bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hemorrhagic Shock Primes for Increased Expression of Cytokine-Induced Neutrophil Chemoattractant in the Lung: Role in Pulmonary Inflammation Following Lipopolysaccharide
Authors: Fan Jie , Marshall John C. , Jimenez Maria , Shek Pang N. , Zagorski John , Rotstein Ori D. 
Published: January 2023

Abstract
Recent studies have suggested that hemorrhagic shock followed by resuscitation renders patients more susceptible to lung injury by priming for an exaggerated response to a second stimulus, the so-called “two-hit” hypothesis. We investigated the role of C-X-C chemokines in mediating the augmented lung inflammation in response to LPS following resuscitated shock. In a rodent model, animals exposed to antecedent shock exhibited enhanced lung neutrophil sequestration and transpulmonary albumin flux in response to intratracheal LPS. This effect correlated with an exaggerated expression of cytokine-induced neutrophil chemoattractant (CINC) protein and mRNA, but not macrophage-inflammatory protein 2. Strategies designed to inhibit CINC, both anti-CINC Ab and supplementation with the antioxidant N-acetyl-cysteine, prevented the enhanced neutrophil sequestration, suggesting that CINC played a central role in the enhanced leukocyte accumulation following shock plus LPS treatment. Shock alone increased lung nuclear factor-κB expression and augmented the response to LPS. Prevention of this effect by N-acetyl-cysteine supplementation of the resuscitation fluid implicates a role for oxidant stress in the priming for lung inflammation following shock. Finally, alveolar macrophages recovered from shock-resuscitated animals released more CINC protein in vitro in response to LPS than macrophages from sham animals. Considered together, these findings show that augmented release of CINC, in part from primed alveolar macrophages, contributes significantly to the enhanced lung leukosequestration and transpulmonary albumin flux in response to LPS following resuscitated shock.
T Cell Epitopes in Japanese Cedar (Cryptomeria japonica) Pollen Allergens: Choice of Major T Cell Epitopes in Cry j 1 and Cry j 2 Toward Design of the Peptide-Based Immunotherapeutics for the Management of Japanese Cedar Pollinosis
Authors: Sone Toshio , Morikubo Keiko , Miyahara Michinori , Komiyama Naoki , Shimizu Kimiko , Tsunoo Hajime , Kino Kohsuke 
Published: January 2023

AbstractJapanese cedar pollinosis is caused by exposure to Japanese cedar (Cryptomeria japonica) pollen, of which two components, Cry j 1 and Cry j 2, are believed to be the major allergens. T cell lines specific to either Cry j 1 or rCry j 2 were reactive to various portions of each panel of overlapping peptides derived from Cry j 1 or Cry j 2. Two peptides, p211–225 and p108–120, from among six major T cell epitopes identified in Cry j 1 sequence, and three peptides, p182–200, p344–355, and p66–80, from among five in Cry j 2, were chosen to design an artificial polypeptide (named Cry-consensus) based on a difference among the types of the restriction molecules capable of presenting these peptides. After construction of a DNA encoding these peptides in order, Cry-consensus was expressed in Escherichia coli. Five of six T cell epitopes, except for Cry j 2 p344–355, in Cry-consensus were recognized by the T cell clones specific to each peptide. PBMC from allergic patients induced higher proliferation under stimulation from Cry-consensus than individual peptides. Eighty-eight percent of the PBMC (15 of 17) showed proliferation under the Cry-consensus stimulation. Thus, several major T cell epitopes from Cry j 1 and Cry j 2 can be chosen in the design of peptide-based immunotherapeutics for the management of Japanese cedar pollinosis in subjects having various types of HLA class II molecules.
Ubiquitination and Dimerization of Complement Receptor Type 2 on Sheep B Cells
Authors: Hein Wayne R. , Dudler Lisbeth , Marston Wendy L. , Landsverk Thor , Young Alan J. , Avila David 
Published: January 2023

AbstractComplement receptor type 2 (CR2) is a membrane-anchored glycoprotein that specifically binds C3d, as well as other ligands, and plays diverse roles in regulating immunity. Here we show that two distinct isoforms of CR2 are expressed on the surface of sheep B lymphocytes. One (CR2no 150 kDa) is structurally similar to known mammalian homologues while the other (CR2ub 190 kDa) has been modified by the covalent attachment of ubiquitin to the cytoplasmic domain and is identified for the first time. CR2no and CR2ub are expressed on the surface of sheep B cells as noncovalently associated dimers and the external topography of the two isoforms differs in some respect. The basis for these unusual higher-order structural properties may lie in the primary sequence of sheep CR2, since the transmembrane domain contains a region resembling a rare 7-amino acid dimerization motif, and two lysine residues in the cytoplasmic domain provide potential sites for posttranslational ubiquitination. The primary structures of sheep ubiquitin and C3d ligand are extensively conserved. In conjunction with the results of separate in vivo studies, these findings suggest that selective ubiquitination plays a role in modulating the higher-order structure and/or expression of CR2 during B cell development.
Demonstration of Human T Lymphotropic Virus Type I (HTLV-I) Tax-Specific CD8+ Lymphocytes Directly in Peripheral Blood of HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis Patients by Intracellular Cytokine Detection
Authors: Kubota Ryuji , Kawanishi Taketo , Matsubara Hidetoshi , Manns Angela , Jacobson Steven 
Published: January 2023

Abstract
Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurologic disease caused by HTLV-I infection and has been associated with elevated levels of several proinflammatory cytokines in both serum and cerebrospinal fluid. It is unknown what kind of cells secrete these cytokines and if HTLV-I Ags are associated with this phenomenon. Here, we investigated the expression of cytokines in PBL from eight HAM/TSP patients, nine HTLV-I-infected asymptomatic carriers, and seven healthy controls by flow cytometry combined with intracellular cytokine staining. PBL were cultured with brefeldin A without mitogen and IL-2 for 14 h. Under these conditions, CD8+ cells produced proinflammatory cytokines including IFN-γ, TNF-α, and IL-2, which were significantly elevated in HAM/TSP patients. The proportion of CD8+ cells producing IFN-γ in HAM/TSP patients, asymptomatic carriers, and healthy controls were, on average, 4.9, 0.4, and 0.3%, respectively. IFN-γ production by these CD8+ cells was suppressed by anti-HLA-class I Ab. Purified CD8+ cells from an HLA-A2 HAM/TSP patient produced IFN-γ by cocultivation with autologous CD4 cells, the main reservoir of HTLV-I in vivo, or allogenic HLA-A2+ B cells pulsed with a known immunodominant HTLV-I tax peptide. These data suggest that high levels of circulating HTLV-I-specific CD8+ T lymphocytes have the potential to produce proinflammatory cytokines and may promote inflammatory responses to HTLV-I in HAM/TSP patients.
IFN-γ Receptor Signaling Is Essential for the Initiation, Acceleration, and Destruction of Autoimmune Kidney Disease in MRL-FaslprMice
Authors: Schwarting Andreas , Wada Takashi , Kinoshita Koji , Tesch Gregory , Rubin Kelley Vicki 
Published: January 2023

AbstractCSF-1 and TNF-α in the kidney of MRL-Faslpr mice are proximal events that precede and promote autoimmune lupus nephritis, while apoptosis of renal parenchymal cells is a feature of advanced human lupus nephritis. In the MRL-Faslpr kidney, infiltrating T cells that secrete IFN-γ are a hallmark of disease. To examine the impact of IFN-γ on renal injury in MRL-Faslpr mice, we constructed a IFN-γR-deficient strain. In MRL-Faslpr mice lacking IFN-γR, circulating and intrarenal CSF-1 were absent, TNF-α was markedly reduced, survival was extended, lymphadenopathy and splenomegaly were prevented, and the kidneys remained protected from destruction. Mesangial cells (MC) that were signaled through the IFN-γR induced CSF-1 and TNF-α in MRL-Faslpr mice. We detected a large number of apoptotic renal parenchymal cells in advanced nephritis and determined that signaling via the IFN-γR induces apoptosis of tubular epithelial cells (TEC), but not MC. By comparison, TNF-α induces apoptosis in MC, but not TEC, of the MRL-Faslpr strain. Thus, IFN-γ is directly and indirectly responsible for apoptosis of TEC and MC in MRL-Faslpr mice, respectively. In conclusion, IFN-γR signaling is essential for the initiation (CSF-1), acceleration (CSF-1 and TNF-α), and apoptotic destruction of renal parenchymal cells in MRL-Faslpr autoimmune kidney disease.
A Viral Peptide with Limited Homology to a Self Peptide Can Induce Clinical Signs of Experimental Autoimmune Encephalomyelitis
Authors: Gautam Anand M. , Liblau Roland , Chelvanayagam Gareth , Steinman Lawrence , Boston Tanya 
Published: January 2023

AbstractMolecular mimicry has been suggested as a mode of autoreactive T cell stimulation in autoimmune diseases. Myelin basic protein (MBP) peptide 1–11 induces experimental autoimmune encephalomyelitis (EAE) in susceptible strains of mice. Here we show that a herpesvirus Saimiri (HVS) peptide, AAQRRPSRPFA, with a limited homology to MBP1–11 peptide, ASQKRPSQRHG (underlined letters showing homology), can stimulate a panel of MBP1–11-specific T cell hybridomas and more importantly cause EAE in mice. We demonstrate that this is due to cross-recognition of these two peptides by TCRs. Results presented in this communication are the first demonstration that a viral peptide with homology at just 5 amino acids with a self peptide can induce clinical signs of EAE in mice. These findings have important implications in understanding the breakdown of T cell tolerance to self Ags in autoimmune diseases by means of cross-reactivity with unrelated peptides.
De Novo-Developed T Cells Have Compromised Response to Existing Alloantigens: Using Ld-Specific Transgenic 2C T Cells as Tracers in a Mouse Heart Transplantation Model
Authors: Luo Hongyu , Chen Huifang , Qi Shijie , Loh Dennis , Daloze Pierre , Veillette André , Xu Dasheng , Wu Jiangping 
Published: January 2023

AbstractIn this study, the phenotype, TCR signaling events, and function of T cells developed de novo during adulthood in the presence of extrathymic alloantigen were investigated. C57BL/6 mice(H-2b) were first transplanted heterotopically with BALB/c hearts (H-2d) and treated with rapamycin for 2 wk to create a tolerant status. Three weeks postoperation, the mice were whole body irradiated and transplanted with bone marrow cells from 2C mice, which are transgenic for TCR, and most of their T cells are Ld-specific CD8 cells. The 2C T cells developed de novo in the C57BL/6 mice were not able to reject the heart allograft. No clonal deletion, TCR down-regulation, or CD8 down-regulation was found in the tolerized 2C T cells. There was no characteristic phenotype of these cells in terms of CD25, ICAM-1, CD44, and MEL-14 expression. Early TCR signaling events such as intracellular calcium concentration flux, tyrosine phosphorylation, Lck and Fyn kinase activities, and Lck and Fyn protein levels in the tolerized 2C T cells were comparable to their normal counterparts, but the tolerized T cells were defective in IL-2 production and proliferation upon H-2d alloantigen stimulation in vitro. Exogenous IL-2 could not reverse the compromised proliferation. The results of this study indicate that during adulthood, the de novo-developed T cells become tolerant to extrathymic Ag without clonal deletion. These newly minted T cells are functionally defective although they are indistinguishable from normal T cells in phenotypes and in some early signaling events.
Cutting Edge Commentary: Immune Responses in the Absence of Costimulation: Viruses Know the Trick
Authors: Bachmann Martin F. , Zinkernagel Rolf M. , Oxenius Annette 
Published: January 2023

Abstract
Costimulatory molecules are crucial for the induction of immune responses after immunization with purified proteins or peptides. However, some viruses and other pathogens are able to induce protective immunity in the absence of such molecules. This review argues that patterns recognized by both the specific and the innate immune system, together with a high and sustained Ag-load, are responsible for these surprisingly efficient immune responses triggered by pathogens.
Cutting Edge: Differential CD5-Dependent Regulation of CD5-Associated CK2 Activity in Mature and Immature T Cells: Implication on TCR/CD3-Mediated Activation
Authors: Raman Chander , Kimberly Robert P. 
Published: January 2023

AbstractCD5 attenuates TCR-induced signals in immature thymocytes but functions as a costimulatory molecule potentiating TCR/CD3-mediated activation in mature, peripheral T cells. We have recently shown that the serine/threonine kinase, casein kinase 2 (CK2), a major regulator of cell growth and signaling, associates with and is activated by CD5. Therefore, we tested the possibility that differential regulation of CK2 activity by CD5 may be associated with these differences in CD5 modulation of TCR signaling. Consistent with our hypothesis, CD5-specific cross-linking activated associated CK2 in thymocytes but not active in mature splenocytes. Differential regulation of CD5-associated CK2 provides, for the first time, a potential mechanism for the differential effects of CD5 signaling in immature and mature cells. We propose that CD5 modulates Ag receptor activity through developmentally regulated activation of CD5-associated CK2.
Extrathymic T Cell Differentiation in the Human Intestine Early in Life
Authors: Howie Duncan , Spencer Jo , DeLord Denise , Pitzalis Costantino , Wathen Neville C. , Dogan Ahmet , Akbar Arne , MacDonald Thomas T. 
Published: January 2023

AbstractIt is clear from experimental studies in mice that T cell maturation can occur outside the thymus, especially in the intestine. There is little sound evidence so far that extrathymic T cell maturation occurs to any significant extent in human gut, and, postnatally, there is abundant evidence that the gut mucosa is an immune effector organ. Here, we describe a large population of T lymphocytes in human fetal intestinal mucosa that are proliferating (Ki67+) in the absence of foreign Ag (CD3+, Ki67+ lamina propria lymphocytes (LPL) 22 ± 1.8% and CD3+, Ki67+ intraepithelial lymphocytes (IEL) 9.1 ± 1.4%), that express the T cell activation markers CD103, HLA-DR, and L-selectinlow, and that express mRNA transcripts for pre-TCR-α. There is also a substantial proportion of CD7+ LPLs that do not express CD3 (CD3−7+, 14 ± 7% of all LPLs) in the fetal gut that may be differentiating into CD3+ cells. Rearranged TCR-β transcripts of fetal LPLs, IELs, and paired blood lymphocytes were cloned and sequenced, and virtually no overlap of clonality was observed between blood and intestine, suggesting that gut T cells may not be derived from the blood. In addition, 30 days after engraftment of SCID mice with fetal intestine, CD3−7+ cells, proliferating T cells, and pre-TCR-α transcripts were abundant, and there is a threefold increase in CD3+ IELs. These data show that in the human intestine before birth a population of precursor T cells exists that may be differentiating into mature T cells in situ
Monocyte Induction of IL-10 and Down-Regulation of IL-12 by iC3b Deposited in Ultraviolet-Exposed Human Skin
Authors: Yoshida Yuichi , Kang Kefei , Berger Melvin , Chen Guofen , Gilliam Anita C. , Moser Autumn , Wu Ling , Hammerberg Craig , Cooper Kevin D. 
Published: January 2023

Abstract
CD11b+ monocytic/macrophagic cells (Mo/Mph), which infiltrate into skin after UV irradiation, play an important role in UV-induced immunosuppression. Because in mice, blockade of CD11b (iC3b receptor) on monocytes and depletion of its ligand, iC3b, reverses UV-induced immunosuppression, we asked whether iC3b is deposited in human skin after UV, and whether iC3b can modulate the cytokine profile of Mo/Mph. Immunofluorescence studies revealed that iC3b was newly deposited in UV-exposed skin and was localized in apposition to infiltrating CD11b+ Mo/Mph. In addition, in situ hybridization studies showed that TNF-α mRNA was also induced in a similar microanatomic localization. To model the effects of these complex signals on infiltrating Mo/Mph following UV exposure, we then tested the effects of immobilized iC3b and TNF-α on resting blood monocytes. Both IL-10 mRNA synthesis and protein secretion were significantly induced by binding of iC3b in vitro and were synergistically increased by the presence of TNF-α. The effect was abrogated by a blocking Ab to CD11b, indicating CD11b-iC3b interaction. In contrast, iC3b binding resulted in suppression of IL-12 p40 mRNA and significantly inhibited the production of IL-12 p70 protein. Our studies thus define a novel mechanism for induction of tissue Mo/Mph into an IL-10high/IL-12low state via iC3b in combination with TNF-α.
Convergence of CD19 and B Cell Antigen Receptor Signals at MEK1 in the ERK2 Activation Cascade
Authors: Li Xiaoli , Carter Robert H. 
Published: January 2023

AbstractCD19 plays a critical role in regulating B cell responses to Ag. We have studied the mechanism by which coligation of CD19 and the B cell Ag receptor, membrane Ig (mIg), augments signal transduction, including synergistic enhancement of release of intracellular Ca2+ and extracellular signal-regulated protein kinase 2 (ERK2) activation, in Daudi human B lymphoblastoid cells. The pathway leading to ERK2 activation was further dissected to determine how signals derived from CD19 and mIgM interact. The best-defined pathway, known to be activated by mIgM, consists of the sequential activation of the mitogen-activated protein kinase (MAPK) cascade that includes Ras, Raf, MAPK kinase 1 (MEK1), and ERK2. Ligation of CD19 alone had little effect on these. CD19-mIgM coligation did not increase activation of Ras or Raf beyond that induced by ligation of mIgM alone. In contrast, coligation resulted in synergistic activation of MEK1. Furthermore, synergistic activation of ERK2 occurred in the absence of changes in intracellular Ca2+, and was not blocked by inhibition of protein kinase C activity and represents a separate pathway by which CD19 regulates B cell function. Thus, the CD19-dependent signal after CD19-mIgM coligation converges with that generated by mIgM at MEK1. The intermediate kinases in the MAPK cascade leading to ERK2 integrate signals from lymphocyte coreceptors.
Two-Domain MHC Class II Molecules Form Stable Complexes with Myelin Basic Protein 69–89 Peptide That Detect and Inhibit Rat Encephalitogenic T Cells and Treat Experimental Autoimmune Encephalomyelitis
Authors: Burrows Gregory G. , Bebo Bruce F. , Adlard Kirsten L. , Vandenbark Arthur A. , Offner Halina 
Published: January 2023

AbstractWe designed and expressed in bacteria a single-chain two-domain MHC class II molecule capable of binding and forming stable complexes with antigenic peptide. The prototype “β1α1” molecule included the β1 domain of the rat RT1.B class II molecule covalently linked to the amino terminus of the α1 domain. In association with the encephalitogenic myelin basic protein (MBP) 69–89 peptide recognized by Lewis rat T cells, the β1α1/MBP-69–89 complex specifically labeled and inhibited activation of MBP-69–89 reactive T cells in an IL-2-reversible manner. Moreover, this complex both suppressed and treated clinical signs of experimental autoimmune encephalomyelitis and inhibited delayed-type hypersensitivity reactions and lymphocyte proliferation in an Ag-specific manner. These data indicate that the β1α1/MBP-69–89 complex functions as a simplified natural TCR ligand with potent inhibitory activity that does not require additional signaling from the β2 and α2 domains. This new class of small soluble polypeptide may provide a template for designing human homologues useful in detecting and regulating potentially autopathogenic T cells.
Inhibitors of the p38 Mitogen-Activated Kinase Modulate IL-4 Induction of Low Affinity IgE Receptor (CD23) in Human Monocytes
Authors: Marshall Lisa A. , Hansbury Michael J. , Bolognese Brian J. , Gum Rebecca J. , Young Peter R. , Mayer Ruth J. 
Published: January 2023

Abstract
CD23, the low affinity IgE receptor, is up-regulated on the surface of IL-4-treated B cells and monocytes and is immediately proteolytically processed, releasing soluble fragments of CD23. Here, we report that inhibitors of the p38 mitogen-activated kinase (p38 MAPK), SK&F 86002 or the more selective inhibitor, SB 203580, reduce the levels of soluble CD23 formed by IL-4-stimulated human monocytes or the human monocytic cell line, U937. In contrast to compounds such as the metalloprotease inhibitor batimastat ([4-(N-hydroxyamino)-2-(R)-isobutyl-3-(S)-(2-thiophenethiomethyl)succinyl]-(S)-phenylalanine-N-methylamide, sodium salt), p38 MAPK inhibitors do not directly inhibit proteolytic processing of CD23. Further, evaluation of surface intact CD23 (iCD23) by flow cytometry demonstrated that SK&F 86002 and SB 203580 reduced the surface expression of iCD23 in a concentration-dependent fashion, while batimastat increased the surface expression of iCD23. The decrease in surface iCD23 was accompanied by a decrease in total cell-associated CD23 protein levels but not CD23 mRNA. IL-4 induced a late (&gt;4-h) increase in p38 MAPK activity and corresponding activation of its substrate MAPKAPK-2. This activation was blocked by addition of SB 203580 before IL-4 induction, in parallel with the inhibition of CD23 expression. Modulation of CD23 by antibodies has been shown to alleviate the symptoms of murine collagen-induced arthritis, implicating CD23 as an important proinflammatory agent. These data show that in addition to the known cytokine inhibitory actions of SK&F 86002 and SB 203580, they also confer an additional potential anti-inflammatory activity through modulation of CD23 expression.
Degree of TCR Internalization and Ca2+ Flux Correlates with Thymocyte Selection
Authors: Mariathasan Sanjeev , Bachmann Martin F. , Bouchard Denis , Ohteki Toshiaki , Ohashi Pamela S. 
Published: January 2023

AbstractRecent evidence suggests that TCR down-regulation directly reflects the number of TCRs that have engaged MHC/peptide ligand complexes. Here, we examined the influence of defined peptides on thymic selection based on their ability to induce differential TCR internalization. Our results demonstrate that there is a direct correlation: peptides that induce strong TCR down-regulation are most efficient at mediating negative selection, whereas peptides that induce suboptimal TCR internalization are more efficient at triggering positive selection. As a consequence of suboptimal TCR internalization, a proportion of TCR complexes that remain on the cell surface may be able to relay continual signals required for survival and differentiation. In addition, we show that the magnitude of Ca2+ influx set by these peptides reflects the hierarchy of TCR down-regulation and correlates with positive vs negative selection of transgenic thymocytes. Together, our data suggest that T cell selection is mediated by differing intensities of the same TCR-mediated signal, rather than by distinct signals.