bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid induction of autoantibodies by endogenous ovarian antigens and activated T cells: implication in autoimmune disease pathogenesis and B cell tolerance.
Authors: Lou Y H , McElveen M F , Garza K M , Tung K S 
Published: December 2022

Abstract
Animals immunized with nuclear antigenic peptides produce autoantibodies to distant antigenic sites and neighboring Ags within a multimolecular complex. This has led to the hypothesis that induction of autoantibodies in systemic autoimmune diseases might be triggered by a T cell epitope. We have investigated the T to B epitope spreading phenomenon based on the murine autoimmune oophoritis model. Mice immunized with a ZP3 T cell peptide spontaneously produced amplified autoantibodies (amAb) against linear ZP3 B cell epitopes outside the peptide immunogen. Each ZP3 B cell peptide, chimerized to a foreign promiscuous T cell epitope, elicited Ab to the peptide within the native ZP3 molecule. Mice with amAb often had no oophoritis; but more importantly, bilateral ovariectomy 1 day before ZP3 T epitope injection inhibited the induction of the amAb response, whereas ovariectomy 2 to 4 days after immunization was not inhibitory. Because endogenous ovarian Ag depletion before detectable ZP3 T cell response (day 5) and oophoritis (day 7) failed to prevent the amAb response, the autoantibodies are likely stimulated by endogenous ZP3 Ags present outside the normal ovaries. AmAb, of only the IgG class, appeared on day 7; this was 2 to 3 days after detectable T cell response, and 5 to 6 days before A response to the T cell peptide immunogen. The rapid, class-switched amAb response indicates that B cells in female mice are not tolerant to self ovarian Ag and they may normally be primed by ZP3. As evidence for their pathogenic potentials, amAb were produced in response to oophoritogenic, nonovarian T cell peptides that mimic ZP3; moreover, an excellent correlation existed between amAb titers and fertility reduction.
Sublethal levels of oxidative stress stimulate transcriptional activation of c-jun and suppress IL-2 promoter activation in Jurkat T cells.
Authors: Beiqing L , Chen M , Whisler R L 
Published: December 2022

Abstract
Sublethal levels of oxidative stress are well known to alter T cell functional responses, but the underlying mechanisms are unknown. The current study examined the effects of oxidative stress on transcriptional activities mediated by c-Fos/c-Jun AP-1 and the nuclear factor of activated T cells (NF-AT). The present results show that Jurkat T cells acutely exposed to micromolar concentrations of H2O2 exhibit substantial increases in AP-1 binding activity and the expression of c-jun but not c-fos mRNA. The preferential induction of c-jun by H2O2 did not represent redox stabilization of mRNA transcripts, and oxidative signals closely resembled PHA/PMA stimulation by effectively transactivating the full length c-jun promoter via the proximal jun1 tumor promoter-responsive element (TRE)-like promoter element. Similarly, the complexes binding the consensus AP-1 TRE and jun TRE-like motifs in cells exposed to oxidative signals or PHA/PMA were indistinguishable, being composed of c-Fos, c-Jun, and JunD. However, PHA/PMA but not oxidative signals induced the coordinate activation of reporter constructs containing the AP-1-TRE, NF-AT, and IL-2 promoter regions along with IL-2 mRNA expression. Furthermore, sublethal levels of H2O2 actively suppressed the transcriptional activation of NF-AT and IL-2 reporters as well as the expression of IL-2 mRNA in cells stimulated with PHA/PMA. Gel shift analysis revealed that oxidative suppression of NF-AT represented inhibition in the early generation of NFAT complexes rather than the binding of preformed NF-AT complexes. These results suggest that oxidative signals can positively and negatively regulate T cell transcriptional events and that changes in cellular redox can uncouple AP-1 regulation of c-jun from transcriptional up-regulation of IL-2 via NF-AT.
The gamma 1 heavy chain gene includes all of the cis-acting elements necessary for expression of properly regulated germ-line transcripts.
Authors: Elenich L A , Ford C S , Dunnick W A 
Published: December 2022

Abstract
The regulation of heavy chain switch recombination and the production of germ-line transcripts are highly correlated. IL-4 induces the production of murine gamma 1 germ-line transcripts, and much, if not all, of the regulation is transcriptional. We have investigated the cis-acting elements involved in the regulation of expression of germ-line transcripts by preparing transgenes with the gamma 1 locus. A construct that includes 5' flanking regions, I gamma 1, S gamma 1, and C gamma 1, is regulated like the endogenous gene. Deletion of either most of S gamma 1 or most of C gamma 1 does not alter the correctly regulated expression of the transgenes. An element common to these three different gamma 1 transgenes confers insertion-site independence and copy-number dependence on the transgenes. Finally, the absolute amount of gamma 1-line transcripts is regulated, as transgenic mice with more than 30 gamma 1 genes express no more germ-line transcripts than nontransgenic mice.
Complex of the soluble IL-11 receptor and IL-11 acts as IL-6-type cytokine in hepatic and nonhepatic cells.
Authors: Baumann H , Wang Y , Morella K K , Lai C F , Dams H , Hilton D J , Hawley R G , Mackiewicz A 
Published: December 2022

Abstract
The signaling functions of the membrane and soluble form of the mouse IL-11 receptor (mIL-11R) were compared in rat and human hepatoma cells, which have a low endogenous IL-11 response. The expression vectors encoding either the full length or a secretory form of the ligand binding subunit of mIL-11R together with IL-6-responsive reporter gene constructs were transiently transfected into the H-35 and HepG2 cells. An IL-11-specific stimulation of transcription was detected that was qualitatively similar to that mediated by the endogenous IL-6R. HepG2 cells were noted to synthesize constitutively IL-11, resulting in an autocrine stimulation of gene expression. Addition of COS cell-derived soluble mIL-11R to the hepatoma cell cultures prominently enhanced IL-11 regulation of transfected reporter gene constructs and expression of endogenous acute phase plasma protein genes. Similarly, the complex of soluble mIL-11R and IL-11 was capable of mediating an IL-6-type signaling in cells that are naturally deficient in IL-11 response as shown by the activation of STAT1 and STAT3 in mouse embryonal carcinoma cells and human T cells. The results indicate that the IL-11R can serve as a substitute to IL-6R in activating gene expression in target cells that are devoid of the appropriate ligand-binding receptor subunits.
L- and P-selectins, but not CD49d (VLA-4) integrins, mediate monocyte initial attachment to TNF-alpha-activated vascular endothelium under flow in vitro.
Authors: Luscinskas F W , Ding H , Tan P , Cumming D , Tedder T F , Gerritsen M E 
Published: December 2022

Abstract
Monocyte adhesion to the vascular endothelium is a pivotal step during their egress to tissues at sites of inflammation and immune reactions, and during atherogenesis. In this study, an in vitro flow model and blocking mAb were used to define the role of adhesion molecules in monocyte interactions with activated HUVEC under flow conditions. By videomicroscopy, freely flowing monocytes abruptly halted (initial attachment) on 6-h TNF-alpha-activated HUVEC under flow via L- and P-selectin, whereas E-selectin was not involved. CD49d/CD29 integrin (VLA-4), which can mediate initial attachment of certain T cells to VCAM-1 under flow, did not support monocyte initial attachment. Once initially attached, a small number of monocytes began rolling at 9 microns/s through a mechanism involving L-selectin, as well as CD49d and CD11/CD18 integrins, while the remaining monocytes became firmly adherent, or released to the flow stream. Monocyte stable arrest and subsequent transendothelial migration occurred rapidly and efficiently through either CD49d or CD18 integrin adhesion pathways. Transendothelial passage was also dependent on PECAM-1 (CD31). These data reveal monocytes initially attach to activated endothelium via an L-selectin-dependent mechanism, with a smaller contribution from P-selectin and no contribution by CD49d. Subsequent monocyte rolling, arrest, and transmigration require overlapping functions between multiple members of the selectin, integrin, and Ig gene families.
Enhanced response of macrophages to CSF-1 in autoimmune mice: a gene transfer strategy.
Authors: Moore K J , Naito T , Martin C , Kelley V R 
Published: December 2022

Abstract
Mice with the MRL background have a genetic propensity for autoimmune lupus nephritis. The lpr mutation on the MRL, but not the C3H background, induces rapid and fatal renal injury in which macrophages (M phi) are prominent. We previously established that CSF-1 accompanies M phi accumulation in the kidney of MRL-lpr mice. Furthermore, CSF-1 introduced into the kidney incites renal injury in mice with the lpr mutation, but not congenic strains. Notably, CSF-1 induces more severe tissue injury in MRL-lpr than in C3H-lpr mice. We hypothesized that M phi from the MRL background respond more readily to CSF-1 than normal strains. We establish herein the following: 1) glomerular M phi and bone marrow M phi (BMM phi) from MRL-lpr mice proliferate similarly to CSF-1; 2) MRL BMM phi proliferate more vigorously to CSF-1 than normal strains (C3H, BALB/c) or another strain with lpr (C3H-lpr); and 3) modulation of CSF-1 receptor expression by CSF-1 is more rapid in MRL than C3H BMM phi. We used a gene transfer strategy to deliver CSF-1 into the kidney to evaluate M phi response to CSF-1. We genetically modified tubular epithelial cells to produce CSF-1 (CSF-1-TECs) and placed these cells with BMM phi under the renal capsule. CSF-1-TEC + BMM phi caused a greater accumulation of M phi in the implant site and interstitium of MRL +/+ than C3H +/+ mice. Furthermore, CSF-1-TEC + BMM phi caused a lesion consisting of M phi in MRL +/+ mice, extending from the implant into the adjacent cortex. We suggest that the response of MRL M phi to CSF-1 is responsible for the notable accumulation of M phi in the MRL-lpr kidney.
Stimulation of IgE and IgA production by CD45RA T helper cells in atopic patients.
Authors: Nasert S , Burtchen N , Kussebi F , Millner M , Kroczek R , Jung T , Schwinzer R , Wahn U , Renz H 
Published: December 2022

Abstract
The role of CD45RA T cells on allergen-dependent lymphocyte functions was analyzed in atopic patients. As compared with age-matched nonatopic controls, atopic patients exhibited a significantly (p &lt; 0.01) increased frequency of CD45RA T cells in peripheral blood. Concentration of serum IgE correlated with increases in this T cell subset. In contrast to nonatopic controls, not only CD45RO but also CD45RA T cells from atopic patients provide help for allergen-stimulated IgE and IgA production, and they act in a synergistic fashion. Transwell coculture experiments revealed that optimal production of IgE and IgA required physical contact of CD45RA T cells with B cells. Freshly prepared and in vitro-activated CD45RO and CD45RA T cells from atopic patients showed an increased expression of CD40 ligand when compared with nonatopic individuals. In addition, CD45RA (and CD45RO) T cells from atopic individuals produced IL-4, IL-5, and IFN-gamma when stimulated with mitogens. Whereas stimulation of normal lymphocytes with tetanus Ag was followed by conversion of the CD45RA to the CD45RO phenotype, T cells from atopic donors did not acquire the CD45RO isoform to the same degree despite T cell activation. In atopic patients, addition of IL-4 to anti-CD3/anti-TCR stimulated CD45RA T cell prevented the shift towards the CD45RO phenotype. These data indicate that a subset of CD45RA T cells plays a unique role as effector T cells regulating IgE and IgA production in atopic patients.
Peptides corresponding to CD4-interacting regions of murine MHC class II molecules modulate immune responses of CD4+ T lymphocytes in vitro and in vivo.
Authors: Shen X , Hu B , McPhie P , Wu X , Fox A , Germain R N , König R 
Published: December 2022

Abstract
Immune responses mediated by CD4+ T cells depend on Ag-specific alpha beta TCRs that recognize the specific antigenic peptide presented by MHC class II molecules. Interactions between CD4 coreceptors and monomorphic regions of MHC class II molecules contribute to these responses. To examine whether immune reactions could be modulated by specifically interfering with CD4-MHC class II interactions, we have used, in various in vitro and in vivo assays, peptides that correspond to a region of MHC class II molecules previously shown to control interaction with CD4. Depending on the chemical nature and concentration of these peptides, they modulated Ag-specific responses of CD4+ T cells. At high concentrations, these peptides inhibited T cell responses in vitro. However, under conditions that can cause Ag-induced unresponsiveness, the peptides enhanced T cell responses. Also, primary in vivo immune responses to systemically administered soluble protein Ag, keyhole limpet hemocyanin, were enhanced when mice were treated with peptides corresponding to the CD4-interacting region of MHC class II molecules but not when treated with control peptides. Lymphokine profiles suggested that the peptides may favor the differentiation of Th1 cells, because lymphocytes from peptide-treated mice secreted more IL-2 and IFN-gamma than lymphocytes from nontreated or control-peptide-treated mice upon restimulation with Ag in vitro. These results demonstrate that MHC class II-derived peptides can directly interfere with interactions with CD4 and modulate T cell responses in vitro and in vivo.
Afferent phase production of TNF-alpha is required for the development of protective T cell immunity to Cryptococcus neoformans.
Authors: Huffnagle G B , Toews G B , Burdick M D , Boyd M B , McAllister K S , McDonald R A , Kunkel S L , Strieter R M 
Published: December 2022

Abstract
The development of T cell immunity is required to clear a pulmonary Cryptococcus neoformans infection (via the recruitment and activation of inflammatory cells). The objective of our studies was to determine whether TNF-alpha is required during the afferent phase of the response. The levels of TNF-alpha mRNA and protein in the lungs increased following intratracheal inoculation of CBA/J mice with C. neoformans 52 and preceded the development of an inflammatory response in the lungs. Administration of neutralizing TNF-alpha-specific antiserum on days 0, 3, 6, and 9 reduced inflammatory cell recruitment by 80% on day 13, resulting in a 3-fold increase in lung C. neoformans CFU. The number of CD4+ T cells was decreased by 65%, the number of neutrophils was decreased by 84%, and the number of macrophages was decreased by &gt;98%. Strikingly, a single dose of neutralizing anti-TNF-alpha serum was sufficient to prevent the development of protective cell-mediated immunity on day 35 if administered on day 0, but was ineffective if delayed until day 14. Day 0 anti-TNF-alpha-treated mice could not generate cryptococcus-specific delayed type hypersensitivity reactivity, clear the infection from their lungs (10(4)-fold increase in CFU), control dissemination to the spleen and brain (10(5)- and 10(6)-fold increases in CFU), or adoptively transfer cryptococcus-specific immunity (mononuclear cell recruitment into the lungs following intratracheal challenge or footpad delayed type hypersensitivity). Thus, the production of TNF-alpha during the afferent phase of the immune response against a pulmonary C. neoformans infection (before day 14) is critical for the development of protective T cell immunity in both the lungs and extrapulmonary sites.
Intracellular murine IFN-gamma mediates virus resistance, expression of oligoadenylate synthetase, and activation of STAT transcription factors.
Authors: Will A , Hemmann U , Horn F , Röllinghoff M , Gessner A 
Published: December 2022

Abstract
IFN-gamma is a pleiotropic cytokine that plays a major role in anti-infectious immune responses. The physiologic effects of IFN-gamma are thought to be mediated by the binding of extracellular IFN-gamma to its receptor at the cell surface, thereby triggering an intracellular signaling cascade. In this work, we present evidence for a completely intracellular mechanism for IFN-gamma to induce virus protection. Murine fibroblasts were transfected with the cDNA for murine IFN-gamma, and although no detectable amounts of IFN-gamma were released, these cells were resistant to lysis by the cytolytic vesicular stomatitis virus. In contrast to exogenously added IFN-gamma, the effect of the endogenously produced IFN-gamma was not abolished by treatment with neutralizing Abs. To test whether intracellular signal transduction occurs, an IFN-gamma variant was constructed with the carboxyl-terminal endoplasmic reticulum retention signal Lys-Asp-Glu-Leu (KDEL). Transfection of fibroblasts with this mutant IFN-gamma, anchored in the endoplasmic reticulum, led to virus resistance, thus demonstrating that biologic effects of this protein do not necessarily require binding to the receptor at the cell surface. However, the antiviral state induced by transfection with IFN-gamma-KDEL was strictly dependent on the presence of the IFN-gammaR, since fibroblasts derived from IFN-gammaR-deficient mice (IFN-gammaR -/-) were not rendered virus resistant. The virus resistance induced was accompanied by enhanced expression of 2'-5' oligoadenylate synthetase and constitutive activation of STAT1 (signal transducers and activators of transcription). Hence, autocrinous effects of IFN-gamma in cells naturally producing this cytokine might occur even in the absence of its secretion. The mechanisms involved in signaling appear to be identical with or closely related to those occurring after binding of IFN-gamma to its receptor at the cell surface.
Borrelia burgdorferi outer membrane protein A induces nuclear translocation of nuclear factor-kappa B and inflammatory activation in human endothelial cells.
Authors: Wooten R M , Modur V R , McIntyre T M , Weis J J 
Published: December 2022

Abstract
Lyme disease is caused by infection with Borrelia burgdorferi, and is characterized by bacterial persistence and inflammation in a number of host tissues. B. burgdorferi outer surface lipoproteins possess cytokine stimulatory properties that may be responsible for localized inflammation. B. burgdorferi presence is correlated with severity of disease, and the pathology of many tissues, particularly the arthritic joint, is consistent with localized cytokine production. Spirochete invasion of tissues requires interaction with and penetration of vascular endothelium, suggesting endothelial cells may participate in the inflammation of Lyme disease. In this study, outer surface protein A (OspA), a model B. burgdorferi lipoprotein, was found to be a potent stimulant of nuclear factor-kappa B (NF-kappa B) nuclear translocation in human endothelial cells, resulting in nuclear levels similar to those seen in response to known inflammatory mediators. Only the lipid-modified OspA had activity, and activity was not due to contamination with LPS. Nuclear NF-kappa B was detectable within 15 min, suggesting that OspA directly mediates NF-kappa B nuclear translocation. OspA also rapidly up-regulated endothelial cell production of several proteins whose transcription is dependent on NF-kappa B: the cytokine IL-6; the chemokine IL-8; and the adhesion molecules E-selectin, VCAM-1, and ICAM-1. The adhesion molecules were functional, as demonstrated by enhanced binding of neutrophils to OspA-stimulated endothelial monolayers. These data suggest that OspA may initiate synthesis of many proteins essential for localized inflammation via the direct activation of NF-kappa B-dependent transcription. These observations suggest that the interaction of B. burgdorferi lipoproteins with the endothelium may directly induce the inflammation responsible for the symptoms of Lyme disease.
Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice.
Authors: Haskó G , Szabó C , Németh Z H , Kvetan V , Pastores S M , Vizi E S 
Published: December 2022

Abstract
Adenosine released into the extracellular space by immunologic and nonimmunologic stimuli has been shown to regulate various immune functions. In this study we report that i.p. pretreatment of mice with CGS-21680 HCl (CGS), a selective agonist of A2 adenosine receptors, at 0.2 to 2 mg/kg caused an augmentation of plasma IL-10 levels induced by i.p. injection of LPS, but decreased plasma levels of LPS-induced TNF-alpha. 2-Chloro-N6-cyclopentyladenosine (CCPA), an agonist of A1 adenosine receptors, at 0.5 mg/kg diminished LPS-induced plasma TNF-alpha concentrations, but enhanced LPS-induced IL-10 levels only at the highest dose used (2 mg/kg). The specific A3 adenosine receptor agonist 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-beta- D-ribofuranuronamide, at 0.2 and 0.5 mg/kg potentiated LPS-stimulated IL-10 production and inhibited LPS-induced TNF-alpha production. LPS-induced plasma nitrite and nitrate levels (the breakdown products of nitric oxide (NO)) were suppressed by CGS and CCPA. In the RAW 264.7 macrophage cell line, pretreatment of the cells with both CGS and CCPA inhibited LPS-induced IL-10, TNF-alpha, and NO production, each in a concentration-dependent manner. The inhibitory effect of these drugs on cytokine and NO production was associated with improved mitochondrial respiration. Neither CGS nor CCPA affected the LPS-induced nuclear translocation of transcription factor nuclear factor-kappaB in these cells. These results demonstrate that adenosine receptor stimulation differentially modulates the LPS-induced production of IL-10, TNF-alpha, and NO in vitro and in vivo. The increase in LPS-induced IL-10 production and suppression of LPS-induced TNF-alpha and NO production caused by adenosine receptor activation may explain some of the immunomodulatory actions of adenosine released in excess during inflammatory and/or ischemic insult.
E-selectin preferentially supports neutrophil but not eosinophil rolling under conditions of flow in vitro and in vivo.
Authors: Sriramarao P , Norton C R , Borgstrom P , DiScipio R G , Wolitzky B A , Broide D H 
Published: December 2022

Abstract
The selectin family of adhesion molecules is composed of the L-, E-, and P-selectins, which promote leukocyte rolling during inflammation. Although E-selectin supports neutrophil and lymphocyte rolling, its ability to mediate eosinophil rolling under conditions of flow in vitro and in vivo has not been determined. Using function-blocking mAbs raised against rabbit E-selectin, we have determined whether E-selectin supports human eosinophil rolling in comparison to human neutrophil rolling in IL-1-stimulated rabbit mesenteric venules utilizing intravital microscopy. Anti-rabbit E-selectin mAbs 8B9 and 8G9 were found to inhibit neutrophil rolling but had no significant effect on eosinophil rolling. Likewise, mAb 8B9 F(ab')2 fragments were found to block neutrophil rolling, but did not significantly alter the flux of rolling eosinophils. Isotype-matched Abs and a nonblocking anti-rabbit E-selectin mAb 2A5 failed to inhibit both neutrophil and eosinophil rolling on venular endothelium. In support of these in vivo observations, significant numbers of human neutrophils but not eosinophils were found to avidly roll on monolayers of E-selectin transfectants under physiologic condition of flow in vitro. Under subphysiologic conditions of shear (0.17-0.5 dyn/cm2), eosinophils rolled on E-selectin, albeit in lower numbers (three- to sevenfold) compared with neutrophils. In addition, the rolling velocity of eosinophils was significantly higher compared with neutrophils on E-selectin transfectants. These studies suggest that at physiologic shear rates, E-selectin is likely to function as a major vascular adhesion receptor in mediating neutrophil but not eosinophil rolling in inflamed postcapillary venules.