bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mucosal Addressin Is Required for the Development of Diabetes in Nonobese Diabetic Mice
Authors: Hänninen Arno , Jaakkola Ilkka , Jalkanen Sirpa 
Published: January 2023

Abstract
Immune responses are best initiated in the environment of lymphoid tissues wherein circulating lymphocytes enter by interacting with endothelial adhesion molecules. In type 1 diabetes, immune responses against pancreatic islets develop, but the environment in which this occurs remains unidentified. To determine whether lymphocyte homing to lymphoid organs is involved in the pathogenesis of diabetes in nonobese diabetic (NOD) mice, we blocked the function of the mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is a vascular addressin-mediating lymphocyte homing into mucosal lymphoid tissues, in these mice. While ineffective if started later, a blockade started at 3 wk of age reduced the incidence of diabetes from 50% to 9% (p &lt; 0.01). This finding is associated with Peyer’s patch atrophy, a marked decrease of naive (CD44lowCD45RBhigh) T lymphocytes, and a reduction in the relative numbers of memory (CD44high) T lymphocytes in the spleen. The potential of these spleen cells to cause diabetes was diminished. Anti-MAdCAM-1 treatment also inhibited both lymphocyte entry into the pancreas and diabetes development in NOD/SCID recipients after the transfer of lymphocytes derived from the mesenteric lymph nodes of young, but not of diabetic, NOD donors. Therefore, MAdCAM-1 may be required during two distinct steps in an early phase of diabetes development: for the entry of naive lymphocytes into the lymphoid tissues in which diabetes-causing lymphocytes are originally primed, and for the subsequent homing of these lymphocytes into the pancreas. The role of MAdCAM-1 as a mucosal vascular addressin suggests that mucosal lymphoid tissues are involved in the initiation of pathologic immune responses in NOD mice.
The Antibody Response to Fungal Melanin in Mice
Authors: Nosanchuk Joshua D. , Rosas Angel L. , Casadevall Arturo 
Published: January 2023

Abstract
Melanins are associated with virulence in several important human pathogens, but little is known about the immune response to this ubiquitous biologic compound. We hypothesized that melanin produced by the fungus Cryptococcus neoformans was immunogenic. C. neoformans melanin was purified from melanized fungal cells and was used to immunize C57BL/6, BALB/c, and T cell-deficient (nude) BALB/c mice. The Ab response was evaluated by ELISA, immunofluorescence, and agglutination. The results demonstrate that melanin can be immunogenic, and the humoral immune response is T cell independent. Furthermore, the experiments demonstrate 1) a sensitive ELISA for the measurement of Ab to melanin, 2) that mice mount an intense Ab response to fungal melanin that includes Abs of IgM and IgG isotypes, 3) that melanins from different sources have cross-reactive epitopes, and 4) melanin in the cell wall of melanized yeast cells reacts with Abs raised to l-dopa C. neoformans melanin. The biologic significance of Ab to melanin remains to be determined, but the development of Ab suggests that this amorphous insoluble polymer can stimulate the immune system. The serologic techniques described here may prove useful for the evaluation of Ab responses to melanin in a variety of diseases.
Clostridium difficile Toxin A Stimulates Macrophage- Inflammatory Protein-2 Production in Rat Intestinal Epithelial Cells
Authors: Castagliuolo Ignazio , Keates Andrew C. , Wang Chi Chung , Pasha Asiya , Valenick Leyla , Kelly Ciaran P. , Nikulasson Sigfus T. , LaMont J. Thomas , Pothoulakis Charalabos 
Published: January 2023

Abstract
Neutrophil infiltration of the colonic mucosa is a hallmark of Clostridium difficile toxin A-mediated enterocolitis. Macrophage-inflammatory protein-2 (MIP-2) is a potent neutrophil chemoattractant secreted by rat macrophages and epithelial cells in response to inflammatory stimuli. In this work, we report that administration of toxin A into rat ileal loops increased mucosal levels of MIP-2 before the onset of fluid secretion and mucosal neutrophil infiltration. Administration of rabbit anti-MIP-2 IgG, but not control IgG, reduced toxin A-mediated secretion (by 58%), mucosal permeability (by 80%), and myeloperoxidase activity (by 85%). Immunohistochemical analysis demonstrated increased MIP-2 expression in intestinal epithelial and lamina propria cells 1 h after toxin A administration. Intestinal epithelial cells purified from toxin A-exposed ileal loops also showed increased MIP-2 mRNA expression and MIP-2 protein release that was inhibited by pretreatment of rats with the transcriptional inhibitor actinomycin D. These results indicate that C. difficile toxin A induces MIP-2 release from intestinal epithelial cells and that MIP-2 contributes to neutrophil mucosal influx during toxin A enteritis.
Th1 Cells Specific for a Secreted Protein ofListeria monocytogenesAre Protective In Vivo
Authors: Geginat Gernot , Lalic Mio , Kretschmar Marianne , Goebel Werner , Hof Herbert , Palm Dieter , Bubert Andreas 
Published: January 2023

AbstractIn the present study we have investigated the role of the secreted p60 protein from Listeria monocytogenes as an Ag for CD4 T cells. The p60 protein is an abundant extracellular protein that is highly conserved within the members of the genus Listeria. Our results show that L. monocytogenes infection induces a potent p60-specific Th1 immune response. Remarkably, we found that p60-specific Th1 clones mediate significant protection against L. monocytogenes infection. For one p60-specific clone, the peptide epitope was defined. This clone recognized p60 301-312 (EAAKPAPAPSTN) in the context of the H-2Ad molecule. Despite the fact that acquired immunity against L. monocytogenes is primarily mediated by cytotoxic CD8 T lymphocytes, our data clearly demonstrate that secreted bacterial proteins are important CD4 T cell Ags and that Th1 clones specific for a secreted bacterial protein can contribute to the protection against an intracellular pathogen such as L. monocytogenes.
Blockade of Endogenous TNF-α Exacerbates Primary and Secondary Pulmonary Histoplasmosis by Differential Mechanisms
Authors: Allendoerfer Ruth , Deepe George S. 
Published: January 2023

AbstractWe investigated the mechanisms by which endogenous TNF-α modulates host defenses during experimental primary and secondary pulmonary infection with Histoplasma capsulatum (Hc). Neutralization of TNF-α in vivo resulted in increased CFU and 100% mortality in naive and immune mice challenged with Hc intranasally. Levels of IFN-γ and granulocyte macrophage-CSF were elevated in TNF-α-neutralized naive mice, whereas IL-4, -6, -10 and TGF-β did not differ from controls. In contrast, in secondary histoplasmosis, significant elevations of IL-4 and -10 were observed in TNF-α-depleted mice. Alveolar macrophages (Mφ) did not exert fungistatic activity against Hc after exposure to recombinant murine TNF-α, recombinant murine IFN-γ, or both. The increase in susceptibility to primary Hc infection was associated with diminished production of reactive nitrogen intermediates by alveolar Mφ from TNF-α-depleted mice, whereas production of nitric oxide during secondary histoplasmosis was similar in both groups. Upon secondary challenge, TNF-α-depleted mice were rescued by concomitant neutralization of IL-4 and IL-10, but not either cytokine alone. Thus, TNF-α is critical for controlling primary and secondary infection with Hc, and the mechanisms that lead mice to succumb to primary or secondary infection when endogenous TNF-α is blocked are different.
Cutting Edge: A Critical, Invariant Chain-Independent Role for H2-M in Antigen Presentation
Authors: Swier Kevin , Brown2 Daniel R. , Bird Jennifer J. , Martin W. David , Kaer Luc Van , Reiner Steven L. 
Published: January 2023

AbstractAntigen presentation by MHC class II (class II) is facilitated by the accessory molecules, invariant chain (Ii) and H2-M. Ii associates with class II during biosynthesis and promotes transport of class II to Ag-loading compartments. One function of H2-M is the removal of Ii fragments from MHC class II. We have previously demonstrated that Ii-deficient mice, unlike class II-deficient mice, are resistant to L. major infection. In the present study, we found that H2-M-deficient (H2-M0) mice were susceptible to progressive infection with L. major. The dispensability of Ii for control of L. major allowed genetic analysis of whether H2-M functions by association with or independently of Ii. In contrast to Ii-deficient (Ii0) mice, Ii0H2-M0 mice were as susceptible to L. major as H2-M0 mice. Thus, H2-M has an essential, Ii-independent function during presentation of microbial pathogens.
Cutting Edge: T Helper 1 and T Helper 2 Cells Respond Differentially to Chemokines
Authors: Siveke Jens T. , Hamann Alf 
Published: January 2023

AbstractT effector subsets, such as Th1 or Th2 cells, are key players in inflammatory reactions. It is not known whether chemokines are able to recruit these subsets differentially, as has been shown for memory vs naive T cells. Here we demonstrate that Th1 and Th2 cells differ in their intrinsic migratory properties and their chemotactic responsiveness toward distinct chemokines. While the CC-chemokines macrophage inflammatory protein (MIP)-1α, MIP-1β, and RANTES were efficient chemoattractants for Th1 cells, inducing a dose-dependent transmigration, Th2 cells were not attracted by these chemokines. Another CC-chemokine, JE/monocyte chemoattractant protein (MCP)-1, and a CXC-chemokine, stromal cell-derived factor (SDF)-1α, exerted chemotactic effects on both Th1 and Th2 cells, but differences in sensitivity and the percentage of responding cells were recorded between both subsets. These results indicate that chemokines play a distinct role in the regulation of local immune reactions by influencing the local balance between proinflammatory and antiinflammatory T cell subsets.
Cutting Edge: Detection of MCP-4 in Dermal Fibroblasts and Its Activation of the Respiratory Burst in Human Eosinophils
Authors: Petering Holger , Höchstetter Renate , Kimmig Daniela , Smolarski Regina , Kapp Alexander , Elsner Jörn 
Published: January 2023

Abstract
CC-chemokines are an important family of proinflammatory mediators that promote the recruitment and activation of human eosinophils in chronic inflammatory diseases. Recently, a novel human CC-chemokine, monocyte chemotactic protein 4 (MCP-4), has been reported that shows amino acid sequence similarities with eotaxin and RANTES, induces chemotaxis of eosinophils, and signals through specific chemokine receptors. In this study, we investigated the effect of MCP-4 on different eosinophil effector functions leading to the activation of the respiratory burst. In human eosinophils, MCP-4 dose dependently induced the production of reactive oxygen species and actin polymerization as a related event. Pretreatment of eosinophils with different enzyme inhibitors interacting with the signal transduction cascade revealed that Gi protein, protein kinase C, tyrosine kinase, and phosphatidylinositol-3-kinase are involved in the signaling following stimulation with MCP-4. In addition, cytokine-stimulated human dermal fibroblasts expressed high levels of MCP-4 mRNA, suggesting that fibroblasts are a physiologic source of MCP-4. Therefore, this study demonstrates that there is an important role of MCP-4 in the activation of eosinophils and that the interaction between dermal fibroblasts and human eosinophils may play an important role within the cytokine network.
Suppression of Immune Responses by CD8 Cells. II. Qa-1 on Activated B Cells Stimulates CD8 Cell Suppression of T Helper 2 Responses
Authors: Noble Alistair , Zhao Zi-Shan , Cantor Harvey 
Published: January 2023

Abstract
We have investigated the role of MHC class I products and CD8 T cells in regulating Ab responses using β2-microglobulin deficient (β2m−/−) mice. β2m−/− mice produced stronger IgM and IgG responses than did control β2m+/+ mice to both cellular and viral Ags. These Ab responses could be suppressed by infusion of activated B cells from β2m+/+ mice. Further investigation showed that the β2m-associated molecule on activated B cells that induced CD8 suppression was Qa-1 and that the Th2 component of CD4 cells was most affected by CD8-suppressive activity. Our findings suggest a novel pathway of Th inhibition in which B cell presentation of Qa-1-associated peptides stimulates CD8 suppressive activity.
Ovalbumin-Specific, MHC Class I-Restricted, αβ-Positive, Tc1 and Tc0 CD8+ T Cell Clones Mediate the In Vivo Inhibition of Rat IgE
Authors: MacAry Paul A. , Holmes Beverly J. , Kemeny David M. 
Published: January 2023

AbstractIn the following study, we demonstrate that medium responder PVG rats immunized i.p. with OVA complexed to the adjuvant aluminum hydroxide exhibit a moderate IgE response (400–1000 ng/ml). In these rats, we demonstrate that underlying the MHC class II-restricted CD4+ T cell response, there is an MHC class I-restricted CD8+ T cell component that plays an important role in restricting the magnitude and duration of the IgE response. We show that in vivo depletion of CD8+ T cells effects a massive increase in IgE (20-fold), and that they are MHC class I-restricted, OVA-specific, cytolytic cells that universally produce IFN-γ (25–69 ng/ml) and IL-2 (7.6–22 U/ml), and occasionally secrete IL-4 (68–81 U/ml IL-4), and when adoptively transferred into CD8-depleted recipients, can effect a significant reduction in IgE (3- to 50-fold). We also demonstrate that this in vivo inhibition of IgE is dependent on the Ag-specific activation of the CD8+ T cells, and that the activated CD8+ T cells will suppress total/bystander IgE in an Ag-nonspecific manner. These data are consistent with a growing literature demonstrating sensitization of MHC class I-restricted CD8+ T cells by exogenous protein Ags delivered to mucosal sites, and may represent a mechanism whereby a selective pressure can be applied on the functional outcome of an immunoglobulin response to environmental allergens.
Perforin Protects Against Autoimmunity in Lupus-Prone Mice
Authors: Peng Stanford L. , Moslehi Javid , Robert Marie E. , Craft Joe 
Published: January 2023

AbstractThe roles of cytolytic regulatory mechanisms in the immune system of lupus-prone mice were examined in perforin-deficient animals bearing functional or defective (lpr) Fas Ag (CD95). Perforin-deficient Fas+ animals developed accelerated autoimmunity, characterized by increased hypergammaglobulinemia, autoantibody production, and immune deposit-related end-organ disease compared with perforin-intact counterparts. In comparison, perforin-deficient lpr animals had accelerated mortality compared with perforin-intact lpr mice, associated with the abnormal accumulation of CD3+CD4−CD8− αβ T cells in conjunction with unaltered hypergammaglobulinemia, autoantibody production, and immune complex renal disease. These results indicate that cytolytic lymphoid regulation plays critical roles in the immune homeostasis of lupus-prone animals, and identify perforin-mediated cytotoxicity as a specific mechanism in the regulation of systemic autoimmunity.
Positive Selection of Thymocytes Expressing the Same TCR by Different MHC Ligands Results in the Production of Functionally Distinct Thymocytes Distinguished by Differential Expression of the Heat Stable Antigen
Authors: Teh Hung-Sia , Motyka Bruce , Teh Soo-Jeet 
Published: January 2023

Abstract
The issue of whether the signaling process during positive selection can affect the efficiency by which the positively selected T cells respond to antigenic stimulation has not been addressed. We approached this question by determining the consequences of positive selection of a particular transgenic TCR (2C TCR) in the H-2b and the H-2k thymus. The H-2b thymus provides a strong positive-selecting environment for the 2C TCR, whereas the H-2k thymus selects weakly for the 2C TCR. Although the positively selected CD8 thymocytes from the H-2b or H-2k thymus expressed similar levels of the CD8 coreceptor molecule, those for the H-2k thymus expressed a slightly lower level of the 2C TCR. This lower level of 2C TCR expression by H-2k CD8 thymocytes was not a result of coexpression of endogenous TCRs. Interestingly, CD8 thymocytes from H-2k mice were hyporesponsive to Ag stimulation compared with those from the H-2b mice. The functional maturity of positively selected CD8 thymocytes from the H-2b or H-2k thymus was inversely correlated with the level of heat stable Ag expressed by these cells. Furthermore, TCR-derived signals appear to be more efficiently coupled to downstream pathways leading to proliferation and cytokine production in CD8 thymocytes from H-2b 2C mice than those derived from H-2k 2C mice. These results provide the first demonstration that the intensity of the signaling process during positive selection affects the efficiency by which TCR-derived signals in positively selected thymocytes are coupled to downstream effector pathways.
T Cell Growth Cytokines Cause the Superinduction of Molecules Mediating Antigen-Induced T Lymphocyte Death
Authors: Zheng Lixin , Trageser Carol L. , Willerford Dennis M. , Lenardo Michael J. 
Published: January 2023

Abstract
TCR stimulation of T lymphocytes that are activated and cycling in the presence of IL-2 leads to programmed cell death. We now show that this effect is at least partly attributable to the ability of IL-2 to dramatically increase the expression of mRNAs encoding ligands and receptors that mediate apoptosis. We also found that cyclosporin was not able to fully inhibit the TCR induction of death molecule mRNAs or TCR-induced apoptosis, although it could completely turn off IL-2 expression. The effect of growth cytokines was further explored in T cells derived from mice bearing a homozygous deficiency of the IL-2R α-chain. We found that IL-2Rα−/− cells were resistant to death if IL-2 was used to induce apoptosis susceptibility, but that large amounts of other T cell growth cytokines, such as IL-4 and IL-7, could induce cell cycle progression and promote TCR-induced apoptosis. However, our findings suggest that autoimmunity and lymphoproliferation in IL-2Rα−/− mice can result from the loss of IL-2-stimulated feedback apoptosis and that other growth cytokines are not produced at levels sufficient to compensate for this deficit.
Identification and Characterization of the CXCR4 Chemokine Receptor in Human T Cell Lines: Ligand Binding, Biological Activity, and HIV-1 Infectivity
Authors: Hesselgesser Joseph , Liang Meina , Hoxie James , Greenberg Michael , Brass Lawrence F. , Orsini Michael J. , Taub Dennis , Horuk Richard 
Published: January 2023

Abstract
The CXCR4 chemokine receptor has been shown to respond to the C-X-C chemokine stromal-derived factor (SDF-1) and has recently been shown to be an important coreceptor for HIV-1 infection. In the present paper we have tested a number of human T lymphocyte cell lines, including Jurkat, HUT78, CEM, and Sup-T1 for the presence of CXCR4 receptors. We found that these T cell lines bind SDF-1α and SDF-1β with high affinity. The CXCR4 Ab 12G5 inhibited both SDF-1 binding and HIV-1LAI-mediated fusion of CEM. Scatchard analysis revealed the presence of approximately 150,000 SDF-1α-binding sites per cell with a Kd between 5 and 10 nM. Cross-competition experiments using unlabeled SDF-1α and SDF-1β revealed that both chemokines are equally capable of displacing their radiolabeled counterparts. Internalization studies with [125]I-SDF-1α revealed that Jurkat cells internalized greater than 90% of the ligand by 2 h at 37°C. SDF-1α was also chemotactic for Jurkat cells and caused an increase in the rate of extracellular acidification that was half-maximal at 18 nM SDF-1α and could be inhibited by pretreatment with the SDF-1 proteins, pertussis toxin, or the Ab 12G5. Finally, SDF-1α also caused an increase in the cytosolic Ca2+ concentration in Sup-T1 cells that was abolished by preincubating the cells with pertussis toxin or PMA and inhibited by the Ab 12G5. This molecular characterization of CXCR4 receptors should prove useful in clarifying receptor interaction with SDF-1 proteins and with HIV-1 glycoprotein, with the ultimate aim of targeting the viral interaction for therapeutic intervention.
Translational Efficiency Is Up-Regulated by Alternative Exon in Murine IL-15 mRNA
Authors: Nishimura Hitoshi , Washizu Junji , Nakamura Nobuhisa , Enomoto Atsushi , Yoshikai Yasunobu 
Published: January 2023

AbstractIL-15 promotes the growth of T cells and shares properties of IL-2. IL-2 is produced exclusively by T cells, while IL-15 message is expressed by a variety of tissues. However, it has been difficult to demonstrate IL-15 in the supernatants of many cells that express message for this cytokine. This suggests that IL-15 production is regulated by post-transcriptional controls. In this study, we cloned three types of murine IL-15 cDNA isoforms generated by alternative splicing and compared the translational efficiency among these isoforms. The translational efficiency of isoforms with alternative exon 5 containing another 3′ splice site was significantly higher than that of IL-15 cDNA with originally described exon 5, which is generated by internal splicing of alternative exon 5. The translation product of the isoform containing alternative exon 5 has a shorter open reading frame due to stop codons in additional sequence, followed by a new AUG codon, and displays a shorter leader sequence. The shorter isoform of the IL-15 was detected in peritoneal macrophages stimulated with IFN-γ and LPS, which expressed an abundant level of alternative exon 5. These results suggest that normal IL-15 production in stimulated macrophages is regulated by splicing of alternative exon 5.
Anti-CD40 Ligand Antibody Treatment of SNF1 Mice with Established Nephritis: Preservation of Kidney Function
Authors: Kalled Susan L. , Cutler Anne H. , Datta Syamal K. , Thomas David W. 
Published: January 2023

AbstractPrior studies have demonstrated that treatment of young, prenephritic lupus-prone mice with Ab directed against CD40 ligand (CD40L) prolongs survival and decreases the incidence of severe nephritis. In this report, we show that for (SWR × NZB)F1 (SNF1) animals with established lupus nephritis, long-term treatment with anti-CD40L beginning at either 5.5 or 7 mo of age prolonged survival and decreased the incidence of severe nephritis. “Older” mice were chosen for these studies to more closely resemble the clinical presentation of patients with established renal disease. We show that age at the start of treatment, which typically correlates with severity of disease, is an important factor when determining an efficacious therapeutic protocol since animals that began treatment at 7 mo of age required a more aggressive treatment protocol than animals at 5.5 mo of age. Remarkably, several anti-CD40L-treated animals beginning treatment at age 5.5 mo demonstrated a decline in proteinuria, as opposed to increasing proteinuria levels seen in hamster IgG (HIg)-treated controls, and histologic examination of kidneys from anti-CD40L-treated mice revealed dramatically diminished inflammation, sclerosis/fibrosis, and vasculitis, in marked contrast to the massive inflammation and kidney destruction observed in control animals that received hamster IgG. Spleens from anti-CD40L-treated mice also exhibited markedly reduced inflammation and fibrosis compared with controls. Together, these results show that treatment of older, nephritic SNF1 animals with long-term anti-CD40L immunotherapy significantly prolongs survival, reduces the severity of nephritis, and diminishes associated inflammation, vasculitis, and fibrosis.