bluuebunny/crossref_metadata_2025_split huggingface dataset:
Salmonella typhimurium infections in mice deficient in interleukin-4 production: role of IL-4 in infection-associated pathology.
Authors: Everest P , Allen J , Papakonstantinopoulou A , Mastroeni P , Roberts M , Dougan G 
Published: January 2023

Abstract
Mice harboring mutations in the IL-4 gene (IL-4(-/-)) were infected with a range of Salmonella typhimurium HWSH derivatives using different routes of infection. Compared with IL-4(+/+) mice, IL-4(-/-) mice exhibited a delayed time to death following infection with wild-type S. typhimurium HWSH. Groups of IL-4(+/+) mice infected with S. typhimurium HWSH purE, a less virulent derivative, showed sporadic deaths and harbored micro- or macroabscesses in their tissues, particularly associated with the liver. However, IL-4(-/-) mice infected with similar doses of S. typhimurium HWSH purE bacteria were resistant to killing and failed to develop detectable abscesses. Abscess formation in IL-4(-/-) mice could be induced by i.v. administration of rIL-4 during the S. typhimurium HWSH purE infection. The immune response in both IL-4(-/-) and IL-4(+/+) mice was of the Th1-type. Viable salmonella bacteria could be found associated with abscesses. Both IL-4(-/-) and IL-4(+/+) mice were resistant to killing by S. typhimurium aroA.
Presentation via the class I pathway by Leishmania amazonensis-infected macrophages of an endogenous leishmanial antigen to CD8+ T cells.
Authors: Kima P E , Ruddle N H , McMahon-Pratt D 
Published: January 2023

Abstract
CD8+ T cells play a protective role in immunity to cutaneous leishmaniasis. However, it has been unclear how these cells execute this function, since results from several investigations attempting to demonstrate recognition of Leishmania-infected macrophages by CD8+ T cells have been contradictory. In this study, we report the generation of CD8+ T cell lines specific for GP46/M-2, a leishmanial Ag, previously shown to protectively immunize mice against a Leishmania amazonensis challenge. Using T cell cytolysis and IFN-gamma production to assess CD8+ T cell activation, we show that in addition to recognizing mammalian cells transfected with GP46/M-2, these CD8+ T cell lines also recognize macrophages infected with Leishmania amazonensis. MHC class I presentation of GP46/M-2 by infected macrophages can be blocked by treatment with brefeldin A and also by inhibitors of the cytosolic multicatalytic proteasome, N-acetyl-L-leucinyl-L-leucinal-L-norleucinal and N-acetyl-L-leucinyl-L-leucinylmethional. These results suggest that this leishmanial Ag is processed in the macrophage cytoplasm and is presented to CD8+ T cells via the classical pathway of MHC class I presentation. The relevance of these findings as they impact on our understanding of the biology of the parasite within the macrophage is discussed.
Virus dissemination through the brain parenchyma without immunologic control.
Authors: Stevenson P G , Freeman S , Bangham C R , Hawke S 
Published: January 2023

Abstract
After inoculation into the cerebrospinal fluid, the neurovirulent influenza virus A/WSN caused a rapidly progressive encephalitis that was uniformly fatal within 8 days. After inoculation into the brain parenchyma, the same virus replicated for 7 to 20 days without causing clinical illness, but when infection reached the cerebrospinal fluid, encephalitis was lethal within a further 6 days. As the virus spread through the brain parenchyma, there was intense intracerebral inflammation, with up-regulation of MHC class I and MHC class II expression and recruitment of CD44(high) CD49d(high) T cells. However, this was not associated with antiviral Ab production, and the infiltrating cells, unlike primed A/WSN-specific T cells, did not eliminate the virus in vivo or show evidence of virus recognition in vitro. Thus, a neurovirulent virus was able to disseminate widely through the brain parenchyma and induce considerable intracerebral inflammation without eliciting protective immunity.
Matching antibody class with pathogen type and portal of entry: cognate mechanisms regulate local isotype expression patterns in lymph nodes draining the respiratory tract of mice inoculated with respiratory viruses, according to virus replication competence and site of inoculation.
Authors: Sangster M Y , Mo X Y , Sealy R , Coleclough C 
Published: January 2023

Abstract
Intranasal deposition of Sendai virus (SV) in C57BL/6 mice provokes an Ab-forming cell (AFC) reaction in mediastinal (MLN) and cervical lymph nodes (CLN), which drain the lungs and upper respiratory tract, respectively. While the majority of AFC elicited by infectious SV at both sites produced IgG, the CLN response to SV rendered inactive in replication was restricted almost entirely to IgA, although isotype switching in mediastinal continued to be skewed heavily to IgG. However, in vitro restimulation of the accompanying virus-specific T cell populations from the two sites did not reveal any significant difference in lymphokine output, and isotype expression was not altered substantially in mice lacking IL-4 or IL-6 genes. To dissociate the response to specific Ags from the inflammatory reaction to viral infection, we examined the response to inactivated SV in the face of infection with influenza virus A/HKx31. The magnitude and IgA dominance of the anti-SV AFC population in the CLN were unaffected by a simultaneous, vigorous, IgG-dominated CLN anti-influenza reaction. Evidently, the characteristics of this antiviral response are determined primarily by cognate interactions. Moreover, the IgA bias of the CLN AFC response to inactivated SV was observed only when the virus was delivered intranasally: injection under the epidermis of the cheek, a site that has a lymphatic drainage into the CLN, resulted in an IgG-dominated CLN AFC reaction, lacking IgA. The site of deposition of a vaccine can thus have more influence on the pattern of isotypes induced than the site at which the immune response is initiated.
Perforin-mediated cytolysis plays a limited role in host resistance to Toxoplasma gondii.
Authors: Denkers E Y , Yap G , Scharton-Kersten T , Charest H , Butcher B A , Caspar P , Heiny S , Sher A 
Published: January 2023

Abstract
Resistance of perforin knockout (PKO) mice to infection with Toxoplasma gondii was assessed in models of acute infection and during chronic disease. PKO mice vaccinated with the attenuated mutant, ts-4, displayed severely defective CTL responses against tachyzoite-infected targets. Lysis of the NK target, YAC-1, was also severely impaired in PKO mice following ts-4 vaccination. In contrast, wild-type mice developed high levels of CTL and NK lytic activity after ts-4 vaccination. Despite severely defective lytic activity, vaccinated PKO animals were completely resistant to challenge with the virulent strain RH, which normally causes a lethal acute infection. Resistance was attributable to production of IFN-gamma, which remained unimpaired in the PKO animals. In contrast, when PKO mice were infected with low virulence parasite strain ME49, which progresses to the cyst-forming stage after passage through an acute phase, accelerated mortality was observed beginning at 75 days postinfection. A three- to fourfold increase in brain cyst numbers was also found by day 30 in infected PKO animals. Nevertheless, the PKO strain produced normal levels of IFN-gamma after ME49 infection, ruling out impaired production of the latter cytokine as a cause of increased susceptibility. Together, these results show that perforin-dependent cytolytic function is not required for host resistance to lethal acute infection in preimmunized animals, but that the latter activity contributes to the control of infection during the chronic stage.
Expression of leukocyte fucosyltransferases regulates binding to E-selectin: relationship to previously implicated carbohydrate epitopes.
Authors: Wagers A J , Stoolman L M , Kannagi R , Craig R , Kansas G S 
Published: January 2023

Abstract
E-selectin is a carbohydrate-binding endothelial cell adhesion molecule that reportedly interacts with several related sialylated and fucosylated carbohydrates. The activity of leukocyte alpha1,3-fucosyltransferases (FucT-IV or FucT-VII) is an essential step in the synthesis of E-selectin ligands. Using a panel of stably transfected hemopoietic cell lines, we have investigated the role of alpha1,3-fucosyltransferases in generating E-selectin ligands, and the relationship between adhesion to E-selectin and expression of mAb-defined carbohydrates. Expression of FucT-VII was always sufficient for binding to E- and P-selectin, while the ability of FucT-IV to construct E-selectin ligands varied among different cell types. Furthermore, FucT-IV was unable to support any binding to P-selectin in a lymphoid cell line, even when expressed at levels equivalent to those in myeloid cells. FucT-IV expression generated high levels of surface Le(x)/CD15 and CDw65, whereas expression of FucT-VII correlated with a subset of mAb-defined sialyl Lewis X (sLex)-like structures. FucT-IV-associated epitopes were present on both binding and nonbinding cells, whereas all cells that expressed FucT-VII-associated epitopes bound E-selectin. However, treatment of HL60 cells with neuraminidase destroyed FucT-VII-associated epitopes at a faster rate than E-selectin binding sites. Surface expression of a subset of mAb-defined sLex-like carbohydrates is therefore a good marker for high levels of FucT-VII activity, but these carbohydrates are not themselves required for recognition of E-selectin.
Induction of ceruloplasmin synthesis by IFN-gamma in human monocytic cells.
Authors: Mazumder B , Mukhopadhyay C K , Prok A , Cathcart M K , Fox P L 
Published: January 2023

Abstract
Ceruloplasmin is a 132-kDa glycoprotein abundant in human plasma. It has multiple in vitro activities, including copper transport, lipid pro- and antioxidant activity, and oxidation of ferrous ion and aromatic amines; however, its physiologic role is uncertain. Although ceruloplasmin is synthesized primarily by the liver in adult humans, production by cells of monocytic origin has been reported. We here show that IFN-gamma is a potent inducer of ceruloplasmin synthesis by monocytic cells. Activation of human monoblastic leukemia U937 cells with IFN-gamma increased the production of ceruloplasmin by at least 20-fold. The identity of the protein was confirmed by plasmin fingerprinting. IFN-gamma also increased ceruloplasmin mRNA. Induction followed a 2- to 4-h lag and was partially blocked by cycloheximide, indicating a requirement for newly synthesized factors. Ceruloplasmin induction in monocytic cells was agonist specific, as IL-1, IL-4, IL-6, IFN-alpha, IFN-beta, TNF-alpha, and LPS were completely ineffective. The induction was also cell type specific, as IFN-gamma did not induce ceruloplasmin synthesis in endothelial or smooth muscle cells. In contrast, IFN-gamma was stimulatory in other monocytic cells, including THP-1 cells and human peripheral blood monocytes, and also in HepG2 cells. Ceruloplasmin secreted by IFN-gamma-stimulated U937 cells had ferroxidase activity and was, in fact, the only secreted protein with this activity. Monocytic cell-derived ceruloplasmin may contribute to defense responses via its ferroxidase activity, which may drive iron homeostasis in a direction unfavorable to invasive organisms.
Suppression of ongoing ocular inflammatory disease by topical administration of plasmid DNA encoding IL-10.
Authors: Daheshia M , Kuklin N , Kanangat S , Manickan E , Rouse B T 
Published: January 2023

Abstract
Ocular infection with herpes simplex virus leads to an inflammatory lesion in the cornea orchestrated by CD4+ Th1 lymphocytes. This immunopathologic disease, called herpetic stromal keratitis, is an important cause of impaired vision. In this study, we set out to determine whether established lesions of herpetic stromal keratitis could be controlled by topically administering naked plasmid DNA encoding cytokines to the corneal surface. A single topical administration of DNA encoding IL-10 was beneficial to the majority (75%) of treated animals, and 50% (vs 10% in controls) resolved their lesions completely over a 23-day observation period. Topical ocular application of DNA encoding foreign proteins was also shown to be an effective means of inducing systemic and mucosal immune responses. The direct application of DNA encoding cytokines may represent an additional therapeutic option for the management of immunoinflammatory disease.
Listeria monocytogenes potently induces up-regulation of endothelial adhesion molecules and neutrophil adhesion to cultured human endothelial cells.
Authors: Krüll M , Nöst R , Hippenstiel S , Domann E , Chakraborty T , Suttorp N 
Published: January 2023

Abstract
Infection of endothelial cells by Listeria monocytogenes is an essential step in the pathogenesis of listeriosis. Listeriolysin (Hly) is one of its major virulence factors. In the early phase of the disease polymorphonuclear leukocytes (PMN) substantially contribute to the nonspecific anti-listerial resistance. We characterized the effects of L. monocytogenes on the expression of endothelial adhesion molecules and on subsequent PMN adhesion to cultured HUVEC. P-selectin, E-selectin, intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) were up-regulated in HUVEC after cell incubation with L. monocytogenes (wild type), but not with the nonpathogenic Listeria innocua strain. P-selectin expression peaked after 30 min and could be mimicked with similar kinetics by exposure to L. innocua engineered to produce large amounts of Hly or by addition of purified Hly. Listeriolysin production, however, was not necessary for an up-regulation of E-selectin after 6 h or of ICAM-1 and VCAM-1 after 18 to 24 h in HUVEC, because L. monocytogenes defective for Hly synthesis was almost as effective as the wild type. Listeria-induced up-regulation of endothelial adhesion molecules was accompanied by an increased binding of PMN to infected HUVEC. PMN adhesion was significantly reduced in the presence of anti-beta2 integrin, anti-E-selectin, and anti-ICAM-1, but not anti-VCAM-1 Abs. Our data indicate that infection of endothelial cells with L. monocytogenes induced up-regulation of adhesion molecules by two different mechanisms: a Hly-dependent up-regulation of P-selectin and a Hly-independent expression of E-selectin, ICAM-1, and VCAM-1. The ability of L. monocytogenes to stimulate PMN adhesion to endothelial cells may be an important mechanism in the pathogenesis of severe listeriosis.
P- and L-selectin mediate distinct but overlapping functions in endotoxin-induced leukocyte-endothelial interactions in the rat mesenteric microcirculation.
Authors: Davenpeck K L , Steeber D A , Tedder T F , Bochner B S 
Published: January 2023

Abstract
Endotoxin is a potent stimulus of leukocyte infiltration, but the adhesion-related mechanisms responsible for LPS-induced cell recruitment events in vivo remain poorly characterized. Utilizing intravital microscopy, we examined the role of P- and L-selectin in LPS-induced inflammation. We demonstrated that superfusion of rat mesentery with LPS resulted in significant increases in both leukocyte rolling and adherence, which were maintained for at least 2 h. Pretreatment with a P-selectin neutralizing mAb only partially inhibited LPS-induced leukocyte rolling, but completely inhibited LPS-induced leukocyte adherence throughout the 2-h observation period. Pretreatment with an L-selectin neutralizing mAb dramatically inhibited LPS-induced increases in leukocyte rolling, but unlike the P-selectin mAb did not inhibit leukocyte adhesion. Fucoidin, which blocks both P- and L-selectin function, completely inhibited LPS-induced leukocyte rolling and adhesion. Consistent with previous studies, leukocyte rolling velocities on P-selectin were observed to be far less than velocities observed for leukocytes rolling on L-selectin in vivo. These data suggest that P-selectin plays a role in LPS-induced rolling and is essential for LPS-induced leukocyte adherence, while L-selectin functions in LPS-induced rolling, but not in adhesion.
Human T cell leukemia virus type I (HTLV-I)-specific CD8+ CTL clones from patients with HTLV-I-associated neurologic disease secrete proinflammatory cytokines, chemokines, and matrix metalloproteinase.
Authors: Biddison W E , Kubota R , Kawanishi T , Taub D D , Cruikshank W W , Center D M , Connor E W , Utz U , Jacobson S 
Published: January 2023

Abstract
Human T cell leukemia virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive neurologic disease characterized by marked degeneration of the spinal cord and the presence of infiltrating CD8+ T cells and macrophages. HAM/TSP patients have very high frequencies of HTLV-I-specific CD8+ CTL in peripheral blood and in cerebrospinal fluid. In this study, we show that HAM/TSP patients also have elevated levels of peripheral blood CD8+ T cells that produce intracellular IFN-gamma. To address the potential role of soluble mediators secreted by CD8+ T cells in the pathogenesis of HAM/TSP, we have analyzed the capacity of a panel of nine HTLV-I-specific CD8+ CTL clones derived from three HAM/TSP patients to secrete cytokines, chemokines, and matrix metalloproteinases. The results demonstrate that the majority of these CTL clones secrete IFN-gamma, TNF-alpha, macrophage-inflammatory protein-1alpha and -1beta, IL-16, and matrix metalloproteinase-9. These findings indicate that HTLV-I-specific CD8+ CTL are an important source of proinflammatory soluble mediators that may contribute significantly to the pathogenesis of HAM/TSP.
Accumulation of human T lymphotropic virus (HTLV)-I-specific T cell clones in HTLV-I-associated myelopathy/tropical spastic paraparesis patients.
Authors: Höger T A , Jacobson S , Kawanishi T , Kato T , Nishioka K , Yamamoto K 
Published: January 2023

Abstract
Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraperesis (HAM/TSP) is a slowly progressive neurologic disorder following infection with HTLV-I. It is characterized by spasticity and hyper-reflexia of the lower extremities, urinary bladder disturbance, lower extremity muscle weakness, and sensory disturbances. HTLV-I, as an inducer of a strong humoral and cytotoxic response, is a well-known pathogenic factor for the progression of HAM/TSP. Peptides derived from proviral tax and env genes provide epitopes recognized by T cells. We herein report an accumulation of distinct clonotypes of alpha/beta TCR+ peripheral blood T lymphocytes from HAM/TSP patients in comparison with that observed in both asymptomatic carriers and healthy controls, using the reverse-transcriptase PCR/single-strand conformation polymorphism method. We also found that some of the accumulated T cell clones in the peripheral blood and cerebrospinal fluid are HTLV-I Tax(11-19) peptide specific. Such clones were found to expand strongly after being cultured with an HTLV-I Tax(11-19) peptide. Moreover, the cultured samples exhibited a strong MHC class I-restricted cytotoxic activity against HTLV-I Tax(11-19) peptide-expressing targets, and therefore most likely also include the disease-associated T cell clones observed in the patients. This is the first report of a direct assessment of Ag-specific T cell responses in fresh PBL and cerebrospinal fluid.
Qualitative Diversity of Agglutinin Response Among Different Rabbits Treated with the Same Complex Antigen (Streptococcus Scarlatin æ)
Authors: Hooker Sanford B. 
Published: January 2023

Summary and Conclusions
The results suggest that qualitative deficiency of antibody response to scarlatinal streptococci occurs rather infrequently among rabbits. It probably explains some of the discrepant reactions obtained by different investigators who have worked with the same strains. The fact that an immune serum may not faithfully and completely reflect the antigenic features of a complex inoculum receives additional confirmation as does our previous conclusion that the injected animal's individuality may constitute an important variable in experiments of this kind.
T and B Cell Development in BP-1/6C3/Aminopeptidase A-Deficient Mice
Authors: Lin Qun , Taniuchi Ichiro , Kitamura Daisuke , Wang Jiyang , Kearney John F. , Watanabe Takeshi , Cooper Max D. 
Published: January 2023

Abstract
Stage-restricted expression of cell surface molecules serves to delineate B lineage cells during their progressive differentiation within the bone marrow. The BP-1/6C3 Ag, aminopeptidase A (APA), is selectively expressed by the pre-B and immature B cells. This ectoenzyme, which is also present on bone marrow-derived stromal cells, thymic cortical epithelial cells, renal proximal tubular cells, intestinal enterocytes, and endothelial cells, cleaves acidic glutamyl and aspartyl residues from the N-terminus of angiotensin and other biologically active peptides to quench their functional activity. BP-1/6C3/APA expression by early B lineage cells is up-regulated by IL-7, an important growth factor for pre-B cells and T cells. To explore the physiologic role of this peptidase, we generated a mouse model of BP-1 deficiency by gene targeting in embryonal stem cells. While mice homozygous for the BP-1 mutation did not express detectable BP-1 protein or enzyme activity, they developed normally, generated normal numbers of T and B cells, exhibited integrity of Ab responses to both thymus-dependent and -independent Ags, and produced normal serum Ig levels. Phenotypic analysis of bone marrow and thymic lymphocytes indicated a normal pattern of B and T lineage differentiation. B lymphopoiesis in fetal liver cultures and the proliferative responses of bone marrow cells to IL-7 and LPS were also unimpaired. These findings indicate that BP-1 ectoenzyme activity is not essential for normal B and T cell development.
DR/CLIP (Class II-Associated Invariant Chain Peptides) and DR/Peptide Complexes Colocalize in Prelysosomes in Human B Lymphoblastoid Cells
Authors: Stang Espen , Guerra Carolyn B. , Amaya Miguel , Paterson Yvonne , Bakke Oddmund , Mellins Elizabeth D. 
Published: January 2023

Abstract
In APCs, MHC class II molecules (MHC class II) bind antigenic peptides after HLA-DM mediated removal of CLIP. To characterize intracellular sites of peptide loading in human B lymphoblastoid cell lines, we conducted immunoelectron microscopy studies with Abs recognizing MHC class II associated with CLIP or bound peptide, respectively, together with Abs to HLA-DM and endocytic markers. The distribution of these molecules indicates that peptide binding occurs in compartments with characteristics of normal late endosomes, and in compartments that show characteristics of late endosomes, but are not detectably accessed by endocytosed BSA-gold. The latter compartments may represent or give rise to recycling vesicles that deliver peptide-loaded class II molecules to the cell surface. In addition, we have compared cells in which HLA-DM and HLA-DR interaction is defective with cells in which this interaction is intact, and find that DM/DR interaction is not required for the proper localization of either molecule to peptide-loading compartments.