bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved Clearance of Mycobacterium avium Upon Disruption of the Inducible Nitric Oxide Synthase Gene
Authors: Gomes M. Salomé , Flórido Manuela , Pais Teresa F. , Appelberg Rui 
Published: January 2023

Abstract
Mice genetically deficient in the inducible NO synthase gene (iNOS−/−) were used to study the role played by NO during infection by Mycobacterium avium. iNOS−/− macrophages were equally able to restrict M. avium growth in vitro following stimulation by IFN-γ and TNF-α as macrophages from wild-type mice. In vivo, the infection progressed at similar rates in wild-type and NO-deficient mice during the first 2 mo of infection, but the latter mice were subsequently more efficient in clearing the mycobacteria than the former. The increased resistance of iNOS−/− mice was associated with higher IFN-γ levels in the serum and following in vitro restimulation of spleen cells with specific Ag, increased formation of granulomas and increased survival of CD4+ T cells. We show that NO is not involved in the antimycobacterial mechanisms of M. avium-infected macrophages and, furthermore, that it exacerbates the infection by causing the suppression of the immune response to the pathogen.
Mice Lacking Two or All Three Selectins Demonstrate Overlapping and Distinct Functions for Each Selectin
Authors: Jung Unsu , Ley Klaus 
Published: January 2023

Abstract
Selectins support the capture and rolling of leukocytes in venules at sites of inflammation and in lymphocyte homing. Gene-targeted mice with null mutations at the L-, E-, or P-selectin locus develop normally and show mild (E−/−) to moderate (P−/−, L−/−) defects in inflammatory cell recruitment. Mice lacking both P- and E-selectin (E/P−/−) have severe neutrophilia and spontaneous skin infections that limit their life span. Other combinations of selectin deficiency have not been investigated. We have generated novel mice lacking L- and P-selectin (L/P−/−), L- and E-selectin (L/E−/−), or all three selectins (E/L/P−/−) by bone marrow transplantation. L/P−/− mice (only E-selectin present) show an absence of leukocyte rolling after trauma and severely reduced rolling (by ∼90%) in inflammation induced by TNF-α. Residual rolling in L/P−/− mice was very slow (3.6 ± 0.2 μm/s after TNF-α). L/E−/− mice (only P-selectin present) showed rolling similar to that of L−/− at increased velocities (15.1 ± 0.3 μm/s). The number of adherent leukocytes after 2 or 6 h of TNF-α treatment was not significantly reduced in L/E−/− or L/P−/− mice. E/L/P−/− mice showed very little rolling after TNF-α, all of which was blocked by mAb to α4 integrin. Adherent and emigrated neutrophils were significantly reduced at 6 h after TNF-α. We conclude that any one of the selectins can support some neutrophil recruitment but eliminating all three selectins significantly impairs neutrophil recruitment.
Promotion of Neutrophil Chemotaxis Through Differential Regulation of β1 and β2 Integrins
Authors: Harler Mary Beth , Wakshull Eric , Filardo Edward J. , Albina Jorge E. , Reichner Jonathan S. 
Published: January 2023

Abstract
Migration of neutrophils requires sequential adhesive and deadhesive interactions between β1 and β2 integrins and components of the extracellular matrix. Prompted by reports that describe interaction of soluble β-glucan with the β2 integrin Mac-1, a role for β-glucan in regulation of integrin-mediated migration was investigated. Neutrophil migration in response to fMLP was assessed using an agarose overlay method with slides precoated with fibronectin (Fn) ± β-glucan. On Fn, random migration in excess of directed migration was observed. In contrast, migration on Fn + β-glucan was directional, with marked diminution of random migration. This conversion of random to directed migration was seen neither when Fn was supplemented with alternative polysaccharides nor when β-glucan was applied to other components of the extracellular matrix. This effect of β-glucan was shown to be cation dependent and to be effected by Arg-Gly-Asp-containing peptides consistent with an integrin-mediated event. mAb inhibition studies demonstrate that β-glucan effects this shift toward directed migration through suppression of migration mediated by Mac-1 and very late Ag 5 and enhancement of very late Ag 3-mediated migration. Adhesion assays suggest that the prochemotactic influence of β-glucan is due, in part but not entirely, to modulation of PMN adhesion to Fn. In summary, these data support a novel role for β-glucan in regulation of β1- and β2-mediated neutrophil migration on Fn.
Paclitaxel Enhances Macrophage IL-12 Production in Tumor-Bearing Hosts Through Nitric Oxide
Authors: Mullins David W. , Burger Carol J. , Elgert Klaus D. 
Published: January 2023

Abstract
Tumor-induced macrophages (Mφs) mediate immunosuppression, in part, through increased production of factors that suppress T cell responsiveness and underproduction of positive regulatory cytokines. Pretreatment of tumor-bearing host (TBH) Mφs with the anticancer agent paclitaxel (Taxol) partially reverses tumor-induced Mφ suppressor activity, suggesting that paclitaxel may restore TBH Mφ production of proimmune factors. Because paclitaxel demonstrates LPS-mimetic capabilities and increased production of the LPS-induced immunostimulatory cytokine IL-12 could account for enhanced T cell responsiveness, we investigated whether paclitaxel induces Mφ IL-12 production. Tumor growth significantly down-regulated Mφ IL-12 p70 production through selective dysregulation of IL-12 p40 expression. LPS stimulation failed to overcome tumor-induced dysregulation of p40 expression. In contrast, paclitaxel significantly enhanced both normal host and TBH Mφ IL-12 p70 production in vitro, although TBH Mφ IL-12 production was lower than that of similarly treated normal host Mφs. Paclitaxel enhanced p40 expression in a dose-dependent manner. Through reconstituted Mφ IL-12 expression, paclitaxel pretreatment relieved tumor-induced Mφ suppression of T cell alloreactivity. Blocking Mφ NO suppressed paclitaxel’s ability to induce IL-12 production. This suggests that paclitaxel-induced activities may involve a NO-mediated autocrine induction pathway. Collectively, these data demonstrate that paclitaxel restores IL-12 production in the TBH and ascribe a novel immunotherapeutic component to the pleiotropic activities of NO. Through its capacity to induce IL-12 production, paclitaxel may contribute to the correction of tumor-induced immune dysfunction.
Regulation of Pulmonary T Cell Responses to Inhaled Antigen: Role in Th1- and Th2-Mediated Inflammation
Authors: Lee Shiour-Ching , Jaffar Zeina H. , Wan Kong-Sang , Holgate Stephen T. , Roberts Kevan 
Published: January 2023

Abstract
DO11.10 transgenic mice, expressing an OVA-specific TCR, were used to study pulmonary T cell responses to inhaled Ags. Before OVA inhalation, the activation of lung parenchymal T cells elicited both strong proliferative responses and IL-2 production. However, following Ag inhalation the proliferative responses of the lung T cells, when restimulated in vitro with OVA323–339 peptide or immobilized anti-CD3, were severely attenuated and associated with a decrease in the level of production of IL-2 but not IFN-γ. Such immune regulation was tissue-specific, because T cell responses in the lymph nodes and spleens were normal. This dramatic aerosol-induced attenuation of parenchymal T cell proliferation was also observed in BALB/c mice immunized with OVA and in BALB/c mice following adoptive transfer of DO11.10 T cells bearing either a Th1 or Th2 phenotype. In mice that had received Th2 cells, the reduced proliferative responses were associated with a decrease in IL-2 expression but augmented IL-4 and IL-5 production. Invariably, the inhibition of proliferation was a consequence of the action of F4/80+ interstitial macrophages and did not involve alveolar macrophages or their products. These observations demonstrate that clonal expansion of T cells in the lung compartment is prevented following the onset of either Th1- or Th2-mediated inflammation. This form of immune regulation, which appears as a selective defect in IL-2-driven proliferation, may serve to prevent the development of chronic pulmonary lymphoproliferative responses.
HLA-Class II-Associated Control of Antigen Recognition by T Cells in Leprosy: A Prominent Role for the 30/31-kDa Antigens
Authors: Thole Jelle E. R. , Janson Anneke A. M. , Cornelisse Yolanthe , Schreuder Geziena M. T. , Wieles Brigitte , Naafs Ben , de Vries René R. P. , Ottenhoff Tom H. M. 
Published: January 2023

Abstract
The recognition of 16 mycobacterial Ags by a panel of T cell lines from leprosy patients and healthy exposed individuals from an endemic population was examined within the context of expressed HLA-DR molecules. Although overall no significant differences were found between the frequencies of Ag recognition in the different subject groups, when Ag-specific T cell responses were examined within the context of HLA-DR, a highly significant difference was found in the recognition of the 30/31-kDa Ag. HLA-DR3 appeared to be associated with high T cell responsiveness to the 30/31-kDa Ag in healthy contacts (p = 0.01), but, conversely, with low T cell responsiveness to this Ag in tuberculoid patients (p = 0.005). Within the group of HLA-DR3-positive individuals, differences in 30/31-kDa directed T cell responsiveness were highly significant not only between healthy individuals and tuberculoid patients (p &lt; 0.0001), but also between healthy individuals and lepromatous patients (p = 0.009), and consequently between healthy individuals compared with leprosy patients as a group (p &lt; 0.0001). A dominant HLA-DR3-restricted epitope was recognized by healthy contacts in this population. It has been proposed that secreted Ags may dominate acquired immunity early in infection. The low T cell response to the secreted, immunodominant 30/31-kDa Ag in HLA-DR3-positive leprosy patients in this population may result in retarded macrophage activation and delayed bacillary clearance, which in turn may lead to enhanced Ag load followed by T cell-mediated immunopathology.
Cellular Immunity to β2-Glycoprotein-1 in Patients with the Antiphospholipid Syndrome
Authors: Visvanathan Sudha , McNeil H. Patrick 
Published: January 2023

Abstract
Patients with antiphospholipid syndrome (APS) suffer recurrent thromboses, thrombocytopenia, and/or fetal loss in association with Abs that can be detected in phospholipid-dependent assays. Despite the name, the Igs associated with APS are predominantly directed against epitopes on phospholipid-binding plasma proteins, such as β2-glycoprotein-1 (β2GP1) and prothrombin. The aim of this study was to examine the cellular immune response to β2GP1 in patients with APS. Using a serum-free stimulation assay, PBMCs from 8 of 18 patients with APS proliferated to purified β2GP1 or to the β2GP1 present in serum, whereas no stimulation was observed by PBMCs from healthy individuals, patients with other autoimmune diseases, or anticardiolipin Ab-positive patients without histories of thromboses or fetal loss. The immune response was Ag-specific, requiring class II molecules, CD4+ T cells, and APCs, and was associated with a selective expansion of CD4+ but not CD8+ T cells. The proliferating T cells produced IFN-γ but not IL-4, indicating a bias toward a type 1 immune response. Chronic low grade stimulation of autoreactive β2GP1-specific, IFN-γ-producing Th1 CD4+ T cells may contribute to the high risk of thromboses and pregnancy failure in patients with APS.
New Class I and II HLA Alleles Strongly Associated with Opposite Patterns of Progression to AIDS
Authors: Hendel Houria , Caillat-Zucman Sophie , Lebuanec Hélène , Carrington Mary , O’Brien Steve , Andrieu Jean-Marie , Schächter François , Zagury Daniel , Rappaport Jay , Winkler Cheryl , Nelson George W. , Zagury Jean-François 
Published: January 2023

Abstract
The genetics of resistance to infection by HIV-1 cohort consists of 200 slow and 75 rapid progressors to AIDS corresponding to the extremes of HIV disease outcome of 20,000 Caucasians of European descent. A comprehensive analysis of HLA class I and class II genes in this highly informative cohort has identified HLA alleles associated with fast or slow progression, including several not described previously. A quantitative analysis shows an overall HLA influence independent of and equal in magnitude (for the protective effect) to the effect of the CCR5-Δ32 mutation. Among HLA class I genes, A29 (p = 0.001) and B22 (p &lt; 0.0001) are significantly associated with rapid progression, whereas B14 (p = 0.001) and C8 (p = 0.004) are significantly associated with nonprogression. The class I alleles B27, B57, C14 (protective), and C16, as well as B35 (susceptible), are also influential, but their effects are less robust. Influence of class II alleles was only observed for DR11. These results confirm the influence of the immune system on disease progression and may have implications on peptide-based vaccine development.
A Genome-Wide Search Identifies Two Susceptibility Loci for Experimental Autoimmune Encephalomyelitis on Rat Chromosomes 4 and 10
Authors: Roth Marie-Paule , Viratelle Carine , Dolbois Laurence , Delverdier Maxence , Borot Nicolas , Pelletier Lucette , Druet Philippe , Clanet Michel , Coppin Hélène 
Published: January 2023

Abstract
Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that exhibits many pathologic similarities with multiple sclerosis. The genetic loci that contribute to mononuclear cell infiltration of the central nervous system and clinical manifestations of EAE in the rat were investigated in the F2 progeny of the highly susceptible Lewis and resistant Brown Norway strains. The data confirmed that the Lewis allele of a MHC-linked gene is necessary, but not sufficient, to confer EAE susceptibility in the F2 progeny. Subsequent analyses were thus restricted to the subset of the F2 animals with EAE-predisposing MHC genotypes. A genome-wide scan approach was performed using 103 microsatellite markers covering 85% of the genome. Two non-MHC regions were identified, one near the centromere of chromosome 4 and the other on the long arm of chromosome 10, that significantly contributed to the disease. In addition, three regions on chromosomes 9, 13, and 17 were suggestive for linkage. Congenic mapping is now needed to reduce the support intervals encoding the loci of interest to sizes amenable to physical mapping and to eventually demonstrate the involvement of some of the candidate genes of immunologic importance localized in these regions.
TCR-Independent Pathways Mediate the Effects of Antigen Dose and Altered Peptide Ligands on Th Cell Polarization
Authors: Grakoui Arash , Donermeyer David L. , Kanagawa Osami , Murphy Kenneth M. , Allen Paul M. 
Published: January 2023

AbstractWe examined the role of the peptide/MHC ligand in CD4+ T cell differentiation into Th1 or Th2 cells using a TCR αβ transgenic mouse specific for hemoglobin (Hb)(64-76)/I-Ek. We identified two altered peptide ligands of Hb(64-76) that retain strong agonist activity but, at a given dose, induce cytokine patterns distinct from the Hb(64-76) peptide. The ability of these peptides to produce distinct cytokine patterns at identical doses is not due to an intrinsic qualitative property. Each peptide can induce Th2 cytokines at low concentrations and Th1 cytokines at high concentrations and has a unique range of concentrations at which these distinct effects occur. The pattern of cytokines produced from limiting dilution of naive T cells demonstrated that the potential to develop an individual Th1 or Th2 cell is stochastic, independent of Ag dose. We propose that the basis for the observed effects on the Th1/Th2 balance shown by the altered peptide ligands and the amount of Ag dose involves the modification of soluble factors in bulk cultures that are the driving force that polarize the population to either a Th1 or Th2 phenotype.
Lymphotactin Acts as an Innate Mucosal Adjuvant
Authors: Lillard James W. , Boyaka Prosper N. , Hedrick Joseph A. , Zlotnik Albert , McGhee Jerry R. 
Published: January 2023

Abstract
Lymphotactin (Lptn) is a C chemokine produced predominantly by NK and CD8-positive (CD8+) T cells including γδ TCR-positive (TCR+) intraepithelial lymphocytes. Lptn is chemotactic for NK and T cells and likely plays an important role in maintaining the integrity of the epithelium and in mucosal immune responses. In this study, we characterized the immune responses to OVA given intranasally with Lptn to mice. This regimen enhanced OVA-specific serum Ab responses and Ab titers in mucosal secretions. Lptn also enhanced OVA-specific Ab-forming cells in mucosal and systemic compartments. CD4-positive (CD4+) T cells isolated from mucosal compartments and spleens of mice intranasally immunized with OVA plus Lptn displayed higher OVA-specific proliferative responses and greater synthesis of IFN-γ, IL-2, IL-4, IL-5, IL-6, and IL-10 than did CD4+ T cells from mice given OVA without Lptn. These studies indicate that Lptn has adjuvant properties and suggest that Lptn present in the mucosa has the potential to enhance mucosal and systemic Ab responses through help provided by Th1- and Th2-type cells to link the initial innate signals of the mucosa with the acquired immune system.
Intranasally Induced Immunological Tolerance Is Determined by Characteristics of the Draining Lymph Nodes: Studies with OVA and Human Cartilage gp-39
Authors: Wolvers Danielle A. W. , Coenen-de Roo Christina J. J. , Mebius Reina E. , van der Cammen Maarten J. F. , Tirion Felicia , Miltenburg André M. M. , Kraal Georg 
Published: January 2023

AbstractMucosal tolerance is a naturally occurring immunological phenomenon that prevents harmful inflammatory responses to ingested or inhaled environmental, predominantly nondangerous, Ags. The nasal mucosa is an extremely efficient compartment in the induction of immunological tolerance which can be exploited in Ag-specific treatment of autoimmune disease. With the use of a model Ag (OVA) and an Ag implicated in the autoimmune disease rheumatoid arthritis (human cartilage gp-39), we here show in a mouse model that the superficial cervical and internal jugular lymph nodes that drain the nasal mucosa are instrumental in the induction of tolerance. Removal of these lymph nodes abrogates tolerance induction, which can be restored by transplantation of superficial cervical lymph nodes, but not of peripheral lymph nodes. The results indicate that lymph nodes that directly drain the nasal mucosa constitute a unique microenvironment which favors the induction of immunological tolerance.
CD40 Activation Boosts T Cell Immunity In Vivo by Enhancing T Cell Clonal Expansion and Delaying Peripheral T Cell Deletion
Authors: Maxwell Joseph R. , Campbell Jeff D. , Kim Carol H. , Vella Anthony T. 
Published: January 2023

AbstractIn this report we show that activation of APC with an agonist anti-CD40 mAb profoundly alters the behavior of CD4 T cells in vivo. Stimulation of mice with anti-CD40 2 days before, but not 1 day after, administration of superantigen (SAg) enhanced CD4 and CD8 T cell clonal expansion by approximately threefold. Further, CD40 activation also delayed peripheral T cell deletion after activation. Dying, activated T cells were quantitated by detecting extracellular phosphatidylserine with concomitant staining for SAg-reactive T cells using a TCR Vβ-specific mAb. Upon close examination, it was shown that CD40 activation delayed the death of the activated T cells. Additionally, it was found that enhanced survival of CD4 T cells was equally dependent on APC expression of B7-1 and B7-2. This is in contrast to CD8 T cells, which did not depend as much on B7-1 as B7-2. Thus, CD40 activation indirectly promotes T cell growth and delays the death of SAg-stimulated CD4 T cells in vivo. These data suggest that one way CD40 activation promotes a more robust immune response is by indirectly increasing the production of effector T cells and by keeping them alive for longer periods of time.
IL-2, But Not IL-4 and Other Cytokines, Induces Phosphorylation of a 98-kDa Protein Associated with SHP-2, Phosphatidylinositol 3′-Kinase, and Grb2
Authors: Gadina Massimo , Sudarshan Chitra , O’Shea John J. 
Published: January 2023

AbstractBinding of IL-2 to its receptor activates several biochemical pathways, including JAK-STAT, Ras-mitogen-activated protein kinase, and phosphatidylinositol 3′-kinase (PI 3′-kinase) pathways. Recently, it has been shown that the SH2-containing phosphatase, SHP-2, becomes phosphorylated in response to IL-2 stimulation, associates with PI3′-kinase and Grb2, and can exert a positive regulatory role in IL-2 signaling. We now report the identification of a prominent 98-kDa protein (p98) found to be phosphorylated in response to IL-2 stimulation and coprecipitated with SHP-2, the p85 subunit of PI 3′-kinase and Grb2. Interestingly, whereas IL-4 is known to activate PI 3′-kinase, we did not observe any p98 phosphorylation in response to IL-4 stimulation. p98 can form a multipartite complex with all these proteins as immunodepleting with anti-p85 antiserum substantially reduced the amount of p98 immunoprecipitated by SHP-2 and Grb2; the converse was also true. Furthermore, phosphorylation of p98 did not occur in cells lacking JAK3, suggesting that it may be a JAK substrate. Finally, deglycosylation of p98 did not alter its migration, suggesting p98 is not a member of the recently described SHP substrate/signal-regulatory proteins family of transmembrane glycoproteins. Thus p98 is a prominent IL-2-dependent substrate that associates with multiple proteins involved in IL-2 signaling and may play an important role in coupling the different signal transduction pathways activated by IL-2.
Immunosuppressive Leflunomide Metabolite (A77 1726) Blocks TNF-Dependent Nuclear Factor-κB Activation and Gene Expression
Authors: Manna Sunil K. , Aggarwal Bharat B. 
Published: January 2023

Abstract
Leflunomide is a novel immunosuppressive and antiinflammatory agent currently being tested for treatment of autoimmune diseases and transplant rejection. NF-κB is a transcription factor activated in response to a wide variety of inflammatory stimuli, including TNF, but whether leflunomide blocks NF-κB activation is not known. In the present report we demonstrate that treatment of a human T cell line (Jurkat) with leflunomide blocks TNF-mediated NF-κB activation in a dose- and time-dependent manner, with maximum inhibition at 5–10 μM. Inhibition was not restricted to TNF-induced activation, because leflunomide also inhibited NF-κB activation induced by other inflammatory agents, including phorbol ester, LPS, H2O2, okadaic acid, and ceramide. Leflunomide blocked the degradation of IκBα and subsequent nuclear translocation of the p65 subunit, steps essential for NF-κB activation. This correlated with inhibition of dual specificity-mitogen-activated protein kinase kinase as well as an Src protein tyrosine kinase, p56lck, by leflunomide. Reducing agents did not reverse the effect of leflunomide. Leflunomide also suppressed the TNF-activated NF-κB-dependent reporter gene expression. Our results thus indicate that leflunomide is a potent inhibitor of NF-κB activation induced by a wide variety of inflammatory stimuli, and this provides the molecular basis for its anti-inflammatory and immunosuppressive effects.