bluuebunny/crossref_metadata_2025_split huggingface dataset:
Administration of mAb Against αEβ7 Prevents and Ameliorates Immunization-Induced Colitis in IL-2−/− Mice
Authors: Lúdvíksson Björn R. , Strober Warren , Nishikomori Ryuta , Hasan Syed K. , Ehrhardt Rolf O. 
Published: January 2023

Abstract
We previously demonstrated that 2,4,6-trinitrophenol (TNP)-OVA immunization leads to a transmural colitis in the IL-2−/− mouse that is caused by IL-12-driven CD4+ Th1 T cells and resembles human Crohn’s disease. The integrin αEβ7 is highly expressed on colonic intraepithelial lymphocytes and has been suggested to function as a homing or retention molecule for intraepithelial lymphocytes. To evaluate the role of αEβ7 in colitis, we administered a mAb against αEβ7 to IL-2−/− mice that were immunized at the same time with TNP-OVA in CFA. To our surprise, this treatment resulted in a significantly reduced colitis severity score, 0–2 vs 3–4, that was associated with a significant reduction in CD4+ lamina propria lymphocyte subpopulation (p &lt; 0.01). In contrast, the total number of splenic CD4+ T cells of treated animals was significantly elevated compared with that of untreated animals (3.2 ± 0.6 × 107 vs 1.2 ± 0.2 × 107; p &lt; 0.05). Similarly, functional studies revealed that IFN-γ production by lamina propria lymphocytes isolated from IL-2−/− TNP-OVA-immunized mice treated with anti-αEβ7 was significantly lower than in untreated IL-2−/− TNP-OVA-immunized mice. In contrast, IFN-γ production by splenic cells isolated from treated IL-2−/− TNP-OVA-immunized mice was significantly higher than in untreated mice. Finally, TNP-OVA-immunized IL-2−/− mice that were treated after the colitis had been established also showed a significant decrease in mucosal inflammation after αEβ7 mAb administration. Thus, the above findings demonstrate that the onset and maintenance of inflammatory bowel disease depends on the colonic localization of lamina propria CD4+ lymphocytes expressing αEβ7.
Induction of Mucosal Immunity by Inactivated Poliovirus Vaccine Is Dependent on Previous Mucosal Contact with Live Virus
Authors: Herremans Tineke M. P. T. , Reimerink Johan H. J. , Buisman Annemarie M. , Kimman Tjeerd G. , Koopmans Marion P. G. 
Published: January 2023

Abstract
The inactivated poliovirus vaccine (IPV) is used for protection against poliomyelitis in The Netherlands. It is not clear, however, whether IPV vaccination can lead to priming of the mucosal immune system and the induction of IgA. It has been demonstrated that IPV vaccination is able to induce strong memory IgA responses in the serum of persons who have been naturally exposed to wild-type poliovirus. This has led to the hypothesis that IPV vaccination is able to induce poliovirus-specific IgA at mucosal sites in persons who have been previously primed with live poliovirus at mucosal sites. To test this hypothesis, the kinetics of the IgA response in serum and saliva after IPV vaccination were examined in persons previously vaccinated with oral poliovirus vaccine (OPV) or IPV. ELISA and enzyme-linked immunospot assays were used for the detection of poliovirus-specific IgA responses. In addition, B cell populations were separated on the basis of the expression of mucosal (α4β7 integrin) and peripheral homing receptors (L-selectin). Parenteral IPV vaccination was able to boost systemic and mucosal IgA responses in previously OPV-vaccinated persons only. None of the previously vaccinated IPV recipients responded with the production of IgA in saliva. In agreement with this finding, a large percentage of the poliovirus-specific IgA-producing lymphocytes detected in previous OPV recipients expressed the α4β7 integrin. It is concluded that IPV vaccination alone is insufficient to induce a mucosal IgA response against poliovirus. In mucosally (OPV-) primed individuals, however, booster vaccination with IPV leads to a strong mucosal IgA response.
Cutting Edge: Recognition of Gram-Positive Bacterial Cell Wall Components by the Innate Immune System Occurs Via Toll-Like Receptor 2
Authors: Yoshimura Atsutoshi , Lien Egil , Ingalls Robin R. , Tuomanen Elaine , Dziarski Roman , Golenbock Douglas 
Published: January 2023

Abstract
Invasive infection with Gram-positive and Gram-negative bacteria often results in septic shock and death. The basis for the earliest steps in innate immune response to Gram-positive bacterial infection is poorly understood. The LPS component of the Gram-negative bacterial cell wall appears to activate cells via CD14 and Toll-like receptor (TLR) 2 and TLR4. We hypothesized that Gram-positive bacteria might also be recognized by TLRs. Heterologous expression of human TLR2, but not TLR4, in fibroblasts conferred responsiveness to Staphylococcus aureus and Streptococcus pneumoniae as evidenced by inducible translocation of NF-κB. CD14 coexpression synergistically enhanced TLR2-mediated activation. To determine which components of Gram-positive cell walls activate Toll proteins, we tested a soluble preparation of peptidoglycan prepared from S. aureus. Soluble peptidoglycan substituted for whole organisms. These data suggest that the similarity of clinical response to invasive infection by Gram-positive and Gram-negative bacteria is due to bacterial recognition via similar TLRs.
Invariant or Highly Conserved TCR α Are Expressed on Double-Negative (CD3+CD4−CD8−) and CD8+ T Cells
Authors: Han Mei , Harrison Lisa , Kehn Patricia , Stevenson Kimberly , Currier Jeffrey , Robinson Mary Ann 
Published: January 2023

Abstract
TCR α (TCRA) expression was examined in RNA samples from PBMC and isolated populations of CD4+, CD8+, and DN T cells from 15 healthy individuals. The expressed TCR repertoire was surveyed using spectratype analysis, a technique that displays the distribution of complementarity determining region 3 (CDR3) lengths for each TCRAV gene family. The results revealed the presence of unusual populations of double-negative (DN; CD4−CD8−CD3+) T cells that express invariant or conserved TCRAV4A, AV7, AV19, and AV24 chains. Each of the conserved TCRA families was over-represented in &gt;70% of the individuals studied, and all individuals expressed at least one of the over-represented TCRAV families. Over-represented conserved AV4A or AV7 sequences were also present in CD8+ T cells from most donors. The extent of TCRA sequence conservation is unparalleled. TCRAV4A, AV19, and AV24 sequences were invariant, although AV4A and AV19 transcripts contained N region additions. TCRAV24 transcripts derived from the direct juxtaposition of V and J gene segments. TCRAV7 sequences showed some diversity in two amino acids encoded at junctions of V and J gene segments. Although derivation of DN T cells with conserved TCRA chains is puzzling, the wide-spread expression of these unusual cells suggests an important function.
Characterization of Eosinophil Adhesion to TNF-α-Activated Endothelium Under Flow Conditions: α4 Integrins Mediate Initial Attachment, and E-Selectin Mediates Rolling
Authors: Ulfman Laurien H. , Kuijper Philip H. M. , van der Linden Jan A. M. , Lammers Jan-Willem J. , Zwaginga Jaap Jan , Koenderman Leo 
Published: January 2023

AbstractThe multistep model of leukocyte adhesion reveals that selectins mediate rolling interactions and that integrins mediate firm adhesion processes. In this study, the interaction between eosinophils and TNF-α-activated HUVEC (second or third passage) was studied under flow conditions (0.8 and 3.2 dynes/cm2). Especially the role of α4 integrins on eosinophils and E-selectin on HUVEC was studied. Inhibition of the integrin α4 chain on eosinophils reduced the number of firmly adhered resting eosinophils to TNF-α-stimulated endothelium by 43% whereas the percentage rolling cells increased 2.2-fold compared with untreated control eosinophils. Blocking of E-selectin on the endothelium reduced the number of adherent eosinophils by only 23% and 16%. In this situation, however, hardly any rolling adhesion was observed, and the few rolling cells showed a low rolling velocity. Blocking both α4 integrin on eosinophils and E-selectin on HUVEC reduced the number of adhered eosinophils by 95%. P-selectin did not significantly participate in eosinophil adhesion to TNF-α-activated HUVEC. Inhibition of both α4 integrins and β2 integrins on eosinophils resulted in a reduction of adhered cells by 65% and a 3-fold increase in percentage rolling cells. Taken together, these results clearly show that resting eosinophils preferentially use constitutively active α4 integrins (α4β1, α4β7) for the first attachment to TNF-α-activated HUVEC. In addition, α4 integrins and E-selectin work synergistically in eosinophil adherence to TNF-α-activated HUVEC. Although E-selectin is important for eosinophil rolling under these conditions, P-selectin plays only a minor role.
Deficiency of 5-Lipoxygenase Abolishes Sex-Related Survival Differences in MRL-lpr/lpr Mice
Authors: Goulet Jennifer L. , Griffiths Robert C. , Ruiz Phillip , Spurney Robert F. , Pisetsky David S. , Koller Beverly H. , Coffman Thomas M. 
Published: January 2023

Abstract
Leukotrienes, the 5-lipoxygenase (5LO) products of arachidonic acid metabolism, have many proinflammatory actions that have been implicated in the pathogenesis of a variety of inflammatory diseases. To investigate the role of LTs in autoimmune disease, we generated an MRL-lpr/lpr mouse line with a targeted disruption of the 5lo gene. MRL-lpr/lpr mice spontaneously develop autoimmune disease that has many features resembling human systemic lupus erythematosus, including sex-related survival differences; female MRL-lpr/lpr mice experience significant early mortality compared with males. Unexpectedly, we found that mortality was accelerated in male 5LO-deficient MRL-lpr/lpr mice compared with male wild-type MRL-lpr/lpr animals. In contrast, the 5lo mutation had no effect on survival in females. Mortality was also accelerated in male MRL-lpr/lpr mice that were treated chronically with a pharmacological inhibitor of LT synthesis. Furthermore, LT-dependent inflammatory responses are enhanced in male MRL-lpr/lpr mice compared with females, and the 5lo mutation has greater impact on these responses in males. Because immune complex-mediated glomerulonephritis is the major cause of death in MRL-lpr/lpr mice and has been related to arachidonic acid metabolites, we also assessed kidney function and histopathology. In male MRL-lpr/lpr mice, renal plasma flow was significantly reduced in the 5lo−/− compared with the 5lo+/+ group, although there were no differences in the severity of renal histopathology, lymphoid hyperplasia, or arthritis between the groups. These findings suggest that the presence of a functional 5lo gene confers a survival advantage on male MRL-lpr/lpr mice and that, when 5LO function is inhibited, either genetically or pharmacologically, this advantage is abolished.
A Complementary Peptide Vaccine That Induces T Cell Anergy and Prevents Experimental Allergic Neuritis in Lewis Rats
Authors: Araga Shigeru , Kishimoto Masahiro , Doi Satoko , Nakashima Kenji 
Published: January 2023

AbstractWe have developed and described a new method of altering T cell-mediated autoimmune diseases by immunization with the complementary peptide against T cell epitopes. The complementary peptide (denoted NAE 07-06) to the bovine P2 protein, residues 60–70 (denoted EAN 60–70), was tested in the Lewis rat model of experimental allergic neuritis (EAN). Immunization with NAE 07-06 induced polyclonal and monoclonal Abs that inhibited the proliferation of the P2-specific T cell line, stimulated with EAN 60–70, and recognized Vβ, but not Vα, of TCRs. Proliferation of T cells treated with anti-NAE 07-06 Abs could be partially restored by treatment with rIL-2, in accordance with an anergy model. A homologous sequence was found between NAE 07-06 and the VDJ junction of the TCR β-chain from an EAN 60–70-specific T cell line. Rats preimmunized with NAE 07-06 in vivo before EAN induction showed less disease severity clinically and histologically. These data suggest a new therapeutic approach for T cell-mediated autoimmune disorders through the induction of anti-TCR Abs with complementary peptide Ags.
Degradation of ZAP-70 Following Antigenic Stimulation in Human T Lymphocytes: Role of Calpain Proteolytic Pathway
Authors: Penna Doris , Müller Sabina , Martinon Fabio , Demotz Stephane , Iwashima Makio , Valitutti Salvatore 
Published: January 2023

Abstract
T cell activation by the specific Ag results in dramatic changes of the T cell phenotype that include a rapid and profound down-regulation and degradation of triggered TCRs. In this work, we investigated the fate of the TCR-associated ZAP-70 kinase in Ag-stimulated T cells. T cells stimulated by peptide-pulsed APCs undergo an Ag dose-dependent decrease of the total cellular content of ZAP-70, as detected by FACS analysis and confocal microscopy on fixed and permeabilized T cell-APC conjugates and by Western blot on total cell lysates. The time course of ZAP-70 consumption overlaps with that of ζ-chain degradation, indicating that ZAP-70 is degraded in parallel with TCR internalization and degradation. Pharmacological activation of protein kinase C (PKC) does not induce ZAP-70 degradation, which, on the contrary, requires activation of protein tyrosine kinases. Two lines of evidence indicate that the Ca2+-dependent cysteine protease calpain plays a major role in initiating ZAP-70 degradation: 1) treatment of T cells with cell-permeating inhibitors of calpain markedly reduces ZAP-70 degradation; 2) ZAP-70 is cleaved in vitro by calpain. Our results show that, in the course of T cell-APC cognate interaction, ZAP-70 is rapidly degraded via a calpain-dependent mechanism.
Endogenous CD8+ T Cell Expansion During Regression of Monoclonal EBV-Associated Posttransplant Lymphoproliferative Disorder
Authors: Khatri Vijay P. , Baiocchi Robert A. , Peng Ruoqi , Oberkircher Adam R. , Dolce Jean M. , Ward Pamela M. , Herzig Geoffrey P. , Caligiuri Michael A. 
Published: January 2023

Abstract
There are experimental data which suggest that the primary immune effector cell responsible for maintaining immune surveillance against the outgrowth of EBV-transformed B cells in humans is the CTL, but in vivo proof of this is lacking. In this study we perform a series of cellular and molecular assays to characterize an autologous, endogenous immune response against a transplantation-associated, monoclonal, EBV+ posttransplant lymphoproliferative disorder (PTLD). Following allogeneic bone marrow transplantation, a patient developed a monoclonal PTLD of donor B cell origin. With a decrease in immune suppression, we document the emergence of endogenous, donor-derived CD3+CD8+ CTLs, followed by regression of the PTLD. The TCR Vβ repertoire went from a polyclonal pattern prior to the development of PTLD to a restricted TCR Vβ pattern during the outgrowth and regression of PTLD. Donor-derived CD3+CD8+ T lymphocytes displayed MHC class I-restricted cytolytic activity against the autologous EBV+ B cells ex vivo without additional in vitro sensitization. The striking temporal relationship between the endogenous expansion of a TCR Vβ-restricted, CD3+CD8+ population of MHC class I-restricted CTL, and the regression of an autologous monoclonal PTLD, provides direct evidence in humans that endogenous CD3+CD8+ CTLs can be responsible for effective immune surveillance against malignant transformation of EBV+ B cells.
Early Autoantibody Responses in Prediabetes Are IgG1 Dominated and Suggest Antigen-Specific Regulation
Authors: Bonifacio Ezio , Scirpoli Miriam , Kredel Katharina , Füchtenbusch Martin , Ziegler Anette-G. 
Published: January 2023

Abstract
The islet autoimmunity of preclinical type 1 diabetes remains poorly characterized in humans. In this paper, the IgG subclass response to the islet autoantigens insulin, glutamic acid decarboxylase, and IA-2 was studied sequentially from birth to diabetes onset or current follow-up in 26 autoantibody positive offspring of parents with diabetes. Islet autoantibody appearance was characterized by an early IgG1 peak response to one or more Ags, most commonly to insulin, at a median age of 2.2 yr (interquartile range, 2–2.9 yr). In five offspring, an acute fulminant β-cell destruction and diabetes onset occurred during this initial Ab response. In the remainder, early Ab levels declined markedly, and Ab peaks against other β cell Ags arose sequentially over several years suggesting regulation and spreading of autoimmunity. Second peak Ab responses to the same Ag were observed in only two offspring, both developing diabetes at this time. Two others developed diabetes with declining Ab levels. Abs of IgG1 subclass dominated against each Ag, and other subclasses, were usually only detected during peak IgG1 responses. The IgG4 response to insulin was exceptional, being dominant over IgG1 in four offspring and in five others appeared and/or persisted after IgG1 levels declined. These Th2-associated IgG4 responses were not correlated with protection from diabetes. The presence of IgG1-restricted responses to DA2 were associated with diabetes development. These findings suggest that type 1 diabetes has an early acute destructive phase of β cell autoimmunity, which may be regulated and which spreads chronically until diabetes onset.
Expression of a Variant of CD28 on a Subpopulation of Human NK Cells: Implications for B7-Mediated Stimulation of NK Cells
Authors: Galea-Lauri Joanna , Darling David , Gan Shu-Uin , Krivochtchapov Leonid , Kuiper Marcel , Gäken Joop , Souberbielle Bernard , Farzaneh Farzin 
Published: January 2023

Abstract
The ability of NK cells to kill tumor cells is controlled by a balance between activating and inhibitory signals transduced by distinct receptors. In murine tumor models, the costimulatory molecule B7.1 not only acts as a positive trigger for NK-mediated cytotoxicity but can also overcome negative signaling transduced by MHC class I molecules. In this study, we have evaluated the potential of human B7.1-CD28 interaction as an activating trigger for human blood NK cells. Using multiparameter flow cytometric analysis and a panel of different CD28 mAbs, we show that human peripheral blood NK cells (defined by CD56+, CD16+, and CD3− surface expression) express the CD28 costimulatory receptor, with its detection totally dependent on the mAb used. In addition, the level of CD28 varies among individuals and on different NK cell lines, irrespective of CD28 steady-state mRNA levels. By performing Ab binding studies on T cells, our data strongly suggest that binding of two of the anti-CD28 Abs (clones 9.3 and CD28.2) is to a different epitope to that recognized by clones L293 and YTH913.12, which is perhaps modified in the CD28 molecule expressed by the NK cells. We also show that B7.1 enhances the NK-mediated lysis of NK-sensitive but not of NK-resistant tumor cells and that this increased lysis is dependent on CD28-B7 interactions as shown by the ability of Abs to block this lysis. Coculture of the B7.1-positive NK-sensitive cells also led to the activation of the NK cells, as determined by the expression of CD69, CD25, and HLA class II.
The Regulatory Role of CD45 on Rat NK Cells in Target Cell Lysis
Authors: Giezeman-Smits Katinka M. , Gorter Arko , van Vlierberghe Ronald L. P. , v. Eendenburg Jaap D. H. , Eggermont Alexander M. M. , Fleuren Gert Jan , Kuppen Peter J. K. 
Published: January 2023

Abstract
To investigate the role of CD45 in rat NK cell function, we developed new mAbs directed against rat CD45. mAb ANK12 binds to a high molecular isoform of CD45 and mAb ANK74 binds to the common part on all known CD45 isoforms, as has been described for the anti-rat CD45 mAb OX1. The ability of these mAbs to affect NK cell-mediated lysis was tested using the Fc receptor-positive target cell line P815. mAb ANK12 was found to significantly enhance the lysis of P815, whereas ANK74 and the anti-CD45 mAb OX1 did not. In addition, cross-linking of the CD45 isoform by ANK12 induced tyrosine phosphorylation of specific proteins in NK cells. Subsequently, the involvement of CD45 in the negative signaling after “self” MHC class I recognition by rat NK cells was investigated. The anti-CD45 mAbs were found to affect NK cell-mediated lysis of syngeneic tumor cell lines, depending upon the expression level of MHC class I on target cells. mAbs ANK74 and OX1 only inhibited lysis of the syngeneic tumor cell lines that expressed low levels of MHC class I. Furthermore, both mAbs caused an inhibition of NK cell-mediated lysis of these tumor cell lines when MHC class I molecules on the tumor cell lines were masked by an Ab. These results suggest that CD45 regulates the inhibitory signal pathway after self MHC class I recognition, supposedly by dephosphorylation of proteins.
Cutting Edge: IFN-γ Regulated Germline Transcripts Are Expressed from γ2a Transgenes Independently of the Heavy Chain 3′ Enhancers
Authors: Collins John T. , Dunnick Wesley A. 
Published: January 2023

AbstractSeveral results indicate that transcriptional enhancers lying 3′ of the Cα gene regulate RNA expression and switch recombination of heavy chain genes. To investigate this regulation we prepared transgenic mice with a 10.5-kb transgene that included the germline form of the murine γ2α gene, including promoter, I, S, and C regions. RNA was expressed from these γ2a transgenes with correct IFN-γ regulation, in spite of the fact that they lacked the 3′ enhancers. This RNA expression was independent of insertion site and dependent on copy number, indicating that the γ2a gene includes locus control region-like elements. Addition of either a cassette containing 3′ enhancer DNase I hypersensitive sites 1, 2, 3B, and 4 or the intronic μ enhancer increased transcription from the γ2a transgene by ∼75-fold in B cells. However, this increased transcription was not responsive to IFN-γ treatment of the transgenic B cells.
Crosslinking of the Human Fc Receptor for IgA (FcαRI/CD89) Triggers FcR γ-Chain-Dependent Shedding of Soluble CD89
Authors: van Zandbergen Ger , Westerhuis Ralf , Mohamad Ngaisah Klar , van de Winkel Jan G. J. , Daha Mohamed R. , van Kooten Cees 
Published: January 2023

AbstractCD89/FcαRI is a 55- to 75-kDa type I receptor glycoprotein, expressed on myeloid cells, with important immune effector functions. At present, no information is available on the existence of soluble forms of this receptor. We developed an ELISA for the detection of soluble CD89 (sCD89) forms and investigated the regulation of sCD89 production. PMA/ionomycin stimulation of monocytic cell lines (U937, THP-1, and MM6), but not of neutrophils, resulted in release of sCD89. Crosslinking of CD89 either via its ligand IgA or with anti-CD89 mAbs similarly resulted in sCD89 release. Using CD89-transfected cells, we showed ligand-induced shedding to be dependent on coexpression of the FcR γ-chain subunit. Shedding of sCD89 was dependent on signaling via the γ-chain and prevented by addition of inhibitors of protein kinase C (staurosporine) or protein tyrosine kinases (genistein). Western blotting revealed sCD89 to have an apparent molecular mass of 30 kDa and to bind IgA in a dose-dependent fashion. In conclusion, the present data document a ligand-binding soluble form of CD89 that is released upon activation of CD89-expressing cells. Shedding of CD89 may play a role in fine-tuning CD89 immune effector functions.