bluuebunny/crossref_metadata_2025_split huggingface dataset:
An ovalbumin-IL-12 fusion protein is more effective than ovalbumin plus free recombinant IL-12 in inducing a T helper cell type 1-dominated immune response and inhibiting antigen-specific IgE production.
Authors: Kim T S , DeKruyff R H , Rupper R , Maecker H T , Levy S , Umetsu D T 
Published: December 2022

Abstract
Optimal treatment of allergic diseases requires that the cytokine profile of allergen-specific T cells be redirected, with the conversion of Th2 profiles into Th1 cytokine profiles. This conversion, however, is difficult, since Th2 effector cells have relatively fixed cytokine profiles. To more effectively redirect the cytokine profiles of T cells, we constructed a cytokine fusion protein that contained the Ag OVA, fused to IL-12. Immunization with the OVA-IL-12 fusion protein induced anti-OVA IgG2a Ab and large quantities of OVA-specific IFN-gamma production. The Ag specificity of this response was dependent upon covalent linkage of Ag and IL-12, since immunization of mice with OVA alone induced little or no IFN-gamma, while immunization with OVA and free rIL-12 enhanced T cell production of IFN-gamma, but the IFN-gamma production was not OVA specific. To examine the effects of OVA-IL-12 in reversing ongoing Th2-dominated immune responses, BALB/c mice previously primed with OVA in alum to induce a Th2-dominated response, were vaccinated with the OVA-IL-12 protein. In such mice, OVA-IL-12 was much more effective than OVA plus free rIL-12 in significantly increasing Ag-specific IFN-gamma production and significantly decreasing Ag-specific IL-4 production. Moreover, OVA-IL-12 increased serum anti-OVA IgG2a and decreased anti-OVA IgE. These studies indicate that OVA-IL-12 can convert immune responses characterized by high IL-4 and high IgE synthesis into Th1-dominated responses in an Ag-specific manner.
Immunogenicity and immunopathogenicity of an autoimmune epitope are potentiated by increasing MHC binding through residue substitution.
Authors: Kozhich A T , Caspi R R , Berzofsky J A , Gery I 
Published: December 2022

Abstract
We have previously shown that in Lewis rats, peptide 273-283 (TWEGSGVLPCV) of rat interphotoreceptor retinoid-binding protein (IRBP) serves as a "surrogate" epitope for pathogenic lymphocytes sensitized against peptide 1181-1191 (SWEGVGVVPDV) of bovine IRBP. Yet, peptide 273-283 itself causes experimental autoimmune uveoretinitis (EAU) only at 200 nmol/rat, whereas peptide 1181-1191 is pathogenic even at 0.2 nmol. This difference was attributed to the higher affinity of 1181-1191 to MHC molecules. Here we demonstrate that substitution of putative MHC binding-residues of peptide 273-283 with the corresponding ones of 1181-1191 results in increased binding to MHC and in remarkably elevated immunologic capacities. Analogs of 273-283 were synthesized, in which residues 277 and 282 were substituted with one or both the corresponding amino acids of peptide 1181-1191, V and D, respectively. The main findings were: 1) substitutions drastically increased MHC affinity, namely, 273-283(V277,D282) &gt; 273-283(D282) &gt; 273-283; 2) the substituted analogs were much more immunogenic than the native peptide, inducing cellular responses at much lower doses; 3) the analogs were more antigenic in vitro than the native peptide; 4) the analogs were exceedingly pathogenic; peptide 273-283(V277,D282) caused disease even at 0.02 nmol/rat; and 5) the analogs were superior to the native peptide in their capacity to stimulate production of IFN-gamma by sensitized lymphocytes. Thus, enhancement of affinity of an autoimmune peptide for MHC molecules increases both immunogenicity and pathogenicity.
IFN regulatory factor-1 plays a central role in the regulation of the expression of class I and II MHC genes in vivo.
Authors: Hobart M , Ramassar V , Goes N , Urmson J , Halloran P F 
Published: December 2022

Abstract
Transcription factor interferon regulatory factor-1 (IRF-1) is implicated in regulating class I MHC expression in vitro. We investigated the in vivo relationship between IRF-1 and MHC expression in kidney and other nonlymphoid organs, assessing MHC expression in mice with disrupted IRF-1 genes (IRF-1 KO) compared with mice with intact IRF-1 genes (WT). In kidneys of IRF-1 KO mice, basal class I expression was decreased, particularly on arterial endothelium, but basal class II expression was unchanged. The induction of both class I and class II expression by injected rIFN-gamma was reduced in IRF-1 KOs, compared with WT mice. Similarly, stimuli that induce endogenous IFN-gamma production (LPS or oxazolone) massively increased MHC expression in kidneys of WT mice, with little increase in IRF-1 KO mice. Impaired class II induction by rIFN-gamma in IRF-1 KO mice probably reflects the role of IRF-1 in regulating class II transactivator (CIITA) expression: rIFN-gamma induced CIITA mRNA less in kidneys of IRF-1 KO mice than in WT mice. In organs of WT mice, IRF-1 mRNA was expressed in the basal state, and rIFN-gamma treatment increased IRF-1 mRNA before the induction of class I or CIITA mRNA. Treatment of WT mice with cycloheximide plus rIFN-gamma superinduced IRF-1 mRNA expression, but partially inhibited CIITA mRNA expression, indicating that IRF-1 mRNA induction is not dependent on new protein synthesis, unlike CIITA. Thus, in vivo, IRF-1 plays a major role in basal and induced class I expression and in induction of class II by IFN-gamma, probably via CIITA induction.
Efficient priming of CD8+ memory T cells specific for a subdominant epitope following Sendai virus infection.
Authors: Cole G A , Hogg T L , Coppola M A , Woodland D L 
Published: December 2022

Abstract
The relationship between the primary effector CTL response to viral infection and the subsequent pool of memory CTL precursors (CTLp) is poorly understood. Here, we have analyzed the induction of both effector CTL and memory CTLp to dominant and subdominant epitopes following Sendai virus infection of C57BL/6 mice. A single peptide derived from the Sendai virus nucleoprotein (NP(324-332)) binds to both H-2 Kb and Db MHC class I molecules, generating both immunodominant (NP(324-332)/Kb) and subdominant (NP(324-332)/Db) epitopes. Following intranasal Sendai virus infection, NP(324-332)/Kb-specific CTL dominated the primary effector CTL response in the lung and were present at high frequency in the memory CTLp pool. In contrast, NP(324-332)/Db-specific CTL were not a detectable component of the effector response to primary Sendai virus infection. However, memory CTLp specific for this subdominant epitope were induced at frequencies approaching those of CTLp specific for the immunodominant epitope. These data indicate that memory CTLp specific for subdominant epitopes can be primed by Sendai virus infection in the absence of a detectable effector response. To determine whether CTLp memory to subdominant epitopes is functional in the context of Sendai virus infection, memory CTLp specific for a subdominant epitope were selectively primed by vaccination. These cells dominated the subsequent effector CTL response to Sendai virus infection, demonstrating that memory CTLp primed against subdominant epitopes can participate in an immune response and effectively compete with T cells specific for immunodominant epitopes. These data have implications for the development of vaccines designed to emphasize cellular immunity.
Surfactant protein A-deficient mice are susceptible to group B streptococcal infection.
Authors: LeVine A M , Bruno M D , Huelsman K M , Ross G F , Whitsett J A , Korfhagen T R 
Published: December 2022

Abstract
To determine the role of surfactant protein A (SP-A) in host defense, the murine SP-A locus was targeted by homologous recombination to produce mice lacking SP-A. SP-A -/- and control mice were infected with group B streptococcus (GBS) by intratracheal instillation. Pulmonary infiltration 6 and 24 h following infection was more severe in SP-A -/- than in control mice, and was associated with increased numbers of GBS in lung homogenates. Dissemination of GBS to the spleen was observed more frequently in SP-A -/- mice. Pulmonary infiltration with macrophages was similar in both groups; however, the number of bacteria associated with alveolar macrophages was decreased in the SP-A-deficient mice. There was no detectable compensatory increase in surfactant protein D, the other known pulmonary collectin, in response to GBS instillation. SP-A plays an important role in vivo, enhancing clearance of GBS from the lung and inhibiting systemic dissemination of the organism.
Potent anti-feline immunodeficiency virus and anti-human immunodeficiency virus effect of IFN-tau.
Authors: Pontzer C H , Yamamoto J K , Bazer F W , Ott T L , Johnson H M 
Published: December 2022

Abstract
Ovine IFN-tau is a newly described protein related to IFN-alpha that is responsible for maternal recognition of pregnancy in sheep. It has been shown to exhibit potent antiviral and antiproliferative activity. To determine its antiviral activity against feline immunodeficiency virus (FIV) and HIV, the activity of the RNA-dependent DNA polymerase, reverse transcriptase, was assayed in FIV- and HIV-infected feline and human PBL treated with IFN-tau. Significant dose-dependent inhibition of reverse transcriptase activity by IFN-tau was detected by day 6 of culture and was maintained through the peak of virus replication. In addition, production of the FIV core protein, p25, was blocked by IFN-tau. Both the amino- and carboxyl-terminal regions of IFN-tau, as identified by synthetic peptides, appear to be involved in its antiretroviral activity. Comparison of the anti-HIV activities of IFN-tau and recombinant human IFN-alpha2 (rHuIFN-alpha2) indicated that while rHuIFN-alpha2 was toxic to cells at 10,000 U/ml, IFN-tau antiretroviral activity was not associated with a decrease in either cell viability or immunologic reactivity. Thus, IFN-tau displayed potent anti-FIV and anti-HIV activity without the cytotoxicity associated with high concentrations of rHuIFN-alpha2.
Promiscuity of clinical Plasmodium falciparum isolates for multiple adhesion molecules under flow conditions.
Authors: Udomsangpetch R , Reinhardt P H , Schollaardt T , Elliott J F , Kubes P , Ho M 
Published: December 2022

Abstract
The central pathologic process in severe Plasmodium falciparum malaria is the cytoadherence of parasitized erythrocytes to capillary and postcapillary venular endothelium, with resultant tissue hypoxia, metabolic disturbances, and multiorgan dysfunction. The molecular basis of this process has been studied extensively using static adhesion assays. In the present study, we determined whether infected red blood cells (IRBC) from clinical parasite isolates would roll and adhere on CD36, ICAM-1, E-selectin, P-selectin, and VCAM-1 using a laminar flow system that allowed for the direct visualization of IRBC-substratum interactions. The results indicate that IRBC could tether and roll on CD36, ICAM-1, P-selectin, and VCAM-1 in a shear-dependent fashion, but significant adhesion was restricted to CD36. There was no interaction with E-selectin. When both CD36 and ICAM-1 were expressed on the same cellular substratum such as C32 melanoma cells, adhesion was significantly greater than when CD36 was present alone. The adhesive interactions were different from those between leukocytes and the same adhesion molecules. Furthermore, IRBC rolling on P-selectin and VCAM-1 was not inhibitable by Abs that entirely prevented leukocyte-receptor interactions. These findings suggest that cytoadherence under physiologic conditions may be a multistep process similar to that involved in the recruitment of a number of different cell types. Further elucidation of the molecular basis of these novel interactions is crucial for the development of therapeutic interventions aimed at inhibiting or reversing the process.
In vivo production and function of IL-12 p40 homodimers.
Authors: Heinzel F P , Hujer A M , Ahmed F N , Rerko R M 
Published: December 2022

Abstract
The bioactivity of IL-12 is mediated by heterodimers of disulfide-linked p35 and p40 protein subunits. Homodimeric p40 competes with heterodimer for binding to the high affinity IL-12R and inhibits IL-12 bioactivity in vitro. However, the production and significance of p40 homodimer as a cytokine antagonist in vivo have not been determined. In these studies, we observed increased amounts of both IL-12 p40 monomer and homodimer in the serum of C57BL/6 mice following injection of 300 microg of Salmonella enteritidis LPS. Homodimer constituted between 20 and 40% of the total circulating p40 in endotoxemic sera, as confirmed by both Sephacryl S-100 gel filtration and p40-specific immunoprecipitation analyses. Similar relative amounts of homodimer and monomer were observed in endotoxemic BALB/c, C57BL/6, IFN-gamma-deficient C57BL/6 mice and C57BL/6 mice previously infected with bacille Calmette-Guérin. To determine whether IL-12 p40 homodimer was capable of antagonizing IL-12-dependent IFN-gamma responses in vivo, we pretreated C57BL/6 mice with purified rIL-12 p40 homodimer before i.p. challenge with endotoxin. Mice treated with 40 to 80 microg of p40 homodimer generated 80 to 82% less circulating IFN-gamma during acute endotoxemia than saline controls (p &lt; 0.01). We conclude that p40 homodimer is produced in vivo, functions as a cytokine antagonist in the context of the mouse model of acute endotoxemia, and may represent a novel form of self-regulating cytokine response.
A metabolite of the lupus-inducing drug procainamide prevents anergy induction in T cell clones.
Authors: Kretz-Rommel A , Rubin R L 
Published: December 2022

Abstract
Therapeutic treatment with procainamide is occasionally associated with the development of drug-induced lupus. This syndrome has become the prototype for an aseptic systemic autoimmune disease caused by a known environmental agent, but the underlying mechanisms remain puzzling. We explored the possibility that lupus-inducing drugs affect processes involved in T cell tolerance to self-Ag. An in vitro model of anergy using established T cell clones was used to determine whether procainamide or one of its metabolites could prevent development of T cell nonresponsiveness to cognate Ag. Addition of procainamide-hydroxylamine, but not procainamide or its further oxidation products during anergy induction by CD3 engagement, caused a dose-dependent recovery of the capacity of T cells to proliferate and secrete IFN-gamma upon subsequent Ag challenge. Resistance to anergy induction required 2 h of exposure to procainamide-hydroxylamine, and this state remained for 8 h, suggesting that uptake of the drug caused a reversible interference in signaling pathways involved in establishing anergy. We suggest that prevention of anergy induction by procainamide-hydroxylamine may also take place in vivo during establishment of T cell tolerance to self-Ag, thereby allowing the production of autoreactive T cells.
Fc epsilonRI gamma can support T cell development and function in mice lacking endogenous TCR zeta-chain.
Authors: Shores E , Flamand V , Tran T , Grinberg A , Kinet J P , Love P E 
Published: December 2022

Abstract
Fc epsilonRI gamma (Fc gamma) is a member of the zeta family of signal transducing molecules that function as components of both the TCR and Fc receptors (FcR). While the majority of thymocytes and T cells express TCRs containing zeta-chain homodimers, certain unique populations of T cells express TCRs that contain both zeta and Fc gamma. To examine the ability of Fc gamma to substitute for zeta-chain in T cell development and function, we introduced a transgene encoding Fc gamma into mice made genetically deficient for zeta-chain (zeta(e)-/-). Analysis of thymocyte development in zeta(e)-/-;Fc gamma Tg mice demonstrated that Fc gamma was able to support the maturation of both gammadelta TCR+ and alphabeta TCR+ T cells. However, positive selection of alphabeta TCR+ thymocytes was less efficient in zeta(e)-/-;Fc gamma Tg mice than in zeta(e)-/- mice reconstituted with zeta-chain. This difference may be due to the fact that Fc gamma contains a single immunoreceptor tyrosine-based activation motif (ITAM) whereas zeta-chain contains three ITAMs. Interestingly, the peripheral T cells that develop in zeta(e)-/- mice reconstituted with Fc gamma are functional and respond to TCR-specific stimuli. These data suggest that Fc gamma and zeta are interchangeable in their ability to mediate T cell development and function, however zeta-chain is more efficient at promoting positive selection and T cell maturation. The difference in efficiency between zeta and Fc gamma may be responsible in part for the unusual developmental and functional properties of T cells that constitutively express Fc gamma as a signaling component of their TCRs.
The alpha subunit cytoplasmic domain regulates the assembly and adhesiveness of integrin lymphocyte function-associated antigen-1.
Authors: Lu C F , Springer T A 
Published: December 2022

Abstract
The integrin LFA-1 mediates activation-dependent leukocyte adhesion. The beta subunit cytoplasmic domain has been demonstrated previously to modulate the adhesiveness of LFA-1. To investigate whether the alpha subunit cytoplasmic domain is also involved in the regulation of LFA-1-adhesive function, we stably expressed cytoplasmic domain truncated forms of the alpha subunit in a Jurkat mutant (Jurkat-beta2.7) deficient in the endogenous LFA-1 alpha subunit and in K562 cells. Clones expressing similar levels of cell surface LFA-1 were tested for their ability to bind to immobilized ICAM-1. Truncation of the alpha subunit cytoplasmic domain before, but not after, the conserved GFFKR sequence motif resulted in constitutive ICAM-1 binding of both Jurkat-beta2.7 and K562 transfectants. However, truncation after the GFFKR motif reduced sensitivity to stimulation by PMA or stimulatory Abs. Internal deletion of the GFFKR motif, or point mutations of the Gly (G), the two Phe (F), or the Arg (R) in the GFFKR motif to Ala (A) rendered LFA-1 constitutively active. Mutation of the Lys (K) did not affect LFA-1 adhesion to ICAM-1. These findings indicate that the GFFKR motif maintains the low adhesive state of LFA-1, possibly by restraining the receptor conformation. We further demonstrate that the alpha subunit cytoplasmic domain and the conserved GFFKR motif are also required for efficient formation of LFA-1 alphabeta heterodimers.
Determinants of T cell reactivity to the Mycobacterium leprae GroES homologue.
Authors: Kim J , Sette A , Rodda S , Southwood S , Sieling P A , Mehra V , Ohmen J D , Oliveros J , Appella E , Higashimoto Y , Rea T H , Bloom B R , Modlin R L 
Published: December 2022

Abstract
The 10-kDa protein Ag of Mycobacterium leprae, a human GroES hsp10 cognate, is a major T cell Ag in human leprosy infection. We investigated the mechanism for T cell responsiveness to this Ag according to the trimolecular interaction between T cell, peptide, and Ag-presenting element. This research was accomplished by mapping T cell epitopes in leprosy patients and correlating these responses with peptide-MHC binding affinities. We found that the majority of tuberculoid leprosy patients responded to peptides corresponding to residues 25-39 and 28-42. Truncation analysis of these peptides mapped the exact epitope to be within the overlapping region comprising residues 28-39. Responsiveness was correlated with the HLA-DRB5*0101 allele, which bound the peptides with moderate affinity. This allele is linked to HLA-DR2, which is associated with the resistant form of leprosy. Therefore, T cell responsiveness in tuberculoid leprosy may be mediated by the ability of HLA-DRB5*0101 to bind and present peptides of the immunodominant 10-kDa Ag.
Fc receptor-triggered insertion of secretory granules into the plasma membrane of human neutrophils: selective retrieval during phagocytosis.
Authors: Tapper H , Grinstein S 
Published: December 2022

Abstract
We studied the kinetics of secretion in human neutrophils stimulated by IgG-opsonized zymosan. Secretion of azurophilic and specific granules was quantified measuring the appearance of the granule markers CD63 and CD66b, respectively, at the cell surface. The kinetics of secretion was compared with the course of phagocytosis, revealed by the trapping of the fluid phase marker, Lucifer Yellow, in vacuoles containing zymosan particles. We found that secretion of both azurophilic and specific granules precedes phagosome sealing. An initial rapid phase of secretion was followed by a decrease in the amount of CD63 and CD66b at the cell surface. This subsequent disappearance of surface CD63 and CD66b was inhibited by cytochalasin B and probably represents internalization of the granular markers into the forming phagosome. The decrease in the amount of CD63 and CD66b exposed at the cell surface was not accompanied by a commensurate reduction in cell surface area, measured with the amphiphilic fluorescent dye FM1-43. These findings imply that CD63 and CD66b are selectively retrieved from the plasma membrane following secretion. Evidence is also presented that calcium is not the sole mediator of the rapid secretion of azurophilic and specific granules triggered by IgG-opsonized particles and that cytochalasin does not impair signaling of the calcium transient elicited by Fc receptors. Instead, actin disassembly appears to reduce the efficiency of the interaction between opsonized particles and their receptors, an effect that can be overcome by increasing the concentration of the stimulating particles.
Genetic dissection of systemic lupus erythematosus pathogenesis: Sle2 on murine chromosome 4 leads to B cell hyperactivity.
Authors: Mohan C , Morel L , Yang P , Wakeland E K 
Published: December 2022

Abstract
Susceptibility to systemic lupus erythematosus in the NZM2410 murine model maps to Sle1, Sle2, Sle3, and the H2 loci. To unravel how these loci contribute to the pathogenesis of lupus, individual NZM2410-derived genomic intervals bearing these loci have been successfully backcrossed onto the resistant C57BL/6 (B6) background. The focus of this study was to understand how Sle2 on murine chromosome 4 impacts the immune system. Compared with C57BL/6 (B6) mice, B6 mice congenic for Sle2 exhibit a variety of immunophenotypes affecting their B cells. They have an early, but transient, expansion of splenic, CD23(low) B cells. Thereafter, their B cells appear activated by surface phenotype and functional criteria, paralleled by elevated serum levels of polyreactive/polyclonal IgM. Importantly, Sle2 leads to a heightened B cell responsiveness to in vitro stimuli and to in vivo antigenic challenge. Finally, they exhibit increased levels of peritoneal and splenic B1 cells. Thus, Sle2 harbors a gene that leads to B cell hyperactivity and elevated B1 cell formation. However, Sle2 by itself on the normal B6 background is insufficient to generate IgG antinuclear Abs (ANA) or nephritis. By reducing the B cell signaling threshold, Sle2 might serve to amplify an ongoing autoimmune response.