bluuebunny/crossref_metadata_2025_split huggingface dataset:
Very late antigen-5 and complement receptor type 3 cooperatively mediate the interaction between Bordetella pertussis and human monocytes.
Authors: Hazenbos W L , van den Berg B M , van Furth R 
Published: January 2023

Abstract
Nonopsonized Bordetella pertussis, the causative agent of whooping cough, can attach to and become ingested by human monocytes. It has been reported that complement receptor type 3 (CR3) on human monocyte-derived macrophages binds filamentous hemagglutinin expressed on B. pertussis. In the present study, the role of very late antigen-5 (VLA-5) in the attachment of B. pertussis to adherent human monocytes was investigated. It was found that soluble fibronectin and soluble mAb against VLA-5 markedly inhibited the attachment of B. pertussis to monocytes. When VLA-5 on monocytes was cross-linked by plating these cells onto surfaces precoated with fibronectin or mAb against VLA-5, the binding of both B. pertussis and C3bi-coated sheep erythrocytes to these cells was significantly enhanced, whereas the binding of a B. pertussis mutant strain deficient in filamentous hemagglutinin was not affected. The enhanced attachment of B. pertussis to monocytes plated onto fibronectin-coated surfaces was markedly inhibited by soluble mAb against CR3. Neutrophils, which express similar levels of CR3 and about 10-fold lower levels of VLA-5 as compared with monocytes, did not bind B. pertussis. Together, these results indicate that VLA-5 is involved in the attachment of B. pertussis to monocytes and that cross-linking of VLA-5 enhances the attachment of B. pertussis to monocytes by augmenting the binding activity of CR3. We propose that the attachment of B. pertussis to monocytes occurs in two steps: binding and cross-linking of VLA-5 by B. pertussis enhances the binding activity of CR3, which in turn facilitates the subsequent binding of these bacteria to the latter receptor.
Differential expression in rheumatoid synovium and synovial fluid of alpha 4 beta 7 integrin. A novel receptor for fibronectin and vascular cell adhesion molecule-1.
Authors: Lazarovits A I , Karsh J 
Published: January 2023

Abstract
T lymphocyte adhesion to vascular endothelium plays an important role in the immunopathogenesis of rheumatoid arthritis. The migration of T lymphocytes into the synovium is mediated by a variety of adhesion molecules, notably the integrins. We have prepared Act I, a murine mAb that identifies a novel integrin termed alpha 4 beta 7. The natural ligands for alpha 4 beta 7 are vascular cell adhesion molecule-1 and fibronectin; both molecules are up-regulated in the rheumatoid synovium. We investigated the expression of alpha 4 beta 7 in the three compartments of rheumatoid arthritis, the peripheral blood, synovial fluid, and synovial membrane, utilizing the FACS and immunoperoxidase microscopy of frozen tissues. The results of our experiments show a striking differential expression of alpha 4 beta 7 integrin in rheumatoid arthritis. Sixty-two percent of synovial membrane T cells expressed high density alpha 4 beta 7, in contrast to only 4.7% of synovial fluid and 9.1% of PBL. These data suggest that the expression of alpha 4 beta 7 integrin may provide a mechanism whereby certain T cells adhere to rheumatoid synovium while others remain in the synovial fluid. The augmented expression of alpha 4 beta 7 in the synovial membrane T cells may contribute to the development and perpetuation of rheumatoid arthritis.
Polyclonal B cell activation arises from different mechanisms in lupus-prone (NZB x NZW)F1 and MRL/MpJ-lpr/lpr mice.
Authors: Merino R , Iwamoto M , Fossati L , Izui S 
Published: January 2023

Abstract
The polyclonal B cell activation is the earliest and most common immunologic abnormality in lupus-prone mice. However, its cellular mechanism(s) has not been well defined. To determine the contribution of CD4+ T cells in this immunologic abnormality, we have depleted CD4+ T cells in lupus-prone (NZB x NZW)F1 and MRL/MpJ-lpr/lpr mice by treating them with anti-CD4 mAb from birth and determined the development of IgM and IgG polyclonal antibody formation. Our results indicate that first, different mechanisms control the development of IgM polyclonal B cell activation in these two autoimmune mice; in (NZB x NZW)F1 mice, IgM polyclonal B cell activation is likely to be a result of an intrinsic B cell defect, whereas CD4+ T cells seem to be responsible for this immunologic abnormality in MRL/MpJ-lpr/lpr mice. Second, the increased production of IgG antibodies, including the IgG3 subclass, was totally regulated by CD4+ T cells in both autoimmune mice. Because IgG3 antibodies can be highly nephritogenic, independent of their immunologic specificities, which is the result of the antibodies' cryoglobulin activity, the active role of CD4+ T cells in the production of IgG3 antibodies in lupus-prone autoimmune mice further strengthens the implication of CD4+ T cells in murine systemic lupus erythematosus.
Preferential use of a H chain V region in antitumor-associated glycoprotein-72 monoclonal antibodies.
Authors: Rixon M W , Gourlie B B , Kaplan D A , Schlom J , Mézes P S 
Published: January 2023

Abstract
The DNA sequence of the mouse H chain V regions from five hybridomas directed against the human tumor Ag tumor-associated glycoprotein-72 (TAG-72) have been determined. This includes a previously determined VH gene sequence from a first-generation anti-TAG-72 mAb, B72.3, and the VH gene sequences from four second-generation anti-TAG-72 mAb, CC49, CC83, CC46, and CC92. A sequence comparison revealed a high degree of shared sequence identity between the five productively rearranged VH genes, suggesting derivation from a common germ line V region gene. In the process of cloning the unrearranged germ line gene, two highly related VH germ line genes were identified and designated VH alpha TAG-1 and VH alpha TAG-2. A comparison of the productively rearranged anti-TAG-72 VH sequences with the two germ line VH genes demonstrated that they were all derived from VH alpha TAG-1. In contrast, the L chain V regions are all derived from separate germ line V region genes. The preferential use of VH alpha TAG-1 in these five mouse hybridomas suggests that VH alpha TAG-1 is a preferred anti-TAG-72 H V chain region germ line gene and that the H chain plays a predominant role in the recognition of this Ag.
VH4.21-encoded natural autoantibodies with anti-i specificity mirror those associated with cold hemagglutinin disease.
Authors: Schutte M E , van Es J H , Silberstein L E , Logtenberg T 
Published: January 2023

Abstract
The Ig VH regions of virtually all human pathogenic cold agglutinin (CA) anti-i/l autoantibodies are encoded by a single Ig VH gene segment, VH4.21, in conjunction with a highly variable CDR3 structure. The anti-I specificity is often associated with V kappa III-encoded L chains, whereas anti-i autoantibodies appear to use a broader array of kappa and lambda VL gene segments. B cells expressing VH4.21 are abundantly present in adult lymphoid tissues from healthy individuals but their relationship with B cells secreting pathogenic CA is unknown. Herein we have analyzed the distribution of VH4.21-expressing B cells in fetal, neonatal, and adult B cell populations using the monoclonal anti-VH4.21 antibody 9G4. In addition, we have analyzed the anti-i and anti-I binding capacity and V regions of 19 VH4.21-encoded mAb secreted by cord and adult blood-derived cell lines from healthy individuals. The results show that VH4.21 expressing B cells are overrepresented in all repertoires studied and are evenly distributed over cord blood CD5+ and CD5- B cell populations. VH4.21-encoded H chains strongly predispose for anti-i binding capacity, regardless of the VL regions or H chain CDR3 structure. The avidity of some of these antibodies was similar to those of pathogenic CA. In addition, we found evidence for monospecific anti-I binding in antibodies encoded by other members of the VH4 gene family. We conclude that VH4.21-encoded antibodies with anti-i specificity from the normal B cell repertoire mirror their pathogenic counterparts and that naturally occurring anti-I antibodies may be encoded by a more diverse array of VH4 genes.
TSG-6: a TNF-, IL-1-, and LPS-inducible secreted glycoprotein associated with arthritis.
Authors: Wisniewski H G , Maier R , Lotz M , Lee S , Klampfer L , Lee T H , Vilcek J 
Published: January 2023

Abstract
TSG-6 (TNF-stimulated gene 6) was originally discovered by differential screening of a cDNA library prepared from TNF-stimulated human diploid FS-4 fibroblasts. We show that the 35-kDa protein encoded by TSG-6 was undetectable in the medium of untreated FS-4 cultures, whereas its production reached approximately 1400 and 700 ng/10(6) cells after 24-h treatment with IL-1 or TNF, respectively. Stimulation of TSG-6 protein and mRNA levels was also demonstrated in normal human mononuclear cells by treatment with TNF and, especially, by LPS. In view of the inducibility of TSG-6 by inflammatory cytokines and its earlier demonstrated affinity for hyaluronan, we examined the presence of TSG-6 protein in the synovial fluids from patients with various forms of arthritis. TSG-6 protein was undetectable in the joint fluids of persons with no known history of arthritis, but high levels of TSG-6 oere demonstrated in the synovial fluids of a majority of arthritis patients. TSG-6 protein was also detected in the sera of some of the arthritis patients, albeit at concentrations that were less than in the joint fluids. To investigate the source of TSG-6 in the synovial fluids, we examined the production of TSG-6 protein in cultures of synovial cells. Synoviocytes from rheumatoid arthritis patients produced TSG-6 protein constitutively, and this production was increased by treatment with TNF or IL-1, but not with TGF-beta. Steady-state levels of TSG-6 mRNA were also increased in synoviocytes after treatment with TNF or IL-1. The presence of high levels of TSG-6 protein in the synovial fluids of arthritis patients and its inducibility by inflammatory cytokines in fibroblasts, mononuclear cells, synoviocytes, and chondrocytes suggest a role for TSG-6 in arthritis and inflammation.
Cryptic epitopes on the nicotinic acetylcholine receptor are recognized by autoreactive CD4+ cells.
Authors: Bellone M , Ostlie N , Karachunski P , Manfredi A A , Conti-Tronconi B M 
Published: January 2023

Abstract
Experimental autoimmune myasthenia gravis is induced in C57BL/6 mice by injection of Torpedo nicotinic acetylcholine receptor (TAChR). We investigated here the presence of cryptic CD4+ epitopes on the TAChR molecule, and their relationship with potentially autoreactive CD4+ cells, which survived clonal deletion. CD4+ cells from C57BL/6 mice immunized with native or denatured TAChR were challenged in vitro with overlapping synthetic peptides, 20-residue long, screening the sequences of TAChR alpha, gamma, and delta subunits. Only three epitopes on the alpha subunit were recognized consistently. Mice immunized with large doses (nanomoles) of TAChR clearly recognized only the immunodominant sequence T alpha 150-169. Anti-TAChR CD4+ cells did not cross-react with murine alpha subunit sequences, or with any synthetic sequence of human gamma and delta subunits, which are very similar to the corresponding murine subunits. To facilitate recognition of cryptic epitopes, we injected mice with pools of synthetic peptides corresponding to the sequences of TAChR alpha, gamma, and delta subunits. In addition to the three immunodominant alpha subunit epitopes, other epitopes were recognized by CD4+ cells within the sequences T alpha 304-322, T gamma 105-124, T gamma 120-139, T gamma 401-420, T gamma 357-376, T delta 16-35, T delta 61-80, T delta 121-140, and T delta 301-320. CD4+ cells thus sensitized cross-reacted with the mammalian sequences alpha 304-322, gamma 105-124, gamma 120-139, and delta 301-320. Mice were immunized with large doses (approximately 40 nmol) of individual TAChR synthetic cryptic epitopes. CD4+ cells sensitized to five cryptic epitopes (the ones listed above plus delta 121-140) cross-reacted with autologous sequences. We determined the dose dependence of the sensitization of CD4+ cells in vivo to the strongly immunodominant epitope peptide T alpha 150-169 and to the cryptic epitope peptides T gamma 120-139 and T delta 301-320 by immunizing mice with increasing doses of peptide (approximately 1.2 to approximately 20 nmol), and testing the in vitro anti-peptide response of the CD4+ cells. No difference was found for the epitopes tested. Doses of 3 to 10 micrograms induced a strong CD4+ sensitization, and the dose dependence of the in vitro response of the sensitized cells to the relevant peptide was comparable. Production of cryptic epitopes upon in vitro TAChR processing was investigated by testing peptide-sensitized CD4+ cells with native TAChR: only two cryptic epitopes were produced.
Rapamycin treatment depresses intragraft expression of KC/MIP-2, granzyme B, and IFN-gamma in rat recipients of cardiac allografts.
Authors: Wieder K J , Hancock W W , Schmidbauer G , Corpier C L , Wieder I , Kobzik L , Strom T B , Kupiec-Weglinski J W 
Published: January 2023

Abstract
Rapamycin (RPM) treatment prevents accelerated rejection of cardiac allografts in sensitized rats. The prominent feature of this brisk 24-h rejection, which includes a panoply of both cellular and humoral host immune responses, is a massive infiltration of rejecting grafts with neutrophils. In this study we tested the hypothesis that RPM-mediated therapeutic effects on accelerated rejection may be linked to decreased expression of protein encoded by gro/melanoma-growth stimulatory activity gene (KC) and macrophage inflammatory protein-2 (MIP-2) genes, the operational rat homologues of the human intercrine-alpha cytokines with proinflammatory IL-8-like neutrophil activation/chemotactic properties. The induction of these genes was then correlated with mRNA profiles encoding for Th1-selective IFN-gamma and CTL-specific granzyme B proteins. Northern blot analysis of RNA from cardiac allografts of sensitized untreated recipients, revealed maximal levels of KC and MIP-2 mRNA at 3 to 6 h after transplantation. In contrast, IFN-gamma mRNA, which was at most very weakly expressed at 3 h, peaked between 6 to 12 h. As with IFN-gamma, granzyme B transcripts were undetectable at 3 h, but peaked around the time of actual graft rejection at 24 h. RPM therapy abrogated accelerated rejection and prolonged cardiac allograft survival to ca. 46 days. This effect was associated with markedly reduced expression of KC and MIP-2 mRNA in the first 24 h as well as at 7 and 34 days after transplantation. Moreover, RPM completely blocked intragraft appearance of granzyme B and IFN-gamma mRNA in long term cardiac allografts. Immunohistologic analysis has revealed that accelerated rejection was associated with extensive neutrophil infiltration, which peaked at 18 to 24 h. At this time, leukocytes and endothelium were intensely stained for IL-8 and IFN-gamma antibodies. In contrast, the allografts from RPM-treated hosts showed essentially no neutrophil infiltration and minor, focal staining for IL-8 and IFN-gamma. This study demonstrates an association between the early expression of genes for proinflammatory IL-8-dependent neutrophil chemotactic activity, and later expression of genes associated with activation/effector activity of CTL and NK cells. It also documents a novel effect of RPM in vivo, which results in the suppression of intragraft IL-8-like and CTL-dependent mRNA/protein production and diminished neutrophil infiltration; these may contribute to the striking efficacy of RPM therapy in sensitized graft recipients.
Functionally anergic lpr and gld B220+ T cell receptor (TCR)-alpha/beta+ double-negative T cells express CD28 and respond to costimulation with phorbol myristate acetate and antibodies to CD28 and the TCR.
Authors: Giese T , Allison J P , Davidson W F 
Published: January 2023

Abstract
Mice homozygous for lpr and gld develop lymphadenopathy characterized by the progressive accumulation of an unusual population of CD4-, CD8-, CD2-, IL-2R- double-negative (DN) T cells that express reduced levels of TCR-alpha/beta, high levels of CD45 (B220) and Ly-6C and variable levels of CD69. These cells are refractory to most stimuli, including staphylococcal entertoxins and cross-linking of the TCR, Ly-6C, and CD69. For normal T cells, the binding of ligand to the TCR alone is insufficient to induce a proliferative response and can result in the induction of a state of prolonged anergy. Efficient stimulation is dependent on the delivery of a second or costimulatory signal. Recently it was reported that CD28 can provide costimulatory signals to T cells and, that these signals can prevent anergy induction in T cell clones. We investigated the possibility that lpr and gld DN T cells are unresponsive because they fail to transduce signals via CD28. These studies showed that highly purified B220+ TCR-alpha/beta+ DN T cells expressed high levels of CD28, responded weakly to stimulation with PMA and anti-CD28 mAb and quite strongly to PMA, anti-CD28 antibody and high concentrations of immobilized anti-TCR-alpha/beta antibodies. The latter stimulus also induced low levels of expression of CD2 and IL-2R and secretion of modest amounts of IL-2. Although DN T cells proliferated and secreted IL-2, these responses differed qualitatively and quantitatively from those of +/+ and lprB220- T cells. Consistent with its effects on normal T cells, cyclosporin A partially inhibited the response of DN T cells to TCR cross-linking and CD28 ligation. Studies of synergism between CD28-, Ly-6C-, and CD69-mediated signals revealed that ligation of CD28 enhanced the proliferative response induced by cross-linking of Ly-6C or CD69 on +/+, lpr and gld B220- T cells but had no effect on the unresponsiveness of DN T cells to these stimuli. Ligation of CD28 did not reverse the unresponsiveness of DN T cells to SEB and had only a weak synergistic effect on the response of B220- T cells. Together, these observations suggest that the mechanisms leading to immunosuppression of DN T cells are complex and appear to involve abnormalities in signal transduction via the TCR and CD28 and possibly via Ly-6C and CD69 as well.
Effect of bcl-2 on Fas antigen-mediated cell death.
Authors: Itoh N , Tsujimoto Y , Nagata S 
Published: January 2023

Abstract
Fas Ag is a cell surface protein that can mediate apoptosis and belongs to the TNF receptor family. The product of protooncogene bcl-2, a membrane-associated protein, has been shown to inhibit apoptosis in various hematopoietic cells including B cells and T cells. To examine the possible interaction of the Fas Ag and bcl-2, we coexpressed human Fas Ag and bcl-2 cDNA in murine IL-3-dependent FDC-P1 cell line and murine lymphoma WR19L. FDC-P1 transformants expressing bcl-2 showed a prolonged survival to IL-3 depletion. FDC-P1 transformants expressing the Fas Ag alone were killed by anti-Fas antibody in the presence of IL-3. Overexpression of bcl-2 in FDC-P1 resulted in a partial inhibition of Fas-induced cell death. WR19L transformants expressing bcl-2 were partially resistant to the cytolytic activities of the TNF-alpha and anti-Fas antibody treatment. These results suggest that the Fas Ag and TNF receptor may share the same signaling pathway, and that bcl-2 interferes with the apoptotic process mediated by the Fas Ag and TNF receptor.
Tyrosine phosphorylation of phospholipase C concomitant with its activation by platelet-activating factor in a human B cell line.
Authors: Kuruvilla A , Putcha G , Poulos E , Shearer W T 
Published: January 2023

Abstract
Platelet-activating factor (PAF) is a powerful inflammatory mediator in a variety of systems. Upon binding its receptor on B lymphocytes, it activates phospholipases C and A2, thus initiating a cascade of events culminating in changes in the program of the target cell. We have now extended our previous studies of the effects of PAF on EBV-transformed human B cell lines to examine the mechanism by which phospholipase C (PLC) is activated. PAF-induced incorporation of 32P into phosphatidylinositol (PtdIns) was markedly diminished by the tyrosine kinase inhibitors, genistein, and those of the tyrphostin family, tyrphostins 25, 47, and 51. The generation of inositol phosphates induced by PAF was also significantly inhibited by these inhibitors. Correlating with this inhibition of PtdIns turnover, the elevation of intracellular calcium concentrations stimulated by PAF was observed to be inhibited in the presence of inhibitors of tyrosine kinases. In addition, the induction of expression of the proto-oncogene, c-fos, was substantially attenuated by these inhibitors. Finally, employing anti-phosphotyrosine immunoprecipitates of lysates from PAF-stimulated cells in an in vitro PLC assay, we have provided evidence for an increase in the tyrosine phosphorylation levels of PLC upon stimulation, and the inhibition of this increase by tyrosine kinase inhibitors. In summary, we have shown that in B cells tyrosine kinase activity is essential for the PtdIns turnover, the generation of inositol phosphates, and the calcium flux induced by PAF and that platelet-activating factor-induced tyrosine phosphorylation of PLC is likely to be required for the activation of this enzyme.
T-cell presentation of antigen requires cell-to-cell contact for proliferation and anergy induction. Differential MHC requirements for superantigen and autoantigen.
Authors: LaSalle J M , Toneguzzo F , Saadeh M , Golan D E , Taber R , Hafler D A 
Published: January 2023

Abstract
MHC class II+ human T-cell clones are able to simultaneously present and respond to peptide Ag and superantigen resulting in both proliferation and subsequent anergy. A major question remains as to whether a single T cell can present to itself or whether T-T cell interactions are required. We have employed a novel technique for inhibiting cell-to-cell contact that encapsulates individual T cells in agarose gel microdrops. Myelin basic protein-reactive individual CD4+ T-cell clones entrapped within these microdrops neither proliferated nor became anergized to either peptide Ag or Staphylococcal enterotoxin B (SEB), suggesting that cell-to-cell contact was required for T-cell presentation of Ag leading to proliferation and anergy. PMA treatment induced T-cell migration out of gel microdrops, restoring cell-to-cell contact and resulting in proliferation and anergy after T-cell coculture with peptide or superantigen. However, analysis of [Ca+2]i release revealed differences in T-cell responses to SEB versus peptide Ag. The addition of SEB, but not peptide Ag, induced a calcium flux in solitary T cells. Additionally, alpha HLA-DR mAb blocked peptide but not SEB-induced proliferation and anergy induction. Thus, SEB generated an early signal in solitary T cells that may not be a result of self stimulation via MHC class II. However, subsequent cell-to-cell contact was required for proliferation and anergy induction by SEB. These results indicate that peptide Ag requires a MHC class II-dependent cell-to-cell interaction for calcium flux, proliferation, and anergy induction, whereas SEB requires a MHC class II independent cell-to-cell interaction for proliferation and anergy induction after a TCR-generated calcium flux.