bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of the Integral Membrane Protein RM3/1 on Human Monocytes as a Glucocorticoid-Inducible Member of the Scavenger Receptor Cysteine-Rich Family (CD163)
Authors: Högger Petra , Dreier Jens , Droste Anne , Buck Friedrich , Sorg Clemens 
Published: December 2022

Abstract
The RM3/1 Ag is a membrane glycoprotein restricted to human monocytes and macrophages that evolve in the late phase of inflammation. Peptide sequence analysis of the RM3/1 protein revealed similarity to CD163, a member of the scavenger receptor cysteine-rich family. Using specific Abs (RM3/1, Ki-M8), we demonstrate an identical cellular regulation for the RM3/1 and the CD163 protein. Most notably, we show for the first time that CD163 is significantly up-regulated by glucocorticoids. In contrast, the protein is down-regulated by the immunosuppressant cyclosporin A and by phorbol esters, while the inflammatory mediator LPS has no significant influence on the expression. We describe the first isolation of a full-length cDNA of CD163 and expression of the corresponding protein. Several splice variants of CD163 exist, and we elucidated the kinetics of induction of three major mRNA splice variants by fluticasone propionate; another splice variant was proved to be unresponsive to this glucocorticoid. Taken together with a previous result showing an involvement of RM3/1 in adhesion of monocytes to the activated endothelium, we discuss that CD163 might play an important role in inflammatory processes.
IL-4 Protects Adult C57BL/6 Mice from ProlongedCryptosporidium parvumInfection: Analysis of CD4+αβ+IFN-γ+ and CD4+αβ+IL-4+ Lymphocytes in Gut-Associated Lymphoid Tissue During Resolution of Infection
Authors: Aguirre Shirley A. , Perryman Lance E. , Davis William C. , McGuire Travis C. 
Published: December 2022

AbstractResistance of adult C57BL/6 mice to severe Cryptosporidium parvum infection is dependent on CD4+αβ+ TCR lymphocytes. In this study, we demonstrated that treatment with anti-IFN-γ mAb extended oocyst excretion 18 days longer, and anti-IL-4 mAb extended oocyst excretion at least 11 days longer than isotype control mAb treatment. Analysis of the specific activity of anti-IFN-γ mAb present in treated mouse sera suggested that IFN-γ may have a limited role in the resolution phase of infection. Changes were also documented in numbers of CD4+αβ+IFN-γ+ and CD4+αβ+IL-4+ lymphocytes in Peyer’s patches and intraepithelium of adult C57BL/6 mice during resolution of C. parvum infection. Resistance to initial severe infection was associated with CD4+αβ+IFN-γ+ lymphocytes, and eventual resolution of infection was associated with CD4+αβ+IL-4+ lymphocytes. Analysis of cytokine expression following in vitro stimulation with C. parvum Ags during resolution of infection demonstrated consistent increases in CD4+αβ+IL-4+ lymphocytes, but not CD4+αβ+IFN-γ+ lymphocytes. The relevance of CD4+αβ+IL-4+ lymphocytes in protection against C. parvum was then evaluated in C57BL/6 IL-4 gene knockout mice (IL-4−/−). Adult IL-4−/− mice excreted oocysts in feces approximately 23 days longer than IL-4+/+ mice. Further, anti-IFN-γ mAb treatment increased the severity and the duration of infection in IL-4−/− mice compared with those in IL-4+/+ mice. Together, the data demonstrated that IFN-γ was important in the control of severity of infection, and either IFN-γ or IL-4 accelerated termination of infection. However, neither IL-4 nor IFN-γ was required for the final clearance of infection from the intestinal tract of adult mice.
Role of Stress-Activated Mitogen-Activated Protein Kinase (p38) in β2-Integrin-Dependent Neutrophil Adhesion and the Adhesion-Dependent Oxidative Burst
Authors: Detmers Patricia A. , Zhou Dahua , Polizzi Elizabeth , Thieringer Rolf , Hanlon William A. , Vaidya Sanskruti , Bansal Vinay 
Published: December 2022

Abstract
Bacterial LPS elicits both rapid activation of the stress-activated MAP kinase p38 in polymorphonuclear leukocytes (PMN) and rapid adhesion of the PMN to ligands for the leukocyte integrin CD11b/CD18. The functional correlation between these two events was examined. The time course for tyrosine phosphorylation of p38 in PMN in response to 10 ng/ml LPS in 1% normal human serum was consistent with participation in signaling for leukocyte integrin-dependent adhesion, with transient phosphorylation peaking at 10 to 20 min. The concentration dependence of p38 phosphorylation also resembled that for PMN adhesion, with &lt;1 ng/ml LPS eliciting a response. Phosphorylation was inhibited by mAb 60b against CD14, but not by mAb 26ic, a nonblocking anti-CD14. The function of p38 in integrin-dependent adhesion and the adhesion-dependent oxidative burst was tested using a specific inhibitor of p38, SB203580. SB203580 inhibited adhesion by diminishing the initial rate of adherence in response to both LPS and TNF, with a half-maximal concentration in the range of 0.1 to 0.6 μM. It did not, however, block adhesion in response to formyl peptide or PMA. The p38 inhibitor also blocked the adhesion-dependent oxidative burst with a half-maximal concentration similar to that for adhesion. Timed delivery of the compound during the lag phase preceding H2O2 production suggested that p38 kinase activity was required throughout the lag but not after the oxidase was assembled. These results suggest that p38 functions in PMN to signal leukocyte integrin-dependent adhesion and the subsequent massive production of reactive oxygen intermediates.
Inducible Nitric Oxide: An Autoregulatory Feedback Inhibitor of Vascular Inflammation
Authors: Peng Hai-Bing , Spiecker Martin , Liao James K. 
Published: December 2022

AbstractInducible nitric oxide (iNO) is produced at sites of vascular inflammation by resident and nonresident vascular wall cells, but its role in the inflammatory process is not known. In this study, we show that a novel function of iNO is to terminate inflammatory processes. We find that iNO produced by murine macrophage-like cells, RAW264.7, can inhibit cytokine-induced endothelial cell activation in a separated and mixed endothelial-RAW264.7 coculture system. Both iNO production and endothelial VCAM-1 expression were induced simultaneously with bacterial LPS and murine-specific IFN-γ. Inhibition of iNO synthase (iNOS) activity with Nω-monomethyl-l-arginine in endothelial-RAW264.7 cocultures, stimulated with murine-specific IFN-γ and LPS, decreased iNO production by 86%, augmented VCAM-1 and iNOS expression in endothelial and RAW264.7 cells, respectively, and increased monocyte adhesion to the endothelial cell surface. Transient transfection studies using various VCAM-1 promoter constructs demonstrated that inhibitory effects of iNO on VCAM-1 gene transcription were mediated, in part, by inhibitory effects of iNO on κB cis-acting elements. Immunofluorescence studies using an Ab to the RelA (p65) subunit of nuclear factor-κB revealed that iNO inhibited the activation of nuclear factor-κB. These studies indicate that iNO attenuates iNOS expression in macrophages and inhibits monocyte adhesion to endothelial cells, and suggest that endogenously derived iNO may be an important autoregulatory inhibitor of vascular inflammation.
Vaccination with BV8S2 Protein Amplifies TCR-Specific Regulation and Protection Against Experimental Autoimmune Encephalomyelitis in TCR BV8S2 Transgenic Mice
Authors: Offner Halina , Adlard Kirsten , Bebo Bruce F. , Schuster Jeanette , Burrows Gregory G. , Buenafe Abigail C. , Vandenbark Arthur A. 
Published: December 2022

AbstractTCR determinants overexpressed by autopathogenic Th1 cells can naturally induce a second set of TCR-specific regulatory T cells. We addressed the question of whether immune regulation could be induced naturally in a genetically restricted model in which a major portion of TCR-specific regulatory T cells expressed the same target TCR BV8S2 chain as the pathogenic T cells specific for myelin basic protein (MBP). We found vigorous T cell responses to BV8S2 determinants in naive mice that could be further potentiated by vaccination with heterologous BV8S2 proteins, resulting in the selective inhibition of MBP-specific Th1 cells and protection against experimental encephalomyelitis. Moreover, coculture with BV8S2-specific T cells or their supernatants reduced proliferation, IFN-γ secretion, and encephalitogenic activity of MBP-specific T cells. These results suggest that immune regulation occurs through a nondeletional cytokine-driven suppressive mechanism.
Differential Requirements of CD45 Protein Tyrosine Phosphatase for Cytolytic Activities and Intrathymic and Extrathymic Development of Intestinal Intraepithelial Lymphocytes
Authors: Yada Shinichiro , Kishihara Kenji , Kong Young-Yun , Nomoto Kikuo 
Published: December 2022

AbstractCD45 is a transmembrane protein tyrosine phosphatase essential for Ag receptor-mediated signaling in both T and B cells. In this study we investigated roles of CD45 in development and cytolytic activities of murine intestinal intraepithelial lymphocytes (i-IEL) using CD45 exon 6 knockout (CD45−/−) mice. Interestingly, the total cell number of i-IEL was significantly reduced in CD45−/− mice during aging (10–20 wk of age), whereas the i-IEL number was normally increased in the wild-type littermates. Especially, the number of γδTCR+ i-IEL decreased markedly in CD45−/− mice during aging. The i-IEL in CD45−/− mice were more susceptible to in vitro spontaneous apoptosis than the normal i-IEL, implying that CD45 is required for maintenance of the cellularity of i-IEL. Results from in vivo analyses of the extrathymic and intrathymic development of i-IEL suggested that CD45-mediated signaling is required for the intrathymic, but not the extrathymic, development of i-IEL. Moreover, the whole i-IEL from CD45−/− mice showed a significantly reduced cytolytic activity, and the residual cytolytic activity was completely diminished by depleting CD45+ i-IEL, suggesting that CD45 is indispensable for the TCR-mediated cytolytic activity of i-IEL. Furthermore, we found differential contributions of CD45 and p56lck to development and induction of cytolytic activities of i-IEL.
On Histocompatibility Barriers, Th1 to Th2 Immune Deviation, and the Nature of the Allograft Responses
Authors: Li Xian Chang , Zand Martin S. , Li Yongsheng , Zheng Xin Xiao , Strom Terry B. 
Published: December 2022

AbstractIn the present study, we have sought to determine the basis for the frequent failure of Th1 to Th2 immune deviation to blunt the severity of allograft rejection, as such immune deviation has proven highly effective in the treatment of several T cell-dependent autoimmune states. Our study demonstrates that treating islet allograft recipient mice with anti-IL-12 mAb is highly effective in producing Th1 to Th2 immune deviation in several model systems (i.e., fully MHC, partially MHC, or multiple minor Ag barriers). Nevertheless, anti-IL-12 failed to prolong the engraftment of fully MHC-mismatched islet allografts. However, anti-IL-12-treated recipients carrying MHC-matched but multiple minor Ag-mismatched allografts experienced prolonged engraftment; allograft tolerance was frequently achieved in the DBA/2J (H-2d) to BALB/c (H-2d) strain combination. In another model, in which the host response was dominated by CD4+ T cells responding to donor allopeptides presented upon host APCs in the context of self MHC class II molecules, anti-IL-12 treatment proved to be extremely potent. Thus, Th1 to Th2 immune deviation produces prolonged engraftment as compared with recipients of MHC-mismatched allografts when rejection is dependent upon indirectly presented allogeneic peptides and a reduced mass of responding alloreactive T cells.
The Role of Enhancer A in the Locus-Specific Transactivation of Classical and Nonclassical HLA Class I Genes by Nuclear Factor κB
Authors: Gobin Sam J. P. , Keijsers Vivian , van Zutphen Marlijn , van den Elsen Peter J. 
Published: December 2022

AbstractHLA class I expression is tightly controlled at the transcriptional level by several conserved regulatory elements in the proximal promoter region. In this study, the two putative κB motifs of enhancer A (κB1 and κB2) of the classical and nonclassical HLA class I genes were investigated for their binding properties of transcription factors and tested for their contribution to the NF-κB-induced route of transactivation. It was shown that NF-κB-induced transactivation through enhancer A is most important for the HLA-A locus, which contains two NF-κB binding sites. Although the enhancer A of HLA-B contains only one NF-κB binding site (κB1), there was still a moderate transactivation by NF-κB. Since HLA-F, which also possesses one NF-κB binding site but lacks protein binding to its κB2 site, was not transactivated by NF-κB, the NF-κB-mediated transactivation through the κB1 motif in HLA-B is most probably facilitated by binding of the transcription factor Sp1 to the upstream κB2 site. Thus, transcriptional regulation of HLA class I genes by NF-κB is restricted to the HLA-A and HLA-B loci.
Specific Antiviral Activity Demonstrated by TGTP, A Member of a New Family of Interferon-Induced GTPases
Authors: Carlow Douglas Alan , Teh Soo-Jeet , Teh Hung-Sia 
Published: December 2022

AbstractThe GTPase superfamily includes a diversity of molecules whose functions are regulated through the binding and hydrolysis of GTP. This superfamily can be segregated into families of functionally related molecules that typically share amino acid sequence similarity within and around the nucleotide-binding domains. A new family of putative GTPases, including IRG-47, LRG-47, IGTP, and TGTP/Mg21, has recently emerged that share significant sequence identity (25–40%). Expression of these molecules has been shown to be selectively induced by IFN-γ and in some cases by IFN-αβ or bacterial LPS. This induction pattern implicates these putative GTPases as part of the innate defense of cells to infection, but their role in such defense has not yet been defined. We have previously described the cloning of TGTP and now confirm its intrinsic activity as a GTPase. We found that TGTP is strongly induced by endogenous IFN-αβ produced in response to standard lipofection of plasmid DNA or polyinosinic polycytidilic acid. The ability of endogenously produced IFN-αβ to efficiently induce expression of TGTP under these conditions suggested that TGTP might participate in defense against viral infection. This proposal was borne out when TGTP-transfected L cells displayed relative resistance to plaque formation by vesicular stomatitis virus but not herpes simplex virus. This observation places TGTP among a small family of innate antiviral agents and has implications for the functions of other members of this family of GTPases.
The Mannose Receptor Mediates Induction of IFN-α in Peripheral Blood Dendritic Cells by Enveloped RNA and DNA Viruses
Authors: Milone Michael C. , Fitzgerald-Bocarsly Patricia 
Published: December 2022

Abstract
Peripheral blood dendritic cells (DC) produce IFN-α in response to challenge by many enveloped viruses including herpes simplex virus (HSV) and HIV, whereas Sendai virus predominantly stimulates IFN-α production by monocytes. Glycosylated viral envelope proteins are known to be important for the induction of IFN-α. In this study we demonstrate that stimulation of IFN-α synthesis by HSV is inhibited by a number of monosaccharides, including fucose, N-acetylglucosamine, and N-acetylgalactosamine as well as the yeast polysaccharide mannan, supporting a role for lectin(s) in the IFN-α stimulation pathway. Furthermore, antiserum to the mannose receptor (MR) also inhibited HSV, vesicular stomatitis virus, and HIV-induced IFN-α production, but failed to inhibit the IFN-α induced by Sendai virus. We further demonstrated that freshly isolated blood DC and IFN-α-producing cells responding to HSV stimulation express the MR. This study therefore implicates the MR as an important receptor for the nonspecific recognition of enveloped viruses by DC and the subsequent stimulation of IFN-α production by these viruses. Thus, the MR probably serves as a critical link between innate and adaptive immunity to viruses, especially given the role of the MR in Ag capture by DC and the importance of IFN-α in shaping immunity.
CTL Response toMycobacterium tuberculosis: Identification of an Immunogenic Epitope in the 19-kDa Lipoprotein
Authors: Mohagheghpour Nahid , Gammon Dawn , Kawamura Loyce Masae , van Vollenhoven Annika , Benike Claudia J. , Engleman Edgar G. 
Published: December 2022

AbstractThe successful resolution of infection with Mycobacterium tuberculosis (M.tb) is believed to involve the induction of CTLs that are capable of killing cells harboring this pathogen, although little information is known about the MHC restriction or fine specificity of such CTLs. In this study, we used knowledge of the HLA-A*0201-binding motif and an immunofluorescence-based peptide-binding assay to screen for potential HLA-A*0201-binding epitopes contained in the 19-kDa lipoprotein of M.tb (M.tb19). CD8+ T cells derived from HLA-A*0201+ patients with active tuberculosis (TB) as well as tuberculin skin test-positive individuals who had no history of TB were used as effector cells to determine whether these epitopes are recognized by in vivo-primed CTLs. An in vitro vaccination system using HLA-A*0201+ dendritic cells (DCs) as APCs was used to determine whether these epitopes can sensitize naive CD8+ T cells in vitro, leading to the generation of Ag-specific CTLs. The results show that an HLA-A*0201-binding peptide comprised of residues 88 to 97 of M.tb19 (P88–97) is recognized by circulating CD8+ CTLs from both healthy tuberculin skin test-positive individuals and patients with active TB but not by tuberculin skin test-negative subjects. Moreover, dendritic cells pulsed with this peptide induced class I MHC-restricted CTLs from the T cells of healthy unsensitized persons. Finally, CTL lines that were specific for P88–97 were shown to lyse autologous monocytes that had been infected acutely with the H37Ra strain of M.tb. These results demonstrate that M.tb19 elicits HLA class I-restricted CTLs in vitro and in vivo that recognize endogenously processed Ag. Epitopes of the type identified here may prove useful in the design of an M.tb vaccine.
B7-1, But Not CD28, Is Crucial for the Maintenance of the CD4+ T Cell Responses in Human Leprosy
Authors: Schlienger Katia , Uyemura Koichi , Jullien Denis , Sieling Peter A. , Rea Thomas H. , Linsley3 Peter S. , Modlin Robert L. 
Published: December 2022

AbstractWe used human leprosy as a model to compare patterns of costimulatory molecule expression in respect to the clinical/immunologic spectrum of disease. We found that B7-1, B7-2, and CD28 transcripts dominated in tuberculoid leprosy patients, who have potent T cell responses to Mycobacterium leprae. In contrast, CTLA-4 was more strongly expressed in lesions from lepromatous patients, who manifest specific T cell anergy to the leprosy bacterium. T cell clones from tuberculoid lesions were CD4+CD28+ or CD4+CD28−, and T cell clones from lepromatous lesions were predominantly CD8+CD28−. The M. leprae-specific recall response of CD4+ T cell clones from tuberculoid lesions was blocked by anti-B7-1 mAb, but not by anti-B7-2 mAb or CTLA-Ig. However, anti-CD28 and anti-CTLA-4 mAbs did not block activation of clones from tuberculoid lesions, suggesting that B7-1 may utilize another costimulatory pathway. Peripheral blood T cell responses in the lepromatous form were strongly regulated by CD28 during T cell activation, in contrast to the tuberculoid form. Thus, B7-1 costimulation could play a role in maintaining a strong immune response to the pathogen.
Pathogenic Mycobacterium tuberculosis Evades Apoptosis of Host Macrophages by Release of TNF-R2, Resulting in Inactivation of TNF-α
Authors: Balcewicz-Sablinska M. Katarzyna , Keane Joseph , Kornfeld Hardy , Remold Heinz G. 
Published: December 2022

Abstract
Infection by Mycobacterium tuberculosis (MTB) induces human alveolar macrophage (AMφ) apoptosis by a TNF-α-dependent mechanism. The apoptotic response is postulated to be a defense mechanism, limiting the growth of this intracellular pathogen. Consistent with that model, recent studies showed that the virulent MTB strain H37Rv induces substantially less AMφ apoptosis than the attenuated strain H37Ra. We now report that AMφ infection with either H37Rv or H37Ra induces comparable levels of TNF-α measured by ELISA but that TNF-α bioactivity is reduced in supernatants of H37Rv-infected AMφ. Differential release of soluble TNFR2 (sTNFR2), with formation of inactive TNF-α-TNFR2 complexes accounted for the difference in TNF-α bioactivity in these cultures. Release of sTNFR2 by H37Rv-infected AMφ was IL-10 dependent since it was inhibited by neutralizing anti-IL-10 Ab. Thus, the effect of TNF-α produced by AMφ following infection can be modulated by virulent MTB, using IL-10 as an upstream mediator.
cDNA Encoding a Single-Chain Antibody to HIV p17 with Cytoplasmic or Nuclear Retention Signals Inhibits HIV-1 Replication
Authors: Tewari Deepanker , Goldstein Simoy L. , Notkins Abner L. , Zhou Paul 
Published: December 2022

AbstractHIV-1 gag p17 protein is an attractive target for molecular intervention, because it is involved in the viral replication cycle at both the pre- and postintegration levels. In the present experiments, we targeted p17 by intracellularly expressing a cDNA encoding an Ab to p17. cDNA from a hybridoma-secreting Ab to p17 was cloned, sequenced, reconstructed as a single-chain Ab fragment (scFv), and expressed in the cytoplasm or nucleus with appropriate retention signals. The expressed scFvs had no effect on T cell growth or CD4 expression and bound specifically to HIV-1 p17. Human CD4+ Jurkat T cells that expressed scFvs and were infected with HIV-1 showed a marked reduction in virus replication compared with cells expressing vector alone. The inhibition of virus replication was more pronounced when scFvs were expressed in the cytoplasm rather than the nucleus. From these studies, we conclude that the intracellular expression of a single-chain Ab to p17 inhibits HIV replication; in addition, the degree of inhibition is related to the intracellular targeting site.
Cloning of BY55, a Novel Ig Superfamily Member Expressed on NK Cells, CTL, and Intestinal Intraepithelial Lymphocytes
Authors: Anumanthan Anukanth , Bensussan Armand , Boumsell Laurence , Christ Andreas D. , Blumberg Richard S. , Voss Stephan D. , Patel Amish T. , Robertson Michael J. , Nadler Lee M. , Freeman Gordon J. 
Published: December 2022

AbstractExpression of the BY55 protein has been shown to be tightly associated with NK and CD8+ T lymphocytes with cytolytic effector activity. To determine the function of this protein, we molecularly cloned BY55 cDNA. The cDNA sequence predicts a cysteine-rich, glycosylphosphatidylinositol-anchored protein of 181 amino acids with a single Ig-like domain weakly homologous to killer inhibitory receptors. Reduction and carboxyamidomethylation of immunoprecipitated BY55 gave a band of 27 kDa, whereas reduction alone led to an 80-kDa species, suggesting that BY55 is a tightly disulfide-linked multimer. RNA blot analysis revealed BY55 mRNAs of 1.5 and 1.6 kb whose expression was highly restricted to NK and T cells. BY55 was expressed on the CD56dim, CD16+ subset of NK cells, which have high cytolytic activity, but was not expressed and was not induced on the CD56bright, CD16− subset of NK cells, a subset with high proliferative, but low cytolytic, capacity. In human tissues, BY55 mRNA was expressed only in spleen, PBL, and small intestine (in gut lymphocytes). BY55 was expressed on all intestinal intraepithelial lymphocytes, which were predominantly CD3+TCRα/β+CD4−CD8+CD11b+CD28−CD45RO+CD56−CD101+CD103+ (αEβ7 integrin). In addition, BY55 was expressed on most CD8+CD28− peripheral blood T cells. These phenotypic relationships suggest that CD8+CD28+ precursor CTL may terminally differentiate into CD8+CD28−BY55+ effector CTL and that some of the peripheral blood CD8+CD28− subset may represent recirculation from mucosal epithelial immune sites.