bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vivo Selection of Neutralization-Resistant Virus Variants But No Evidence of B Cell Tolerance in Lymphocytic Choriomeningitis Virus Carrier Mice Expressing a Transgenic Virus-Neutralizing Antibody
Authors: Seiler Peter , Senn Beatrice M. , Bründler Marie-Anne , Zinkernagel Rolf M. , Hengartner Hans , Kalinke Ulrich 
Published: January 2023

AbstractB cell tolerance is maintained by active deletion and functional anergy of self-reactive B cells depending on the time, amount, and site of the self-antigen expression. To study B cell tolerance toward a transplacentally transmitted viral Ag, we crossed transgenic mice expressing the μ heavy and the κ light chain of the lymphocytic choriomeningitis virus (LCMV)-neutralizing mAb KL25 (HL25-transgenic mice) with persistently infected LCMV carrier mice. Although HL25-transgenic LCMV carrier mice exhibited the same high virus titers as nontransgenic LCMV carrier mice, no evidence for B cell tolerance was found. In contrast, enhanced LCMV-neutralizing Ab titers were measured that, however, did not clear the virus. Instead, LCMV isolates from different tissues turned out to be neutralization resistant Ab escape variants expressing different substitutions of amino acid Asn119 of the LCMV-glycoprotein 1 that displays the neutralizing B cell epitope. Virus variants with the same mutations were also selected in vitro in the presence of the transgenic mAb KL25 confirming that substitutions of Asn119 have been selected by LCMV-neutralizing Abs. Thus, despite abundant expression of viral neo-self-antigen in HL25-transgenic LCMV carrier mice, transgenic B cells expressing LCMV-neutralizing Abs were rather stimulated than tolerized and neutralization resistant Ab escape variants were selected in vivo.
Unique Superantigen Activity of Staphylococcal Exfoliative Toxins
Authors: Monday Steven R. , Vath Gregory M. , Ferens Witold A. , Deobald Claudia , Rago James V. , Gahr Pamala J. , Monie Dileep D. , Iandolo John J. , Chapes Stephen K. , Davis William C. , Ohlendorf Douglas H. , Schlievert Patrick M. , Bohach Gregory A. 
Published: January 2023

Abstract
Certain strains of Staphylococcus aureus express one or both of two related, but immunologically distinct, exfoliative toxins (ETA and ETB). These toxins induce the symptoms associated with staphylococcal scalded skin syndrome. Both ETs have been shown to stimulate T cell proliferation. Recently, it was reported that ETA is a superantigen that stimulates T cells bearing human Vβ2 or several murine Vβs. However, other investigators have proposed that the superantigenicity reported for ETA resulted from contaminants in commercial preparations. This present study addresses those conflicting reports by assessing the biological and immunologic activities of highly purified rETs. ETA and ETB required APCs to induce selective polyclonal expansion of several human Vβs (huVβs), although, neither toxin expanded huVβ2. ETB induced expansion of murine T cells bearing Vβs 7 and 8, those that have the highest homology to the huVβs expanded by ETA and ETB. Although flow cytometry of ETB-stimulated T cells matched PCR results, stimulation by ETA reduced percentages of T cells positive for several huVβs that had been shown to have increased levels of mRNA transcripts. ETA and ETB induced contrasting reactions in vivo. In rabbits, ETB was moderately pyrogenic and enhanced susceptibility to lethal shock, while ETA lacked both activities. Predictions based on comparisons with other superantigens suggest molecular regions potentially involved in receptor binding in the ETA crystal structure and a modeled ETB three-dimensional structure. These results show that ETs are superantigens with unique properties that could account for the discrepancies reported.
Autoantigen-Independent Deletion of Diabetogenic CD4+ Thymocytes by Protective MHC Class II Molecules
Authors: Schmidt Dennis , Amrani Abdelaziz , Verdaguer Joan , Bou Sonny , Santamaria Pere 
Published: January 2023

AbstractSome MHC class II genes provide dominant resistance to certain autoimmune diseases via mechanisms that remain unclear. We have shown that thymocytes bearing a highly diabetogenic, I-Ag7-restricted β-cell-reactive TCR (4.1-TCR) undergo negative selection in diabetes-resistant H-2g7/x mice by engaging several different antidiabetogenic MHC class II molecules on thymic (but not peripheral) hemopoietic cells, independently of endogenous superantigens. Here we have investigated 1) whether this TCR can also engage protective MHC class II molecules (I-Ab) on cortical thymic epithelial cells in the absence of diabetogenic (I-Ag7) molecules, and 2) whether deletion of 4.1-CD4+ thymocytes in I-Ab-expressing mice might result from the ability of I-Ab molecules to present the target β-cell autoantigen of the 4.1-TCR. We show that, unlike I-Ag7 molecules, I-Ab molecules can restrict neither the positive selection of 4.1-CD4+ thymocytes in the thymic cortex nor the presentation of their target autoantigen in the periphery. Deletion of 4.1-CD4+ thymocytes by I-Ab molecules in the thymic medulla, however, is a peptide-specific process, since it can be triggered by hemopoietic cells expressing heterogeneous peptide/I-Ab complexes, but not by hemopoietic cells expressing single peptide/I-Ab complexes. Thus, unlike MHC-autoreactive or alloreactive TCRs, which can engage deleting MHC molecules in the thymic cortex, thymic medulla, and peripheral APCs, the 4.1-TCR can only engage deleting MHC molecules (I-Ab) in the thymic medulla. We therefore conclude that this form of MHC-induced protection from diabetes is based on the presentation of an anatomically restricted, nonautoantigenic peptide to highly diabetogenic thymocytes.
IFN-γ Regulation of the Type IV Class II Transactivator Promoter in Astrocytes
Authors: Dong Yuanshu , Rohn Wolfgang M. , Benveniste Etty N. 
Published: January 2023

Abstract
The transcriptional activation of class II MHC genes requires the class II transactivator (CIITA) protein, a regulator that is essential for both constitutive and IFN-γ-inducible class II MHC expression. The CIITA gene is controlled by multiple independent promoters; two promoters direct constitutive expression, while another, the type IV CIITA promoter, mediates IFN-γ-induced expression. We investigated the molecular regulation of IFN-γ-induced type IV CIITA promoter activity in astrocytes. IFN-γ inducibility of the type IV CIITA promoter is dependent on three cis-acting elements contained within a 154-bp fragment of the promoter; the proximal IFN-γ activation sequence (GAS) element, the E box, and the proximal IFN regulatory factor (IRF) element. Two IFN-γ-activated transcription factors, STAT-1α and IRF-1, bind the proximal GAS and IRF elements, respectively. The E box binds upstream stimulating factor-1 (USF-1), a constitutively expressed transcription factor. Furthermore, STAT-1α binding to the proximal GAS element is dependent on the binding of USF-1 to the adjacent E box. Functionally, the proximal IRF element is essential for IFN-γ induction of type IV CIITA promoter activity, while the proximal GAS and E box elements contribute to the IFN-γ inducibility of this promoter. In astrocytes, TNF-α enhances IFN-γ-induced class II MHC transcription. Our results demonstrate that TNF-α does not enhance IFN-γ-induced transcriptional activation of the type IV CIITA promoter, indicating that the enhancing effect of TNF-α is mediated downstream of CIITA transcription. These results define the molecular basis of IFN-γ activation of the type IV CIITA promoter in astrocytes.
Persistent HIV-1-Specific CTL Clonal Expansion Despite High Viral Burden Post In Utero HIV-1 Infection
Authors: Brander Christian , Goulder Philip J. R. , Luzuriaga Katherine , Yang Otto O. , Hartman Kelly E. , Jones Norman G. , Walker Bruce D. , Kalams Spyros A. 
Published: January 2023

Abstract
To address the issue of clonal exhaustion in humans, we monitored HLA class I-restricted, epitope-specific CTL responses in an in utero HIV-1-infected infant from 3 mo through 5 years of age. Serial functional CTL precursor assays demonstrated persistent, vigorous, and broadly directed HIV-1 specific CTL activity with a dominant response against an epitope in HIV-1 Gag-p17 (SLYNTVATL, aa 77–85). A clonal CTL response directed against the immunodominant, HLA-A*0201-restricted epitope was found to persist over the entire observation period, as shown by TCR analysis of cDNA libraries generated from PBMC. The analysis of autologous viral sequences did not reveal any escape mutations within the targeted epitope, and viral load measurement indicated ongoing viral replication. Furthermore, inhibition of viral replication assays indicated that the epitope was properly processed from autologous viral protein. These data demonstrate that persistent exposure to high levels of viral Ag does not necessarily lead to clonal exhaustion and that epitope-specific clonal CTL responses induced within the first weeks of life can persist for years without inducing detectable viral escape variants.
Host B7-1 and B7-2 Costimulatory Molecules Contribute to the Eradication of B7-1-Transfected P815 Tumor Cells Via a CD8+ T Cell-Dependent Mechanism
Authors: Motte Ross N. La , Sharpe Arlene H. , Bluestone Jeffrey A. , Mokyr Margalit B. 
Published: January 2023

AbstractB7-1 (CD80)-transfected P815 tumor cells were previously shown to elicit tumor-eradicating immunity that leads to the regression of B7-1+ P815 tumors after transient growth in normal syngeneic (DBA/2) mice. Here, we show that not only the B7-1 molecule but also the B7-2 (CD86) molecule contributed to the eradication of B7-1+ P815 tumors. The B7-1 molecule that contributed to the eradication of B7-1+ P815 tumors was expressed not only on the tumor cells but also on host APCs, including MAC-1+ cells. The B7-2 molecule that contributed to the eradication of B7-1+ P815 tumors was expressed only on host APCs, such as B220+ cells, and not on the tumor cells. In spite of the fact that B7-expressing host APCs contributed to the eradication of B7-1+ P815 tumors, only CD8+ T cells without help from CD4+ T cells were important for tumor eradication. Taken together, these findings indicate that in addition to the ability of B7-1-transfected tumor cells to stimulate CD8+ T cell-mediated tumor-eradicating immunity directly, such tumor cells can also stimulate CD8+ T cell-mediated tumor-eradicating immunity indirectly as a result of cross-priming through B7-expressing host APCs.
Signal Transduction Pathways Activated in Endothelial Cells Following Infection with Chlamydia pneumoniae
Authors: Krüll Matthias , Klucken Andrea C. , Wuppermann Frederik N. , Fuhrmann Oliver , Magerl Christian , Seybold Joachim , Hippenstiel Stefan , Hegemann Johannes H. , Jantos Christian A. , Suttorp Norbert 
Published: January 2023

Abstract
Chlamydia pneumoniae is an important respiratory pathogen. Recently, its presence has been demonstrated in atherosclerotic lesions. In this study, we characterized C. pneumoniae-mediated activation of endothelial cells and demonstrated an enhanced expression of endothelial adhesion molecules followed by subsequent rolling, adhesion, and transmigration of leukocytes (monocytes, granulocytes). These effects were blocked by mAbs against endothelial and/or leukocyte adhesion molecules (β1 and β2 integrins). Additionally, activation of different signal transduction pathways in C. pneumoniae-infected endothelial cells was shown: protein tyrosine phosphorylation, up-regulation of phosphorylated p42/p44 mitogen-activated protein kinase, and NF-κB activation/translocation occurred within 10–15 min. Increased mRNA and surface expression of E-selectin, ICAM-1, and VCAM-1 were noted within hours. Thus, C. pneumoniae triggers a cascade of events that could lead to endothelial activation, inflammation, and thrombosis, which in turn may result in or may promote atherosclerosis.
Differential Effects of Leukotactin-1 and Macrophage Inflammatory Protein-1α on Neutrophils Mediated by CCR1
Authors: Zhang Shangming , Youn Byung-S. , Gao Ji-Liang , Murphy Philip M. , Kwon Byoung S. 
Published: January 2023

Abstract
The human CC chemokine leukotactin-1 (Lkn-1) is both a strong chemoattractant for neutrophils, monocytes, and lymphocytes and a potent agonist for CCR1 and CCR3. However, human neutrophils do not migrate when the cells are stimulated with other human CC chemokines, such as human macrophage inflammatory protein-1α (hMIP-1α) and eotaxin, which also use the CCR1 and CCR3 as their receptors. In this report, we demonstrate that while hMIP-1α induced a negligible level of calcium flux and chemotaxis, Lkn-1 produced a high level of calcium flux and chemotaxis in human neutrophils. Lkn-1 cross-desensitized hMIP-1α-induced calcium flux, but hMIP-1α had little effect on the Lkn-1-induced response in human neutrophils. The same pattern was observed in peritoneal neutrophils from wild-type mice, whereas neutrophils from CCR1−/− mice failed to respond to either MIP-1α or Lkn-1. Scatchard analysis revealed a single class of receptor for both hMIP-1α and Lkn-1 on human neutrophils with dissociation constants (Kd) of 3.2 nM and 1.1 nM, respectively. We conclude that CCR1 is a receptor mediating responses to both MIP-1α and Lkn-1 on neutrophils and produces different biological responses depending on the ligand bound.
Development of an Animal Model of Autoimmune Thyroid Eye Disease
Authors: Many M.-C. , Costagliola S. , Detrait M. , Denef J.-F. , Vassart G. , Ludgate M. 
Published: January 2023

Abstract
In previous studies we have transferred thyroiditis to naive BALB/c and NOD mice with human thyrotropin (TSH) receptor (TSHR)-primed splenocytes. Because the TSHR has been implicated in the pathogenesis of thyroid eye disease (TED) we have examined the orbits of recipients of TSHR-primed T cells, generated using a TSHR fusion protein or by genetic immunization. In the NOD mice, 25 of 26 animals treated with TSHR-primed T cells developed thyroiditis with considerable follicular destruction, numerous activated and CD8+ T cells, and immunoreactivity for IFN-γ. Thyroxine levels were reduced. Thyroiditis was not induced in controls. None of the NOD animals developed any orbital pathology. Thirty-five BALB/c mice received TSHR-primed spleen cells. Thyroiditis was induced in 60–100% and comprised activated T cells, B cells, and immunoreactivity for IL-4 and IL-10. Autoantibodies to the receptor were induced, including TSH binding inhibiting Igs. A total of 17 of 25 BALB/c orbits displayed changes consisting of accumulation of adipose tissue, edema caused by periodic acid Schiff-positive material, dissociation of the muscle fibers, the presence of TSHR immunoreactivity, and infiltration by lymphocytes and mast cells. No orbital changes or thyroiditis were observed in control BALB/c mice. We have induced orbital pathology having many parallels with human TED, only in BALB/c mice, suggesting that a Th2 autoimmune response to the TSHR may be a prerequisite for the development of TED.
Identification and Characterization of Epitopes Recognized by T Lymphocytes and Autoantibodies from Patients with Herpes Gestationis
Authors: Lin M.-S. , Gharia M. A. , Swartz S. J. , Diaz L. A. , Giudice G. J. 
Published: January 2023

Abstract
Autoantibodies associated with herpes gestationis (HG), a pregnancy-associated autoimmune skin disease, target the hemidesmosomal protein BP180. It was shown that the major noncollagenous stretch of the BP180 ectodomain (NC16A) harbors epitopes recognized by HG sera. Furthermore, Abs reactive with the homologous domain of murine BP180 are known to trigger a cutaneous blistering disease in mice by passive transfer experiments. The present study was aimed at characterizing the T cell responses and specificities of autoantibodies from two HG patients. Using immunoblotting and T cell proliferation assays, we have identified a 14-amino-acid stretch of the BP180 ectodomain (MCW-1; aa 507–520) that is recognized by both T cells and autoantibodies produced by the HG patients. The neonate born to one of these HG patients showed no signs of skin disease and had no detectable T cell response to the BP180 Ag, but did have a low titer of circulating anti-BP180 autoantibodies, presumably of maternal origin. BP180-specific T cell lines and clones developed from an HG patient specifically reacted with the MCW-1 epitope. The proliferative responses of these clones were restricted to HLA-DR, but not -DQ or -DP. These Ag-specific T cells expressed α/β TCRs and a CD4 memory T cell phenotype and secreted IFN-γ and IL-2, but not IL-4 or IL-6, suggesting that they are Th1-type lymphocytes. Further characterization of these Ag-specific T cells and autoantibodies will aid in elucidating the autoimmune mechanism(s) leading to the development of HG.
Glutamate Augments Retrovirus-Induced Immunodeficiency Through Chronic Stimulation of the Hypothalamic-Pituitary- Adrenal Axis
Authors: Espey Michael Graham , Basile Anthony S. 
Published: January 2023

AbstractThe mechanisms for activating the hypothalamic-pituitary-adrenal (HPA) axis and the roles glucocorticoids play in the pathogenesis of chronic infectious disease are largely undefined. Using the LP-BM5 model of retrovirus-induced immunodeficiency, we found alterations in HPA axis function, manifested as an increase in circulating levels of adrenocorticotropic hormone and corticosterone, beginning after only 3 mo of infection. These changes occurred contemporaneously with a shift in the profile of circulating cytokines from a Th1-dominant (IFN-γ) to Th2-dominant (IL-4, IL-10) phenotype. No significant changes in either circulating IL-1β, IL-6, or TNF-α levels were observed in infected mice. Administering the N-methyl-d-aspartate receptor antagonist MK-801 to infected mice normalized plasma adrenocorticotropic hormone and corticosterone levels, indicating that glutamate was a major activator of the HPA axis. Moreover, MK-801 treatment of late-stage mice also reversed the type 1 to type 2 cytokine shift to a degree comparable or superior to treatment with the glucocorticoid receptor antagonist RU-486. These findings indicate that HPA axis activation during LP-BM5 retrovirus infection is mediated by the chronic hyperactivation of glutamatergic pathways in the hypothalamus. Through this mechanism, the degree of peripheral immunodeficiency observed in the late-stage disease is profoundly augmented.
Mutations That Cause the Wiskott-Aldrich Syndrome Impair the Interaction of Wiskott-Aldrich Syndrome Protein (WASP) with WASP Interacting Protein
Authors: Stewart Donn M. , Tian Lan , Nelson David L. 
Published: January 2023

Abstract
Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, eczema, immune deficiency, and a proclivity toward lymphoid malignancy. Lymphocytes of affected individuals show defects of activation, motility, and cytoskeletal structure. The disease gene encodes a 502-amino acid protein named the WAS protein (WASP). Studies have identified a number of important interactions that place WASP in a role of integrating signaling pathways with cytoskeletal function. We performed a two-hybrid screen to identify proteins interacting with WASP and cloned a proline-rich protein as a specific WASP interactor. Our clone of this protein, termed WASP interacting protein (WIP) by others, shows a difference in seven amino acid residues, compared with the previously published sequence revealing an additional profilin binding motif. Deletion mutant analysis reveals that WASP residues 101–151 are necessary for WASP-WIP interaction. Point mutant analyses in the two-hybrid system and in vitro show impairment of WASP-WIP interaction with three WASP missense mutants known to cause WAS. We conclude that impaired WASP-WIP interaction may contribute to WAS.
Cutting Edge: A Short Polypeptide Domain of HIV-1-Tat Protein Mediates Pathogenesis
Authors: Boykins Robert A. , Mahieux Renaud , Shankavaram Uma T. , Gho Yong Song , Lee Sherwin F. , Hewlett Indira K. , Wahl Larry M. , Kleinman Hynda K. , Brady John N. , Yamada Kenneth M. , Dhawan Subhash 
Published: January 2023

Abstract
HIV-1 encodes the transactivating protein Tat, which is essential for virus replication and progression of HIV disease. However, Tat has multiple domains, and consequently the molecular mechanisms by which it acts remain unclear. In this report, we provide evidence that cellular activation by Tat involves a short core domain, Tat21–40, containing only 20 aa including seven cysteine residues highly conserved in most HIV-1 subtypes. Effective induction by Tat21–40 of both NF-κB-mediated HIV replication and TAR-dependent transactivation of HIV-long terminal repeat indicates that this short sequence is sufficient to promote HIV infection. Moreover, Tat21–40 possesses potent angiogenic activity, further underscoring its role in HIV pathogenesis. These data provide the first demonstration that a 20-residue core domain sequence of Tat is sufficient to transactivate, induce HIV replication, and trigger angiogenesis. This short peptide sequence provides a potential novel therapeutic target for disrupting the functions of Tat and inhibiting progression of HIV disease.
CD30 Overexpression Enhances Negative Selection in the Thymus and Mediates Programmed Cell Death Via a Bcl-2-Sensitive Pathway
Authors: Chiarle Roberto , Podda Antonello , Prolla Gabriel , Podack Eckhard R. , Thorbecke G. Jeanette , Inghirami Giorgio 
Published: January 2023

AbstractThe biological function of CD30 in the thymus has been only partially elucidated, although recent data indicate that it may be involved in negative selection. Because CD30 is expressed only by a small subpopulation of medullary thymocytes, we generated transgenic (Tg) mice overexpressing CD30 in T lymphocytes to further address its role in T cell development. CD30 Tg mice have normal thymic size with a normal number and subset distribution of thymocytes. In vitro, in the absence of CD30 ligation, thymocytes of CD30 Tg mice have normal survival and responses to apoptotic stimuli such as radiation, dexamethasone, and Fas. However, in contrast to controls, CD30 Tg thymocytes are induced to undergo programmed cell death (PCD) upon cross-linking of CD30, and the simultaneous engagement of TCR and CD30 results in a synergistic increase in thymic PCD. CD30-mediated PCD requires caspase 1 and caspase 3, is not associated with the activation of NF-κB or c-Jun, but is totally prevented by Bcl-2. Furthermore, CD30 overexpression enhances the deletion of CD4+/CD8+ thymocytes induced by staphylococcal enterotoxin B superantigen and specific peptide. These findings suggest that CD30 may act as a costimulatory molecule in thymic negative selection.
Development of T Lymphocytes at Extrathymic Sites
Authors: Antica Mariastefania , Scollay Roland 
Published: January 2023

Abstract
T lymphocytes expressing both CD4 and CD8 are the predominant cell type in the thymic cortex but are extremely rare outside the thymus of normal mice. In this article, we show that if precursor thymocytes (CD4−CD8−) from fetal or adult donors are injected i.v. into irradiated recipients, some of these cells will lodge in lymph nodes and develop into both CD4+CD8+ (double-positive) and CD4+ or CD8+ (single-positive) cells. This phenomenon also occurred in thymectomized recipients, strongly suggesting it is genuine extrathymic development. Prethymic precursors (e.g., fetal liver), were unable to use the lymph node for T cell development, without thymic processing. The data suggest that given unusual circumstances (irradiation or thymectomy and availability of appropriate precursors), the lymph nodes can support T cell development.