bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct Effector Mechanisms in the Development of Autoimmune Neuropathy versus Diabetes in Nonobese Diabetic Mice
Authors: Bour-Jordan Hélène , Thompson Heather L. , Bluestone Jeffrey A. 
Published: April 2014

Abstract
NOD mice deficient for the costimulatory molecule B7-2 (NOD-B7-2KO mice) are protected from autoimmune diabetes but develop a spontaneous autoimmune peripheral neuropathy that resembles human diseases Guillain-Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. Similar observations have now been made in conventional NOD mice. We have shown previously that this disease was mediated by autoreactive T cells inducing demyelination in the peripheral nervous system. In this study, we analyzed the molecular pathways involved in the disease. Our data showed that neuropathy developed in the absence of perforin or fas, suggesting that classic cytotoxicity pathways were dispensable for nerve damage in NOD-B7-2KO mice. In contrast, IFN-γ played an obligatory role in the development of neuropathy as demonstrated by the complete protection from disease and infiltration in the nerves in NOD-B7-2KO mice deficient for IFN-γ. This result was consistent with the inflammatory phenotype of T cells infiltrating the peripheral nerves. Importantly, the relative role of perforin, fas, and IFN-γ appears completely different in autoimmune diabetes vs neuropathy. Thus, there are sharp contrasts in the pathogenesis of autoimmune diseases targeting different tissues in the same NOD background.
TGF-β1 Inhibits T-bet Induction by IFN-γ in Murine CD4+ T Cells through the Protein Tyrosine Phosphatase Src Homology Region 2 Domain-Containing Phosphatase-1
Authors: Park Il-Kyoo , Shultz Leonard D. , Letterio John J. , Gorham James D. 
Published: April 2014

Abstract
TGF-β1 prevents the development of autoimmune disease by restraining the development of autoreactive Th1 cells. TGF-β1 inhibits Th1 development in part by suppressing the expression of T-bet, an IFN-γ-induced transcription factor that promotes Th1 differentiation, but how TGF-β1 suppresses T-bet is not known. In this study we show that TGF-β1 suppresses IFN-γ-induced T-bet expression through the hemopoietic protein tyrosine phosphatase (PTP) Src homology region 2 domain-containing phosphatase-1 (Shp-1). In murine CD4+ T cells, IFN-γ rapidly induced the expression of T-bet as well as of IFN regulatory factor-1, another transcription factor important for Th1 development. TGF-β1 antagonized the effects of IFN-γ, inhibiting IFN-γ’s induction of both Th1 transcription factors. In the presence of IFN-γ, TGF-β1 rapidly induced in Th cells the synthesis of the PTP Shp-1, but did not induce Shp-2 or several members of the suppressor of cytokine signaling family of Jak-Stat inhibitors. We tested the requirement for Shp-1 by using T cells from the Shp-1-deficient mev/mev mouse strain. Shp-1 was required for TGF-β1’s suppressive effects, because its suppression of T-bet and IFN regulatory factor-1 was completely abrogated in mev/mev CD4+ T cells. Receptor-proximal responses to IFN-γ, such as the induction of Jak-Stat phosphorylation, were inhibited by TGF-β1 in wild-type T cells, but not in mev/mev T cells. Consistent with a direct role for Shp-1, TGF-β1’s inhibition of IFN-γ-induced Stat1 phosphorylation was sensitive to the general PTP inhibitor pervanadate. Together, these data show that TGF-β1 suppresses IFN-γ signaling and transcriptional responses in CD4+ T cells through the PTP Shp-1.
Molecular Signature of Recent Thymic Selection Events on Effector and Regulatory CD4+ T Lymphocytes
Authors: Romagnoli Paola , Hudrisier Denis , van Meerwijk Joost P. M. 
Published: April 2014

Abstract
Natural CD4+CD25+ regulatory T lymphocytes (Treg) are key protagonists in the induction and maintenance of peripheral T cell tolerance. Their thymic origin and biased repertoire continue to raise important questions about the signals that mediate their development. We validated analysis of MHC class II capture by developing thymocytes from thymic stroma as a tool to study quantitative and qualitative aspects of the cellular interactions involved in thymic T cell development and used it to analyze Treg differentiation in wild-type mice. Our data indicate that APCs of bone marrow origin, but, surprisingly and importantly, not thymic epithelial cells, induce significant negative selection among the very autoreactive Treg precursors. This fundamental difference between thymic development of regulatory and effector T lymphocytes leads to the development of a Treg repertoire enriched in cells specific for a selected subpopulation of self-Ags, i.e., those specifically expressed by thymic epithelial cells.
Promiscuous Thymic Expression of an Autoantigen Gene Does Not Result in Negative Selection of Pathogenic T Cells
Authors: Allen Stacey , Read Simon , DiPaolo Richard , McHugh Rebecca S. , Shevach Ethan M. , Gleeson Paul A. , van Driel Ian R. 
Published: April 2014

Abstract
“Promiscuous” thymic expression of peripheral autoantigens can contribute to immunological tolerance in some cases. However, in this study we show that thymic mRNA expression alone cannot predict a contribution to thymic tolerance. Autoimmune gastritis is caused by CD4+ T cells directed to the α (H/Kα) and β (H/Kβ) subunits of the gastric membrane protein the H+/K+ ATPase. H/Kα mRNA is expressed in the thymus, but H/Kβ expression is barely detectable. In this study, we demonstrate that thymic H/Kα in wild-type mice or mice that overexpressed H/Kα did not result in negative selection of pathogenic anti-H/Kα T cells. However, negative selection of anti-H/Kα T cells did occur if H/Kβ was artificially overexpressed in the thymus. Given that H/Kα cannot be exported from the endoplasmic reticulum and is rapidly degraded in the absence of H/Kβ, we conclude that H/Kα epitopes are unable to access MHC class II loading compartments in cells of the normal thymus. This work, taken together with our previous studies, highlights that thymic autoantigen expression does not necessarily result in the induction of tolerance.
Inhibition of Histone Deacetylase Suppresses Osteoclastogenesis and Bone Destruction by Inducing IFN-β Production
Authors: Nakamura Takahiro , Kukita Toshio , Shobuike Takeo , Nagata Kengo , Wu Zhou , Ogawa Kenji , Hotokebuchi Takao , Kohashi Osamu , Kukita Akiko 
Published: April 2014

Abstract
Osteoclasts are bone-resorptive multinucleated cells that are differentiated from hemopoietic cell lineages of monocyte/macrophages in the presence of receptor activator of NF-κB ligand (RANKL) and M-CSF. Downstream signaling molecules of the receptor of RANKL, RANK, modulate the differentiation and the activation of osteoclasts. We recently found that histone deacetylase inhibitors (HDIs), known as anticancer agents, selectively suppressed osteoclastogenesis in vitro. However, the molecular mechanism underlying inhibitory action of HDIs in osteoclastogenesis and the effect of HDIs on pathological bone destruction are still not remained to be elucidated. In this study, we show that a depsipeptide, FR901228, inhibited osteoclast differentiation by not only suppressing RANKL-induced nuclear translocation of NFATc1 but also increasing the mRNA level of IFN-β, an inhibitor of osteoclastogenesis. The inhibition of osteoclast formation by FR901228 was abrogated by the addition of IFN-β-neutralizing Ab. In addition, treatment of adjuvant-induced arthritis in rats revealed that FR901228 inhibited not only disease development in a prophylactic model but also bone destruction in a therapeutic model. Furthermore, immunostaining of the joints of therapeutically treated rats revealed significant production of IFN-β in synovial cells. Taken together, these data suggest that a HDI inhibits osteoclastogenesis and bone destruction by a novel action to induce the expression of osteoclast inhibitory protein, IFN-β.
CD4 T Cell-Independent Antibody Response Promotes Resolution of Primary Influenza Infection and Helps to Prevent Reinfection
Authors: Lee Byung O. , Rangel-Moreno Javier , Moyron-Quiroz Juan E. , Hartson Louise , Makris Melissa , Sprague Frank , Lund Frances E. , Randall Troy D. 
Published: April 2014

AbstractIt is generally believed that the production of influenza-specific IgG in response to viral infection is dependent on CD4 T cells. However, we previously observed that CD40-deficient mice generate influenza-specific IgG during a primary infection, suggesting that influenza infection may elicit IgG responses independently of CD4 T cell help. In the present study, we tested this hypothesis and show that mice lacking CD40 or CD4 T cells produce detectable titers of influenza-specific IgG and recover from influenza infection in a manner similar to that of normal mice. In contrast, mice completely lacking B cells succumb to influenza infection, despite the presence of large numbers of functional influenza-specific CD8 effector cells in the lungs. Consistent with the characteristics of a T-independent Ab response, long-lived influenza-specific plasma cells are not found in the bone marrow of CD40−/− and class II−/− mice, and influenza-specific IgG titers wane within 60 days postinfection. However, despite the short-lived IgG response, CD40−/− and class II−/− mice are completely protected from challenge infection with the same virus administered within 30 days. This protection is mediated primarily by B cells and Ab, as influenza-immune CD40−/− and class II−/− mice were still resistant to challenge infection when T cells were depleted. These data demonstrate that T cell-independent influenza-specific Ab promotes the resolution of primary influenza infection and helps to prevent reinfection.
A Defect in Deletion of Nucleosome-Specific Autoimmune T Cells in Lupus-Prone Thymus: Role of Thymic Dendritic Cells
Authors: Michaels Marissa A. , Kang Hee-Kap , Kaliyaperumal Arunan , Satyaraj Ebenezar , Shi Yan , Datta Syamal K. 
Published: April 2014

Abstract
To study central tolerance to the major product of ongoing apoptosis in the thymus, we made new lines of transgenic (Tg) mice expressing TCR of a pathogenic autoantibody-inducing Th cell that was specific for nucleosomes and its histone peptide H471–94. In the lupus-prone (SWR × NZB)F1 (SNF1) thymus, introduction of the lupus TCR transgene caused no deletion, but marked down-regulation of the Tg TCR and up-regulation of endogenous TCRs. Paradoxically, autoimmune disease was suppressed in the αβTCR Tg SNF1 mice with induction of highly potent regulatory T cells in the periphery. By contrast, in the MHC-matched, normal (SWR × B10. D2)F1 (SBF1), or in the normal SWR backgrounds, marked deletion of transgenic thymocytes occurred. Thymic lymphoid cells of the normal or lupus-prone mice were equally susceptible to deletion by anti-CD3 Ab or irradiation. However, in the steady state, spontaneous presentation of naturally processed peptides related to the nucleosomal autoepitope was markedly greater by thymic dendritic cells (DC) from normal mice than that from lupus mice. Unmanipulated thymic DC of SNF1 mice expressed lesser amounts of MHC class II and costimulatory molecules than their normal counterparts. These results indicate that apoptotic nucleosomal autoepitopes are naturally processed and presented to developing thymocytes, and a relative deficiency in the natural display of nucleosomal autoepitopes by thymic DC occurs in lupus-prone SNF1 mice.
Ig Gene Rearrangement Steps Are Initiated in Early Human Precursor B Cell Subsets and Correlate with Specific Transcription Factor Expression
Authors: van Zelm Menno C. , van der Burg Mirjam , de Ridder Dick , Barendregt Barbara H. , de Haas Edwin F. E. , Reinders Marcel J. T. , Lankester Arjan C. , Révész Tom , Staal Frank J. T. , van Dongen Jacques J. M. 
Published: April 2014

Abstract
The role of specific transcription factors in the initiation and regulation of Ig gene rearrangements has been studied extensively in mouse models, but data on normal human precursor B cell differentiation are limited. We purified five human precursor B cell subsets, and assessed and quantified their IGH, IGK, and IGL gene rearrangement patterns and gene expression profiles. Pro-B cells already massively initiate DH-JH rearrangements, which are completed with VH-DJH rearrangements in pre-B-I cells. Large cycling pre-B-II cells are selected for in-frame IGH gene rearrangements. The first IGK/IGL gene rearrangements were initiated in pre-B-I cells, but their frequency increased enormously in small pre-B-II cells, and in-frame selection was found in immature B cells. Transcripts of the RAG1 and RAG2 genes and earlier defined transcription factors, such as E2A, early B cell factor, E2-2, PAX5, and IRF4, were specifically up-regulated at stages undergoing Ig gene rearrangements. Based on the combined Ig gene rearrangement status and gene expression profiles of consecutive precursor B cell subsets, we identified 16 candidate genes involved in initiation and/or regulation of Ig gene rearrangements. These analyses provide new insights into early human precursor B cell differentiation steps and represent an excellent template for studies on oncogenic transformation in precursor B acute lymphoblastic leukemia and B cell differentiation blocks in primary Ab deficiencies.
Dendritic Cell Maturation, but Not CD8+ T Cell Induction, Is Dependent on Type I IFN Signaling during Vaccination with Adenovirus Vectors
Authors: Hensley Scott E. , Giles-Davis Wynetta , McCoy Kimberly C. , Weninger Wolfgang , Ertl Hildegund C. J. 
Published: April 2014

Abstract
To understand how vaccines initiate adaptive immune responses, it is necessary to study how they interact with APCs such as dendritic cells (DCs). In this study, we analyzed interactions between recombinant adenovirus (Ad) vectors and mouse DCs. Mouse bone marrow-derived DCs transduced with Ad vectors produced type I IFN, which promoted the maturation of both transduced and bystander DCs. DCs transduced with a vector derived from a chimpanzee Ad serotype (AdC68) produced more type I IFN and matured more efficiently compared with DCs transduced with a vector derived from a human Ad serotype (AdHu5). Both vectors stimulated type I IFN production independently of viral transcription, replication, and TLR signaling. However, each vector induced type I IFN through distinct pathways; whereas AdHu5 vectors required phosphoinositide-3-OH kinase for type I IFN induction, AdC68 vectors did not. Both vectors induced strong transgene product-specific CD8+ T cell responses in wild-type mice. DCs isolated from mice that have a defect in type I IFN signaling failed to undergo full maturation after Ad vaccination, but surprisingly, these mice mounted strong transgene product-specific CD8+ T cell responses. In these mice, we were able to detect a small number of transduced DCs that expressed high levels of costimulatory molecules, and these DCs were able to stimulate transgene product-specific CD8+ T cells. Thus, type I IFN signaling is an important component of Ad-mediated DC maturation but is dispensable during the generation of transgene product-specific CD8+ T cell responses.
The MyD88-Dependent, but Not the MyD88-Independent, Pathway of TLR4 Signaling Is Important in Clearing Nontypeable Haemophilus influenzae from the Mouse Lung
Authors: Wieland Catharina W. , Florquin Sandrine , Maris Nico A. , Hoebe Kasper , Beutler Bruce , Takeda Kiyoshi , Akira Shizuo , van der Poll Tom 
Published: April 2014

Abstract
TLRs are important for the recognition of conserved motifs expressed by invading bacteria. TLR4 is the signaling receptor for LPS, the major proinflammatory component of the Gram-negative cell wall, whereas CD14 serves as the ligand-binding part of the LPS receptor complex. Triggering of TLR4 results in the activation of two distinct intracellular pathways, one that relies on the common TLR adaptor MyD88 and one that is mediated by Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF). Nontypeable Haemophilus influenzae (NTHi) is a common Gram-negative respiratory pathogen that expresses both TLR4 (LPS and lipooligosaccharide) and TLR2 (lipoproteins) ligands. To determine the roles of CD14, TLR4, and TLR2 during NTHi pneumonia, the following studies were performed: 1) Alveolar macrophages from CD14 and TLR4 knockout (KO) mice were virtually unresponsive to NTHi in vitro, whereas TLR2 KO macrophages displayed a reduced NTHi responsiveness. 2) After intranasal infection with NTHi, CD14 and TLR4 KO mice showed an attenuated early inflammatory response in their lungs, which was associated with a strongly reduced clearance of NTHi from the respiratory tract; in contrast, in TLR2 KO mice, lung inflammation was unchanged, and the number of NTHi CFU was only modestly increased at the end of the 10-day observation period. 3) MyD88 KO, but not TRIF mutant mice showed an increased bacterial load in their lungs upon infection with NTHi. These data suggest that the MyD88-dependent pathway of TLR4 is important for an effective innate immune response to respiratory tract infection caused by NTHi.
Arginine-Specific Gingipains from Porphyromonas gingivalis Stimulate Production of Hepatocyte Growth Factor (Scatter Factor) through Protease-Activated Receptors in Human Gingival Fibroblasts in Culture
Authors: Uehara Akiko , Muramoto Koji , Imamura Takahisa , Nakayama Koji , Potempa Jan , Travis James , Sugawara Shunji , Takada Haruhiko 
Published: April 2014

Abstract
Cystein proteinases (gingipains) from Porphyromonas gingivalis cleave a broad range of in-host proteins and are considered to be key virulence factors in the onset and development of adult periodontitis and host defense evasion. In periodontitis, an inflammatory disease triggered by bacterial infection, the production of hepatocyte growth factor (HGF) is induced not only by various factors derived from the host, such as inflammatory cytokines, but also by bacterial components. In this study we examined the possible enhanced production of HGF produced by human gingival fibroblasts upon stimulation with gingipains. Arginine-specific gingipain (Rgp) caused a marked production of HGF into the supernatant, the induction of HGF expression on the cell surface, and the up-regulation of HGF mRNA expression in a dose-dependent and an enzymatic activity-dependent manner. Because it has been reported that Rgp activated protease-activated receptors (PARs), we examined whether the induction of HGF triggered by Rgps on human gingival fibroblasts occurred through PARs. An RNA interference assay targeted to PAR-1 and PAR-2 mRNA revealed that gingipains-induced secretion of HGF was significantly inhibited by RNA interference targeted to PAR-1 and PAR-2. In addition, the Rgps-mediated HGF induction was completely inhibited by the inhibition of phospholipase C and was clearly inhibited by RNA interference targeted to p65, which is an NF-κB component. These results suggest that Rgps activated human gingival fibroblasts to secrete HGF in the inflamed sites and the mechanism(s) involved may actively participate in both inflammatory and reparative processes in periodontal diseases.
Lipopolysaccharide Induces Formyl Peptide Receptor 1 Gene Expression in Macrophages and Neutrophils via Transcriptional and Posttranscriptional Mechanisms
Authors: Mandal Palash , Novotny Michael , Hamilton Thomas A. 
Published: April 2014

AbstractBacterial infection promotes the infiltration of inflammatory leukocytes mediated in part by receptors for formyl-methionine-terminated peptides. In this study, we show that LPS can markedly enhance the expression of the formyl peptide receptor gene (FPR1) in mouse macrophages and neutrophils by enhancing transcription and by stabilization of the mRNA. In untreated cells, FPR1 mRNA exhibits a half-life of ∼90 min and this is markedly increased (to &gt;6 h) following stimulation with LPS. Although FPR1 mRNA levels remained elevated over baseline for &gt;20 h after stimulation, the half-life of the message is prolonged only transiently. LPS-induced FPR1 mRNA expression is mediated in part by the intermediate production of secreted factors. First, the response to LPS is partially blocked by the translational inhibitor cycloheximide. Second, a heat-labile but polymyxin B-insensitive factor present in supernatants from LPS-treated cells stimulates enhanced expression of FPR1 mRNA and, like LPS, promotes stabilization of FPR1 mRNA. Furthermore, supernatants from LPS-treated wild-type macrophages can stimulate FPR1 mRNA expression in LPS-insensitive macrophages from TLR4-mutant mice. Elevated FPR1 mRNA expression is also induced in response to ligands for TLR2 and TLR3. TNF-α but not IL-1, IL-6, IFN-β, and IFN-γ can mimic the effects of LPS although other factors apparently also contribute. Collectively, these findings define a distinct molecular pattern of response to TLR stimulation in inflammatory phagocytes and demonstrate that regulation of FPR1 expression is achieved through both transcriptional and posttranscriptional mechanisms.
Differences in Potency of CXC Chemokine Ligand 8-, CC Chemokine Ligand 11-, and C5a-Induced Modulation of Integrin Function on Human Eosinophils
Authors: Ulfman Laurien H. , Alblas Jacqueline , van Aalst Corneli W. , Zwaginga Jaap Jan , Koenderman Leo 
Published: April 2014

Abstract
The hypothesis was tested that different chemoattractants have different effects on the activity of integrins expressed by the human eosinophil. Three chemoattractants, CXCL8 (IL-8), CCL11 (eotaxin-1), and C5a were tested with respect to their ability to induce migration and the transition of eosinophils from a rolling interaction to a firm arrest on activated endothelial cells under flow conditions. CCL11 and C5a induced a firm arrest of eosinophils rolling on an endothelial surface, whereas CXCL8 induced only a transient arrest of the cells. The CXCL8- and CCL11-induced arrest was inhibited by simultaneously blocking α4 integrins (HP2/1) and β2 integrins (IB4). In contrast, the C5a-induced arrest was only inhibited by 30% under these conditions. The potency differences of C5a&gt;CCL11&gt;CXCL8 to induce firm adhesion under flow condition was also observed in migration assays and for the activation of the small GTPase Rap-1, which is an important signaling molecule in the inside-out regulation of integrins. Interestingly, only C5a was able to induce the high activation epitope of αMβ2 integrin recognized by MoAb CBRM1/5. The C5a-induced appearance of this epitope and Rap activation was controlled by phospholipase C (PLC), as was shown with the PLC inhibitor U73122. These data show that different chemoattractants are able to induce distinct activation states of integrins on eosinophils and that optimal chemotaxis is associated with the high activation epitope of the αMβ2 integrin. Furthermore, PLC plays an important role in the inside-out signaling and, thus, the activation status of integrins on eosinophils.