bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Levels of TNF, Soluble TNF Receptors, Soluble ICAM-1, and IFN-γ, but Low Levels of IL-5, Are Associated with Hepatosplenic Disease in Human Schistosomiasis Mansoni
Authors: Mwatha Joseph K. , Kimani Gachuhi , Kamau Timothy , Mbugua Gabriel G. , Ouma John H. , Mumo Jasper , Fulford Anthony J. C. , Jones Frances M. , Butterworth Anthony E. , Roberts Morven B. , Dunne David W. 
Published: December 2022

AbstractIn a case-control study based in two areas of Kenya, hepatosplenic schistosomiasis mansoni was shown to be linked with low levels of IL-5 and with correspondingly high IFN-γ, TNF, and circulating soluble TNF receptor I (sTNFR-I), sTNFR-II, and sICAM-1. PBMC from the hepatosplenic cases responded to in vitro Ag stimulation with significantly higher levels of IFN-γ and TNF, but lower levels of IL-5, compared with nonhepatosplenic controls matched for age and infection intensity. Most of these correlations were confounded by differences between geographical areas. However, principle component analysis identified a high IFN-γ and TNF, and low IL-5 axis in the data as the first principle component; this was significantly associated with hepatosplenomegaly (p &lt; 0.0005) even after controlling for area. High plasma levels of sTNFR-I (p &lt; 0.001), sTNFR-II, (p &lt; 0.0001), and sICAM-1 (p &lt; 0.009) were also significantly associated with hepatosplenomegaly, independently of area, in the case of the soluble forms of both TNF receptors. These parameters were negatively related to IL-5. These results suggest that proinflammatory cytokines are involved in the hepatosplenic disease process in infected individuals who have low anti-inflammatory Th2 responses and that sTNFR may be a useful circulating marker for this disease process, perhaps reflecting the level of TNF activity in hepatic tissues.
HIV-1 Neutralizing Antibodies in the Genital and Respiratory Tracts of Mice Intranasally Immunized with Oligomeric gp160
Authors: VanCott Thomas C. , Kaminski Robert W. , Mascola John R. , Kalyanaraman Vaniambadi S. , Wassef Nabila M. , Alving Carl R. , Ulrich J.Terry , Lowell George H. , Birx Deborah L. 
Published: December 2022

AbstractBecause mucosal surfaces are a primary route of HIV-1 infection, we evaluated the mucosal immunogenicity of a candidate HIV-1 vaccine, oligomeric gp160 (o-gp160). In prior studies, parenteral immunization of rabbits with o-gp160 elicited broad neutralizing serum Ab responses against both T cell line-adapted HIV-1 and some primary HIV-1 isolates. In this study, nasal immunization of mice with o-gp160, formulated with liposomes containing monophosphoryl lipid A (MPL), MPL-AF, proteosomes, emulsomes, or proteosomes with emulsomes elicited strong gp160-specific IgG and IgA responses in serum as well as vaginal, lung, and intestinal washes and fecal pellets. The genital, respiratory, and intestinal Abs were determined to be locally produced. No mucosal immune responses were measurable when the immunogen was given s.c. Abs from sera and from vaginal and lung washes preferentially recognized native forms of monomeric gp120, suggesting no substantial loss in protein tertiary conformation after vaccine formulation and mucosal administration. Inhibition of HIV-1MN infection of H9 cells was found in sera from mice immunized intranasally with o-gp160 formulated with liposomes plus MPL, proteosomes, and proteosomes plus emulsomes. Formulations of o-gp160 with MPL-AF, proteosomes, emulsomes, or proteosomes plus emulsomes elicited HIV-1MN-neutralizing Ab in lung wash, and formulations with proteosomes, emulsomes, or proteosomes plus emulsomes elicited HIV-1MN-neutralizing Ab in vaginal wash. These data demonstrate the feasibility of inducing both systemic and mucosal HIV-1-neutralizing Ab by intranasal immunization with an oligomeric gp160 protein.
Epitope-Specific Antibody and Suppression of Autoantibody Responses Against a Hybrid Self Protein
Authors: Lohnas Gerald L. , Roberts Steven F. , Pilon Aprile , Tramontano Alfonso 
Published: December 2022

AbstractThis study addresses the relationship of epitope-specific Ab responses and alternative autoantibody responses in a model system in which an antigenized self protein serves as the carrier for a defined heterologous B cell epitope. Ubiquitin, a nonimmunogenic self protein, was engineered to present heterologous B and T cell epitopes in the recombinant molecule. Fusion to the C terminus introduced a universal T cell epitope from a Mycobacterium tuberculosis Ag. The B cell epitope was created by inserting a 12-residue loop sequence of HIV-1 gp120 at a surface-exposed position of ubiquitin. These modifications preserved the ubiquitin fold, allowing a new conformational epitope to be presented among native self epitopes. Mice immunized with the hybrid protein bearing only the mycobacterial T cell epitope elicited a strong autoantibody response to native ubiquitin. In contrast, antisera elicited against hybrid ubiquitin presenting the HIV B cell epitope reacted specifically with the foreign epitope but not with native ubiquitin. Absence of autoantibody in the response was attributed to poor competition of autoreactive B cells for limiting T cell help. Both types of responses were associated with Th responses to defined epitopes of the ubiquitin hybrid protein. These results may have implications for a tolerance mechanism dependent on B-T cell cooperation.
Complement Opsonization Is Required for Presentation of Immune Complexes by Resting Peripheral Blood B Cells
Authors: Boackle Susan A. , Morris Margaret A. , Holers V. Michael , Karp David R. 
Published: December 2022

AbstractComplement receptor 2 (CD21, CR2) is a B cell receptor for complement degradation products bound to Ag or immune complexes. The role of CD21 in mediating Ag presentation of soluble immune complexes by resting B cells was studied. Complement-coated immune complexes were formed by the incubation of influenza virus with serum from immune donors. These complexes bound to peripheral blood B cells in a complement-dependent manner. The binding required CD21 or, to a lesser extent, complement receptor 1 (CR1, CD35). B cells pulsed with immune complexes containing complement elicited a response from a panel of influenza-specific T cell clones, while those pulsed with immune complexes formed in the absence of complement did not. The expression of the early activation marker CD69 and the costimulatory molecule CD86 were not induced by CD21 ligation alone, suggesting that CD21-mediated Ag presentation occurs independently of B cell activation. Up-regulation of these markers required exposure to T cell factors elicited by the recognition of Ag derived from complement-containing immune complexes. These findings suggest that binding of Ag to CD21 enables Ag-nonspecific B cells to participate in the activation of Ag-specific T cells in a process that occurs independently of well-characterized B cell activation events.
Coreceptor-Independent T Cell Activation in Mice Expressing MHC Class II Molecules Mutated in the CD4 Binding Domain
Authors: Mostaghel Elahe A. , Riberdy Janice M. , Steeber Douglas A. , Doyle Carolyn 
Published: December 2022

AbstractWe have previously reported that efficient selection of the mature CD4+ T cell repertoire requires a functional interaction between the CD4 coreceptor on the developing thymocyte and the MHC class II molecule on the thymic epithelium. Mice expressing a class II protein carrying the EA137/VA142 double mutation in the CD4 binding domain develop fewer than one-third the number of CD4+ T cells found in wild-type mice. In this report we describe the functional characteristics of this population of CD4+ T cells. CD4+ T cells that develop under these conditions are predicted to be a CD4-independent subset of T cells, bearing TCRs of sufficient affinity for the class II ligand to undergo selection despite the absence of accessory class II-CD4 interactions. We show that CD4+ T cells from the class II mutant mice are indeed CD4 independent in their peripheral activation requirements. Surprisingly, we find that CD4+ T cells from the class II mutant mice, having been selected in the absence of a productive class II-CD4 interaction, fail to functionally engage CD4 even when subsequently provided with a wild-type class II ligand. Nevertheless, CD4+ T cells from EA137/VA142 class II mutant mice can respond to T-dependent Ags and support Ig isotype switching.
CBFα3 (AML2) Is Induced by TGF-β1 to Bind and Activate the Mouse Germline Ig α Promoter
Authors: Shi Meng-Jiao , Stavnezer Janet 
Published: December 2022

AbstractTGF-β1 directs class switching to IgA by splenic B cells and by the surface IgM+ B cell line, I.29μ, by inducing germline (GL) Ig α transcripts. The promoter segment between −130 and +46, relative to the first initiation site for mouse GL α transcripts, is sufficient for expression and TGF-β1 inducibility of a reporter gene in B cell lines. Within this segment resides a TGF-β1-responsive element (TβRE) that is required for induction of the promoter by TGF-β1 and, when multimerized, is sufficient to transfer TGF-β1 inducibility to another promoter. In this report we show that a TGF-β1-inducible complex binds the TβRE and contains the transcription factor core-binding factor (CBF; also known as acute myeloid leukemia, AML). Although all three CBFα family members activate the GL α promoter, only CBFα3 (AML-2) is induced by TGF-β1 in splenic B and I.29μ cells. The TβRE contains two CBF binding sites. Mutation of both sites reduces but does not eliminate induction of the GL α promoter by TGF-β1 or by overexpression of CBF, possibly due to the presence of an additional CBF site in the promoter. In addition, the TβRE contains two copies of another sequence motif. Mutation of these motifs eliminates TGF-β1 induction of the GL α promoter. Together the data indicate that TGF-β1 induction of the α promoter involves induction of CBFα3, which binds to the TβRE of the promoter along with one or more proteins.
MRL/lprand MRL+/+ Macrophage DNA Synthesis in the Absence and the Presence of Colony-Stimulating Factor-1 and Granulocyte-Macrophage Colony-Stimulating Factor
Authors: Hamilton John A. , Chan James , Byrne Robert J. , Bischof Robert J. , Jaworowski Anthony , Kanagasundaram Varuni 
Published: December 2022

AbstractMacrophage accumulation and proliferation as well as altered macrophage properties have been observed in autoimmune MRL mice. To determine whether there might be innate differences in the proliferative responses, we examined the DNA synthesis responses of peritoneal macrophages and macrophages derived in vitro from bone marrow precursors (bone marrow-derived macrophages (BMM)). Murine peritoneal exudate macrophages normally require the addition of macrophage CSF (CSF-1) to enter cell cycle in vitro. In contrast, we have found that many thioglycollate-induced adherent peritoneal macrophages, but not resident peritoneal macrophages, from both MRL/lpr and MRL+/+ mice atypically underwent DNA synthesis even in the absence of added CSF-1. They also responded very well to granulocyte-macrophage CSF. These findings may help to explain the appearance of increased macrophage numbers in MRL lesions. In contrast to a previous report, it was found that MRL/lpr and MRL+/+ BMM did not have an enhanced response to CSF-1 and that modulation of CSF-1 receptor expression was not more rapid in MRL BMM. We also found no evidence for abnormal CSF-1 internalization and degradation or for the lpr mutation to have any enhanced effect on BMM survival in the absence of CSF-1. TNF-α lowered the DNA synthesis response to CSF-1 of MRL/lpr BMM rather than enhanced it, as has been reported. Our data suggest that the enhanced accumulation of macrophages in the MRL/lpr kidney cannot be explained by a proposed model of enhanced responsiveness of MRL/lpr BMM to CSF-1, including a contribution by TNF-α.
Interaction of Very Late Antigen-4 with VCAM-1 Supports Transendothelial Chemotaxis of Monocytes by Facilitating Lateral Migration
Authors: Weber Christian , Springer Timothy A. 
Published: December 2022

AbstractThe transient regulation of very late antigen (VLA)-4 avidity by CC chemokines may promote chemotaxis of monocytes across VCAM-1-bearing barriers, whereas late and prolonged activation of VLA-5 may mediate subsequent localization in the extracellular matrix. We demonstrate that interactions of VLA-4 with VCAM-1, fibronectin, or a 40-kDa fragment but not a 120-kDa fragment of fibronectin supported the lateral random migration of isolated blood monocytes induced by CC chemokines, termed chemokinesis. This effect was optimal at intermediate substrate concentrations. Moreover, coimmobilization of VCAM-1 with ICAM-1 allowed better migration than ICAM-1 alone. Chemokinesis on VCAM-1 appeared to be associated with transient regulation of VLA-4 avidity by CC chemokines, given that locking VLA-4 in a high avidity state markedly inhibited migration and the locomotion rate was inversely correlated with the adhesive strength of VLA-4 to VCAM-1 following stimulation with monocyte chemoattractant protein-1. Induction of VCAM-1 expression by endothelial activation with IL-4 improved chemokinesis and lateral migration toward a monocyte chemoattractant protein-1 or a monocyte inflammatory protein-1α gradient on endothelium and increased transendothelial chemotaxis of monocytes by a VLA-4-dependent mechanism. In contrast, endothelial activation with IL-4 did not affect the time required for diapedesis of monocytes itself. Hence, VCAM-1 may facilitate transendothelial chemotaxis by supporting lateral migration of attached monocytes along endothelium.
Lymphotoxin α3 Induces Chemokines and Adhesion Molecules: Insight into the Role of LTα in Inflammation and Lymphoid Organ Development
Authors: Cuff Carolyn A. , Schwartz Jessica , Bergman Cheryl M. , Russell Kerry S. , Bender Jeffrey R. , Ruddle Nancy H. 
Published: December 2022

AbstractLymphotoxin (LT) plays an important role in inflammation and lymphoid organ development, though the mechanisms by which it promotes these processes are poorly understood. Toward this end, the biologic activities of a recently generated recombinant murine (m) LTα preparation were evaluated. This cytokine preparation was effective at inducing cytotoxicity of WEHI target cells with 50% maximal killing observed with 1.2 ng/ml. mLTα also induced the expression of inflammatory mediators in the murine endothelial cell line bEnd.3. rmLTα induced expression of the adhesion molecules VCAM, ICAM, E-selectin, and the mucosal addressin cellular adhesion molecule, MAdCAM-1. When mLTα, human (h) LTα, and mTNF-α were compared, mLTα was the most potent inducer of MAdCAM-1. None of these cytokines induced the peripheral node addressin, PNAd. mLTα also induced expression of the chemokines RANTES, IFN-inducible protein 10 (IP-10), and monocyte chemotactic protein 1 (MCP-1). mRNA levels peaked 4 h following treatment with mLTα and declined through the 24-h treatment period. LTα also induced chemokine protein within 8 h of treatment, which increased through the 24-h treatment period. These data demonstrate that the proinflammatory effects of LTα3 may be mediated in part through the induction of adhesion molecule and chemokine expression. Further, LTα3 may promote development of lymphoid tissue through induction of chemokines and the mucosal addressin MAdCAM-1. These data confirm previous observations in transgenic and knockout mice that LTα3 in the absence of LTβ carries out unique biologic activities.
Antineutrophil Cytoplasmic Antibodies Preferentially Engage FcγRIIIb on Human Neutrophils
Authors: Kocher Markus , Edberg Jeffrey C. , Fleit Howard B. , Kimberly Robert P. 
Published: December 2022

AbstractAntineutrophil cytoplasmic Abs (ANCA) are found in the circulation of many patients with systemic vasculitis. ANCA bind to ANCA target, such as proteinase 3 and myeloperoxidase, and activate neutrophils in an FcγR-dependent manner. Human neutrophils constitutively express FcγRIIa (CD32) and FcγRIIIb (CD16), and there is clear in vitro experimental evidence of ANCA-mediated engagement of FcγRIIa. However, direct experimental evidence of ANCA engagement of neutrophil FcγRIIIb has been obscured by technical problems related to activation-induced receptor shedding and activation-induced expression of receptor on the surface of neutrophils. In this study, by blocking receptor shedding and using appropriate reporter anti-FcγR mAb, we show that human cANCA and pANCA, and murine mAb with corresponding reactivities, can indeed engage FcγRIIIb. Furthermore, our data suggest that FcγRIIIb is preferentially engaged by ANCA relative to FcγRIIa presumably due to the nearly 10-fold excess of FcγRIIIb expression relative to FcγRIIa expression. These results clearly demonstrate that the Fc region of ANCA bound to an ANCA target on the neutrophil surface engage FcγRIIIb and indicate that FcγRIIIb and FcγRIIa may both be active participants in ANCA-induced neutrophil activation. However, given the low levels of ANCA target expression on neutrophils from patients with systemic vasculitis, FcγRIIIb is likely to play a critical role in initiating and perpetuating ANCA-induced neutrophil activation.
The Role of Adhesion Molecules in Human Leukocyte Attachment to Porcine Vascular Endothelium: Implications for Xenotransplantation
Authors: Robinson Lisa A. , Tu LiLi , Steeber Douglas A. , Preis Ori , Platt Jeffrey L. , Tedder Thomas F. 
Published: December 2022

AbstractMany obstacles still prevent successful xenotransplantation of porcine donor organs. When hyperacute rejection is averted, transplanted pig organs are subject to acute vascular and cellular rejection. In autologous systems, leukocyte recruitment into inflamed tissues involves selectins, integrins, and Ig family members. To determine whether these mechanisms allow human leukocytes to effectively enter porcine grafts, the pathways by which human leukocytes adhere to TNF-α-stimulated porcine aortic endothelium were examined under static and physiologic flow conditions. L-selectin and E-selectin had overlapping functions in neutrophil capture and rolling, whereas Ab blockade of E-selectin and the β2 integrins inhibited firm arrest of rolling neutrophils. Combined blockade of selectins and β2 integrins resulted in negligible human neutrophil attachment to pig endothelium. Lymphocyte attachment to porcine endothelium was primarily L-selectin mediated, whereas β2 integrin and VCAM-1/very late Ag-4 (VLA-4) interactions promoted static adhesion. Concurrent β2 integrin, VLA-4, VCAM-1, and L-selectin blockade completely inhibited lymphocyte attachment. Thus, interactions between leukocyte-endothelial cell adhesion receptor pairs remained remarkably intact across the human-porcine species barrier. Moreover, disrupting the adhesion cascade may impair the ability of human leukocytes to infiltrate a transplanted porcine organ during rejection.
Immunostimulatory DNA Sequences Inhibit IL-5, Eosinophilic Inflammation, and Airway Hyperresponsiveness in Mice
Authors: Broide David , Schwarze Jurgan , Tighe Helen , Gifford Tim , Nguyen Minh-Duc , Malek Siamak , Van Uden John , Martin-Orozco Elena , Gelfand Erwin W. , Raz Eyal 
Published: December 2022

AbstractWe have used a mouse model of allergen-induced airway hyperresponsiveness to demonstrate that immunostimulatory DNA sequences (ISS) containing a CpG DNA motif significantly inhibit airway eosinophilia and reduce responsiveness to inhaled methacholine. ISS not only inhibited eosinophilia of the airway (by 93%) and lung parenchyma (91%), but also significantly inhibited blood eosinophilia (86%), suggesting that ISS was exerting a significant effect on the bone marrow production of eosinophils. The inhibition of the bone marrow production of eosinophils by 58% was associated with a significant inhibition of T cell-derived cytokine generation (IL-5, granulocyte-macrophage CSF, and IL-3). ISS exerted this inhibitory effect on T cell cytokine production indirectly by stimulating monocytes/macrophages and NK cells to generate IL-12 and IFNs. The onset of the ISS effect on reducing the number of tissue eosinophils was both immediate (within 1 day of administration) and sustained (lasted 6 days), and was not due to ISS directly inducing eosinophil apoptosis. ISS was effective in inhibiting eosinophilic airway inflammation when administered either systemically (i.p.), or mucosally (i.e., intranasally or intratracheally). Interestingly, a single dose of ISS inhibited airway eosinophilia as effectively as daily injections of corticosteroids for 7 days. Moreover, while both ISS and corticosteroids inhibited IL-5 generation, only ISS was able to induce allergen-specific IFN-γ production and redirect the immune system toward a Th1 response. Thus, systemic or mucosal administration of ISS before allergen exposure could provide a novel form of active immunotherapy in allergic diseases.
CD148: A Receptor-Type Protein Tyrosine Phosphatase Involved in the Regulation of Human T Cell Activation
Authors: Tangye Stuart G. , Phillips Joseph H. , Lanier Lewis L. , de Vries Jan E. , Aversa Gregorio 
Published: December 2022

AbstractFollowing ligation of the TCR and costimulatory molecules such as CD28, T cells proliferate and secrete cytokines. Several other cell surface molecules have been identified that are capable of augmenting activation mediated via the TCR. These include CD2, CD27, CD40 ligand, and signaling lymphocytic activation molecule. Here, we have characterized the expression and function of CD148, a recently identified receptor-type protein tyrosine phosphatase. CD148 is expressed at low levels on resting T cells, but is up-regulated following in vitro activation. Cross-linking CD148 with immobilized anti-CD148 mAb induced vigorous proliferation of anti-CD3 mAb-activated, highly purified peripheral blood T cells in an IL-2-dependent, cyclosporin A-sensitive manner. This effect was greatest after 8 days of in vitro culture, suggesting that this molecule is involved in the latter stages of a T cell response. CD148-induced proliferation was significantly greater for CD8+ T cells than for CD4+ T cells. Thus, CD148 is a receptor-type protein tyrosine phosphatase involved in the activation of T lymphocytes.
The Tetraspan Protein CD82 Is a Resident of MHC Class II Compartments Where It Associates with HLA-DR, -DM, and -DO Molecules
Authors: Hammond Craig , Denzin Lisa K. , Pan Mary , Griffith Janice M. , Geuze Hans J. , Cresswell Peter 
Published: December 2022

AbstractIn specialized APCs, MHC class II molecules are synthesized in the endoplasmic reticulum and transported through the Golgi apparatus to organelles of the endocytic pathway collectively called MHC class II compartments (MIICs). There, the class II-associated invariant chain is degraded, and peptides derived from internalized Ag bind to empty class II in a reaction that is facilitated by the class II-like molecule HLA-DM. An mAb raised to highly purified, immunoisolated MIICs from human B lymphoblastoid cells recognized CD82, a member of the tetraspan family of integral membrane proteins. Subcellular fractionation, immunofluorescence microscopy, and immunoelectron microscopy showed that CD82 is highly enriched in MIICs, particularly in their internal membranes. Coprecipitation analysis showed that CD82 associates in MIICs with class II, DM, and HLA-DO (an inhibitor of peptide loading that binds DM). Similar experiments showed CD63, another tetraspan protein found in MIICs, also associates with these molecules in the compartment and that CD82 and CD63 associate with each other. Preclearing experiments demonstrated that both CD82 and CD63 form complexes with DM-associated class II and DM-associated DO. The ability of CD82 and CD63 to form complexes with class II, DM, and DO in MIICs suggests that the tetraspan proteins may play an important role in the late stages of MHC class II maturation.