bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generation of the Germline Peripheral B Cell Repertoire: VH81X-λ B Cells Are Unable to Complete All Developmental Programs
Authors: Martin Flavius , Won Woong-Jai , Kearney John F. 
Published: January 2023

AbstractThe generation of VH81X heavy chain λ-light chain-expressing B cells (VH81X-λ+ B cells) was studied in VH81X heavy chain transgenic mice as well as in VH81X JH −/− and VH81X JH −/− Ck −/− mice, in which competition resulting from expression of heavy and light chains from the endogenous heavy and κ light chain loci was prevented. We show that although λ light chain gene rearrangements occur normally and give rise to light chains that associate with the transgenic heavy chain to form surface and soluble IgM molecules, further B cell development is almost totally blocked. The few VH81X-λ+ B cells that are generated progress into a mature compartment (expressing surface CD21, CD22, CD23, and low CD24 and having a relatively long life span) but they also have reduced levels of surface Ig receptor and express higher amounts of Fas Ag than VH81X-κ+ B cells. These VH81X-λ+ B cells reach the peripheral lymphoid organs and accumulate in the periarteriolar lymphoid sheath but are unable to generate primary B cell follicles. In other heavy chain transgenic mice (MD2, M167, and M54), λ+ B cells are generated. However, they seem to be preferentially selected in the peripheral repertoire of some transgenic heavy chain mice (M54) but not in others (MD2, M167). These studies show that a crucial selection step is necessary for B cell survival and maintenance in which B cells, similar to T cells, receive signals depending on their clonal receptors.
Transgenic Expression of Fas in T Cells Blocks Lymphoproliferation But Not Autoimmune Disease in MRL-lprMice
Authors: Fukuyama Hidehiro , Adachi Masashi , Suematsu Sachiko , Miwa Keiko , Suda Takashi , Yoshida Nobuaki , Nagata Shigekazu 
Published: January 2023

AbstractFas is a member of the TNF receptor family. Binding of Fas ligand to Fas induces apoptosis in Fas-bearing cells. Fas is expressed in various cells, including thymocytes, peripheral T cells, and activated B cells. The mouse lpr mutation is a loss of function mutation of Fas. MRL-lpr/lpr mice develop lymphadenopathy and splenomegaly, and produce multiple autoantibodies, which results in autoimmune disease. In this report, we describe the establishment of a line of Fas transgenic MRL-lpr mice in which mouse Fas cDNA was expressed using the T cell-specific murine lck promoter. The transgenic mice expressed functional Fas in thymocytes and peripheral T cells, but not in B cells. The transgenic mice did not accumulate abnormal T cells (Thy-1+ B220+), but still accumulated B cells (Thy-1− B220+); they produced a large quantity of Igs (IgG1 and IgG2a), including anti-DNA Abs, and developed glomerulonephritis. These results suggest that autoreactive or activated B cells must be killed through Fas expressed in the B cells by the Fas ligand expressed in activated T cells.
Critical Roles of Glycosaminoglycan Side Chains of Cartilage Proteoglycan (Aggrecan) in Antigen Recognition and Presentation
Authors: Glant Tibor T. , Buzás Edit I. , Finnegan Alison , Negroiu Gabriela , Cs-Szabó Gabriella , Mikecz Katalin 
Published: January 2023

Abstract
Systemic immunization of BALB/c mice with proteoglycan (aggrecan) from fetal human cartilage induces progressive polyarthritis, an experimental disease similar to human rheumatoid arthritis. The development of the disease in this genetically susceptible murine strain is based on cross-reactive immune responses between the immunizing fetal human and mouse self-proteoglycans. One of the cross-reactive and arthritogenic T cell epitopes (92GR/QVRVNSA/IY) is localized in the G1 domain of human/murine proteoglycan. Susceptible BALB/c mice, however, develop arthritis only if both the chondroitin sulfate (CS) and keratan sulfate (KS) side chains of the arthritogenic human proteoglycans are removed. The function of these two glycosaminoglycan side chains is opposite. The presence of a KS side chain in adult proteoglycan inhibits the recognition of arthritogenic T cell epitopes, prevents the development of T cell response, and protects animals from autoimmune arthritis. In contrast, the depletion of the CS side chain generates clusters of CS stubs and provokes a strong B cell response. These carbohydrate-specific B cells are the most important proteoglycan APC. Taken together, proteoglycan-induced progressive polyarthritis is dictated by three major components: genetic background of the BALB/c strain, highly specific T cell response to epitope(s) masked by a KS chain in aging tissue, and the presence of proteoglycan (CS stub)-specific B cells required for sufficient Ag presentation.
Mouse Cell Surface Antigens: Nomenclature and Immunophenotyping
Authors: Lai Lily , Alaverdi Noosheen , Maltais Lois , Morse Herbert C. 
Published: January 2023

AbstractThis paper reviews cell surface Ags expressed on mouse hemopoietic and nonhemopoietic cells. The review will cover molecules included in the cluster of differentiation (CD) from CD1 to CD166 and lymphocyte Ag (Ly) series from Ly-1 to Ly-81 as well as some new Ags without current CD or Ly assignments. In addition to an update on mouse nomenclature, there will be a discussion of some known functions of the molecules and brief comments on the use of particular Ags for immunophenotyping of cell subsets. Several novel markers mentioned may prove useful in mouse immunology research.
Differentiation-Specific, Octamer-Dependent Costimulation of κ Transcription
Authors: Liberg David , Sigvardsson Mikael , Bemark Mats , Leanderson Tomas 
Published: January 2023

AbstractBy mutational analysis of the octamer-TATA box intervening region in the mouse SP6 κ promoter, we have mapped two octamer-dependent, costimulatory regions, A and B. The A region was active in late B cells only, while the B region was active throughout B cell differentiation. The B region was TATA proximal and contained a heptamer and an E box of the E2A type that is common in Vκ promoters. Mutation of the heptamer element did not decrease transcriptional stimulation from this region, but mutations in, or immediately 5′ of, the E box core sequence did. A protein binding to this region could be detected in nuclear extracts. The complex could only partially be competed with a μE5 binding site and could not be supershifted with Abs raised to E2A gene products, indicating that it may represent a novel E-box binding complex. The A region was located proximal to the octamer and contained a CCCT element that is conserved both with regard to position and sequence in human VκII promoters. By mutational analysis, the transcriptional stimulatory activity was mapped to the CCCT element that also is part of an early B cell factor (EBF) binding site. In late B cells, a novel protein (FA), which did not bind to the EBF binding site in the mb1 promoter, interacted with the A region. This protein was found to be expressed at lower levels in early B cells as well as in HeLa cells. Thus, the octamer-flanking sequence contains positive control elements that may act independently but that differ in the stage of B cell differentiation at which they are active. One of these factors is an example of an ubiquitously expressed transcription factor that participate in differentiation-specific transcriptional activation.
IFN-γ Induction of the Human Monocyte Chemoattractant Protein (hMCP)-1 Gene in Astrocytoma Cells: Functional Interaction Between an IFN-γ-Activated Site and a GC-Rich Element
Authors: Zhou Z-H Lucy , Chaturvedi Priya , Han Yu-long , Aras Sumer , Li Yi-shuan , Kolattukudy Pappachan E. , Ping Dongsheng , Boss Jeremy M. , Ransohoff Richard M. 
Published: January 2023

AbstractWe characterized regulation of the human monocyte chemoattractant protein-1 (hMCP-1) gene by IFN-γ in astrocytoma cells, because astroglial cells express chemokines in several central nervous system inflammatory states. It was found that IFN-γ-induced hMCP-1 transcription was rapid, transient, and mediated by a 213-bp promoter-proximal regulatory region of the gene. Our studies on both in vitro and in vivo states of the hMCP-1 regulatory region established requirement of an IFN-γ-activated site (GAS) and the presence of IFN-γ-inducible GAS-binding activity involving at least STAT-1α for IFN-γ-induced hMCP-1 expression. Unexpectedly, in vivo genomic footprinting of the proximal regulatory region of the IFN-γ-induced gene revealed protection of a GC-rich sequence (GC box) with the same temporal pattern as that seen at the GAS; in vitro, this GC-rich element is associated with nuclear factor Sp1. These observations suggested a cooperative interaction between the GAS and the GC box element. Interestingly, site-specific mutations that abolished GC-box or GAS-element function produced clearly disparate results. Disruption of the GC box did not affect fold induction by IFN-γ but reduced promoter-reporter expression by half. Conversely, GAS mutation abrogated induction but did not affect the magnitude of expression. These results establish the importance of the GAS element for induction of hMCP-1 and further our understanding of IFN-γ-mediated transcriptional induction by providing the first evidence in vivo for inducible signaling to the GC box by this cytokine.
Regulation of E-Cadherin-Mediated Adhesion in Langerhans Cell-Like Dendritic Cells by Inflammatory Mediators That Mobilize Langerhans Cells In Vivo
Authors: Jakob Thilo , Udey Mark C. 
Published: January 2023

AbstractAdhesion of Langerhans cells (LC) to keratinocytes is mediated by E-cadherin. IL-1, TNF-α, and LPS mobilize LC from epidermis and presumably attenuate LC-keratinocyte adhesion. To determine whether these mediators modulated LC E-cadherin-dependent adhesion directly, we characterized their effects on LC-like dendritic cells expanded from murine fetal skin (FSDDC). FSDDC were propagated from day 16 C57BL/6 fetal skin and isolated as aggregates (FSDDC-A) in which homophilic adhesion was mediated by E-cadherin. IL-1, TNF-α, and LPS induced dissociation of FSDDC-A that began within 4 to 8 h and was complete within 20 h. Anti-IL-1RI mAb inhibited disaggregation caused by IL-1α and IL-1β, but not that induced by TNF-α or LPS. Anti-TNF-α mAb inhibited the effect of TNF-α and LPS, but not that caused by IL-1α or IL-1β. Flow cytometry of FSDDC-A revealed that IL-1, TNF-α, and LPS induced increased expression of MHC class II, CD40, and CD86 and decreased E-cadherin expression that was temporally related to dissociation of aggregates. IL-1 and TNF-α caused a rapid reduction in FSDDC E-cadherin mRNA levels that preceded the decrease in E-cadherin surface expression. These results demonstrate that cytokines that induce LC emigration in vivo act directly on LC-like cells in vitro, reduce E-cadherin mRNA levels, down-regulate E-cadherin surface expression, and induce a loss of E-cadherin-mediated adhesion.
Disparate Roles for TNF-α and Fas Ligand in Concanavalin A-Induced Hepatitis
Authors: Ksontini Riadh , Colagiovanni Dorothy B. , Josephs Michael D. , Edwards Carl K. , Tannahill Cynthia L. , Solorzano Carmen C. , Norman James , Denham Woody , Clare-Salzler Michael , MacKay Sally L. D. , Moldawer Lyle L. 
Published: January 2023

Abstract
Apoptosis is a physiologic process that serves to eliminate cells during development or in response to immunologic regulation. In acute inflammation, however, apoptosis triggered by the overproduction of “death factors” such as TNF-α or Fas ligand (FasL) may contribute to tissue injury. Both TNF-α and FasL are presumed to convey an apoptotic signal by activating a cascade of cysteine-aspartate proteases, which includes IL-1β-converting enzyme or caspase-1. In the present study, we evaluated the contribution of TNF-α and FasL, as well as the role of caspase-1, in Con A-induced hepatitis. We report here that TNF-α and FasL mRNA and protein levels are both increased in the livers of Con A-challenged mice. Using a novel inhibitor of TNF-α, we can confirm that Con A-induced hepatitis is primarily TNF-α dependent. Blockade of FasL with a soluble Fas immunoadhesin does not prevent liver injury in animals treated with Con A alone. However, administration of a matrix metalloproteinase inhibitor exacerbates liver injury, in part through a FasL-dependent process, since pretreatment with the soluble Fas immunoadhesin reduces liver injury in this model. In addition, mice lacking functional caspase-1 are resistant to Con A-induced hepatitis, even after pretreatment with a matrix metalloproteinase inhibitor. We conclude that TNF-α plays a predominant role in Con A-induced liver injury, although concomitant activation of FasL can also lead to apoptotic injury. Furthermore, Con A-induced hepatitis is caspase-1 dependent.
Dendritic Cells Are Required for the Development of Chronic Eosinophilic Airway Inflammation in Response to Inhaled Antigen in Sensitized Mice
Authors: Lambrecht Bart N. , Salomon Benoı̂t , Klatzmann David , Pauwels Romain A. 
Published: January 2023

AbstractAsthma is characterized by chronic eosinophilic inflammation of the airways, and allergen-specific Th2 lymphocytes are thought to play a major role in the development and maintenance of this type of inflammation in allergic asthma. It is generally accepted that airway dendritic cells (DC) are essential for stimulating naive T cells in a primary immune response to inhaled Ag and for the development of allergic sensitization. We have examined the role of airway DC in stimulating memory T cells in a secondary response to inhaled Ag and the subsequent development of chronic airway inflammation. In our mouse model of asthma, OVA aerosol challenge in OVA-sensitized mice leads to CD4-dependent peribronchial and perivascular eosinophilic inflammation, lung Th2 cytokine production, and systemic IgE production. We have used conditional depletion of airway DC by treatment of thymidine kinase-transgenic mice with the antiviral drug ganciclovir to deplete DC during the secondary exposure to OVA. In sensitized thymidine kinase-transgenic mice, a significant decrease in the number of bronchoalveolar CD4 and CD8 T lymphocytes and B lymphocytes was seen after ganciclovir treatment. In addition, Th2 cytokine-associated eosinophilic airway inflammation was almost completely suppressed. These studies demonstrate for the first time that the DC is essential for presenting inhaled Ag to previously primed Th2 cells in the lung, leading to chronic eosinophilic airway inflammation. Altering the function of airway DC may therefore be an important target for new anti-asthma therapy.
Flt-3 Ligand Increases Microchimerism But Can Prevent the Therapeutic Effect of Donor Bone Marrow in Transiently Immunosuppressed Cardiac Allograft Recipients
Authors: Antonysamy Mary A. , Steptoe Raymond J. , Khanna Ajai , Rudert William A. , Subbotin Vladimir M. , Thomson Angus W. 
Published: January 2023

AbstractC3H (H2k) mice received 50 × 106 B10 (H2b) bone marrow (BM) cells either alone or with flt-3 ligand (FL) (10 μg/day), tacrolimus (2 mg/kg/day), or both agents for 7 days. Donor MHC class II+ (IAb+) cells were quantitated in spleens by immunohistochemical analysis, and donor class II DNA detected in BM by PCR. Donor cells were rare in the BM alone and BM + FL groups, whereas there was a substantial increase in chimerism in the BM + tacrolimus group. Addition of FL to BM + tacrolimus led to a further eightfold increase in donor cells and enhanced donor DNA compared with the BM + tacrolimus group. This increase in donor cells was almost 500-fold compared with BM alone. C3H recipients of B10 heart allografts given perioperative B10 BM and tacrolimus (days 0–13) exhibited a markedly extended median graft survival time (MST, 42 days) compared with those given tacrolimus alone (MST, 22 days). Addition of FL (10 μg/day; 7 days) to BM + tacrolimus prevented the beneficial effect of donor BM (MST, 18 days). BM alone or BM + FL resulted in uniform early heart graft failure (MST &lt; 8 days). Functional studies revealed maximal antidonor MLR and CTL activities in the BM- and BM + FL-treated groups, with minimal activity in the tacrolimus-treated groups. Thus, dramatic growth factor-induced increases in chimerism achieved under cover of immunosuppression may result in augmented antidonor T cell reactivity and reduced graft survival after immunosuppressive drug withdrawal. With FL, this may reflect striking augmentation of immunostimulatory dendritic cells.
Requirement for In Vivo Production of IL-4, But Not IL-10, in the Induction of Proliferative Suppression by Filarial Parasites
Authors: MacDonald Andrew S. , Maizels Rick M. , Lawrence Rachel A. , Dransfield Ian , Allen Judith E. 
Published: January 2023

Abstract
Loss of T lymphocyte proliferation and the emergence of a host response that is dominated by a Th2-type profile are well-established features of human filariasis. We have previously reported that adherent peritoneal exudate cells (PEC) from mice transplanted with adult Brugia malayi parasites suppress the proliferation of lymphocytes without blocking Ag-cytokine production in vitro. We now show that infection of mice with the infective larval (L3) stage of B. malayi generates a similar population of PEC. Suppressive cells are generated within 7 days of infection and mediate their effects through a nitric oxide-independent pathway. Both L3 and adult infection elicit high levels of host IL-4 whereas the microfilarial stage of the parasite induces IFN-γ production and does not generate a similar form of suppression. Production of host IL-4 was necessary to allow the generation of suppressive PEC, given that IL-4-deficient mice implanted with adult parasites failed to induce proliferative block. However, IL-10-deficient mice implanted with adult parasites resulted in T cell suppression, indicating that IL-10 is not essential for the induction of hyporesponsiveness. Neither IL-4 nor IL-10 were directly responsible for ablating cellular proliferation in vitro, as the addition of neutralizing Ab to either cytokine did not reverse the proliferative block. Thus, IL-4 produced in vivo in response to filarial L3 and adult parasites is essential for the induction of proliferative suppression but is not itself the suppressive factor.
Cutting Edge: IL-4 Induces Functional Cell-Surface Expression of CXCR4 on Human T Cells
Authors: Jourdan Patrick , Abbal Claire , Nora Nelly , Hori Toshiyuki , Uchiyama Takashi , Vendrell Jean-Pierre , Bousquet Jean , Taylor Naomi , Pène Jérôme , Yssel Hans 
Published: January 2023

AbstractHere we report that IL-4 specifically enhances cell surface expression of CXCR4 on resting peripheral and cord blood T cells. Whereas polarized Th2 clones express variable levels of CXCR4, expression of this receptor is undetectable on polarized Th1 clones but can be induced on the latter cells as well, following short-term culture in the presence of IL-4. The IL-4-induced CXCR4 is functional since interaction with its ligand, stromal-derived factor (SDF)-1, activates the p42 MAP-kinase ERK-2. In addition, although CXCR4 expression is down-regulated following stimulation of T cells and T cell clones via CD28 or CD3 and CD2 cell surface molecules, respectively, it is re-induced by IL-4. These data indicate an important role for IL-4 in rendering CD4+ T cells susceptible to infection with HIV via CXCR4, as well as in promoting SDF-1-induced migration of these cells.
Newborn Mice Develop Balanced Th1/Th2 Primary Effector Responses In Vivo But Are Biased to Th2 Secondary Responses
Authors: Adkins Becky , Du Rong-Qing 
Published: January 2023

AbstractNewborn mice are impaired in their abilities to mount protective immune responses. For decades, it was generally held that the poor responses of newborns were largely due to the developmentally immature state of the T cells. In vitro studies showing that neonatal T cells were deficient in Th1 cytokine production, proliferation, and secondary responsiveness strongly supported this idea. Recently, several studies have challenged this view; animals exposed to Ag as neonates were shown to have mature Th1 responses in adulthood. However, it is not clear whether the mature immune responses were actually mounted by T cells generated after the neonatal stage. We have reexamined this issue by analyzing the capabilities of neonatal lymph node T cells to develop into Ag-specific effector cells during the actual neonatal period. Our results demonstrate that the capacity to develop a balanced Th1/Th2 primary effector response is fully mature within the first week of life. However, while neonatal and adult primary cytokine profiles were very similar, Th2 secondary responses predominated in animals first immunized as newborns. Moreover, we have observed other differences between adults and neonatal responses, including 1) the kinetics of cytokine production and responsiveness to adjuvant during the primary response, and 2) the contribution of spleen and lymph node to secondary responses. We propose that these differences reflect developmental regulation of effector cell function that has important consequences to neonatal immune function.
Matrix Metalloproteinases Produced by Rat IL-2-Activated NK Cells
Authors: Kitson Richard P. , Appasamy Pierette M. , Nannmark Ulf , Albertsson Per , Gabauer Megan K. , Goldfarb Ronald H. 
Published: January 2023

AbstractWe have previously documented that adoptively transferred IL-2-activated NK (A-NK) cells can accumulate within cancer metastases. Electron microscopic studies of pulmonary metastases have revealed that adoptively transferred A-NK cells that accumulate within metastases bind to endothelial cells and are able to traverse basement membranes. We have now extended these morphologic studies. We report that rat A-NK cells produce two matrix metalloproteinases: MMP-2 and MMP-9, as determined by SDS-PAGE gelatin zymography. These activities are inhibited following incubation with BB-94 (batimastat), a specific inhibitor of matrix metalloproteinases but not with 3,4-dichloroisocoumarin, an inhibitor of neutral serine proteases. The identity of MMP-2 was confirmed by Western blots using a polyclonal Ab against human MMP-2, whereas reverse transcriptase-PCR analysis of mRNA extracts of A-NK cells has confirmed the presence of MMP-9. In addition, we report for the first time that A-NK cells can migrate through a model basement membrane-like extracellular matrix. Moreover, the ability of A-NK cells to migrate through this model basement membrane was partially inhibited by BB-94; however, BB-94 has no effect on A-NK cell-mediated cytotoxicity, suggesting that matrix metalloproteinases do not contribute to cytolytic function of A-NK cells. In sum, our studies show that A-NK cells employ BB-94-inhibitable matrix metalloproteinases to degrade extracellular matrices. This suggests that matrix metalloproteinases may play a role in the accumulation of A-NK cells within cancer metastases.