bluuebunny/crossref_metadata_2025_split huggingface dataset:
The fate of pro-TNF-alpha following inhibition of metalloprotease-dependent processing to soluble TNF-alpha in human monocytes.
Authors: Solomon K A , Covington M B , DeCicco C P , Newton R C 
Published: January 2023

Abstract
Human monocytes rapidly produce TNF-alpha following activation by bacterial LPS. The message for TNF-alpha encodes a 26-kDa protein that is proteolytically processed to the secreted 17-kDa form. Sequencing of the N terminus of the protein secreted by monocytes shows processing of the 26-kDa pro-TNF-alpha to a mature form at the projected metalloprotease cleavage site to generate 17-kDa TNF-alpha with the N terminus VRSSSR-. The addition of hydroxamic acid-based metalloprotease inhibitors to the cell culture is capable of blocking &gt;95% of the production of soluble TNF-alpha and leads to a transient, but reproducible, increase in cell surface TNF-alpha as measured by FACS analysis. The cell surface TNF-alpha was demonstrated to increase the cell's ability to kill L929 tumor targets and induce PG production from human gingival fibroblasts. The buildup of cell surface TNF-alpha is unable to account for the TNF-alpha that is not secreted when inhibitor is present. Pulse-chase analysis of the cells demonstrates rapid degradation of the pro-TNF-alpha that remains unprocessed in the monocytes. Through inhibition of processing and secretion by brefeldin A, processing was shown to occur at a postendoplasmic reticulum site and is closely associated with movement to the cell surface.
Increased expression of eotaxin in bronchoalveolar lavage and airways of asthmatics contributes to the chemotaxis of eosinophils to the site of inflammation.
Authors: Lamkhioued B , Renzi P M , Abi-Younes S , Garcia-Zepada E A , Allakhverdi Z , Ghaffar O , Rothenberg M D , Luster A D , Hamid Q 
Published: January 2023

Abstract
Presently, there is considerable evidence for the participation of eosinophils in the pathophysiology of human bronchial asthma. Although increased numbers of eosinophils are present in the airways and bronchoalveolar lavage (BAL) fluid of atopic asthmatics, the mechanisms responsible for their preferential accumulation are still largely unknown. Eotaxin is a chemokine that promotes the selective recruitment of eosinophils. We report that atopic asthmatic patients have high concentrations of eotaxin in BAL fluid and an increased expression of eotaxin mRNA and protein in the epithelium and submucosa of their airways when compared with normal controls. In the BAL cells from asthmatic patients, eotaxin immunoreactivity colocalized predominantly to macrophages (62.2%), with a lesser contribution from T cells (16.3%) and eosinophils (8.9%). BAL fluid from asthmatics contained chemotactic activity for eosinophils that was attributable in part to the presence of eotaxin. Moreover, eotaxin was more effective at inducing in vitro eosinophil chemotaxis when eosinophils were stimulated with IL-5 (a cytokine that enhances the effector capacity of mature eosinophils). These observations suggest that eotaxin contributes to the pathogenesis of asthma by the specific recruitment of eosinophils into the airways.
Myelin protein expression is increased in lymph nodes of mice with relapsing experimental autoimmune encephalomyelitis.
Authors: MacKenzie-Graham A J , Pribyl T M , Kim S , Porter V R , Campagnoni A T , Voskuhl R R 
Published: January 2023

Abstract
Myelin proteins had been thought to be sequestered behind the blood-brain barrier. Recently, however, myelin proteins have been found to be expressed in lymphoid tissues. The myelin basic protein (MBP) gene is embedded within a larger transcription unit called the golli-MBP gene. This larger gene encodes both the "classic" MBPs as well as the structurally related golli-MBPs. In this study, golli-MBP expression in lymph nodes was examined in four different models of relapsing experimental autoimmune encephalomyelitis (rEAE). Disease in these rEAE models was induced by the adoptive transfer of T lymphocytes specific for 18.5-kDa MBP, MBP peptide 83-102, or PLP peptide 139-151 in the SJL/J mouse and the adoptive transfer of T lymphocytes specific for MBP peptide Ac1-9 in the (SJL/J x PL/J)F1 mouse. In all four models, expression of golli-MBP BG21 mRNA was increased two- to fivefold in lymph nodes of mice 45 to 60 days post-transfer. Immunohistochemical analysis indicated that expression occurred principally in macrophages within lymph nodes. Endogenous golli-MBP epitopes within lymph node cells stimulated "classic" MBP 1-44-specific T lymphocytes, and this stimulatory ability resided within the adherent lymph node cell population. An increase in myelin protein expression within lymph nodes during rEAE has implications with regard to intra- and intermolecular epitope spreading. This is the first report describing an increase in target autoantigen expression within lymphoid tissue during an autoimmune disease.
Skin-homing, CLA+ memory T cells are activated in atopic dermatitis and regulate IgE by an IL-13-dominated cytokine pattern: IgG4 counter-regulation by CLA- memory T cells.
Authors: Akdis M , Akdis C A , Weigl L , Disch R , Blaser K 
Published: January 2023

Abstract
Cutaneous lymphocyte-associated Ag (CLA) is a skin-homing receptor displayed by memory/effector T cells recognizing skin-related allergens. Here we demonstrate that peripheral blood CLA+ CD45RO+ T cells in patients with atopic dermatitis (AD) are in vivo activated. They spontaneously proliferate and release an IL-13-dominated Th2 cytokine profile and are capable of inducing IgE in autologous B cells without further activation. The spontaneous cytokine release occurred within the first hour of culture and was not inhibited by cycloheximide or by other immunosuppressive drugs, indicating that cytokine transcription and translation had been completed in vivo. In contrast, the CLA- CD45RO+ T cells from the same patients and from nonatopic controls represented a resting memory T cell subset, secreted borderline quantities of cytokines, and induced IgG4. Polyclonal activation by the anti-CD2/anti-CD3/anti-CD28 mAb mixture generated distinct cytokine patterns in the two memory/effector T cell subsets. CLA+ T cells secreted Th2 cytokines with high IL-13 levels, and the CLA- subset mainly produced IFN-gamma. There was no difference in in vitro activated cytokine pattern between AD patients and nonatopic subjects. These results indicate that the CLA+ memory/effector T cells of AD patients are activated in vivo and play a pivotal role in allergic inflammation by production of IL-13 and induction of IgE Abs. In contrast, the CLA- resting memory T cell population may exert immunoprotective properties toward allergen by high IFN-gamma secretion and induction of IgG4.
CD40 ligand-CD40 interactions are necessary for the initiation of insulitis and diabetes in nonobese diabetic mice.
Authors: Balasa B , Krahl T , Patstone G , Lee J , Tisch R , McDevitt H O , Sarvetnick N 
Published: January 2023

Abstract
The nonobese diabetic (NOD) mouse spontaneously develops T cell-dependent autoimmune diabetes. Here, we investigate the role of CD40 ligand (CD40L)-CD40 costimulation in the initiation and progression of this disease. Anti-CD40L mAb treatment of 3- to 4-wk-old NOD females (the age at which insulitis typically begins) completely prevented the insulitis and diabetes. In contrast, treatment of such mice with anti-CD40L at &gt;9 wk of age did not inhibit the disease process. These results suggest that a costimulatory signal by CD40L is required early but not in the effector phase of disease development. Anti-CD40L treatment affected the priming of islet Ag-specific T cell responses in vivo. Cytokine analysis revealed a dramatic decrease in IFN-gamma and IL-2 release without a concomitant increase in IL-4 production by T cells from anti-CD40L-treated mice. Thus, anti-CD40L impaired the islet Ag-specific Th1 cell response in vivo, and the prevention of diabetes by anti-CD40L was not associated with switching of the response from a Th1 to a Th2 profile. Cotransfer of splenocytes from anti-CD40L-treated mice with splenocytes from diabetic NOD mice into NOD/scid mice did not inhibit the transfer of disease, indicating that anti-CD40L does not prevent the disease by inducing regulatory cells. Since anti-CD40L clearly prevented the insulitis by inhibiting the development and further accumulation of pathogenic Th1 cells to islets of Langerhans, we conclude that CD40L-CD40 costimulation is required for early events in the development of spontaneous autoimmune diabetes.
Cutting Edge: CTLA-4 Ligation Delivers a Unique Signal to Resting Human CD4 T Cells That Inhibits Interleukin-2 Secretion but Allows Bcl-XL Induction
Authors: Blair Patrick J. , Riley James L. , Levine Bruce L. , Lee Kelvin P. , Craighead Nancy , Francomano Tara , Perfetto Steven J. , Gray Gary S. , Carreno Beatriz M. , June Carl H. 
Published: January 2023

Abstract
We have assessed the functional effects of a panel of CTLA-4 mAbs on resting human CD4+ T cells. Our results demonstrate that some CTLA-4 mAbs can inhibit proliferative responses of resting CD4+ cells and cell cycle transition from G0 to G1. The inhibitory effects of CTLA-4 were evident within 4 h, at a time when cell surface CTLA-4 expression remained undetectable. Other CTLA-4 mAbs had no detectable inhibitory effects, indicating that binding of Ab to CTLA-4 alone is not sufficient to mediate down-regulation of T cell responses. Interestingly, while IL-2 production was shut off, inhibitory anti-CTLA-4 mAbs permitted induction and expression of the cell survival gene bcl-XL. Consistent with this observation, cells remained viable and apoptosis was not detected after CTLA-4 ligation.
Reduced Cell Surface Expression of HLA-C Molecules Correlates with Restricted Peptide Binding and Stable TAP Interaction
Authors: Neisig Anne , Melief Cornelis J. M. , Neefjes Jacques 
Published: January 2023

Abstract
HLA-C molecules are poorly expressed at the cell surface compared with HLA-A and HLA-B locus products. The reason for the low surface expression and the underlying mechanism is unclear. We show that the HLA-C4 allele is expressed intracellularly in amounts similar to HLA-A and HLA-B alleles. However, the majority of the HLA-C4 molecules is not transported, but is retained in the endoplasmic reticulum by stable interaction with TAP. This pool does not appear to participate in the formation of HLA-C4/peptide complexes, but is degraded in the endoplasmic reticulum. HLA-C4 molecules can dissociate from TAP upon binding of specific peptide. However, they require a 10-fold higher concentration of a completely degenerated 9-mer peptide mixture for release from TAP than the HLA-A and HLA-B alleles. Our data show that the HLA-C molecules tested are more selective in their peptide binding than HLA-A and HLA-B molecules, resulting in prolonged association with TAP and a reduced formation of intracellular HLA-C/peptide complexes. The restricted peptide binding of certain HLA-C alleles provides one explanation for the reduced expression of HLA-C molecules at the cell surface. Other mechanisms will be discussed.
Cutting Edge: Identification of the Mouse IgG3 Receptor: Implications for Antibody Effector Function at the Interface Between Innate and Adaptive Immunity
Authors: Gavin Amanda L. , Barnes Nadine , Dijstelbloem Hilde M. , Hogarth P. Mark 
Published: January 2023

Abstract
Mouse IgG3 appears early in immune responses independently of T cell help and, as such, is an early effector molecule of the immune system. Yet, a specific IgG3 cellular receptor remains undefined. In transfection experiments, mouse FcγRI was clearly able to bind immune complexes of IgG3, whereas mouse FcγRII could not. Furthermore, macrophages from mice expressing FcγRII and FcγRIII but lacking FcγRI were unable to phagocytose IgG3 immune complexes, thus identifying mouse FcγRI as the sole receptor for IgG3 immune complexes. Competition studies demonstrated that monomeric mouse IgG3 could inhibit IgG2a binding to mouse FcγRI with an ID50 ≈10−7 M (fivefold lower than IgG2a). The identification of mouse FcγRI as the IgG3 receptor establishes FcγRI as a participant in events at the interface between innate and adaptive immunity, implying a greater role for this receptor in the development of normal and pathologic immune responses than previously recognized.
Monoclonal Anti-Cardiolipin Antibodies from New Zealand Black × New Zealand White F1 Mice React to Thrombomodulin
Authors: Haruta Kazuhiko , Kobayashi Shigeto , Hirose Sachiko , Horiai Aiko , Ohyanagi Mutsuko , Tanaka Mitsuhiko , Kawano Terunaga , Shirai Toshikazu , Takasaki Yoshinari , Hashimoto Hiroshi 
Published: January 2023

Abstract
The reactivity with and affinity for thrombomodulin (TM) of monoclonal anti-cardiolipin Abs (MoaCL), derived from a New Zealand Black × New Zealand White F1 (NZB/W F1) mouse, were studied to investigate the pathogenicity of anti-cardiolipin Abs (aCL). Four of eighteen MoaCL were found to react with rabbit TM when examined using ELISA. These four MoaCL also reacted with synthetic peptide that included the epidermal growth factor-like domain of human TM, a binding site for thrombin. The reaction with TM of these four MoaCL was inhibited by bovine thrombin. When the affinity for TM of the MoaCL was determined, the dissociation constants (Kd) ranged from 4.8 × 10−9 to 4.7 × 10−8 M. By contrast, examination of the affinity for cardiolipin (CL) gave values from 8.3 × 10−6 to 7.4 × 10−5 M. Thus, these MoaCL reacted to TM with a higher affinity than to CL. Moreover, these MoaCL also bound to TM on HUVEC and down-regulated the expression level of TM on the surface of HUVEC due to internalization of TM. The binding of thrombin to TM is known to initiate rapid protein C activation, and complexes of activated protein C and protein S show anticoagulatory activity. Thus, the present studies suggest that certain pathogenic aCL cross-react with TM and induce down-regulation of TM on endothelial cells, followed by induction of thrombosis.
VH Repertoire of a Marsupial (Monodelphis domestica)
Authors: Miller Robert D. , Grabe Hilary , Rosenberg George H. 
Published: January 2023

AbstractWhen contrasted with information available for placental mammals, very little is known about the development of immunocompetence in marsupials. Marsupials, however, provide interesting immunology problems, since most appear to be born at a stage of development much less mature than that of placental mammals. To further understand the marsupial immune system, the Ig repertoire of the short-tailed opossum, Monodelphis domestica, was characterized. The majority of the VH clones were isolated in an unbiased manner by screening a spleen cDNA phage library, using C region probes, or anchored PCR, using C region-specific primers paired with vector specific primers. Analysis of 54 unique VH sequences from this marsupial revealed the presence of two VH families in the expressed Ig repertoire. The larger family, which contributed the majority of the clones identified, appears to be derived from 10 to 12 germline VH segments. The second family of clones is derived from a single germline VH. Both VH families are related to the group III sequences described in other vertebrates. Unusual codon bias differences between the two families may result in very different patterns of somatic mutation within the opossum Ig repertoire.
Molecular Analysis of the Major MHC Recombinational Hot Spot Located Within the G7c Gene of the Murine Class III Region That Is Involved in Disease Susceptibility
Authors: Snoek Margriet , Teuscher Cory , van Vugt Huub 
Published: January 2023

Abstract
Recombination within the MHC does not occur at random, but crossovers are clustered in hot spots. We previously described a recombinational hotspot within the 50-kb Hsp70.3–G7 interval in the class III region of the mouse MHC. The parental haplotypes of recombinants with crossovers in this region represent the majority of the laboratory haplotypes (a, b, d, dx, k, m, p, px, q, s, and u). Using microsatellite markers and sequence-based nucleotide polymorphisms, the breakpoint intervals of 30 recombinants were mapped to a 5-kb-long interval within the G7c gene adjacent to G7a. Recombination within the G7c hot spot does not appear to be restricted to certain haplotypes. Sequence motifs that had been suggested to be associated with site-restricted meiotic recombination were absent in the vicinity of the G7c hot spot, and hence, these sequence motifs are no prerequisite for meiotic recombination. The G7c hot spot resides in a region to which a number of disease susceptibility loci have been mapped, including susceptibility to cleft palate, experimental autoimmune allergic orchitis, and chemically induced alveolar lung tumors. The exact localization of crossovers in recombinants that have been used in functional studies is important for mapping susceptibility genes and limits the number of candidate genes.
Mechanism of Protective Immunity Against Influenza Virus Infection in Mice Without Antibodies
Authors: Epstein Suzanne L. , Lo Chia-Yun , Misplon Julia A. , Bennink Jack R. 
Published: January 2023

AbstractThere is considerable interest in developing viral vaccines intended to induce T cell immunity, especially cytotoxic CD8+ T lymphocytes, when Abs are not protective or are too narrow in viral strain specificity. We have studied protective immunity in doubly inactivated (DI) mice devoid of Abs and mature B cells. When infected with influenza B virus, these mice cleared the virus in a process dependent upon CD8+ T lymphocytes. Cytotoxic activity was detected in lung lymphocytes of DI mice after primary or secondary infection, and was abrogated by depletion of CD8+ cells in vivo. Challenge experiments showed that DI mice could be protected by immunization against reinfection 1 mo later, and protection was virus specific. Depletion of CD4+ or CD8+ T cells in vivo during the challenge period partially abrogated, and depletion of both subsets completely abrogated, the protection. This indicates that both CD4+ and CD8+ T cells are required effectors in the optimal control of virus replication. Thus, when Abs fail to protect against varying challenge viruses, as is the case with variant strains of influenza and HIV, there is hope that T cells might be able to act alone.
IL-1 and TNF Antagonists Inhibit the Inflammatory Response and Bone Loss in Experimental Periodontitis
Authors: Assuma R. , Oates T. , Cochran D. , Amar S. , Graves D. T. 
Published: January 2023

Abstract
Periodontal disease is the most frequent cause of tooth loss in humans and is the most prevalent disease associated with bone loss, including osteoporosis. Periodontal destruction is initiated by bacteria that colonize the tooth surface, leading to inflammation and bone resorption. To assess the roles of IL-1 and TNF in this process, studies were conducted in a Macaca fascicularis primate model of experimental periodontitis. Function-blocking soluble receptors to IL-1 and TNF were applied by local injection to sites with induced periodontal destruction and compared with similar sites injected with vehicle alone. The results indicate that injection of soluble receptors to IL-1 and TNF inhibited by approximately 80% the recruitment of inflammatory cells in close proximity to bone. The formation of osteoclasts was reduced by 67% at the experimental sites compared with that at the control sites, and the amount of bone loss was reduced by 60%. All results were statistically significant (p &lt; 0.01). These findings indicate that a significant component of the pathologic process of periodontitis is due to IL-1/TNF activity, since inhibiting IL-1/TNF reduces both inflammatory cell recruitment and bone loss. The data also suggest that inflammation associated with gingivitis is actively protective, since blocking further up-regulation of the host response with IL-1/TNF inhibitors does not cause periodontal damage. Furthermore, these results coupled with recent evidence that IL-1 and TNF participate in endocrine-associated osteoporosis suggest that multiple pathologies involving excessive loss of bone may operate through a common mechanism involving IL-1 and/or TNF.
RANTES-Induced T Cell Activation Correlates with CD3 Expression
Authors: Dairaghi Daniel J. , Soo Kenneth S. , Oldham Elizabeth R. , Premack Brett A. , Kitamura Toshio , Bacon Kevin B. , Schall Thomas J. 
Published: January 2023

Abstract
The chemokine RANTES induces a unique biphasic cytoplasmic Ca2+ signal in T cells. The first phase of this signal, similar to that of other chemokines, is G-protein mediated and chemotaxis associated. The second phase of this signal, unique to RANTES and evident at concentrations greater than 100 nM, is tyrosine kinase linked and results in a spectrum of responses similar to those seen with antigenic stimulation of T cells. We show here that certain Jurkat T cells responded to RANTES solely through this latter pathway. A direct correlation between the RANTES-induced second phase response and CD3 expression was demonstrated in these cells. Sorting the Jurkat cells into CD3high and CD3low populations revealed that only the CD3high cells were responsive to RANTES. Furthermore, stimulation of these Jurkat cells with anti-CD3 mAb significantly depresses their subsequent response to RANTES. While a RANTES-specific chemokine receptor is expressed at a low level on these Jurkat cells, the RANTES-induced activation is dependent on the presence of the TCR. Thus, stimulation through TCR may partially account for RANTES’ unique pattern of signaling in T cells.
Regulation of Chemokine Gene Expression in Human Peripheral Blood Neutrophils Phagocytosing Microbial Pathogens
Authors: Hachicha Mohamed , Rathanaswami Palaniswami , Naccache Paul H. , McColl Shaun R. 
Published: January 2023

Abstract
Production of chemokines (chemotactic cytokines) by neutrophils is likely to be important in the regulation of inflammation and the control of infection. In this study we show that exposure of human neutrophils to various microbial pathogens leads to the production of both macrophage inflammatory protein 1α (MIP-1α) and IL-8. The bacterial microbes, Salmonella typhimurium and Pseudomonas aeruginosa, and Staphylococcus aureus all strongly induced both IL-8 and MIP-1α secretion, whereas Streptococcus pneumoniae, Staphylococcus epidermidis, and the opportunistic yeast Candida albicans were less potent. Saccharomyces cerevisiae and zymosan both induced IL-8 secretion but failed to stimulate that of MIP-1α. Coincubation of neutrophils with the proinflammatory cytokine TNF-α and the micro-organisms also led to differential expression of MIP-1α and IL-8. Significant enhancement of the induction of both MIP-1α and IL-8 by S. typhimurium, P. aeruginosa, and S. pneumoniae as well as by C. albicans was observed. In contrast, while IL-8 production in response to S. cerevisiae and zymosan was enhanced in the presence of TNF-α, no MIP-1α was produced. These combined results indicate that while neutrophils exposed to some micro-organisms alone or in the presence of inflammatory cytokines such as TNF-α will produce both MIP-1α and IL-8, resulting in generation of signals for the recruitment of mononuclear leukocytes and neutrophils, respectively, certain types of micro-organisms can skew this response toward synthesis of IL-8.