expression and regulatory T (Treg) cell development remain unknown. In this study, we investigated the role of STAT4 and STAT6 in agonist-driven generation of Ag-specific Foxp3-expressing Treg cells. Our findings indicate that fully efficient induction of Foxp3 expression and development of Ag-specific Treg cells requires the synergistic action of two signals: a TCR-mediated signal and a second signal mediated by STAT6. Indeed, by comparing the development of wild-type and STAT4- and STAT6-deficient hemagglutinin-specific T cells in the presence of hemagglutinin Ag, we found that the absence of STAT6 impaired the generation of Ag-specific CD4+CD25+Foxp3+ cells. Moreover, in transgenic mice expressing a constitutively active form of STAT6, we found that the fraction of CD4+Foxp3+ cells exceeds that of control wild-type littermates. Overall these findings support a role for the STAT6 pathway in Treg cell development and maintenance.
A Novel Role of Complement Factor C1q in Augmenting the Presentation of Antigen Captured in Immune Complexes to CD8+ T Lymphocytes
Authors: van Montfoort Nadine , de Jong Judith M. H. , Schuurhuis Danita H. , van der Voort Ellen I. H. , Camps Marcel G. M. , Huizinga Tom W. J. , van Kooten Cees , Daha Mohamed R. , Verbeek J. Sjef , Ossendorp Ferry , Toes René E. M. 
Published: April 2014

Abstract
Ag-IgG immune complexes (IC) are efficiently taken up, and Ag-derived peptides are subsequently processed and presented by APC. In vitro experiments indicate that IgG Fc Receptors (FcγR) facilitate the efficient uptake of IC by dendritic cells. Previous experiments showed that the cross-presentation of Ag-derived peptides after s.c. administration of IC is FcγR-dependent. To study the role of different FcγR and complement in MHC class I Ag presentation after i.v. administration, we used mice deficient for FcγRs and complement components. These mice were injected with CFSE-labeled OVA-specific CD8+ T cells followed by administration of IC composed of OVA and rabbit anti-OVA IgG i.v. to measure MHC class I presentation of OVA-derived peptides. The Ag presentation was partly reduced in FcRγ-chain-deficient mice, but not affected in FcγRI/II/III-deficient mice, complement factor C3-deficient mice, or FcγRI/II/III × C3-deficient mice. Importantly, CD8+ T cell proliferation was significantly reduced in mice deficient for C1q. This proliferation could be restored when IC were incubated with purified human C1q before injection. Likewise, purified C1q could strongly enhance the uptake and presentation of IC by dendritic cells in vitro. Heat inactivation abrogated the C1q-mediated uptake of IC. In addition, in vivo uptake of OVA-IC in the spleen was significantly reduced in C1q-deficient mice compared with wild-type mice. Together, these results indicate a novel function of C1q, which is present in high levels in the bloodstream, by directly enhancing the uptake and MHC class I presentation of Ag captured in IC by APC to CD8+ T cells.
Uptake of Human Papillomavirus Virus-Like Particles by Dendritic Cells Is Mediated by Fcγ Receptors and Contributes to Acquisition of T Cell Immunity
Authors: Da Silva Diane M. , Fausch Steven C. , Verbeek J. Sjef , Kast W. Martin 
Published: April 2014

Abstract
Chimeric human papillomavirus virus-like particles (HPV cVLP) are immunogens able to elicit potent CTL responses in mice against HPV16-transformed tumors; however, the mechanism of T cell priming has remained elusive. HPV VLP bind to human MHC class II-positive APCs through interaction with FcγRIII, and immature dendritic cells (DC) become activated after incubation with HPV VLP; however, it is unclear whether FcγR on DC are involved. In mice, FcγRII and FcγRIII are homologous and bind similar ligands. In this study, we show that binding and uptake of VLP by DC from FcγRII, FcγRIII, and FcγRII/III-deficient mice are reduced by up to 50% compared with wild-type mice. Additionally, maturation of murine DC from FcγRII/III-deficient mice by VLP is also reduced, indicating that DC maturation, and thus Ag presentation, is diminished in the absence of expression of FcγR. To investigate the in vivo contribution of FcγR in the induction of cellular immunity, FcγR single- and double-knockout mice were immunized with HPV16 L1/L2-E7 cVLP, and the frequency of E7-specific T cells was analyzed by tetramer binding, IFN-γ ELISPOT, and cytotoxicity assays. All readouts indicated that the frequency of E7-specific CD4+ and CD8+ T cells induced in all FcγR-deficient mice after immunization with cVLP was significantly diminished. Based on these results, we propose that the low-affinity FcγR contribute to the high immunogenicity of HPV VLP during T cell priming by targeting VLP to DC and inducing a maturation state of the DC that facilitates Ag presentation to and activation of naive T cells.
IL-27 Synthesis Induced by TLR Ligation Critically Depends on IFN Regulatory Factor 3
Authors: Molle Céline , Nguyen Muriel , Flamand Véronique , Renneson Joelle , Trottein François , De Wit Dominique , Willems Fabienne , Goldman Michel , Goriely Stanislas 
Published: April 2014

Abstract
IL-27 is a heterodimeric cytokine composed of EBV-induced gene 3 and p28. Produced by dendritic cells (DCs) in response to TLR ligands, IL-27 recently emerged as a key regulator of inflammatory responses. In this study, we first demonstrate that Toll/IL-1R-containing adaptor inducing IFN-β and its associated IFN regulatory factor (IRF) 3 transcription factor are critically involved in IL-27p28 expression in mouse DCs stimulated by TLR ligands. We then show that IL-27 serum levels are dramatically reduced in IRF3−/− upon LPS injection, indicating a critical role for IRF3 in TLR4-mediated IL-27 production in vivo. We identified an IRF3-binding site within the IL-27p28 promoter region which is required for IL-27p28 gene activation in reporter gene assays. In human DCs, IL-27p28 mRNA was preferentially induced by Toll/IL-1R-containing adaptor inducing IFN-β-coupled TLR ligands and following CMV infection. Furthermore, chromatin immunoprecipitation studies demonstrate that IRF3 is recruited to the endogenous p28 promoter in TLR4-stimulated human DCs. We conclude that IRF3 activation is a master switch for IL-27 synthesis.
Disregulated Influenza A Virus-Specific CD8+ T Cell Homeostasis in the Absence of IFN-γ Signaling
Authors: Turner Stephen J. , Olivas Elvia , Gutierrez Astrid , Diaz Gabriela , Doherty Peter C. 
Published: April 2014

Abstract
Recent studies indicate that IFN-γ may influence both the expansion and the trafficking of virus-specific CD8+ CTL, though the effects are not necessarily consistent for different models of viral and bacterial disease. Influenza A virus infection of mice deficient for IFN-γ (IFN-γ−/−) or deficient for the IFN-γ receptor 1 (IFNGR1−/−) was, when compared with the wild-type (WT) B6 controls, associated with increased Ag-specific CD8+ T cell counts in the spleen and mediastinal lymph nodes. At the same time, fewer of these CTL effectors were found in the bronchoalveolar lavage population recovered from the IFN-γ−/− mice. Comparable effects were observed for WT mice treated with a neutralizing IFN-γ-specific mAb. Transfer of WT memory Thy1.1+ CD8+ populations into Thy1.2+ B6 IFN-γ−/− or IFNGR1−/− mice followed by intranasal virus challenge demonstrated both that IFN-γ produced by the host was important for the regulation of Ag-specific CTL numbers and that IFN-γ was likely to act directly on the T cells themselves. In addition, the prevalence of CTLs undergoing apoptosis in spleen was lower when measured directly ex vivo for IFN-γ−/− vs WT B6 mice. The present analysis is the first comprehensive demonstration that IFN-γ signaling can differentially regulate both Ag-specific CTL homeostasis in secondary lymphoid organs and trafficking to a site of virus-induced pathology.