bluuebunny/crossref_metadata_2025_split huggingface dataset:
FcγRIII and FcγRIV Are Indispensable for Acute Glomerular Inflammation Induced by Switch Variant Monoclonal Antibodies
Authors: Giorgini Angela , Brown Heather J. , Lock Helen R. , Nimmerjahn Falk , Ravetch Jeffrey V. , Verbeek J. Sjef , Sacks Steven H. , Robson Michael G. 
Published: April 2014

AbstractThe relative ability of IgG subclasses to cause acute inflammation and the roles of specific effector mechanisms in this process are not clear. We explored this in an in vivo model of glomerular inflammation in the mouse. Trinitrophenol was planted on the glomerular basement membrane after conjugation to nephrotoxic Ab. The relative nephritogenicity of anti-trinitrophenol switch variant mAbs was then explored and shown to be IgG2a &gt; IgG2b, with no disease caused by IgG1. Using knockout mice, we showed that FcγRIII was necessary for both neutrophil influx and glomerular damage induced by IgG2a and IgG2b. Surprisingly, IgG1 did not cause disease although it binds to FcγRIII. Using blocking Abs, we showed that this was explained by an additional requirement for FcγRIV, which does not bind to IgG1. IgG2a- or IgG2b-induced neutrophil influx was not affected by deficiency of either FcγRI or C3. Bone marrow chimeras were constructed to test the effect of combined deficiency of FcγRI and C3, and there was no effect on IgG2a- or IgG2b-mediated neutrophil influx. However, IgG2b-induced albuminuria and thrombosis were reduced in C3-deficient mice, showing an additional role for complement in IgG2b-mediated glomerular damage. The results show that IgG2a and IgG2b are the pathogenic subclasses in acute neutrophil-mediated glomerular inflammation, with an indispensable role for both FcγRIII and FcγRIV. Additionally, complement contributes to IgG2b-induced glomerular injury.
Targeting of Myelin Protein Zero in a Spontaneous Autoimmune Polyneuropathy
Authors: Kim Hye-Jung , Jung Cha-Gyun , Jensen Mark A. , Dukala Danuta , Soliven Betty 
Published: April 2014

Abstract
Elimination of the costimulatory molecule B7-2 prevents autoimmune diabetes in NOD mice, but leads to the development of a spontaneous autoimmune polyneuropathy (SAP), which resembles the human disease chronic inflammatory demyelinating polyneuropathy (CIDP). In this study, we examined the immunopathogenic mechanisms in this model, including identification of SAP Ags. We found that B7-2-deficient NOD mice exhibit changes in cytokine and chemokine gene expression in spleens over time. There was an increase in IL-17 and a decrease in IL-10 transcript levels at 4 mo (preclinical phase), whereas IFN-γ expression peaked at 8 mo (clinical phase). There was also an increase in transcript levels of Th1 cytokines, CXCL10, and RANTES in sciatic nerves of mice that developed SAP. Splenocytes from SAP mice exhibited proliferative and Th1 cytokine responses to myelin P0 (180–199), but not to other P0 peptides or P2 (53–78). Adoptive transfer of P0-reactive T cells generated from SAP mice induced neuropathy in four of six NOD.SCID mice. Data from i.v. tolerance studies indicate that myelin P0 is one of the autoantigens targeted by T cells in SAP in this model. The expression of P0 by peri-islet Schwann cells provides a potential mechanism linking islet autoimmunity and inflammatory neuropathy.
Expanded Double Negative T Cells in Patients with Systemic Lupus Erythematosus Produce IL-17 and Infiltrate the Kidneys
Authors: Crispín José C. , Oukka Mohamed , Bayliss George , Cohen Robert A. , Van Beek Christine A. , Stillman Isaac E. , Kyttaris Vasileios C. , Juang Yuang-Taung , Tsokos George C. 
Published: April 2014

AbstractDouble negative (DN) T cells are expanded in patients with systemic lupus erythematosus (SLE) and stimulate autoantibody production as efficiently as CD4+ T cells. In this study, we demonstrate that DN T cells from patients with SLE produce significant amounts of IL-17 and IFN-γ, and expand when stimulated in vitro with an anti-CD3 Ab in the presence of accessory cells. Furthermore, IL-17+ and DN T cells are found in kidney biopsies of patients with lupus nephritis. Our findings establish that DN T cells produce the inflammatory cytokines IL-17 and IFN-γ, and suggest that they contribute to the pathogenesis of kidney damage in patients with SLE.
Comparison of Biological Activity of Human Anti-Apical Membrane Antigen-1 Antibodies Induced by Natural Infection and Vaccination
Authors: Miura Kazutoyo , Zhou Hong , Moretz Samuel E. , Diouf Ababacar , Thera Mahamadou A. , Dolo Amagana , Doumbo Ogobara , Malkin Elissa , Diemert David , Miller Louis H. , Mullen Gregory E. D. , Long Carole A. 
Published: April 2014

Abstract
Vaccines represent a significant potential means of decreasing global morbidity and mortality due to malaria. Clinical trials in the United States with Plasmodium falciparum Apical Membrane Antigen 1 (AMA1) showed that the vaccine induced biologically active Abs judged by an in vitro parasite growth inhibition assay (GIA). However, the same vaccine in Malian adults did not increase biological activity, although it elevated ELISA titers. Because GIA has been used to evaluate the biological activity of Abs induced by blood stage malarial vaccine candidates, we explored this discrepancy in this study. We affinity purified AMA1-specific Abs from both U.S. vaccinees and nonvaccinated individuals living in a malaria-endemic area of Mali and performed ELISA and GIA. Both AMA1-specifc Abs induced by vaccination (U.S.) and by natural infection (Mali) have comparable biological activity in GIA when the ELISA titer is normalized. However, a fraction of Malians’ IgG that did not bind to AMA1 protein (Mali-non-AMA1 IgG) reduced the biological activity of the AMA1 Abs from U.S. vaccinees; in contrast, U.S.-non-AMA1 IgGs did not show a reduction of the biological activity. Further investigation revealed that the reduction was due to malaria-specific IgGs in the Mali-non-AMA1 IgGs. The fact that both U.S.- and Mali-AMA1-specific Abs showed comparable biological activity supports further development of AMA1-based vaccines. However, the reduction of biological activity of AMA1-specific Ab by other malaria-specific IgGs likely explains the limited effect on growth-inhibitory activity of Abs induced by AMA1 vaccination in Malian adults and may complicate efforts to develop a blood stage malaria vaccine.
Immune Opsonins Modulate BLyS/BAFF Release in a Receptor-Specific Fashion
Authors: Li Xinrui , Su Kaihong , Ji Chuanyi , Szalai Alexander J. , Wu Jianming , Zhang Yan , Zhou Tong , Kimberly Robert P. , Edberg Jeffrey C. 
Published: April 2014

Abstract
TNF ligand superfamily member 13B (B lymphocyte stimulator (BLyS), B cell activating factor (BAFF)) promotes primary B cell proliferation and Ig production. While the soluble form of BLyS/BAFF is thought to be the primary biologically active form, little is known about the regulation of its cleavage and processing. We provide evidence that Fcγ receptor cross-linking triggers a rapid release of soluble, biologically active BLyS/BAFF from myeloid cells. Surprisingly, this function is primarily mediated by FcγRI, but not FcγRIIa as defined by specific mAb, and can be initiated by both IgG and C reactive protein as ligands. The generation of a B cell proliferation and survival factor by both innate and adaptive immune opsonins through engagement of an Fcγ receptor, which can also enhance Ag uptake and presentation, provides a unique opportunity to facilitate Ab production. These results provide a mechanism by which Fcγ receptors can elevate circulating BLyS levels and promote autoantibody production in immune complex-mediated autoimmune diseases.
IFN-α Induces Transcription of Hypoxia-Inducible Factor-1α to Inhibit Proliferation of Human Endothelial Cells
Authors: Gerber Scott A. , Pober Jordan S. 
Published: April 2014

Abstract
Expression of hypoxia-inducible factor (HIF)-1α, a transcription factor subunit increased by protein stabilization in response to hypoxia, is increased in human endothelial cells (ECs) by IFN-α under normoxic conditions. IFN-α increases HIF-1α transcript levels within 2 h by up to 50% and doubles HIF-1α protein expression. Based on pharmacological inhibition studies, the increase in HIF-1α mRNA involves new transcription, is independent of new protein synthesis, and requires JAK signaling. Protein knockdown by small interfering RNA confirms the involvement of JAK1 and TYK2, as well of IFN-stimulated gene factor 3 (ISGF3). IFN-γ does not significantly induce HIF-1α mRNA, but increases the magnitude and duration of the IFN-α effect. IFN-α-induced HIF-1α protein translocates to the nucleus and can bind to hypoxia response elements in DNA. However, IFN-α treatment fails to induce transcription of several prototypic HIF-responsive genes (VEGF-A, PPARγ, and prostacyclin synthase) due to an insufficient increase in HIF-1α protein levels. Although certain other HIF-responsive genes (PHD3 and VEGF-C) are induced following IFN-α and/or IFN-γ treatment, these responses are not inhibited by siRNA knockdown of HIF-1α. Additionally, IFN-α induction of ISGF3-dependent genes involved in innate immunity (viperin, OAS2, and CXCL10) are also unaffected by knockdown of HIF-1α. Interestingly, knockdown of HIF-1α significantly reduces the capacity of IFN-α to inhibit endothelial cell proliferation. We conclude that IFN-α induces the transcription of HIF-1α in human endothelial cells though a JAK-ISGF3 pathway under normoxic conditions, and that this response contributes to the antiproliferative activity of this cytokine.
CD27 Instructs CD4+ T Cells to Provide Help for the Memory CD8+ T Cell Response after Protein Immunization
Authors: Xiao Yanling , Peperzak Victor , Keller Anna M. , Borst Jannie 
Published: April 2014

Abstract
For optimal quality, memory CD8+ T cells require CD4+ T cell help. We have examined whether CD4+ T cells require CD27 to deliver this help, in a model of intranasal OVA protein immunization. CD27 deficiency reduced the capacity of CD4+ T cells to support Ag-specific CD8+ T cell accumulation at the tissue site after primary and secondary immunization. CD27-dependent CD4+ T cell help for the memory CD8+ T cell response was delivered during priming. It did not detectably affect formation of CD8+ memory T cells, but promoted their secondary expansion. CD27 improved survival of primed CD4+ T cells, but its contribution to the memory CD8+ T cell response relied on altered CD4+ T cell quality rather than quantity. CD27 induced a Th1-diagnostic gene expression profile in CD4+ T cells, which included the membrane molecule MS4A4B. Accordingly, CD27 increased the frequency of IFN-γ- and IL-2-producing CD4+ T cells. It did not affect CD40L expression. Strikingly, MS4A4B was also identified as a unique marker of CD8+ memory T cells that had received CD27-proficient CD4+ T cell help during the primary response. This apparent imprinting effect suggests a role for MS4A4B as a downstream effector in CD27-dependent help for CD8+ T cell memory.
Microbial Challenge Promotes the Regenerative Process of the Injured Central Nervous System of the Medicinal Leech by Inducing the Synthesis of Antimicrobial Peptides in Neurons and Microglia
Authors: Schikorski David , Cuvillier-Hot Virginie , Leippe Matthias , Boidin-Wichlacz Céline , Slomianny Christian , Macagno Eduardo , Salzet Michel , Tasiemski Aurélie 
Published: April 2014

Abstract
Following trauma, the CNS of the medicinal leech, unlike the mammalian CNS, has a strong capacity to regenerate neurites and synaptic connections that restore normal function. In this study, we show that this regenerative process is enhanced by a controlled bacterial infection, suggesting that induction of regeneration of normal CNS function may depend critically upon the coinitiation of an immune response. We explore the interaction between the activation of a neuroimmune response and the process of regeneration by assaying the potential roles of two newly characterized antimicrobial peptides. Our data provide evidence that microbial components differentially induce the transcription, by microglial cells, of both antimicrobial peptide genes, the products of which accumulate rapidly at sites in the CNS undergoing regeneration following axotomy. Using a preparation of leech CNS depleted of microglial cells, we also demonstrate the production of antimicrobial peptides by neurons. Interestingly, in addition to exerting antibacterial properties, both peptides act as promoters of the regenerative process of axotomized leech CNS. These data are the first to report the neuronal synthesis of antimicrobial peptides and their participation in the immune response and the regeneration of the CNS. Thus, the leech CNS appears as an excellent model for studying the implication of immune molecules in neural repair.
Critical Role of CD4 Help in CD154 Blockade-Resistant Memory CD8 T Cell Activation and Allograft Rejection in Sensitized Recipients
Authors: Wu Zheng , Wang Yue , Gao Feng , Shen Xiuda , Zhai Yuan , Kupiec-Weglinski Jerzy W. 
Published: April 2014

Abstract
Allograft rejection in sensitized recipients remains the major problem in clinical organ transplantation. We have developed a donor-type skin-sensitized mouse cardiac allograft model (BALB/c→C57BL/6) in which both rejection (&lt;5 days) and alloreactive CD8 activation are resistant to CD154 blockade. First, we attempted to elucidate why CD154 blockade fails to protect cardiac grafts in sensitized recipients. The gene array analysis has revealed that treatment with anti-CD154 mAb (MR1) had distinctive impact on host immunity in naive vs sensitized animals. Unlike in naive counterparts, host sensitization mitigated the impact of CD154 blockade on critical immune signaling pathways. Indeed, we identified 3234 genes in cardiac grafts that were down-regulated by MR1 in naive (at least 5-fold), but remained unaffected in sensitized hosts. Moreover, MR1 treatment failed to prevent accumulation of CD4 T cells in cardiac allografts of sensitized recipients. Then, to determine the role of CD4 help in CD154 blockade-resistant immune response, we used CD4-depleting and CD4-blocking Ab, in conjunction with MR1 treatment. Our data revealed that CD154 blockade-resistant CD8 activation in sensitized mice was dependent on CD4 T cells. In the absence of CD4 help, CD154 blockade prevented differentiation of alloreactive CD8 T cells into CTL effector/memory cells and abrogated acute rejection (cardiac graft survival for &gt;30 days), paralleled by selective target gene depression at the graft site. These results provide the rationale to probe potential synergy of adjunctive therapy targeting CD4 and CD154 to overcome graft rejection in sensitized recipients.
Epidermal Receptor Activator of NF-κB Ligand Controls Langerhans Cells Numbers and Proliferation
Authors: Barbaroux Jean-Baptiste O. , Beleut Manfred , Brisken Cathrin , Mueller Christopher G. , Groves Richard W. 
Published: April 2014

Abstract
Langerhans cells (LC) are the dendritic APC population of the epidermis, where they reside for long periods and are self-replicating. The molecular signals underlying these characteristics are unknown. The TNF superfamily member receptor activator of NF-κB ligand (RANKL, TNFSF11) has been shown to sustain viability of blood dendritic cells in addition to its role in promoting proliferation and differentiation of several cell types, notably osteoclasts. In this study, we have studied expression of the RANKL system in skin and have defined a key role for this molecule in LC homeostasis. In vitro and in vivo, human KC expressed RANKL and epidermal LC expressed cell surface RANK. In vitro, RANKL sustained CD34+ progenitor-derived LC viability following 72-h cultures in cytokine-free medium (79.5 ± 1% vs 55.2 ± 5.7% live cells, respectively; n = 4; p &lt; 0.05). In vivo, RANKL-deficient mice displayed a marked reduction in epidermal LC density (507.1 ± 77.2 vs 873.6 ± 41.6 LC per mm2; n = 9; p &lt; 0.05) and their proliferation was impaired without a detectable effect on apoptosis. These data indicate a key role for the RANKL system in the regulation of LC survival within the skin and suggest a regulatory role for KC in the maintenance of epidermal LC homeostasis.
The Dynamics of Mouse Cytomegalovirus-Specific CD4 T Cell Responses during Acute and Latent Infection
Authors: Walton Senta M. , Wyrsch Philippe , Munks Michael W. , Zimmermann Albert , Hengel Hartmut , Hill Ann B. , Oxenius Annette 
Published: April 2014

Abstract
The dynamics of mouse cytomegalovirus (MCMV)-specific CD4 T cell responses and the mechanisms by which these cells contribute to viral control are not well understood, mainly due to lack of appropriate tools to characterize MCMV-specific CD4 T cells. We therefore generated MCMV-specific CD4 T cell hybridomas, then used an MCMV expression library and overlapping peptides to identify CD4 T cell epitopes. We used these novel tools to study the long-term kinetics and organ distribution of MCMV-specific CD4 T cells in comparison to MCMV-specific CD8 T cell responses. We demonstrate that the overall MCMV-specific CD4 T cell response stabilizes during the latent stage, which stands in contrast to subpopulations of MCMV-specific CD8 T cells and HCMV-specific CD4 T cells which accumulate over the course of CMV latency. Furthermore, MCMV-specific CD4 T cells displayed a Th1 phenotype, secreting high levels of IFN-γ and TNF-α and to some extent IL-2, cytokines which are involved in protection from CMV disease.
Expression of Wiskott-Aldrich Syndrome Protein in Dendritic Cells Regulates Synapse Formation and Activation of Naive CD8+ T Cells
Authors: Pulecio Julian , Tagliani Elisa , Scholer Alix , Prete Francesca , Fetler Luc , Burrone Oscar R. , Benvenuti Federica 
Published: April 2014

Abstract
The Wiskott-Aldrich syndrome protein (WASp) is a key regulator of actin polimerization in hematopoietic cells. Mutations in WASp cause a severe immunodeficiency characterized by defective initiation of primary immune response and autoimmunity. The contribution of altered dendritic cells (DCs) functions to the disease pathogenesis has not been fully elucidated. In this study, we show that conventional DCs develop normally in WASp-deficient mice. However, Ag targeting to lymphoid organ-resident DCs via anti-DEC205 results in impaired naive CD8+ T cell activation, especially at low Ag doses. Altered trafficking of Ag-bearing DCs to lymph nodes (LNs) accounts only partially for defective priming because correction of DCs migration does not rescue T cell activation. In vitro and in vivo imaging of DC-T cell interactions in LNs showed that cytoskeletal alterations in WASp null DCs causes a reduction in the ability to form and stabilize conjugates with naive CD8+ T lymphocytes both in vitro and in vivo. These data indicate that WASp expression in DCs regulates both the ability to traffic to secondary lymphoid organs and to activate naive T cells in LNs.
Enterocyte-Derived TAK1 Signaling Prevents Epithelium Apoptosis and the Development of Ileitis and Colitis
Authors: Kajino-Sakamoto Rie , Inagaki Maiko , Lippert Elisabeth , Akira Shizuo , Robine Sylvie , Matsumoto Kunihiro , Jobin Christian , Ninomiya-Tsuji Jun 
Published: April 2014

Abstract
Recent studies have revealed that TAK1 kinase is an essential intermediate in several innate immune signaling pathways. In this study, we investigated the role of TAK1 signaling in maintaining intestinal homeostasis by generating enterocyte-specific constitutive and inducible gene-deleted TAK1 mice. We found that enterocyte-specific constitutive TAK1-deleted mice spontaneously developed intestinal inflammation as observed by histological analysis and enhanced expression of IL-1β, MIP-2, and IL-6 around the time of birth, which was accompanied by significant enterocyte apoptosis. When TAK1 was deleted in the intestinal epithelium of 4-wk-old mice using an inducible knockout system, enterocytes underwent apoptosis and intestinal inflammation developed within 2–3 days following the initiation of gene deletion. We found that enterocyte apoptosis and intestinal inflammation were strongly attenuated when enterocyte-specific constitutive TAK1-deleted mice were crossed to TNF receptor 1−/− mice. However, these mice later (&gt;14 days) developed ileitis and colitis. Thus, TAK1 signaling in enterocytes is essential for preventing TNF-dependent epithelium apoptosis and the TNF-independent development of ileitis and colitis. We propose that aberration in TAK1 signaling might disrupt intestinal homeostasis and favor the development of inflammatory disease.
B Cells Induce Tolerance by Presenting Endogenous Peptide-IgG on MHC Class II Molecules via an IFN-γ-Inducible Lysosomal Thiol Reductase-Dependent Pathway
Authors: Su Yan , Carey Gregory , Marić Maja , Scott David W. 
Published: April 2014

Abstract
We have previously demonstrated that splenic B cells, transduced with peptide-IgG fusion proteins, are efficient tolerogenic APCs in vivo. Specific hyporesponsiveness to epitopes encoded in the peptide-IgG fusion protein has been achieved to over one dozen Ags, and clinical efficacy has been established in animal models for several autoimmune diseases and hemophilia. Previous studies also demonstrated that tolerance in this system requires MHC class II expression by the transduced B cells. Yet, the mechanisms of this B cell tolerogenic processing pathway remain unclear. In this study, we show that MHC class II molecules on tolerogenic B cells present epitopes derived from endogenous, but not exogenous (secreted), peptide-IgG fusion protein. These class II epitopes from the IgG fusion protein are processed in lysosomes/endosomes in an IFN-γ-inducible lysosomal thiol reductase-dependent manner. We suggest that the MHC class II presentation of endogenously produced fusion protein epitopes represents a novel mechanism for tolerance induced by peptide-IgG-transduced B cells. An understanding of this process might provide insights into central and peripheral tolerance induced by other professional and nonprofessional APCs.
A Novel Virus Carrier State to Evaluate Immunotherapeutic Regimens: Regulatory T Cells Modulate the Pathogenicity of Antiviral Memory Cells
Authors: Truong Phi , McGavern Dorian B. 
Published: April 2014

Abstract
Restrictions in the diversity of an adaptive immune repertoire can facilitate viral persistence. Because a host afflicted with an immune deficiency is not likely to purge a persistent infection using endogenous mechanisms, it is important to explore adoptive therapies to supplement the host with a functional immune defense. In this study, we describe a virus carrier state that results from introducing lymphocytic choriomeningitis virus (LCMV) into adult mice possessing a restricted T cell repertoire. On infection of these mice, LCMV establishes systemic persistence, and within the CNS the virus infects astrocytes (and later oligodendrocytes) rather than its traditional parenchymal target neurons. To determine whether LCMV could be purged from a novel target selection in the absence of an endogenous immune repertoire, we adoptively transferred virus-specific memory cells into adult carrier mice. The memory cells purged virus from the periphery as well as the CNS, but they induced fatalities not typically associated with adoptive immunotherapy. When the repertoire of the recipient mice was examined, a deficiency in natural regulatory T cells was noted. We therefore supplemented carrier mice with regulatory T cells and simultaneously performed adoptive immunotherapy. Cotransfer of regulatory T cells significantly reduced mortality while still permitting the antiviral memory cells to purge the persistent infection. These data indicate that regulatory T cells can be used therapeutically to lessen the pathogenicity of virus-specific immune cells in an immunodeficient host. We also propose that the novel carrier state described herein will facilitate the study of immunotherapeutic regimens.