bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Expression and Activation of p38 Mitogen-Activated Protein Kinase α, β, γ, and δ in Inflammatory Cell Lineages
Authors: Hale Karin K. , Trollinger David , Rihanek Marynette , Manthey Carl L. 
Published: January 2023

AbstractFour p38 mitogen-activated protein kinases (p38α, β, γ, δ) have been described. To understand the role of p38 family members in inflammation, we determined their relative expression in cells that participate in the inflammatory process. Expression was measured at the level of mRNA by reverse-transcriptase PCR and protein by Western blot analysis. p38α was the dominant form of p38 in monocytes; expression of p38δ was low and p38β was undetected. In macrophages, p38α and p38δ were abundant, but p38β was undetected. p38α and p38δ were also expressed by neutrophils, CD4+ T cells, and endothelial cells. Again, p38β was not detected in neutrophils, although low amounts were present in CD4+ T cells. In contrast, p38β was abundant in endothelial cells. p38γ protein was not detected in any cell type, although p38γ mRNA was present in endothelial cells. Immunokinase assays showed a strong activation of p38α and a lesser activation of p38δ in LPS-stimulated macrophages. Abs specific for mono- and dual-phophorylated forms of p38 suggested that LPS induces dual phosphorylation of p38α, but primarily mono-phosphorylation of p38δ. IL-1β activated p38α and p38β in endothelial cells. However, p38α was the more activated form based on kinase assays and phosphorylation analysis. Expression and activation patterns of p38α in macrophages and endothelial cells suggest that p38α plays a major role in the inflammatory response. Additional studies will be needed to define the contribution of p38δ to macrophage, neutrophil, and T cell functions, and of p38β to signaling in endothelial cells and T cells.
Importance of CD23 for Collagen-Induced Arthritis: Delayed Onset and Reduced Severity in CD23-Deficient Mice
Authors: Kleinau Sandra , Martinsson Pernilla , Gustavsson Susanne , Heyman Birgitta 
Published: January 2023

Abstract
Increased expression of the low affinity receptor for IgE, FcεRII/CD23 has been observed in rheumatoid arthritis. In view of this, we have investigated the expression and influence of CD23 in collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis. CD23+ cells were analyzed in lymph nodes of DBA/1 mice immunized with bovine collagen type II (BCII) in CFA or with CFA only. The percentage of CD23+ lymph node cells was increased in both BCII/CFA- and CFA-immunized mice at 1, 3, and 7 wk after immunization compared with unimmunized mice, indicating a role for the adjuvant to trigger general inflammation and CD23 expression. To investigate the functional role of CD23 in CIA, CD23-deficient mice on the DBA/1 genetic background were studied. After immunization with BCII/CFA, these mice developed CIA with delayed onset and reduced severity compared with wild-type mice. These findings suggest that an increased number of CD23+ cells is part of an inflammatory response and that CD23 expression is of pathogenic importance in the arthritic process.
A Novel Glycosylphosphatidyl Inositol-Anchored Protein on Human Leukocytes: A Possible Role for Regulation of Neutrophil Adherence and Migration
Authors: Suzuki Kichiya , Watanabe Tadashi , Sakurai Shin-ichi , Ohtake Kazuhisa , Kinoshita Taroh , Araki Akemi , Fujita Teizo , Takei Hiroshi , Takeda Yuji , Sato Yukiko , Yamashita Takao , Araki Yoshihiko , Sendo Fujiro 
Published: January 2023

Abstract
We report here a novel glycosylphosphatidyl-inositol (GPI)-anchored glycoprotein on human leukocytes. Treatment of neutrophils with a mAb (3H9) to this molecule sequentially up-regulates and down-regulates β2 integrin-dependent adhesion of these cells as well as their transendothelial migration in vitro. In addition, this mAb simultaneously modulates the avidity of β2 integrin for its ligand, iC3b, with kinetics similar to those observed in 3H9 modulation of neutrophil adherence. This mAb also induces β2 integrin-dependent cytoskeletal remodeling. This novel GPI-anchored protein (GPI-80) is highly homologous with Vanin-1, a recently reported GPI-anchored protein that is expressed on perivascular thymic stromal cells and is involved in thymus homing in mice. The finding that both GPI-80 and Vanin-1 are 40% homologous with human biotinidase suggests the existence of a biotinidase superfamily of molecules that may be involved in the regulation of leukocyte trafficking.
Contribution of Renal Secreted Complement C3 to the Circulating Pool in Humans
Authors: Tang Sydney , Zhou Wuding , Sheerin Neil S. , Vaughan Robert W. , Sacks Steven H. 
Published: January 2023

Abstract
Complement C3 produced within the kidney may be an important mediator of local inflammatory and immunological injury. The overall level of renal C3 production and consequently its contribution to the total circulating C3 level are, however, unknown. This was investigated by using the conversion of C3 from recipient to donor allotype following renal transplantation. The C3 F and S allotypes of 80 consecutive renal donor-recipient pairs (148 individuals) were determined by amplification refractory mutation system analysis. The extent of allotype conversion in C3 F/S mismatched recipients was quantified at different stages after transplantation, using an enzyme-linked immunosorbent assay specific for the HAV 4-1 polymorphism of C3 that is strongly associated with C3F. Twenty-one of the eighty recipients were potentially informative, i.e., were C3 SS recipients of C3 FF or FS donor kidneys. In the early postoperative period, donor-derived C3 (HAV 4-1-positive) was undetectable, increasing to 9.6% of the total circulating C3 at times of acute allograft rejection. When graft dysfunction occurred from causes other than rejection, donor C3 remained undetectable. After stable graft function was attained (3–13 mo after transplantation), donor C3 made up 4.5% of the total circulating C3 pool. Our findings demonstrate that human transplant kidney in the resting state is a significant source of extrahepatic C3. Its heightened local synthesis during rejection episodes suggests a possible pathogenic role for C3 in this immunological process.
IL-12-Mediated NKRP1A Up-Regulation and Consequent Enhancement of Endothelial Transmigration of Vδ2+ TCRγδ+ T Lymphocytes from Healthy Donors and Multiple Sclerosis Patients
Authors: Poggi Alessandro , Zocchi Maria Raffaella , Costa Paola , Ferrero Elisabetta , Borsellino Giovanna , Placido Roberta , Galgani Simona , Salvetti Marco , Gasperini Claudio , Ristori Giovanni , Brosnan Celia F. , Battistini Luca 
Published: January 2023

Abstract
γδ T lymphocytes are thought to play a role in the pathogenesis of multiple sclerosis (MS) contributing to demyelinization and fibrosis in the central nervous system. In this study, we show that, in MS patients with active disease, the percentage of circulating Vδ2+ γδ T cells coexpressing NKRP1A is significantly increased compared with healthy donors. Vδ2+ and Vδ1+ T cells were sorted from MS patients and healthy volunteers and cloned. At variance with Vδ1+ clones, all Vδ2+ clones expressed NKRP1A, which was strongly up-regulated upon culture with IL-12; this effect was neutralized by specific anti-IL-12 Abs. No up-regulation of NKRP1A by IL-12 was noted on Vδ1+ clones. RNase protection assay showed that IL-12R β2 subunit transcript was significantly less represented in Vδ1+ than Vδ2+ clones. This finding may explain the different effect exerted by IL-12 on these clones. In transendothelial migration assays, Vδ2+ NKRP1A+ clones migrated more effectively than Vδ1+ clones, and this migratory potential was enhanced following culture with IL-12. Migration was strongly inhibited by the F(ab′)2 of an anti-NKRP1A Ab, suggesting that this lectin is involved in the migration process. We also show that, in freshly isolated PBMC from MS patients, the migrated population was enriched for Vδ2+ NKRP1A+ cells. We conclude that the expression of NKRP1A on Vδ2+ cells is associated with increased ability to migrate across the vascular endothelium and that this phenomenon may be regulated by IL-12 present in the microenvironment.
The Dependence for Leukocyte Function-Associated Antigen-1/ICAM-1 Interactions in T Cell Activation Cannot Be Overcome by Expression of High Density TCR Ligand
Authors: Abraham Clara , Griffith Justin , Miller Jim 
Published: January 2023

AbstractThe leukocyte-specific integrin, LFA-1, can enhance T cell activation. However, it is unclear whether the binding of LFA-1 to its ligand, ICAM-1, functions through intercellular adhesion alone, resulting in an augmentation of the TCR signal, or involves an additional LFA-1-mediated cellular signal transduction pathway. We have previously shown that naive CD4+ lymph node T cells, isolated from DO11.10 TCR transgenic mice, are activated by increasing doses of exogenous OVA peptide presented by transfectants expressing both class II and ICAM-1, but not by cells expressing class II alone. To determine whether LFA-1/ICAM-1 interactions were simply enhancing the presentation of low concentrations of specific MHC/peptide complexes generated from exogenously added peptide, we transfected cells with class II that is covalently coupled to peptide, alone or in combination with ICAM-1. These cells express 100-fold more specific class II/peptide complexes than can be loaded onto class II-positive cells at maximum concentrations of exogenous peptide. Despite this high density of TCR ligand, activation of naive CD4+ T cells still requires the coexpression of ICAM-1. LFA-1/ICAM-1 interactions are not required for effective conjugate formation and TCR engagement because presentation of class II/peptide complexes in the absence of ICAM-1 does induce up-regulation of CD25 and CD69. Thus, high numbers of engaged TCR cannot compensate for the lack of LFA-1/ICAM-1 interactions in the activation of naive CD4+ T cells.
Antigen Receptor Engagement Selectively Induces Macrophage Inflammatory Protein-1α (MIP-1α) and MIP-1β Chemokine Production in Human B Cells
Authors: Krzysiek Roman , Lefèvre Eric A. , Zou Weiping , Foussat Arnaud , Bernard Jérôme , Portier Alain , Galanaud Pierre , Richard Yolande 
Published: January 2023

AbstractWe show herein that B cell Ag receptor (BCR) triggering, but not stimulation by CD40 mAb and/or IL-4, rapidly induced the coordinated expression of two closely related T cell chemoattractants, macrophage inflammatory protein-1β (MIP-1β) and MIP-1α, by human B cells. Naive, memory, and germinal center B cells all produced MIP-1α/β in response to BCR triggering. In contrast to MIP-1α/β, IL-8, which is spontaneously produced by germinal center B cells but not by naive and memory B cells, was not regulated by BCR triggering. Culturing follicular dendritic cell-like HK cells with activated B cells did not regulate MIP-1α/β production, but it did induce production of IL-8 by HK cells. Microchemotaxis assays showed that CD4+CD45RO+ T cells of the effector/helper phenotype actively migrated along a chemotactic gradient formed by BCR-stimulated B cells. This effect was partially blocked by anti-MIP-1β and anti-CC chemokine receptor 5 Ab, but not by anti-MIP-1α Ab suggesting that MIP-1β plays a major role in this chemoattraction. Since maturation of the B cell response to a peptide Ag is mostly dependent on the availability of T cell help, the ability of Ag-stimulated B cells to recruit T cells via MIP-1α/β, may represent one possible mechanism enabling cognate interactions between rare in vivo Ag-specific T and B cells.
Virus-Induced CD8+ T Cell Clonal Expansion Is Associated with Telomerase Up-Regulation and Telomere Length Preservation: A Mechanism for Rescue from Replicative Senescence
Authors: Maini Mala K. , Soares Maria Vieira D. , Zilch Christian F. , Akbar Arne N. , Beverley Peter C. L. 
Published: January 2023

Abstract
In acute infectious mononucleosis (AIM), very large clones of Ag-specific CD8+ effector T cells are generated. Many clones persist as memory cells, although the clone size is greatly reduced. It would be expected that the large number of cell divisions occurring during clonal expansion would lead to shortening of telomeres, predisposing to replicative senescence. Instead, we show that clonally expanded CD8+ T cells in AIM have paradoxical preservation of telomere length in association with marked up-regulation of telomerase. We postulate that this allows a proportion of responding T cells to enter the memory pool with a preserved capacity to continue dividing so that long-term immunological memory can be maintained.
Pancreatic Infiltration But Not Diabetes Occurs in the Relative Absence of MHC Class II-Restricted CD4 T Cells: Studies Using NOD/CIITA-Deficient Mice
Authors: Mora Conchi , Wong F. Susan , Chang Cheong-Hee , Flavell Richard A. 
Published: January 2023

AbstractThe NOD (nonobese diabetic) mouse is a good animal model for human IDDM. MHC class II-restricted CD4 T cells are necessary for the onset of diabetes in NOD mice. Here, we demonstrate that NOD mice lacking the CIITA (class II transactivator) molecule, and hence deficient in MHC class II expression and peripheral CD4 T cells, show significant pancreatic infiltration but do not develop diabetes. CD4 T cell deficiency, then, does not prevent initial pancreatic infiltration, but does stop progression to insulitis. Adoptive transfer studies show that the paucity of CD4 T cells in NOD-CIITA knockout mice is responsible for the absence of diabetes, since the CD8 T cell and B cell compartments are functional. An autoaggressive CD8+ T cell clone can, however, transfer diabetes in CIITA knockout recipient mice without CD4 T cell help, albeit with some delay compared with that in CIITA-sufficient recipients. This highlights the fact that a high number of in vitro activated autoaggressive CD8 T cells can over-ride the requirement for CD4 T cell help for the onset of diabetes.
TNF Receptor 1-Dependent β Cell Toxicity as an Effector Pathway in Autoimmune Diabetes
Authors: Kägi David , Ho Alexandra , Odermatt Bernhard , Zakarian Arsen , Ohashi Pamela S. , Mak Tak W. 
Published: January 2023

Abstract
Autoimmune diabetes is characterized by a chronic progressive inflammatory autoimmune reaction that ultimately causes the selective elimination of pancreatic β cells. To address the question of whether the cell death-inducing cytokines TNF and lymphotoxin α are involved in this process, we generated nonobese diabetic (NOD) mice that are deficient for TNF receptor 1 (TNFR1 or TNFRp55). Insulitis developed in these mice similarly to that in normal control NOD mice, but progression to diabetes was completely abrogated. Since this was probably due to the complex immunomodulatory effects of TNF and lymphotoxin α signaled via TNFR1 on lymphohemopoietic cells, adoptive transfer experiments with spleen cells from diabetic NOD mice were conducted. It was found that the absence of TNFR1 in recipients delayed diabetes induced by normal control and precluded diabetes induced by perforin-deficient spleen cells. In a CD8+ T cell-mediated model of diabetes, however, diabetes induced by adoptive transfer of TCR transgenic lymphocytic choriomeningitis virus glycoprotein-specific CD8+ T cells was not delayed by the absence of TNFR1 in recipient mice. Together with the described expression patterns of perforin and TNF in the mononuclear islet infiltrates of NOD mice, these results indicate that two diabetogenic effector mechanisms are delivered by distinct cell populations: CD8+ T cells lyse β cells via perforin-dependent cytotoxicity, whereas CD4+ T cells, macrophages, and dendritic cells contribute to diabetes development via TNFR1-dependent β cell toxicity.
Type 1 and Type 2 Cytokine Regulation of Macrophage Endocytosis: Differential Activation by IL-4/IL-13 as Opposed to IFN-γ or IL-10
Authors: Montaner Luis J. , da Silva Rosangela P. , Sun Junwei , Sutterwala Shaheen , Hollinshead Michael , Vaux David , Gordon Siamon 
Published: January 2023

Abstract
Cytokine regulation of endocytic activity in primary human macrophages was studied to define ultrastructural changes and mechanisms of pinocytic regulation associated with cytokines secreted by activated T cells. The effects of IFN-γ (type 1) and IL-4/IL-13 and IL-10 (type 2) cytokines on fluid phase and mannose receptor-mediated endocytosis were assessed by horseradish peroxidase and colloidal gold-BSA uptake and computer-assisted morphometric analysis. IL-4 and IL-13 enhanced fluid phase pinocytosis and mannose receptor-mediated uptake by activation of phosphatidylinositol 3-kinase. Inhibition of actin assembly showed that both cytokines exerted actin-dependent and -independent effects. Ultrastructurally, IL-4 and IL-13 increased tubular vesicle formation underneath the plasma membrane and at pericentriolar sites, concurrent with decreased particle sorting to lysosomes. By contrast, IL-10 or IFN-γ decreased both fluid phase pinocytosis and mannose receptor-mediated uptake. IFN-γ stimulated increased particle sorting to perinuclear lysosomes, while IL-10 decreased this activity. In summary, our data document differential effects on macrophage endocytic functions by type 1 or type 2 cytokines associated with induction and effector pathways in immunity.
TAP Association Influences the Conformation of Nascent MHC Class I Molecules
Authors: Owen Barbara A. L. , Pease Larry R. 
Published: January 2023

Abstract
The influence of TAP-MHC class I interactions on peptide binding to the class I heavy chain is assessed during TAP-dependent assembly using Kb-specific Abs that recognize conformational changes induced by assembly with β2-microglobulin (β2m) and by peptide binding. A significant portion (45%) of Kb molecules in TAP+, RMA-derived microsomes are associated with the TAP complex as measured by coimmunoisolation of Kb using anti-TAP1 Abs, while only 20% of the Kb heavy chain molecules are isolated as Kbβ2m complexes with the α-Kb-specific Abs, Y-3 or K-10-56. The amount of Kb isolated with Y-3 and K-10-56 increases in proportion to transport and binding of peptide to the Kb molecules within the RMA microsomes. In contrast, less than 5% of the Kb within TAP2-RMA-S microsomes associated with the remaining TAP1 subunit. However, greater than 60% of Kb heavy chain is isolated as K-10-56- and Y-3-reactive Kbβ2m complexes. We propose that a TAP-MHC class I interaction serves to stabilize the MHC class I:β2m complex in an immature conformation (Y-3 and K-10-56 nonreactive) prior to high affinity peptide binding, preventing the export of class I molecules complexed with low affinity peptide ligands from the ER.
An 11-Amino Acid Sequence in the Cytoplasmic Domain of CD40 Is Sufficient for Activation of c-Jun N-Terminal Kinase, Activation of MAPKAP Kinase-2, Phosphorylation of IκBα, and Protection of WEHI-231 Cells from Anti-IgM-Induced Growth Arrest
Authors: Sutherland Claire L. , Krebs Danielle L. , Gold Michael R. 
Published: January 2023

AbstractWe have previously shown that CD40 causes strong activation of the c-Jun N-terminal kinase (JNK), the p38 mitogen-activated protein kinases (MAPK) and MAPKAP kinase-2, a downstream target of p38 MAPK. To identify signaling motifs in the CD40 cytoplasmic domain that are responsible for activation of these kinases, we have created a set of 11 chimeric receptors consisting of the extracellular and transmembrane domains of CD8 fused to portions of the murine CD40 cytoplasmic domain. These chimeric receptors were expressed in WEHI-231 B lymphoma cells. We found that amino acids 35–45 of the CD40 cytoplasmic domain constitute an independent signaling motif that is sufficient for activation of the JNK and p38 MAPK pathways, as well as for induction of IκBα phosphorylation and degradation. Amino acids 35–45 were also sufficient to protect WEHI-231 cells from anti-IgM-induced growth arrest. This is the same region of CD40 required for binding the TNF receptor-associated factor-2 (TRAF2), TRAF3, and TRAF5 adapter proteins. These data support the idea that one or more of these TRAF proteins couple CD40 to the kinase cascades that activate NF-κB, JNK, and p38 MAPK.
MHC-Restricted, Glycopeptide-Specific T Cells Show Specificity for Both Carbohydrate and Peptide Residues
Authors: Deck M. Brian , Sjölin Petter , Unanue Emil R. , Kihlberg Jan 
Published: January 2023

Abstract
We examined the antigenic specificity of two T cell hybridomas elicited against the disaccharide galabiose attached to the fifth residue of the I-Ak binding peptide 52–61 of lysozyme. By making changes in the saccharide molecule and in the peptide, we conclude that the outer galactose residue of the galabiose moiety is directly recognized by the T cells together with the exposed side chains of the peptide. The overall spatial display of this galactose moiety on the 52–61 peptide is likewise important.
Human Glioma-Induced Immunosuppression Involves Soluble Factor(s) That Alters Monocyte Cytokine Profile and Surface Markers
Authors: Zou Jian-Ping , Morford Lorri A. , Chougnet Claire , Dix Amy R. , Brooks Andrew G. , Torres Naomi , Shuman Jon D. , Coligan John E. , Brooks William H. , Roszman Thomas L. , Shearer Gene M. 
Published: January 2023

AbstractPatients with gliomas exhibit deficient in vitro and in vivo T cell immune activity, and human glioblastoma culture supernatants (GCS) inhibit in vitro T lymphocyte responses. Because APC are essential for initiating and regulating T cell responses, we investigated whether GCS would affect cytokines produced by monocytes and T cells from healthy donors of PBMC. Incubation of PBMC with GCS decreased production of IL-12, IFN-γ, and TNF-α, and increased production of IL-6 and IL-10. The GCS-induced changes in IL-12 and IL-10 occurred in monocytes, and involved changes in IL-12 p40 and IL-10 mRNA expression. Incubation with GCS also resulted in reduced expression of MHC class II and of CD80/86 costimulatory molecules on monocytes. The immunosuppressive effects were not the result of IL-6 or TGF-β1 that was detected in GCS. However, it was due to a factor(s) that is resistant to pH extremes, differentially susceptible to temperature, susceptible to trypsin, and has a minimum molecular mass of 40 kDa. Our findings show that glioblastoma-generated factors that are known to suppress T cell responses alter the cytokine profiles of monocytic APC that, in turn, inhibit T cell function. This model indicates that monocytes can serve as an intermediate between tumor-generated immune-suppressive factors and the T cell responses that are suppressed in gliomas.