bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epitope Spreading Is Not Required for Relapses in Experimental Autoimmune Encephalomyelitis
Authors: Jones Richard E. , Bourdette Dennis , Moes Nicole , Vandenbark Arthur , Zamora Alex , Offner Halina 
Published: April 2014

AbstractThe sequential emergence of specific T lymphocyte-mediated immune reactivity directed against multiple distinct myelin epitopes (epitope spreading) has been associated with clinical relapses in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Based on this association, an appealing and plausible model for immune-mediated progression of the advancing clinical course in MS and EAE has been proposed in which epitope spreading is the cause of clinical relapses in T cell-mediated CNS inflammatory diseases. However, the observed association between epitope spreading and disease progression is not universal, and absolute requirements for epitope spreading in progressive EAE have not been tested in the absence of multiple T cell specificities, because most prior studies have been conducted in immunocompetent mouse strains that possessed broad TCR repertoires. Consequently, the precise nature of a causal relationship between epitope spreading and disease progression remains uncertain. To determine whether relapsing or progressive EAE can occur in the absence of epitope spreading, we evaluated the course of disease in mice which possessed only a single myelin-specific TCR. These mice (transgenic/SCID +/+) exhibited a progressive and sometimes remitting/relapsing disease course in the absence of immune reactivity to multiple, spreading myelin epitopes. The results provide direct experimental evidence relevant to discussions on the mechanisms of disease progression in MS and EAE.
HIV-1 Nef Induces the Release of Inflammatory Factors from Human Monocyte/Macrophages: Involvement of Nef Endocytotic Signals and NF-κB Activation
Authors: Olivetta Eleonora , Percario Zulema , Fiorucci Gianna , Mattia Gianfranco , Schiavoni Ilaria , Dennis Caitriona , Jäger Joachim , Harris Mark , Romeo Gianna , Affabris Elisabetta , Federico Maurizio 
Published: April 2014

Abstract
It has been recently reported that the endogenous expression of HIV-1 Nef in human monocyte/macrophages induces the release of chemokines and other as yet unidentified soluble factors leading to multiple effects of pathogenic significance, such as the recruitment and activation of quiescent lymphocytes. However, the description of underlying molecular mechanisms remained elusive. We recently demonstrated that human monocyte-derived macrophages (MDM) efficiently internalize soluble rNef, thereby inducing effects largely resembling those observed in cells endogenously expressing Nef. By exploiting the rNef/MDM model, we sought to gain more insights on the molecular mechanisms underlying the response of MDM to Nef. Array analysis for the detection of transcripts from a large number of monokines, chemokines, cytokines, and receptors thereof showed that MDM promptly responded to rNef treatment by increasing the transcription of genes for several inflammatory factors. Analysis of supernatants revealed that rNef treatment induced the release of macrophage inflammatory proteins 1α and 1β, IL-1β, IL-6, and TNF-α. Conversely, rNefs mutated in domains critical for the interaction with the endocytotic machinery (i.e., EE155-156QQ, and DD174-175AA) were ineffective. Interestingly, we found that the Nef-dependent release of inflammatory factors correlated with the activation of the NF-κB transcription factor, mainly in its p50/p50 homodimeric form, and in a de novo protein synthesis-independent manner. Our data add new hints supporting the idea that the presence of Nef is per se heavily detrimental for monocyte/macrophages and relative cross-talking cell types.
The Leishmania mexicana Cysteine Protease, CPB2.8, Induces Potent Th2 Responses
Authors: Pollock Kevin G. J. , McNeil Katherine S. , Mottram Jeremy C. , Lyons Russell E. , Brewer James M. , Scott Phillip , Coombs Graham H. , Alexander James 
Published: April 2014

Abstract
We have previously identified that Leishmania mexicana cysteine proteases (CPs) are virulence factors. We have now produced a recombinant L. mexicana CP, CPB2.8, which has similar enzymatic activity to native enzyme. Inoculation of CPB2.8 (≤5 μg) into the footpads of BALB/c mice not only up-regulated mRNA transcripts for IL-4 and IL-4 production in the draining popliteal lymph nodes, but also polarized splenocyte anti-CD3 stimulated responses toward a Th2 bias as measured by increased IL-5 production compared with controls. In agreement with promoting a Th2 response, CPB2.8 also induced strong specific IgE responses in treated mice as well as increasing whole IgE levels. Inhibition of the enzyme activity of CPB2.8 by treatment with E-64 ablated the enzyme’s ability to induce IgE. Significantly, infection of mice with CPB-deficient parasites failed to stimulate production of IgE, unlike infection with wild-type parasites. Furthermore, enzymatically active (&lt;0.1 U/ml) but not E-64-inactivated CPB2.8 was able to proteolytically cleave CD23 and CD25, although not B220 or CD4 from murine lymphocytes. These properties are similar to those demonstrated by the house dust mite allergen Der p I and provide an explanation for the immunomodulatory activity of the CPB2.8 virulence factor. Vaccination with CPB2.8 enhanced L. mexicana lesion growth compared with control animals. Nevertheless, vaccination with IL-12 and CPB2.8 resulted in a degree of protection associated with inhibition of lesion growth and a Th1 response. Thus, CPB2.8 is a potent Th2-inducing molecule capable of significant vaccine potential if administered with a suitable adjuvant.
NF-κB Hyperactivation Has Differential Effects on the APC Function of Nonobese Diabetic Mouse Macrophages
Authors: Sen Pradip , Bhattacharyya Sandip , Wallet Mark , Wong Carmen P. , Poligone Brian , Sen Maitreyee , Baldwin Albert S. , Tisch Roland 
Published: April 2014

Abstract
Type 1 diabetes is characterized by a chronic inflammatory response resulting in the selective destruction of the insulin-producing β cells. We have previously demonstrated that dendritic cells (DCs) prepared from nonobese diabetic (NOD) mice, a model for spontaneous type 1 diabetes, exhibit hyperactivation of NF-κB resulting in an increased capacity to secrete proinflammatory cytokines and stimulate T cells compared with DCs of nondiabetic strains of mice. In the current study, the activational status of NF-κB and its role in regulating the APC function of macrophages (Mφ) prepared from NOD, nonobese resistant (NOR), and BALB/c mice was investigated. Independent of the stimulus, splenic and bone marrow-derived Mφ prepared from NOD mice exhibited increased NF-κB activation relative to NOR and BALB/c Mφ. This hyperactivation was detected for different NF-κB complexes and correlated with increased IκBα degradation. Furthermore, increased NF-κB activation resulted in an enhanced capacity of NOD vs NOR or BALB/c Mφ to secrete IL-12(p70), TNF-α, and IL-1α, which was inhibited upon infection with an adenoviral recombinant encoding a modified form of IκBα. In contrast, elevated NF-κB activation had no significant effect on the capacity of NOD Mφ to stimulate CD4+ or CD8+ T cells in an Ag-specific manner. These results demonstrate that in addition to NOD DCs, NOD Mφ exhibit hyperactivation of NF-κB, which correlates with an increased ability to mediate a proinflammatory response. Furthermore, NF-κB influences Mφ APC function by regulating cytokine secretion but not T cell stimulation.
Antibody Repertoire Development in Fetal and Neonatal Piglets. VI. B Cell Lymphogenesis Occurs at Multiple Sites with Differences in the Frequency of In-frame Rearrangements
Authors: Šinkora Marek , Sun Jishan , Šinkorová Jana , Christenson Ronald K. , Ford Steven P. , Butler John E. 
Published: April 2014

Abstract
B cell lymphogenesis in mammals occurs in various tissues during development but it is generally accepted that it operates by the same mechanism in all tissues. We show that in swine, the frequency of in-frame (IF) VDJ rearrangements differs among yolk sac, fetal liver, spleen, early thymus, bone marrow, and late thymus. All VDJ rearrangements recovered and analyzed on the 20th day of gestation (DG20) from the yolk sac were 100% IF. Those recovered at DG30 in the fetal liver were &gt;90% IF, and this predominance of cells with apparently a single IF rearrangement continued in all organs until approximately DG45, which corresponds to the time when lymphopoiesis begins in the bone marrow. Thereafter, the proportion of IF rearrangements drops to ∼71%, i.e., the value predicted whether VDJ rearrangement is random and both chromosomes were involved. Unlike other tissues, VDJs recovered from thymus after DG50 display a pattern suggesting no selection for IF rearrangements. Regardless of differences in the proportion of IF rearrangements, we observed no significant age- or tissue-dependent changes in CDR3 diversity, N region additions, or other characteristics of fetal VDJs during ontogeny. These findings indicate there are multiple sites of B cell lymphogenesis in fetal piglets and differences in the frequency of productive VDJ rearrangements at various sites. We propose the latter to result from differential selection or a developmentally dependent change in the intrinsic mechanism of VDJ rearrangement.
The Th2 Cell Cytokines IL-4 and IL-13 Regulate Found in Inflammatory Zone 1/Resistin-Like Molecule α Gene Expression by a STAT6 and CCAAT/Enhancer-Binding Protein-Dependent Mechanism
Authors: Stütz Adrian M. , Pickart Louise A. , Trifilieff Alexandre , Baumruker Thomas , Prieschl-Strassmayr Eva , Woisetschläger Maximilian 
Published: April 2014

AbstractThe onset of allergic inflammation in the lung is driven by a complex genetic program. This study shows that found in inflammatory zone (FIZZ)1 and FIZZ2, but not FIZZ3, gene expression was up-regulated 6 h after Ag challenge in a mouse model of acute pulmonary inflammation. Induction of both genes was abolished in allergen-challenged STAT6-deficient mice. FIZZ1, but not FIZZ2, mRNA was up-regulated upon incubation of the myeloid cell line BMnot with IL-4. The promoter region of FIZZ1 contains functional binding sites for STAT6 and C/EBP. FIZZ1 promoter reporter gene constructs responded to IL-4 and IL-13 stimulation in transiently transfected cells. Point mutations in the STAT6 or the C/EBP site led to loss of cytokine responsiveness indicating that IL-4-mediated induction of murine FIZZ1 is orchestrated by the coordinate action of STAT6 and C/EBP. It is concluded that the expression of the genes encoding FIZZ1 and FIZZ2, but not FIZZ3, is induced in allergen-challenged lungs in a STAT6-dependent fashion. STAT6 directly regulates IL-4- and IL-13-triggered induction of FIZZ1 expression at the transcriptional level by cooperation with C/EBP. Induction of FIZZ2 gene expression most likely occurs independent of a direct effect by these cytokines and may be due to indirect STAT6-driven mechanisms.
Cooperation of TNF Family Members CD40 Ligand, Receptor Activator of NF-κB Ligand, and TNF-α in the Activation of Dendritic Cells and the Expansion of Viral Specific CD8+ T Cell Memory Responses in HIV-1-Infected and HIV-1-Uninfected Individuals
Authors: Yu Qigui , Gu Jenny X. , Kovacs Colin , Freedman John , Thomas Elaine K. , Ostrowski Mario A. 
Published: April 2014

Abstract
Members of the TNF superfamily have been shown to be instrumental in enhancing cell-mediated immune responses, primarily through their interactions with dendritic cells (DCs). We systematically evaluated the ability of three TNF superfamily molecules, CD40 ligand (CD40L), receptor activator of NF-κB ligand (RANKL), and TNF-α, to expand ex vivo EBV-specific CTL responses in healthy human individuals and ex vivo HIV-1-specific CTL responses in HIV-1-infected individuals. In both groups of individuals, we found that all three TNF family molecules could expand CTL responses, albeit at differing degrees. CD40L treatment alone was better than RANKL or TNF-α alone to mature DCs and to expand CTL. In healthy volunteers, TNF-α or RANKL could cooperate with CD40L to maximize the ability of DCs to expand virus-specific CTL responses. In HIV-1 infection, cooperative effects between TNF-α or RANKL in combination with CD40L were variable. TNF-α and RANKL cooperated with CD40L via differing mechanisms, i.e., TNF-α enhanced IL-12 production, whereas RANKL enhanced survival of CD40L-stimulated DCs. These findings demonstrate that optimal maturation of DCs requires multiple signals by TNF superfamily members that include CD40L. In HIV-1 infection, DCs may only require CD40L to maximally expand CTL. Finally, CTL responses were higher in CD4+ T cell-containing conditions even in the presence of TNF family molecules, suggesting that CD4+ T cells can provide help to CD8+ T cells independently of CD40L, RANKL, or TNF-α.
Naturally Occurring Human IgM Antibody That Binds B7-DC and Potentiates T Cell Stimulation by Dendritic Cells
Authors: Radhakrishnan Suresh , Nguyen Loc T. , Ciric Bogoljub , Ure Daren R. , Zhou Bin , Tamada Koji , Dong Haidong , Tseng Su-Yi , Shin Tahiro , Pardoll Drew M. , Chen Lieping , Kyle Robert A. , Rodriguez Moses , Pease Larry R. 
Published: April 2014

Abstract
A human IgM Ab, serum-derived human IgM 12 (sHIgM12), is identified that binds mouse and human dendritic cells (DC), inducing dramatic immunopotentiation following treatment of the mouse DC in vitro. Competition, transfection, and knockout studies identified the ligand on mouse DC as the costimulatory molecule family member B7-DC. Potent T cell responses are stimulated by Ag-pulsed DC treated with the sHIgM12 Ab in vitro and upon adoptive transfer of Ab-treated Ag-pulsed DC into animals. The multivalent structure of pentameric IgM provides the potential for cross-linking cell surface targets, endowing the soluble Abs with biological potential not normally associated with immune function. The ability of the sHIgM12 Ab to potentiate the immune response is dependent on the multimeric structure of IgM, as bivalent monomers do not retain this property. Furthermore, pretreatment of DC with IgM monomers blocks subsequent potentiation by intact IgM pentamers, an indication that cross-linking of B7-DC on the cell surface is critical for potentiation of Ag presentation. These findings imply that, in addition to known costimulatory roles, B7-DC can function as a receptor for signals delivered by cells expressing B7-DC ligands.
Role of Double-Negative Regulatory T Cells in Long-Term Cardiac Xenograft Survival
Authors: Chen Wenhao , Ford Megan S. , Young Kevin J. , Cybulsky Myron I. , Zhang Li 
Published: April 2014

Abstract
A novel subset of CD3+CD4−CD8− (double negative; DN) regulatory T cells has recently been shown to induce donor-specific skin allograft acceptance following donor lymphocyte infusion (DLI). In this study, we investigated the effect of DLI on rat to mouse cardiac xenotransplant survival and the ability of DN T cells to regulate xenoreactive T cells. B6 mice were given either DLI from Lewis rats, a short course of depleting anti-CD4 mAb, both DLI and anti-CD4 treatment together, or left untreated. DLI alone did not prolong graft survival when compared with untreated controls. Although anti-CD4-depleting mAb alone significantly prolonged graft survival, grafts were eventually rejected by all recipients. However, the combination of DLI and anti-CD4 treatment induced permanent cardiac xenograft survival. We demonstrate that recipients given both DLI and anti-CD4 treatment had a significant increase in the total number of DN T cells in their spleens when compared with all other treatment groups. Furthermore, DN T cells harvested from the spleens of DLI plus anti-CD4-treated mice could dose-dependently inhibit the proliferation of syngeneic antidonor T cells. Suppression mediated by these DN T cells was specific for antidonor T cells as T cells stimulated by third-party Ags were not suppressed. These results demonstrate for the first time that a combination of pretransplant DLI and anti-CD4-depleting mAb can induce permanent survival of rat to mouse cardiac xenografts and that DN T regulatory cells play an important role in preventing long-term concordant xenograft rejection through the specific suppression of antidonor T cells.
Human Activation-Induced Cytidine Deaminase Is Induced by IL-4 and Negatively Regulated by CD45: Implication of CD45 as a Janus Kinase Phosphatase in Antibody Diversification
Authors: Zhou Cheng , Saxon Andrew , Zhang Ke 
Published: April 2014

Abstract
Activation-induced cytidine deaminase (AID) plays critical roles in Ig class switch recombination and VH gene somatic hypermutation. We investigated the role of IL-4 in AID mRNA induction, the signaling transduction involved in IL-4-mediated AID induction, and the effect of CD45 on IL-4-dependent AID expression in human B cells. IL-4 was able to induce AID expression in human primary B cells and B cell lines, and IL-4-induced AID expression was further enhanced by CD40 signaling. IL-4-dependent AID induction was inhibited by a dominant-negative STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6 signaling pathway. Moreover, triggering of CD45 with anti-CD45 Abs can inhibit IL-4-induced AID expression, and this CD45-mediated AID inhibition correlated with the ability of anti-CD45 to suppress IL-4-activated JAK1, JAK3, and STAT6 phosphorylations. Thus, in humans, IL-4 alone is sufficient to drive AID expression, and CD40 signaling is required for optimal AID production; IL-4-induced AID expression is mediated via the JAK/STAT signaling pathway, and can be negatively regulated by the JAK phosphatase activity of CD45. This study indicates that the JAK phosphatase activity of CD45 can be induced by anti-CD45 Ab treatment, and this principle may find clinical application in modulation of JAK activation in immune-mediated diseases.
Locus-Specific Constitutive and Cytokine-Induced HLA Class I Gene Expression
Authors: Johnson David R. 
Published: April 2014

AbstractCytokine induction of the MHC class I genes increases the nascent molecules available for binding potentially antigenic peptides. The human H chain loci, HLA-A, -B, and -C, encode highly homologous and polymorphic mRNAs. Here, these transcripts were resolved and measured by competitive PCR of cDNA using locus-specific primers. Endothelial cells expressed many HLA-A and -B, but fewer HLA-C, transcripts. In contrast, HeLa cells expressed many HLA-A and -C, but fewer HLA-B, transcripts. The inflammatory cytokines TNF-α, IFN-β, and IFN-γ induced HLA-B strongly, but HLA-A and -C weakly in both cell types. Combined treatment with IFNs and TNF further increased HLA-A and -B, but not HLA-C transcripts. The constitutive and inducible activities of transfected promoters correlated well with mRNA levels. The weak IFN response of the HLA-A2 promoter was not due to variations in the IFN consensus sequence, the site α, or a 3-bp insertion between them. The HLA-Cw6 promoter was less TNF responsive due to a variant κB enhancer, which also reduced the IFN responses. The NF-κB subunit RelA strongly activated the HLA-A2 and -B7 promoters but only weakly activated the HLA-Cw6 promoter due to the variant κB. Cotransfecting NF-κB1 with RelA further increased activity of the HLA-A2 and -B7, but not HLA-Cw6, promoters. All three promoters were activated by MHC class II trans-activator, but not CREB-binding protein, whereas IFN regulatory factor-1 and -2 weakly activated the HLA-B7 and -Cw6, but not HLA-A2, promoters. These studies illustrate common and locus-specific mechanisms that may be targeted to modulate immune reactions.
CTLA-4 in Filarial Infections: Implications for a Role in Diminished T Cell Reactivity
Authors: Steel Cathy , Nutman Thomas B. 
Published: April 2014

AbstractTo determine the role that CTLA-4 might play in mediating the diminished parasite Ag-specific T cell responsiveness that is characteristically seen in filaria-infected patients, several study populations and methods were used. First, quantitative assessment of mRNA expression determined that PBMC from uninfected adolescents exposed in utero to microfilarial (Mf) Ag demonstrated a strong up-regulation of CTLA-4 to the Mf stage of the parasite in contrast to that observed in cells from children born of uninfected mothers (p = 0.005). Next, the frequency of CTLA-4 expression was examined using flow cytometry in cells from filaria-infected and -uninfected individuals ex vivo. Individuals born in filarial endemic regions of the world (with long-standing infections) had greater percentages of CD4+CTLA-4+ cells than did expatriate infected or uninfected individuals (p = 0.005 and 0.05, respectively); in addition, Mf+ patients demonstrated higher frequencies of CD4+CTLA-4+ and CD8+CTLA-4+ cells (p = 0.027 and 0.037, respectively) than did Mf− infected individuals. Of interest, the greatest intensity of CTLA-4 expression occurred in CD4+CD25+ cells, a population purported to include suppressor cells. Finally, in vitro blocking of CTLA-4 expression in PBMC from filaria-infected individuals induced a mean increase of 44% in IL-5 production to Mf Ag, whereas there was a concurrent mean decrease of 42% in IFN-γ production, suggesting that CTLA-4 also acts to alter the Th1/Th2 balance in filaria-infected individuals. Together, these data indicate a significant role for CTLA-4 in regulating the host response to filarial infections and that factors such as length of exposure and patency are important codeterminants.
Mouse SWAM1 and SWAM2 Are Antibacterial Proteins Composed of a Single Whey Acidic Protein Motif
Authors: Hagiwara Koichi , Kikuchi Tohru , Endo Yoshiyuki , Huqun  , Usui Kazuhiro , Takahashi Mitsu , Shibata Naoko , Kusakabe Takashi , Xin Hong , Hoshi Sachiko , Miki Makoto , Inooka Nozomu , Tokue Yutaka , Nukiwa Toshihiro 
Published: April 2014

Abstract
Antibacterial proteins are important participants in the innate immunity system. Elafin and SLPI are the whey acidic protein (WAP) motif proteins with both antibacterial activity and antiprotease activity, and their role in innate immunity is under intense investigation. We cloned two novel antibacterial WAP motif proteins from mice, SWAM1 and SWAM2. SWAM1 and SWAM2 are composed of a signal sequence and a single WAP motif that has high homologies with the WAP motifs of elafin and SLPI. SWAM1 is constitutively expressed in kidney and epididymis, and is induced in the pneumonic lung. SWAM2 is constitutively expressed in tongue. SWAM1 and SWAM2 inhibit the growth of both Escherichia coli and Staphylococcus aureus at a IC90 (concentration that achieves 90% inhibition) of 10 μM. Human genes LOC149709 and huWAP2 are considered to be human SWAM1 and SWAM2, respectively. These and several WAP motif proteins (WAP1, elafin, SLPI, HE4, eppin, C20orf170, LOC164237, and WFDC3) form a gene cluster on human chromosome 20, suggesting that they may be derived from the same ancestral gene by gene duplication. Our results underscore the role of the WAP motif as a skeletal motif to form antibacterial proteins, and warrant the study of antibacterial activity in other WAP motif proteins.