bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for Evolving Toll-IL-1 Receptor-Containing Adaptor Molecule Function in Vertebrates
Authors: Sullivan Con , Postlethwait John H. , Lage Christopher R. , Millard Paul J. , Kim Carol H. 
Published: April 2014

Abstract
In mammals, Toll-IL-1R-containing adaptor molecule 1 (TICAM1)-dependent TLR pathways induce NF-κB and IFN-β responses. TICAM1 activates NF-κB through two different pathways involving its interactions with TNFR-associated factor 6 and receptor-interacting protein 1. It also activates IFN regulatory factor 3/7 through its interaction with TANK-binding kinase-1, leading to the robust up-regulation of IFN-β. In this study, we describe the role of zebrafish (Danio rerio) TICAM1 in activating NF-κB and zebrafish type I IFN. Zebrafish IFN is unique in that it cannot be categorized as being α- or β-like. Through comprehensive sequence, phylogenetic, and syntenic analyses, we fully describe the identification of a zebrafish TICAM1 ortholog. Zebrafish TICAM1 exhibits sequence divergence from its mammalian orthologs and our data demonstrate that these sequence differences have functional consequences. Zebrafish TICAM1 activates zebrafish IFN; however, it does so in an apparently IFN regulatory factor 3/7-independent manner. Furthermore, zebrafish TICAM1 does not interact with zebrafish TNFR-associated factor 6, thus NF-κB activation is dependent upon its interaction with receptor-interacting protein 1. Comparative genome analysis suggests that TICAM1 and TICAM2 evolved from a common vertebrate TICAM ancestor following a gene duplication event and that TICAM2 was lost in teleosts following the divergence of the rayfin and lobefin fishes 450 million years ago. These studies provide evidence, for the first time, of the evolving function of a vertebrate TLR pathway.
MyD88-Dependent Signals Are Essential for the Host Immune Response in Experimental Brain Abscess
Authors: Kielian Tammy , Phulwani Nirmal K. , Esen Nilufer , Syed Mohsin Md. , Haney Anessa C. , McCastlain Kelly , Johnson Jennifer 
Published: April 2014

Abstract
Brain abscesses form in response to a parenchymal infection by pyogenic bacteria, with Staphylococcus aureus representing a common etiologic agent of human disease. Numerous receptors that participate in immune responses to bacteria, including the majority of TLRs, the IL-1R, and the IL-18R, use a common adaptor molecule, MyD88, for transducing activation signals leading to proinflammatory mediator expression and immune effector functions. To delineate the importance of MyD88-dependent signals in brain abscesses, we compared disease pathogenesis using MyD88 knockout (KO) and wild-type (WT) mice. Mortality rates were significantly higher in MyD88 KO mice, which correlated with a significant reduction in the expression of several proinflammatory mediators, including but not limited to IL-1β, TNF-α, and MIP-2/CXCL2. These changes were associated with a significant reduction in neutrophil and macrophage recruitment into brain abscesses of MyD88 KO animals. In addition, microglia, macrophages, and neutrophils isolated from the brain abscesses of MyD88 KO mice produced significantly less TNF-α, IL-6, MIP-1α/CCL3, and IFN-γ-induced protein 10/CXCL10 compared with WT cells. The lack of MyD88-dependent signals had a dramatic effect on the extent of tissue injury, with significantly larger brain abscesses typified by exaggerated edema and necrosis in MyD88 KO animals. Interestingly, despite these striking changes in MyD88 KO mice, bacterial burdens did not significantly differ between the two strains at the early time points examined. Collectively, these findings indicate that MyD88 plays an essential role in establishing a protective CNS host response during the early stages of brain abscess development, whereas MyD88-independent pathway(s) are responsible for pathogen containment.
Active Suppression of the Pulmonary Immune Response by Francisella tularensis Schu4
Authors: Bosio Catharine M. , Bielefeldt-Ohmann Helle , Belisle John T. 
Published: April 2014

Abstract
Francisella tularensis is an obligate, intracellular bacterium that causes acute, lethal disease following inhalation. As an intracellular pathogen F. tularensis must invade cells, replicate, and disseminate while evading host immune responses. The mechanisms by which virulent type A strains of Francisella tularensis accomplish this evasion are not understood. Francisella tularensis has been shown to target multiple cell types in the lung following aerosol infection, including dendritic cells (DC) and macrophages. We demonstrate here that one mechanism used by a virulent type A strain of F. tularensis (Schu4) to evade early detection is by the induction of overwhelming immunosuppression at the site of infection, the lung. Following infection and replication in multiple pulmonary cell types, Schu4 failed to induce the production of proinflammatory cytokines or increase the expression of MHCII or CD86 on the surface of resident DC within the first few days of disease. However, Schu4 did induce early and transient production of TGF-β, a potent immunosuppressive cytokine. The absence of DC activation following infection could not be attributed to the apoptosis of pulmonary cells, because there were minimal differences in either annexin or cleaved caspase-3 staining in infected mice compared with that in uninfected controls. Rather, we demonstrate that Schu4 actively suppressed in vivo responses to secondary stimuli (LPS), e.g., failure to recruit granulocytes/monocytes and stimulate resident DC. Thus, unlike attenuated strains of F. tularensis, Schu4 induced broad immunosuppression within the first few days after aerosol infection. This difference may explain the increased virulence of type A strains compared with their more attenuated counterparts.
Recognition of Double-Stranded RNA by TLR3 Induces Severe Small Intestinal Injury in Mice
Authors: Zhou Rongbin , Wei Haiming , Sun Rui , Tian Zhigang 
Published: April 2014

Abstract
The role of TLRs on intestinal epithelial cells (IECs) is controversial, and the mechanisms by which TLRs influence mucosal homeostasis are obscure. In this study, we report that genomic dsRNA from rotavirus, and its synthetic analog polyinosinic-polycytidylic acid (poly(I:C)), induce severe mucosal injury in the small intestine. Upon engaging TLR3 on IECs, dsRNA triggers IECs to secrete IL-15, which functions to increase the percentage of CD3+NK1.1+ intestinal intraepithelial lymphocytes (IELs) and enhances the cytotoxicity of IELs. Moreover, The CD3+NK1.1+ IELs are proved as CD8αα+ IELs. These results provide direct evidence that abnormal TLR3 signaling contributes to breaking down mucosal homeostasis and the first evidence of pathogenic effects mediated by CD8αα+ IELs. The data also suggest that genomic dsRNA may be involved in the pathogenesis of acute rotavirus gastroenteritis.
Infection with a Helminth Parasite Prevents Experimental Colitis via a Macrophage-Mediated Mechanism
Authors: Smith Philip , Mangan Niamh E. , Walsh Caitriona M. , Fallon Rosie E. , McKenzie Andrew N. J. , van Rooijen Nico , Fallon Padraic G. 
Published: April 2014

Abstract
The propensity of a range of parasitic helminths to stimulate a Th2 or regulatory cell-biased response has been proposed to reduce the severity of experimental inflammatory bowel disease. We examined whether infection with Schistosoma mansoni, a trematode parasite, altered the susceptibility of mice to colitis induced by dextran sodium sulfate (DSS). Mice infected with schistosome worms were refractory to DSS-induced colitis. Egg-laying schistosome infections or injection of eggs did not render mice resistant to colitis induced by DSS. Schistosome worm infections prevent colitis by a novel mechanism dependent on macrophages, and not by simple modulation of Th2 responses, or via induction of regulatory CD4+ or CD25+ cells, IL-10, or TGF-β. Infected mice had marked infiltration of macrophages (F4/80+CD11b+CD11c−) into the colon lamina propria and protection from DSS-induced colitis was shown to be macrophage dependent. Resistance from colitis was not due to alternatively activated macrophages. Transfer of colon lamina propria F4/80+ macrophages isolated from worm-infected mice induced significant protection from colitis in recipient mice treated with DSS. Therefore, we propose a new mechanism whereby a parasitic worm suppresses DSS-induced colitis via a novel colon-infiltrating macrophage population.
Histamine Release from the Basophils of Control and Asthmatic Subjects and a Comparison of Gene Expression between “Releaser” and “Nonreleaser” Basophils
Authors: Youssef Lama A. , Schuyler Mark , Gilmartin Laura , Pickett Gavin , Bard Julie D. J. , Tarleton Christy A. , Archibeque Tereassa , Qualls Clifford , Wilson Bridget S. , Oliver Janet M. 
Published: April 2014

AbstractMost human blood basophils respond to FcεRI cross-linking by releasing histamine and other inflammatory mediators. Basophils that do not degranulate after anti-IgE challenge, known as “nonreleaser” basophils, characteristically have no or barely detectable levels of the Syk tyrosine kinase. The true incidence of the nonreleaser phenotype, its relationship (if any) to allergic asthma, and its molecular mechanism are not well understood. In this study, we report statistical analyses of degranulation assays performed in 68 control and 61 asthmatic subjects that establish higher basal and anti-IgE-stimulated basophil degranulation among the asthmatics. Remarkably, 28% of the control group and 13% of the asthmatic group were nonreleasers for all or part of our 4-year long study and cycling between the releaser and nonreleaser phenotypes occurred at least once in blood basophils from 8 (of 8) asthmatic and 16 (of 23) control donors. Microarray analysis showed that basal gene expression was generally lower in nonreleaser than releaser basophils. In releaser cells, FcεRI cross-linking up-regulated &gt;200 genes, including genes encoding receptors (the FcεRI α and β subunits, the histamine 4 receptor, the chemokine (C-C motif) receptor 1), signaling proteins (Lyn), chemokines (IL-8, RANTES, MIP-1α, and MIP-1β) and transcription factors (early growth response-1, early growth response-3, and AP-1). FcεRI cross-linking induced fewer, and quite distinct, transcriptional responses in nonreleaser cells. We conclude that “nonreleaser” and “cycler” basophils represent a distinct and reversible natural phenotype. Although histamine is more readily released from basophils isolated from asthmatics than controls, the presence of nonreleaser basophils does not rule out the diagnosis of asthma.
Loss of SLP-76 Expression within Myeloid Cells Confers Resistance to Neutrophil-Mediated Tissue Damage while Maintaining Effective Bacterial Killing
Authors: Clemens Regina A. , Lenox Laurie E. , Kambayashi Taku , Bezman Natalie , Maltzman Jonathan S. , Nichols Kim E. , Koretzky Gary A. 
Published: April 2014

Abstract
The Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) is an adaptor molecule critical for immunoreceptor and integrin signaling in multiple hemopoietic lineages. We showed previously that SLP-76 is required for neutrophil function in vitro, including integrin-induced adhesion and production of reactive oxygen intermediates, and to a lesser extent, FcγR-induced calcium flux and reactive oxygen intermediate production. It has been difficult to determine whether SLP-76 regulates neutrophil responses in vivo, because Slp-76−/− mice exhibit marked defects in thymocyte and vascular development, as well as platelet and mast cell function. To circumvent these issues, we generated mice with targeted loss of SLP-76 expression within myeloid cells. Neutrophils obtained from these animals failed to respond to integrin activation in vitro, similar to Slp-76−/− cells. Despite these abnormalities, SLP-76-deficient neutrophils migrated normally in vivo in response to Staphylococcus aureus infection and efficiently cleared micro-organisms. Interestingly, SLP-76-deficient neutrophils did not induce a robust inflammatory response in the localized Shwartzman reaction. Collectively, these data suggest that disruption of integrin signaling via loss of SLP-76 expression differentially impairs neutrophil functions in vivo, with preservation of migration and killing of S. aureus but reduction in LPS-induced tissue damage and vascular injury.
TGF-β1-Mediated Control of Central Nervous System Inflammation and Autoimmunity through the Inhibitory Receptor CD26
Authors: Preller Vera , Gerber Annegret , Wrenger Sabine , Togni Mauro , Marguet Didier , Tadje Janine , Lendeckel Uwe , Röcken Christoph , Faust Jürgen , Neubert Klaus , Schraven Burkhart , Martin Roland , Ansorge Siegfried , Brocke Stefan , Reinhold Dirk 
Published: April 2014

Abstract
The T cell marker CD26/dipeptidyl peptidase (DP) IV is associated with an effector phenotype and markedly elevated in the human CNS disorder multiple sclerosis. However, little is known about the in vivo role of CD26/DP IV in health and disease, and the underlying mechanism of its function in CNS inflammation. To directly address the role of CD26/DP IV in vivo, we examined Th1 immune responses and susceptibility to experimental autoimmune encephalomyelitis in CD26−/− mice. We show that gene deletion of CD26 in mice leads to deregulation of Th1 immune responses. Although production of IFN-γ and TNF-α by pathogenic T cells in response to myelin Ag was enhanced in CD26−/− mice, production of the immunosuppressive cytokine TGF-β1 was diminished in vivo and in vitro. In contrast to the reduction in TGF-β1 production, responsiveness to external TGF-β1 was normal in T cells from CD26−/− mice, excluding alterations in TGF-β1 sensitivity as a mechanism causing the loss of immune regulation. Natural ligands of CD26/DP IV induced TGF-β1 production in T cells from wild-type mice. However, natural ligands of CD26/DP IV failed to elicit TGF-β1 production in T cells from CD26−/− mice. The striking functional deregulation of Th1 immunity was also seen in vivo. Thus, clinical experimental autoimmune encephalomyelitis scores were significantly increased in CD26−/− mice immunized with peptide from myelin oligodendrocyte glycoprotein. These results identify CD26/DP IV as a nonredundant inhibitory receptor controlling T cell activation and Th1-mediated autoimmunity, and may have important therapeutic implications for the treatment of autoimmune CNS disease.
T Cell Activation by Antibody-Like Immunoreceptors: The Position of the Binding Epitope within the Target Molecule Determines the Efficiency of Activation of Redirected T Cells
Authors: Hombach Andreas A. , Schildgen Verena , Heuser Claudia , Finnern Ricarda , Gilham David E. , Abken Hinrich 
Published: April 2014

Abstract
Recombinant TCRs confer specificity to T cells and trigger their activation. Receptors with Ab-derived binding domains have the advantages of MHC-independent Ag recognition and of targeting a variety of chemically different molecules. We explored the impact of the position of a defined epitope within the target molecule on the efficacy of receptor-mediated T cell activation. T cells were grafted with recombinant immunoreceptors that recognize either the membrane distal N or the proximal A3 domain of carcinoembryonic Ag (CEA). Upon binding to isolated, solid-phase immobilized CEA, receptor-mediated T cell activation correlates with the binding efficiency, irrespectively, of the epitope position. Upon binding to CEA expressed on the cell membrane, in contrast, the A3 epitope mediates more efficiently T cell activation than the N epitope, although the N epitope is bound with higher affinity. The CEA N epitope when expressed in a more membrane proximal position, however, activated receptor grafted T cells with higher efficiency than in the distal position. The position of the targeted epitope within the molecule obviously has major impact on the efficacy of T cell activation independently of the binding efficiency of the immunoreceptor.
Augmentation of NZB Autoimmune Phenotypes by the Sle1c Murine Lupus Susceptibility Interval
Authors: Giles Brendan M. , Tchepeleva Svetlana N. , Kachinski Julie J. , Ruff Katherine , Croker Byron P. , Morel Laurence , Boackle Susan A. 
Published: April 2014

Abstract
The Sle1c lupus susceptibility interval spans a 7-Mb region on distal murine chromosome 1. Cr2 is the strongest candidate gene for lupus susceptibility in this interval, as its protein products are structurally and functionally altered. B6.Sle1c congenic mice develop Abs to chromatin by 9 mo of age with a 30% penetrance and do not develop GN. To determine whether the New Zealand White (NZW)-derived Sle1c interval would interact with New Zealand Black (NZB) genes to result in enhanced autoimmune phenotypes, NZB mice were bred with B6 or B6.Sle1c congenic mice and ∼20 female offspring were selected from each breeding for longitudinal study. These mice differ only at the Sle1c locus at which they have either a NZB/B6 or NZB/NZW genotype. NZB × B6.Sle1c mice had an accelerated onset of anti-chromatin Abs (100 vs 68% at 6 mo, p = 0.006) and anti-dsDNA Abs (45 vs 5% at 9 mo, p = 0.0048). Furthermore, median titers of anti-chromatin and anti-dsDNA Abs were significantly higher in the NZB × B6.Sle1c group compared with the NZB × B6 group. This corresponded with a higher prevalence of proliferative GN at 12 mo (55 vs 16%, p = 0.0214) as well as increased glomerular deposition of C3 (p = 0.0272) and IgG (p = 0.032), although blood urea nitrogen remained normal and significant proteinuria was not identified in either group. These data show that the Sle1c interval accelerates and augments the loss of tolerance to chromatin and dsDNA induced by NZB genes and induces significantly greater end-organ damage.
Intratumoral Injection of α-gal Glycolipids Induces Xenograft-Like Destruction and Conversion of Lesions into Endogenous Vaccines
Authors: Galili Uri , Wigglesworth Kim , Abdel-Motal Ussama M. 
Published: April 2014

Abstract
This study describes a novel cancer immunotherapy treatment that exploits the natural anti-Gal Ab to destroy tumor lesions and convert them into an endogenous vaccine targeted to APC via FcγR. Anti-Gal constitutes 1% of immunoglobulins in humans and interacts specifically with α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R). The binding of anti-Gal to α-gal epitopes on pig cells mediates xenograft rejection. The proposed method uses glycolipid micelles with multiple α-gal epitopes (α-gal glycolipids). These glycolipids are extracted from rabbit red cell membranes and are comprised of ceramides with carbohydrate chains containing 5–25 carbohydrates, all capped with α-gal epitopes. Efficacy of this treatment was demonstrated in α1,3-galactosyltransferase knockout mice producing anti-Gal and bearing B16 melanoma or B16/OVA producing OVA as a surrogate tumor Ag. These mice are unique among nonprimate mammals in that, similar to humans, they lack α-gal epitopes and can produce the anti-Gal Ab. Intratumoral injection of α-gal glycolipids results in local inflammation mediated by anti-Gal binding to the multiple α-gal epitopes and activation of complement. These glycolipids spontaneously insert into tumor cell membranes. The binding of anti-Gal to α-gal expressing tumor cells induces the destruction of treated lesions as in anti-Gal-mediated xenograft rejection. Anti-Gal further opsonizes tumor cells within the lesion and, thus, targets them for effective uptake by APC that transport the tumor Ags to draining lymph nodes. APC further cross-present immunogenic tumor Ag peptides and elicit a systemic anti-tumor immune response. Similar intratumoral injection of α-gal glycolipids in humans is likely to induce the destruction of treated lesions and elicit a protective immune response against micrometastases.
Drosophila Hemopoiesis and Cellular Immunity
Authors: Williams Michael J. 
Published: April 2014

Abstract
In Drosophila melanogaster larvae, three classes of circulating cellular immune surveillance cells (hemocytes) can be identified: plasmatocytes, crystal cells, and lamellocytes. Plasmatocytes are professional phagocytes most similar to the mammalian monocyte/macrophage lineage and make up ∼95% of circulating hemocytes. The other ∼5% of circulating hemocytes consists of crystal cells, which secrete components necessary for the melanization of invading organisms, as well as for wound repair. A third cell type known as lamellocytes are rarely seen in healthy larvae and are involved in the encapsulation of invading pathogens. There are no obvious mammalian counterparts for crystal cells or lamellocytes, and there is no equivalent to the lymphoid lineage in insects. In this review, I will discuss what is currently known about Drosophila hemopoiesis and the cellular immune response and where possible compare it to vertebrate mechanisms.
Cutting Edge: Tlr5−/− Mice Are More Susceptible to Escherichia coli Urinary Tract Infection
Authors: Andersen-Nissen Erica , Hawn Thomas R. , Smith Kelly D. , Nachman Alex , Lampano Aaron E. , Uematsu Satoshi , Akira Shizuo , Aderem Alan 
Published: April 2014

Abstract
Although TLR5 regulates the innate immune response to bacterial flagellin, it is unclear whether its function is essential during in vivo murine infections. To examine this question, we challenged Tlr5−/− mice transurethrally with Escherichia coli. At 2 days postinfection, wild-type mice exhibited increased inflammation of the bladder in comparison to Tlr5−/− mice. By day 5 postinfection, Tlr5−/− mice had significantly more bacteria in the bladders and kidneys in comparison to wild-type mice and showed increased inflammation in both organs. In addition, flagellin induced high levels of cytokine and chemokine expression in the bladder that was dependent on TLR5. Together, these data represent the first evidence that TLR5 regulates the innate immune response in the urinary tract and is essential for an effective murine in vivo immune response to an extracellular pathogen.
Cutting Edge: Antigen Is Not Required for the Activation and Maintenance of Virus-Specific Memory CD8+ T Cells in the Lung Airways
Authors: Kohlmeier Jacob E. , Miller Shannon C. , Woodland David L. 
Published: April 2014

Abstract
Respiratory virus infections establish a population of memory CD8+ T cells in the lung airways that persist for months after infection. However, the relationship between Ag-specific memory T cells in the lung airways and the systemic memory T cell pool is not well understood. The majority of lung airway memory T cells express a highly activated phenotype (CD69+/CD127−), suggesting that recent Ag stimulation is required to drive T cell activation and recruitment to the lung airways. In this study, we demonstrate that the lung airway environment itself in the absence of cognate Ag alters the expression of acute activation markers such as CD69 and CD127 on memory CD8+ T cells. Furthermore, the steady-state recruitment of virus-specific memory CD8+ T cells to the lung airways from the circulation can occur without recent Ag stimulation. These findings alter the current perceptions concerning the contribution of Ag to the maintenance of peripheral T cell memory.