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Sökning: L773:0022 1767 OR L773:1550 6606

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1.
  • Abdillahi, Suado M., et al. (författare)
  • Collagen VI Contains Multiple Host Defense Peptides with Potent In Vivo Activity
  • 2018
  • Ingår i: Journal of Immunology. - : AMER ASSOC IMMUNOLOGISTS. - 0022-1767 .- 1550-6606. ; 201:3, s. 1007-1020
  • Tidskriftsartikel (refereegranskat)abstract
    • Collagen VI is a ubiquitous extracellular matrix component that forms extensive microfibrillar networks in most connective tissues. In this study, we describe for the first time, to our knowledge, that the collagen VI von Willebrand factor type A like domains exhibit a broad-spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria in human skin infections in vivo. In silico sequence and structural analysis of VWA domains revealed that they contain cationic and amphipathic peptide sequence motifs, which might explain the antimicrobial nature of collagen VI. In vitro and in vivo studies show that these peptides exhibited significant antibacterial activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa through membrane disruption. Our findings shed new light on the role of collagen VI derived peptides in innate host defense and provide templates for development of peptide-based antibacterial therapies.
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2.
  • Abu-Humaidan, Anas, et al. (författare)
  • The epidermal growth factor receptor is a regulator of epidermal complement component expression and complement activation.
  • 2014
  • Ingår i: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 192:7, s. 3355-3364
  • Tidskriftsartikel (refereegranskat)abstract
    • The complement system is activated in response to tissue injury. During wound healing, complement activation seems beneficial in acute wounds but may be detrimental in chronic wounds. We found that the epidermal expression of many complement components was only increased to a minor extent in skin wounds in vivo and in cultured keratinocytes after exposure to supernatant from stimulated mononuclear cells. In contrast, the epidermal expression of complement components was downregulated in ex vivo injured skin lacking the stimulation from infiltrating inflammatory cells but with intact injury-induced epidermal growth factor receptor (EGFR)-mediated growth factor response. In cultured primary keratinocytes, stimulation with the potent EGFR ligand, TGF-α, yielded a significant downregulation of complement component expression. Indeed, EGFR inhibition significantly enhanced the induction of complement components in keratinocytes and epidermis following stimulation with proinflammatory cytokines. Importantly, EGFR inhibition of cultured keratinocytes either alone or in combination with proinflammatory stimulus promoted activation of the complement system after incubation with serum. In keratinocytes treated solely with the EGFR inhibitor, complement activation was dependent on serum-derived C1q, whereas in keratinocytes stimulated with a combination of proinflammatory cytokines and EGFR inhibition, complement activation was found even with C1q-depleted serum. In contrast to human keratinocytes, EGFR inhibition did not enhance complement component expression or cause complement activation in murine keratinocytes. These data demonstrate an important role for EGFR in regulating the expression of complement components and complement activation in human epidermis and keratinocytes and, to our knowledge, identify for the first time a pathway important for the epidermal regulation of complement activation.
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3.
  • Adair-Kirk, TL, et al. (författare)
  • A site on laminin alpha 5, AQARSAASKVKVSMKF, induces inflammatory cell production of matrix metalloproteinase-9 and chemotaxis
  • 2003
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 171:1, s. 398-406
  • Tidskriftsartikel (refereegranskat)abstract
    • Several peptide sequences in laminin α1, the α-chain of laminin (Ln)-1, mediate biological responses in vitro, but Ln-1 is rare in vivo. Since Ln-5 and Ln-10, which contain the α3 and α5 chains, respectively, are the most prominent laminin heterotrimers in normal adult tissues and few functional domains in other laminin chains have been identified, we are investigating the α3 and α5 chains for biological activities. Incubation of mouse macrophages with the laminin α5 peptide AQARSAASKVKVSMKF resulted in marked increase in matrix metalloproteinase (MMP)-9 mRNA and gelatinolytic activity in the conditioned media, whereas the corresponding α3 peptide QQARDAANKVAIPMRF had no effect. AQARSAASKVKVSMKF also induced expression of MMP-14, while MMP-2, MMP-3, MMP-7, MMP-12, and MMP-13 were not induced by this peptide. Deletion analyses indicated that a minimal sequence of ASKVKVSMKF was sufficient for increasing MMP-9 expression. AQARSAASKVKVSMKF was also chemotactic for neutrophils and macrophages in vitro, and induced accumulation of neutrophils and macrophages in lung airspaces in vivo following intranasal instillation into mice. Comparable accumulation occurred in MMP-9-deficient mice, indicating that MMP-9 was not required for AQARSAASKVKVSMKF-induced inflammatory cell emigration in the lung. A scrambled version of the minimal peptide, KAKSFVMVSK, was inactive. These data indicate that laminin α5-derived peptides can induce inflammatory cell chemotaxis and metalloproteinase activity.
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4.
  • Adam, Lucille, et al. (författare)
  • Innate Molecular and Cellular Signature in the Skin Preceding Long-Lasting T Cell Responses after Electroporated DNA Vaccination
  • 2020
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 204:12, s. 3375-3388
  • Tidskriftsartikel (refereegranskat)abstract
    • DNA vaccines delivered with electroporation (EP) have shown promising results in preclinical models and are evaluated in clinical trials. In this study, we aim to characterize early mechanisms occurring in the skin after intradermal injection and EP of the auxoGTUmultiSIV DNA vaccine in nonhuman primates. First, we show that EP acts as an adjuvant by enhancing local inflammation, notably via granulocytes, monocytes/macrophages, and CD1a(int)-expressing cell recruitment. EP also induced Langerhans cell maturation, illustrated by CD86, CD83, and HLA-DR upregulation and their migration out of the epidermis. Second, we demonstrate the crucial role of the DNA vaccine in soluble factors release, such as MCP-1 or IL-15. Transcriptomic analysis showed that EP played a major role in gene expression changes postvaccination. However, the DNA vaccine is required to strongly upregulate several genes involved in inflammatory responses (e.g., Saa4), cell migration (e.g., Ccl3, Ccl5, or Cxcl10), APC activation (e.g., Cd86), and IFN-inducible genes (e.g., Ifit3, Ifit5, Irf7, Isg15, orMx1), illustrating an antiviral response signature. Also, AIM-2, a cytosolic DNA sensor, appeared to be strongly upregulated only in the presence of the DNA vaccine and trends to positively correlate with several IFN-inducible genes, suggesting the potential role of AIM-2 in vaccine sensing and the subsequent innate response activation leading to strong adaptive T cell responses. Overall, these results demonstrate that a combined stimulation of the immune response, in which EP and the auxoGTUmultiSIV vaccine triggered different components of the innate immunity, led to strong and persistent cellular recall responses.
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5.
  • Admyre, C, et al. (författare)
  • Exosomes with immune modulatory features are present in human breast milk
  • 2007
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 179:3, s. 1969-1978
  • Tidskriftsartikel (refereegranskat)abstract
    • Breast milk is a complex liquid with immune-competent cells and soluble proteins that provide immunity to the infant and affect the maturation of the infant’s immune system. Exosomes are nanovesicles (30–100 nm) with an endosome-derived limiting membrane secreted by a diverse range of cell types. Because exosomes carry immunorelevant structures, they are suggested to participate in directing the immune response. We hypothesized that human breast milk contain exosomes, which may be important for the development of the infant’s immune system. We isolated vesicles from the human colostrum and mature breast milk by ultracentrifugations and/or immuno-isolation on paramagnetic beads. We found that the vesicles displayed a typical exosome-like size and morphology as analyzed by electron microscopy. Furthermore, they floated at a density between 1.10 and 1.18 g/ml in a sucrose gradient, corresponding to the known density of exosomes. In addition, MHC classes I and II, CD63, CD81, and CD86 were detected on the vesicles by flow cytometry. Western blot and mass spectrometry further confirmed the presence of several exosome-associated molecules. Functional analysis revealed that the vesicle preparation inhibited anti-CD3-induced IL-2 and IFN-γ production from allogeneic and autologous PBMC. In addition, an increased number of Foxp3+CD4+CD25+ T regulatory cells were observed in PBMC incubated with milk vesicle preparations. We conclude that human breast milk contains exosomes with the capacity to influence immune responses.
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6.
  • Adori, M, et al. (författare)
  • Altered Marginal Zone B Cell Selection in the Absence of IκBNS
  • 2018
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 200:2, s. 775-787
  • Tidskriftsartikel (refereegranskat)abstract
    • Marginal zone (MZ) B cells reside in the splenic MZ and play important roles in T cell–independent humoral immune responses against blood-borne pathogens. IκBNS-deficient bumble mice exhibit a severe reduction in the MZ B compartment but regain an MZ B population with age and, thus, represent a valuable model to examine the biology of MZ B cells. In this article, we characterized the MZ B cell defect in further detail and investigated the nature of the B cells that appear in the MZ of aged bumble mice. Flow cytometry analysis of the splenic transitional B cell subsets demonstrated that MZ B cell development was blocked at the transitional-1 to transitional-2–MZ precursor stage in the absence of functional IκBNS. Immunohistochemical analysis of spleen sections from wild-type and bumble mice revealed no alteration in the cellular MZ microenvironment, and analysis of bone marrow chimeras indicated that the MZ B cell development defect in bumble mice was B cell intrinsic. Further, we demonstrate that the B cells that repopulate the MZ in aged bumble mice were distinct from age-matched wild-type MZ B cells. Specifically, the expression of surface markers characteristic for MZ B cells was altered and the L chain Igλ+ repertoire was reduced in bumble mice. Finally, plasma cell differentiation of sorted LPS-stimulated MZ B cells was impaired, and aged bumble mice were unable to respond to NP-Ficoll immunization. These results demonstrate that IκBNS is required for an intact MZ B cell compartment in C57BL/6 mice.
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7.
  • Agarwal, Vaibhav, et al. (författare)
  • An Alternative Role of C1q in Bacterial Infections: Facilitating Streptococcus pneumoniae Adherence and Invasion of Host Cells.
  • 2013
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 191:8, s. 4235-4245
  • Tidskriftsartikel (refereegranskat)abstract
    • Streptococcus pneumoniae (pneumococcus) is a major human pathogen, which evolved numerous successful strategies to colonize the host. In this study, we report a novel mechanism of pneumococcal-host interaction, whereby pneumococci use a host complement protein C1q, primarily involved in the host-defense mechanism, for colonization and subsequent dissemination. Using cell-culture infection assays and confocal microscopy, we observed that pneumococcal surface-bound C1q significantly enhanced pneumococcal adherence to and invasion of host epithelial and endothelial cells. Flow cytometry demonstrated a direct, Ab-independent binding of purified C1q to various clinical isolates of pneumococci. This interaction was seemingly capsule serotype independent and mediated by the bacterial surface-exposed proteins, as pretreatment of pneumococci with pronase E but not sodium periodate significantly reduced C1q binding. Moreover, similar binding was observed using C1 complex as the source of C1q. Furthermore, our data show that C1q bound to the pneumococcal surface through the globular heads and with the host cell-surface receptor(s)/glycosaminoglycans via its N-terminal collagen-like stalk, as the presence of C1q N-terminal fragment and low m.w. heparin but not the C-terminal globular heads blocked C1q-mediated pneumococcal adherence to host cells. Taken together, we demonstrate for the first time, to our knowledge, a unique function of complement protein C1q, as a molecular bridge between pneumococci and the host, which promotes bacterial cellular adherence and invasion. Nevertheless, in some conditions, this mechanism could be also beneficial for the host as it may result in uptake and clearance of the bacteria.
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8.
  • Agarwal, Vaibhav, et al. (författare)
  • Enolase of Streptococcus pneumoniae Binds Human Complement Inhibitor C4b-Binding Protein and Contributes to Complement Evasion.
  • 2012
  • Ingår i: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 189:7, s. 3575-3584
  • Tidskriftsartikel (refereegranskat)abstract
    • Streptococcus pneumoniae (pneumococcus) is a pathogen that causes severe local and life-threatening invasive diseases, which are associated with high mortality rates. Pneumococci have evolved several strategies to evade the host immune system, including complement to disseminate and to survive in various host niches. Thus, pneumococci bind complement inhibitors such as C4b-binding protein (C4BP) and factor H via pneumococcal surface protein C, thereby inhibiting the classical and alternative complement pathways. In this study, we identified the pneumococcal glycolytic enzyme enolase, a nonclassical cell surface and plasminogen-binding protein, as an additional pneumococcal C4BP-binding protein. Furthermore, we demonstrated that human, but not mouse, C4BP bound pneumococci. Recombinant enolase bound in a dose-dependent manner C4BP purified from plasma, and the interaction was reduced by increasing ionic strength. Enolase recruited C4BP and plasminogen, but not factor H, from human serum. Moreover, C4BP and plasminogen bound to different domains of enolase as they did not compete for the interaction with enolase. In direct binding assays with recombinant C4BP mutants lacking individual domains, two binding sites for enolase were identified on the complement control protein (CCP) domain 1/CCP2 and CCP8 of the C4BP α-chains. C4BP bound to the enolase retained its cofactor activity as determined by C4b degradation. Furthermore, in the presence of exogenously added enolase, an increased C4BP binding to and subsequently decreased C3b deposition on pneumococci was observed. Taken together, pneumococci specifically interact with human C4BP via enolase, which represents an additional mechanism of human complement control by this versatile pathogen.
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9.
  • Aggio, JB, et al. (författare)
  • Vaccinia Virus Infection Inhibits Skin Dendritic Cell Migration to the Draining Lymph Node
  • 2021
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 206:4, s. 776-784
  • Tidskriftsartikel (refereegranskat)abstract
    • There is a paucity of information on dendritic cell (DC) responses to vaccinia virus (VACV), including the traffic of DCs to the draining lymph node (dLN). In this study, using a mouse model of infection, we studied skin DC migration in response to VACV and compared it with the tuberculosis vaccine Mycobacterium bovis bacille Calmette–Guérin (BCG), another live attenuated vaccine administered via the skin. In stark contrast to BCG, skin DCs did not relocate to the dLN in response to VACV. Infection with UV-inactivated VACV or modified VACV Ankara promoted DC movement to the dLN, indicating that interference with skin DC migration requires replication-competent VACV. This suppressive effect of VACV was capable of mitigating responses to a secondary challenge with BCG in the skin, ablating DC migration, reducing BCG transport, and delaying CD4+ T cell priming in the dLN. Expression of inflammatory mediators associated with BCG-triggered DC migration were absent from virus-injected skin, suggesting that other pathways invoke DC movement in response to replication-deficient VACV. Despite adamant suppression of DC migration, VACV was still detected early in the dLN and primed Ag-specific CD4+ T cells. In summary, VACV blocks skin DC mobilization from the site of infection while retaining the ability to access the dLN to prime CD4+ T cells.
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10.
  • Ahlen, G, et al. (författare)
  • In vivo electroporation enhances the immunogenicity of hepatitis C virus nonstructural 3/4A DNA by increased local DNA uptake, protein expression, inflammation, and infiltration of CD3+ T cells
  • 2007
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 179:7, s. 4741-4753
  • Tidskriftsartikel (refereegranskat)abstract
    • The mechanisms by which in vivo electroporation (EP) improves the potency of i.m. DNA vaccination were characterized by using the hepatitis C virus nonstructural (NS) 3/4A gene. Following a standard i.m. injection of DNA with or without in vivo EP, plasmid levels peaked immediately at the site of injection and decreased by 4 logs the first week. In vivo EP did not promote plasmid persistence and, depending on the dose, the plasmid was cleared or almost cleared after 60 days. In vivo imaging and immunohistochemistry revealed that protein expression was restricted to the injection site despite the detection of significant levels of plasmid in adjacent muscle groups. In vivo EP increased and prolonged NS3/4A protein expression levels as well as an increased infiltration of CD3+ T cells at the injection site. These factors most likely additively contributed to the enhanced and broadened priming of NS3/4A-specific Abs, CD4+ T cells, CD8+ T cells, and γ-IFN production. The primed CD8+ responses were functional in vivo, resulting in elimination of hepatitis C virus NS3/4A-expressing liver cells in transiently transgenic mice. Collectively, the enhanced protein expression and inflammation at the injection site following in vivo EP contributed to the priming of in vivo functional immune responses. These localized effects most likely help to insure that the strength and duration of the responses are maintained when the vaccine is tested in larger animals, including rabbits and humans. Thus, the combined effects mediated by in vivo EP serves as a potent adjuvant for the NS3/4A-based DNA vaccine.
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11.
  • Ahmed, Aisha S., et al. (författare)
  • Activation of NF-kappa B in Synovium versus Cartilage from Patients with Advanced Knee Osteoarthritis : A Potential Contributor to Inflammatory Aspects of Disease Progression
  • 2018
  • Ingår i: Journal of Immunology. - : AMER ASSOC IMMUNOLOGISTS. - 0022-1767 .- 1550-6606. ; 201:7, s. 1918-1927
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim was to assess the activation and association of the NF-kappa B system across synovial membrane (SM) and articular cartilage (AC) in patients with knee osteoarthritis (OA) and ascertain its potential effects on catabolic mediator expression in advanced OA. SM and AC were obtained from 40 OA patients undergoing total knee arthroplasty and from 19 postmortem control subjects. NF-kappa B subunit RelA in nuclear and cytosolic fractions and NF-kappa B1-DNA binding in nuclear extracts was assessed by ELISA, whereas NFKB1, RELA, IL-8, IL-6, and MMP3 gene expression were analyzed by reverse transcriptase-quantitative PCR in tissues. We observed higher SM nuclear RelA protein levels and upregulated NF-kappa B1-DNA binding in OA patients compared with postmortem controls. However, in AC, lower nuclear RelA levels were observed compared with cytosolic extracts in patients. Nuclear RelA levels correlated positively with NF-kappa B1-DNA binding in SM and AC in patients. SM RELA and MMP3 mRNA levels were upregulated, whereas IL-8 and IL-6 as well as AC RELA were downregulated in patients compared with controls. In SM, nuclear RelA levels correlated positively with MMP3 gene expression in patients. A negative correlation was observed between SM nuclear RelA levels and AC NF-kappa B1-DNA binding, and SM nuclear NF-kappa B1-DNA binding correlated negatively with AC MMP3 and NFKB1 mRNA levels in patients. These findings highlight NF-kappa B-triggered cross-talk and feedback mechanisms between SM and AC in OA. Further, our findings strongly support a role for an activated NF-kappa B system in the transcriptional mechanism of inflammatory processes, especially in SM of patients with advanced OA.
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12.
  • Ahrens, Richard, et al. (författare)
  • Intestinal Macrophage/Epithelial Cell-Derived CCL11/Eotaxin-1 Mediates Eosinophil Recruitment and Function in Pediatric Ulcerative Colitis
  • 2008
  • Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 181:10, s. 7390-7399
  • Tidskriftsartikel (refereegranskat)abstract
    • Clinical studies have demonstrated a link between the eosinophil-selective chemokines, eotaxins (eotaxin-1/CCL11 and eotaxin-2/CCL24), eosinophils, and the inflammatory bowel diseases, Crohn's disease and ulcerative colitis (UC). However, the cellular source and individual contribution of the eotaxins to colonic eosinophilic accumulation in inflammatory bowel diseases remain unclear. In this study we demonstrate, by gene array and quantitative PCR, elevated levels of eotaxin-1 mRNA in the rectosigmoid colon of pediatric UC patients. We show that elevated levels of eotaxin-1 mRNA positively correlated with rectosigmoid eosinophil numbers. Further, colonic eosinophils appeared to be degranulating, and the levels positively correlated with disease severity. Using the dextran sodium sulfate (DSS)-induced intestinal epithelial injury model, we show that DSS treatment of mice strongly induced colonic eotaxin-1 and eotaxin-2 expression and eosinophil levels. Analysis of eosinophil-deficient mice defined an effector role for eosinophils in disease pathology. DSS treatment of eotaxin-2(-/-) and eotaxin-1/2(-/-) mice demonstrated that eosinophil recruitment was dependent on eotaxin-1. In situ and immunofluorescence analysis-identified eotaxin-1 expression was restricted to intestinal F4/80(+)CD11b(+) macrophages in DSS-induced epithelia] injury and to CD68(+) intestinal macrophages and the basolateral compartment of intestinal epithelial cells in pediatric UC. These data demonstrate that intestinal macrophage and epithelial cell-derived eotaxin-1 plays a critical role in the regulation of eosinophil recruitment in colonic eosinophilic disease such as pediatric UC and provides a basis for targeting the eosinophil/eotaxin-1 axis in UC.
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13.
  • Al Adwani, Salma, et al. (författare)
  • Citrullination Alters the Antibacterial and Anti-Inflammatory Functions of the Host Defense Peptide Canine Cathelicidin K9CATH In Vitro
  • 2021
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 207:3, s. 974-984
  • Tidskriftsartikel (refereegranskat)abstract
    • K9CATH is the sole cathelicidin in canines (dogs) and exhibits broad antimicrobial activity against both Gram-positive and Gram-negative bacteria. K9CATH also modulates inflammatory responses and binds to LPS. These activities depend on the secondary structure and a net-positive charge of the peptide. Peptidylarginine deiminases (PAD) convert cationic peptidyl arginine to neutral citrulline. Thus, we hypothesized that citrullination is a biologically relevant modification of the peptide that would reduce the antibacterial and LPS-binding activities of K9CATH. Recombinant PAD2 and PAD4 citrullinated K9CATH to various extents and circular dichroism spectroscopy revealed that both native and citrullinated K9CATH exhibited similar α-helical secondary structures. Notably, citrullination of K9CATH reduced its bactericidal activity, abolished its ability to permeabilize the membrane of Gram-negative bacteria and reduced the hemolytic capacity. Electron microscopy showed that citrullinated K9CATH did not cause any morphological changes of Gram-negative bacteria, whereas the native peptide caused clear alterations of membrane integrity, concordant with a rapid bactericidal effect. Finally, citrullination of K9CATH impaired its capacity to inhibit LPS-mediated release of proinflammatory molecules from mouse and canine macrophages. In conclusion, citrullination attenuates the antibacterial and the LPS-binding properties of K9CATH, demonstrating the importance of a net positive charge for antibacterial lysis of bacteria and LPS-binding effects and suggests that citrullination is a means to regulate cathelicidin activities.
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14.
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15.
  • Almkvist, Jenny, 1971, et al. (författare)
  • Activation of the neutrophil nicotinamide adenine dinucleotide phosphate oxidase by galectin-1.
  • 2002
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - 0022-1767. ; 168:8, s. 4034-4041
  • Tidskriftsartikel (refereegranskat)abstract
    • Galectins are a group of lactose-binding proteins widely distributed in nature. Twelve mammalian galectins have so far been identified, but their functions are to a large extent unknown. In this work we study galectin-1 in its interaction with human neutrophils, with regard to both cell surface binding and activation of the superoxide-producing NADPH-oxidase. We show that galectin-1 is able to activate the neutrophil NADPH-oxidase, provided that the cells have been primed by extravasation from the blood into the tissue, an activation pattern that is similar to that of galectin-3. Using in vitro priming protocols, the galectin-1 responsiveness was found to correlate to granule mobilization and galectin-1 binding to the cells, suggesting the presence of granule-localized receptors that are up-regulated to the cell surface upon priming. By galectin-1 overlay of fractionated neutrophils we identified potential galectin-1 receptor candidates localized in the membranes of the secretory vesicle and gelatinase granules. The binding of galectin-1 and galectin-3 to neutrophil proteins was compared, as were the dose dependencies for activation by the two lectins. The results suggest that, although similarities are found between the two galectins, they appear to activate the NADPH-oxidase using different receptors. In conclusion, galectin-1 appears to have proinflammatory functions, mediated through activation of the neutrophil respiratory burst.
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16.
  • Amara, Umme, et al. (författare)
  • Molecular Intercommunication between the Complement and Coagulation Systems
  • 2010
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 185:9, s. 5628-5636
  • Tidskriftsartikel (refereegranskat)abstract
    • The complement system as well as the coagulation system has fundamental clinical implications in the context of life-threatening tissue injury and inflammation. Associations between both cascades have been proposed, but the precise molecular mechanisms remain unknown. The current study reports multiple links for various factors of the coagulation and fibrinolysis cascades with the central complement components C3 and C5 in vitro and ex vivo. Thrombin, human coagulation factors (F) XIa, Xa, and IXa, and plasmin were all found to effectively cleave C3 and C5. Mass spectrometric analyses identified the cleavage products as C3a and C5a, displaying identical molecular weights as the native anaphylatoxins C3a and C5a. Cleavage products also exhibited robust chemoattraction of human mast cells and neutrophils, respectively. Enzymatic activity for C3 cleavage by the investigated clotting and fibrinolysis factors is defined in the following order: FXa > plasmin > thrombin > FIXa > FXIa > control. Furthermore, FXa-induced cleavage of C3 was significantly suppressed in the presence of the selective FXa inhibitors fondaparinux and enoxaparin in a concentration-dependent manner. Addition of FXa to human serum or plasma activated complement ex vivo, represented by the generation of C3a, C5a, and the terminal complement complex, and decreased complement hemolytic serum activity that defines exact serum concentration that results in complement-mediated lysis of 50% of sensitized sheep erythrocytes. Furthermore, in plasma from patients with multiple injuries (n = 12), a very early appearance and correlation of coagulation (thrombin-antithrombin complexes) and the complement activation product C5a was found. The present data suggest that coagulation/fibrinolysis proteases may act as natural C3 and C5 convertases, generating biologically active anaphylatoxins, linking both cascades via multiple direct interactions in terms of a complex serine protease system. The Journal of Immunology, 2010, 185: 5628-5636.
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17.
  • Anastasi, E, et al. (författare)
  • Expression of activated Notch3 in transgenic mice enhances generation of T regulatory cells and protects against experimental autoimmune diabetes
  • 2003
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 171:9, s. 4504-4511
  • Tidskriftsartikel (refereegranskat)abstract
    • Thymic-derived dysregulated tolerance has been suggested to occur in type 1 diabetes via impaired generation of CD4+CD25+ T regulatory cells, leading to autoimmune β cell destruction. In this study, we demonstrate that Notch3 expression is a characteristic feature of CD4+CD25+ cells. Furthermore, streptozotocin-induced autoimmune diabetes fails to develop in transgenic mice carrying the constitutively active intracellular domain of Notch3 in thymocytes and T cells. The failure to develop the disease is associated with an increase of CD4+CD25+ T regulatory cells, accumulating in lymphoid organs, in pancreas infiltrates and paralleled by increased expression of IL-4 and IL-10. Accordingly, CD4+ T cells from Notch3-transgenic mice inhibit the development of hyperglycemia and insulitis when injected into streptozotocin-treated wild-type mice and display in vitro suppressive activity. These observations, therefore, suggest that Notch3-mediated events regulate the expansion and function of T regulatory cells, leading to protection from experimental autoimmune diabetes and identify the Notch pathway as a potential target for therapeutic intervention in type 1 diabetes.
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18.
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19.
  • Andersson, J, et al. (författare)
  • The prevalence of regulatory T cells in lymphoid tissue is correlated with viral load in HIV-infected patients
  • 2005
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 174:6, s. 3143-3147
  • Tidskriftsartikel (refereegranskat)abstract
    • Inadequate local cell-mediated immunity appears crucial for the establishment of chronic HIV infection. Accumulation of regulatory T cells (Treg) at the site of HIV replication, the lymphoid organs, may influence the outcome of HIV infection. Our data provide the first evidence that chronic HIV infection changes Treg tissue distribution. Several molecules characteristics of Treg (FoxP3, CTLA-4, glucocorticoid-induced TNFR family-related receptor, and CD25) were expressed more in tonsils of untreated patients compared with antiretroviral-treated patients. Importantly, most FoxP3+ cells expressed CTLA-4, but not CD69. Furthermore, a direct correlation between FoxP3 levels and viral load was evident. In contrast, FoxP3 expression was decreased in circulating T cells from untreated patients, but normalized after initiation of treatment. Functional markers of Treg activity (indoleamine 2,3-dioxygenase, TGF-β, and CD80) were markedly increased in the tonsils of untreated patients. Our data could provide a new basis for immune-based therapies that counteract in vivo Treg and thereby reinforce appropriate antiviral immunity.
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20.
  • Andersson, Yvonne, et al. (författare)
  • Formula feeding skews immune cell composition toward adaptive immunity compared to breastfeeding
  • 2009
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists, Inc.. - 0022-1767 .- 1550-6606. ; 183:7, s. 4322-4328
  • Tidskriftsartikel (refereegranskat)abstract
    • The ontogeny of the immune system and the effect thereon by type of infant feeding is incompletely understood. We analyzed frequencies and composition of immune cells in blood of breastfed (BF) and formula-fed (FF) infants at 1.5, 4, and 6 mo of age. Three formulas with the same protein concentration but with varying levels of alpha-lactalbumin and caseinoglycomacropeptide were compared. Twenty-nine exclusively BF infants served as reference, and 17 infants in each formula group completed the study. Whole blood and PBMCs were analyzed by flow cytometry and immunoflow cytometry, respectively. Leukocyte count of BF infants increased with time due to increased frequency of neutrophils. Lymphocyte count was high at 1.5 mo and was unchanged over time, as were the relative proportions of CD4+ alphabetaT cells, CD8+ alphabetaT cells, B cells, NK cells, and gammadeltaT cells. Most CD45R0+CD3+ cells were HLA-DR- and hence memory cells. Compared with breastfeeding, formula feeding resulted in a significant decrease in proportion of NK cells, but a significant increase in naive CD4+ alphabetaT cells and an elevated CD4-to-CD8 ratio, that is, 3.3 in the combined FF groups compared with 2.6 in the BF group. No significant differences were found between the three groups of FF infants. In conclusion, blood cells of lymphoid lineage did not change significantly in frequencies or composition from 1.5 to 6 mo of age in BF infants. In contrast, FF infants displayed an ongoing maturation of adaptive immunity cells and a delayed recruitment of innate immunity cells as compared with BF infants.
  •  
21.
  • Ando, T, et al. (författare)
  • Transduction with the antioxidant enzyme catalase protects human T cells against oxidative stress
  • 2008
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 181:12, s. 8382-8390
  • Tidskriftsartikel (refereegranskat)abstract
    • Patients with diseases characterized by chronic inflammation, caused by infection or cancer, have T cells and NK cells with impaired function. The underlying molecular mechanisms are diverse, but one of the major mediators in this immune suppression is oxidative stress caused by activated monocytes, granulocytes, or myeloid-derived suppressor cells. Reactive oxygen species can seriously hamper the efficacy of active immunotherapy and adoptive transfer of T and NK cells into patients. In this study, we have evaluated whether enhanced expression of the antioxidant enzyme catalase in human T cells can protect them against reactive oxygen species. Human CD4+ and CD8+ T cells retrovirally transduced with the catalase gene had increased intracellular expression and activity of catalase. Catalase transduction made CD4+ T cells less sensitive to H2O2-induced loss-of-function, measured by their cytokine production and ability to expand in vitro following anti-CD3 stimulation. It also enhanced the resistance to oxidative stress-induced cell death after coculture with activated granulocytes, exposure to the oxidized lipid 4-hydroxynonenal, or H2O2. Expression of catalase by CMV-specific CD8+ T cells saved cells from cell death and improved their capacity to recognize CMV peptide-loaded target cells when exposed to H2O2. These findings indicate that catalase-transduced T cells potentially are more efficacious for the immunotherapy of patients with advanced cancer or chronic viral infections.
  •  
22.
  • Ansari, NA, et al. (författare)
  • IL-27 and IL-21 are associated with T cell IL-10 responses in human visceral leishmaniasis
  • 2011
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 186:7, s. 3977-3985
  • Tidskriftsartikel (refereegranskat)abstract
    • IL-10 is believed to underlie many of the immunologic defects in human visceral leishmaniasis (VL). We have identified CD4+CD25−Foxp3− T cells as the major source of IL-10 in the VL spleen. IL-27, a member of the IL-6/IL-12 cytokine family, has been shown to promote development of IL-10–producing T cells, in part by upregulating their production of autocrine IL-21. We investigated whether IL-27 and IL-21 are associated with human VL. IL-27 was elevated in VL plasma, and at pretreatment, spleen cells showed significantly elevated mRNA levels of both IL-27 subunits, IL-27p28 and EBI-3, as well as IL-21, compared with posttreatment biopsies. CD14+ spleen cells were the main source of IL-27 mRNA, whereas CD3+ T cells were the main source of IL-21. IL-27 mRNA could be strongly upregulated in normal donor macrophages with IFN-γ and IL-1β, conditions consistent with those in the VL spleen. Last, a whole-blood assay revealed that most VL patients could produce Ag-specific IFN-γ and IL-10 and that the IL-10 could be augmented with recombinant human IL-21. Thus, proinflammatory cytokines acting on macrophages in the VL spleen have the potential to upregulate IL-27, which in turn can induce IL-21 to expand IL-10–producing T cells as a mechanism of feedback control.
  •  
23.
  • Applequist, SE, et al. (författare)
  • Activation of innate immunity, inflammation, and potentiation of DNA vaccination through mammalian expression of the TLR5 agonist flagellin
  • 2005
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 175:6, s. 3882-3891
  • Tidskriftsartikel (refereegranskat)abstract
    • Improving DNA vaccination remains a fundamental goal in vaccine research. Theoretically, this could be achieved by molecules encoded by DNA capable of activating TLRs to mimic inflammatory responses generated by infection. Therefore, we constructed an expression vector that allows mammalian cells to express the TLR5 agonist flagellin (FliC) at the cell surface. In vitro, cell lines expressing FliC stimulated production of proinflammatory cytokines and the up-regulation of costimulatory molecules on monocytes. Mice given the FliC expression vector intradermally exhibited site-specific inflammation and, in combination with vectors expressing Ags, developed dramatic increases in Ag-specific IgG as well as IgA. Surprisingly, mice also developed strong Ag-specific MHC class I-restricted cellular immunity. To determine whether vaccination using FliC vectors could elicit protective immunity to an infectious agent, mice were given dermal injections of FliC expression vector together with a vector encoding the influenza A virus nucleoprotein. This vaccination strategy elicited protective immunity to lethal influenza A virus infection. These results demonstrate that expression of DNA-encoded TLR agonists by mammalian cells greatly enhance and broaden immune responses, imposing new possibilities on DNA vaccination to infectious agents and cancer.
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24.
  • Arencibia, I, et al. (författare)
  • Yersinia invasin, a bacterial beta1-integrin ligand, is a potent inducer of lymphocyte motility and migration to collagen type IV and fibronectin.
  • 1997
  • Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 159:4, s. 1853-9
  • Tidskriftsartikel (refereegranskat)abstract
    • The Yersinia pseudotuberculosis invasin protein was found to be a potent inducer of pseudopodia formation and chemotactic and haptotactic migration in human T lymphocytes. Checkerboard analysis confirmed that migration was directional. The Yersinia invasin triggered migration of otherwise poorly migratory normal T cells on fibronectin and in particular on collagen type IV, and augmented the migration of leukemic T cell lines on these components. Invasin-induced lymphocyte migration was inhibited by staurosporin that selectively prevented pseudopodia formation but, noteworthy, augmented adhesion. The motogenic and attractant properties of invasin (Inv) were mediated via beta1-integrins, as shown by lack of effect of Inv on the motility of a beta1-integrin-negative lymphoid cell line and inhibition of invasin-induced lymphocyte motility by anti-beta1 Abs. Inv was markedly more effective than the extracellular matrix components fibronectin, collagen type IV, and laminin, which also interact with lymphocyte beta1-integrins, with respect to induction of pseudopodia, chemotaxis, and haptotaxis. Thus, Yersinia invasin is a model ligand for induction of lymphocyte motility via beta1-integrins. The extraordinary capacity of Inv to trigger and guide T lymphocyte motility and potentiate lymphocyte migration to extracellular matrix components may be of pathogenetic significance for the movement of lymphocytes to extraintestinal sites secondary to Yersinia infection.
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25.
  • Arredouani, MS, et al. (författare)
  • MARCO is the major binding receptor for unopsonized particles and bacteria on human alveolar macrophages
  • 2005
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 175:9, s. 6058-6064
  • Tidskriftsartikel (refereegranskat)abstract
    • Alveolar macrophages (AMs) avidly bind and ingest inhaled environmental particles and bacteria. To identify the particle binding receptor(s) on human AMs, we used functional screening of anti-human AM hybridomas and isolated a mAb, PLK-1, which inhibits AM binding of unopsonized particles (e.g., TiO2, latex beads; 63 ± 5 and 67 ± 4% inhibition, respectively, measured by flow cytometry; n = 11) and unopsonized bacteria (∼84 and 41% inhibition of Escherichia coli and Staphylococcus aureus binding by mAb PLK-1, respectively). The PLK-1 Ag was identified as the human class A scavenger receptor (SR) MARCO (macrophage receptor with collagenous structure) by observing specific immunolabeling of COS cells transfected with human MARCO (but not SR-AI/II) cDNA and by immunoprecipitation by PLK-1 of a protein of appropriate molecular mass (∼70 kDa) from both normal human bronchoalveolar lavage cells (>90% AMs) and human MARCO-transfected COS cells. PLK-1 also specifically inhibited particle binding by COS cells, only after transfection with human MARCO cDNA. Immunostaining showed specific labeling of AMs within human lung tissue, bronchoalveolar lavage samples, as well as macrophages in other sites (e.g., lymph node and liver). Using COS transfectants with different truncated forms of MARCO, allowed epitope mapping for the PLK-1 Ab to MARCO domain V between amino acid residues 420 and 431. A panel of Abs to various SRs identified expression on AMs, but failed to inhibit TiO2 or S. aureus binding. The data support a dominant role for MARCO in the human AM defense against inhaled particles and pathogens.
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26.
  • Arredouani, MS, et al. (författare)
  • Scavenger Receptors SR-AI/II and MARCO limit pulmonary dendritic cell migration and allergic airway inflammation
  • 2007
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 178:9, s. 5912-5920
  • Tidskriftsartikel (refereegranskat)abstract
    • The class A scavenger receptors (SR-A) MARCO and SR-AI/II are expressed on lung macrophages (MΦs) and dendritic cells (DCs) and function in innate defenses against inhaled pathogens and particles. Increased expression of SR-As in the lungs of mice in an OVA-asthma model suggested an additional role in modulating responses to an inhaled allergen. After OVA sensitization and aerosol challenge, SR-AI/II and MARCO-deficient mice exhibited greater eosinophilic airway inflammation and airway hyperresponsiveness compared with wild-type mice. A role for simple SR-A-mediated Ag clearance (“scavenging”) by lung MΦs was excluded by the observation of a comparable uptake of fluorescent OVA by wild-type and SR-A-deficient lung MΦs and DCs. In contrast, airway instillation of fluorescent Ag revealed a significantly higher traffic of labeled DCs to thoracic lymph nodes in SR-A-deficient mice than in controls. The increased migration of SR-A-deficient DCs was accompanied by the enhanced proliferation in thoracic lymph nodes of adoptively transferred OVA-specific T cells after airway OVA challenge. The data identify a novel role for SR-As expressed on lung DCs in the down-regulation of specific immune responses to aeroallergens by the reduction of DC migration from the site of Ag uptake to the draining lymph nodes.
  •  
27.
  • Arruda, L. C. M., et al. (författare)
  • Graft γδ TCR Sequencing Identifies Public Clonotypes Associated with Hematopoietic Stem Cell Transplantation Efficacy in Acute Myeloid Leukemia Patients and Unravels Cytomegalovirus Impact on Repertoire Distribution
  • 2019
  • Ingår i: Journal of Immunology. - : NLM (Medline). - 0022-1767 .- 1550-6606. ; 202:6, s. 1859-1870
  • Tidskriftsartikel (refereegranskat)abstract
    • Although the impact of donor graft composition on clinical outcomes after hematopoietic stem cell transplantation (HSCT) has been studied, little is known about the role of intragraft γδ TCR repertoire on clinical outcomes following HSCT. Using a high-throughput sequencing platform, we sought to analyze the TCR γ-chain (TRG) repertoire of γδ T cells within donor stem cell grafts and address its potential impact on clinical response in the corresponding patients. A total of 20 peripheral blood stem cell grafts were analyzed, and donors were classified as CMV+/- The respective acute myeloid leukemia recipients were followed for disease relapse and acute graft-versus-host disease (aGvHD) development post-HSCT. In all samples, TRG repertoire showed a reduced diversity and displayed overrepresented clones. This was more prominent in grafts from CMV+ donors, which presented a more private repertoire, lower diversity, skewed distribution, and reduced usage of the V9-JP pairing. Grafts given to nonrelapse patients presented a more public repertoire and increased presence of long sequence clonotypes. Variable-joining gene segment usage was not associated with aGvHD development, but a higher usage of V2-JP1 pairing and lower usage of V4-J2/V5-J2/V8-JP2 were observed in grafts given to nonrelapse patients. Our work identified five private overrepresented and one public CDR3 sequence (CATWDGPYYKKLF) associated with CMV infection, in addition to 12 highly frequent public sequences present exclusively in grafts given to nonrelapse patients. Our findings show that, despite CMV infection reshaping the TRG repertoire, TRG composition is not associated with aGvHD development, and several public sequences are associated with clinical remission.
  •  
28.
  • Arvidsson, Ida, et al. (författare)
  • Early terminal complement blockade and C6 deficiency are protective in enterohemorrhagic Escherichia coli-infected mice
  • 2016
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 197:4, s. 1276-1286
  • Tidskriftsartikel (refereegranskat)abstract
    • Complement activation occurs during enterohemorrhagic Escherichia coli (EHEC) infection and may exacerbate renal manifestations. In this study, we show glomerular C5b-9 deposits in the renal biopsy of a child with EHEC-associated hemolytic uremic syndrome. The role of the terminal complement complex, and its blockade as a therapeutic modality, was investigated in a mouse model of E. coli O157:H7 infection. BALB/c mice were treated with monoclonal anti-C5 i.p. on day 3 or 6 after intragastric inoculation and monitored for clinical signs of disease and weight loss for 14 d. All infected untreated mice (15 of 15) or those treated with an irrelevant Ab (8 of 8) developed severe illness. In contrast, only few infected mice treated with anti-C5 on day 3 developed symptoms (three of eight, p < 0.01 compared with mice treated with the irrelevant Ab on day 3) whereas most mice treated with anti-C5 on day 6 developed symptoms (six of eight). C6-deficient C57BL/6 mice were also inoculated with E. coli O157:H7 and only 1 of 14 developed disease, whereas 10 of 16 wild-type mice developed weight loss and severe disease (p < 0.01). Complement activation via the terminal pathway is thus involved in the development of disease in murine EHEC infection. Early blockade of the terminal complement pathway, before the development of symptoms, was largely protective, whereas late blockade was not. Likewise, lack of C6, and thereby deficient terminal complement complex, was protective in murine E. coli O157:H7 infection.
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29.
  • Arvidsson, Ida, et al. (författare)
  • Shiga toxin-induced complement-mediated hemolysis and release of complement-coated red blood cell-derived microvesicles in hemolytic uremic syndrome.
  • 2015
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 194:5, s. 2309-2318
  • Tidskriftsartikel (refereegranskat)abstract
    • Shiga toxin (Stx)-producing Escherichia coli (STEC) cause hemolytic uremic syndrome (HUS). This study investigated whether Stx2 induces hemolysis and whether complement is involved in the hemolytic process. RBCs and/or RBC-derived microvesicles from patients with STEC-HUS (n = 25) were investigated for the presence of C3 and C9 by flow cytometry. Patients exhibited increased C3 deposition on RBCs compared with controls (p < 0.001), as well as high levels of C3- and C9-bearing RBC-derived microvesicles during the acute phase, which decreased after recovery. Stx2 bound to P1 (k) and P2 (k) phenotype RBCs, expressing high levels of the P(k) Ag (globotriaosylceramide), the known Stx receptor. Stx2 induced the release of hemoglobin and lactate dehydrogenase in whole blood, indicating hemolysis. Stx2-induced hemolysis was not demonstrated in the absence of plasma and was inhibited by heat inactivation, as well as by the terminal complement pathway Ab eculizumab, the purinergic P2 receptor antagonist suramin, and EDTA. In the presence of whole blood or plasma/serum, Stx2 induced the release of RBC-derived microvesicles coated with C5b-9, a process that was inhibited by EDTA, in the absence of factor B, and by purinergic P2 receptor antagonists. Thus, complement-coated RBC-derived microvesicles are elevated in HUS patients and induced in vitro by incubation of RBCs with Stx2, which also induced hemolysis. The role of complement in Stx2-mediated hemolysis was demonstrated by its occurrence only in the presence of plasma and its abrogation by heat inactivation, EDTA, and eculizumab. Complement activation on RBCs could play a role in the hemolytic process occurring during STEC-HUS.
  •  
30.
  • Assarsson, E, et al. (författare)
  • 2B4/CD48-mediated regulation of lymphocyte activation and function
  • 2005
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 175:4, s. 2045-2049
  • Tidskriftsartikel (refereegranskat)abstract
    • 2B4 (CD244) is a member of the CD2 subset of the Ig superfamily. This molecule is expressed on innate immune cells, including NK cells, and on subsets of T cells. The 2B4 molecule interacts with CD48, which is widely expressed on hemopoietic cells. Although earlier reports demonstrated a role for 2B4 as an activating receptor in both mice and humans, recent studies of 2B4-deficient mice have suggested that 2B4 functions predominantly as an inhibitory receptor in mice. In addition, 2B4 may also act as a costimulatory ligand for cells expressing CD48. Thus, the 2B4 molecule is more multifunctional than previously understood. In this study, we delineate the current view of 2B4-CD48 interactions among lymphocytes and other cells.
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31.
  • Assarsson, E, et al. (författare)
  • CD8+ T cells rapidly acquire NK1.1 and NK cell-associated molecules upon stimulation in vitro and in vivo
  • 2000
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 165:7, s. 3673-3679
  • Tidskriftsartikel (refereegranskat)abstract
    • NKT cells express both NK cell-associated markers and TCR. Classically, these NK1.1+TCRαβ+ cells have been described as being either CD4+CD8− or CD4−CD8−. Most NKT cells interact with the nonclassical MHC class I molecule CD1 through a largely invariant Vα14-Jα281 TCR chain in conjunction with either a Vβ2, -7, or -8 TCR chain. In the present study, we describe the presence of significant numbers of NK1.1+TCRαβ+ cells within lymphokine-activated killer cell cultures from wild-type C57BL/6, CD1d1−/−, and Jα281−/− mice that lack classical NKT cells. Unlike classical NKT cells, 50–60% of these NK1.1+TCRαβ+ cells express CD8 and have a diverse TCR Vβ repertoire. Purified NK1.1−CD8α+ T cells from the spleens of B6 mice, upon stimulation with IL-2, IL-4, or IL-15 in vitro, rapidly acquire surface expression of NK1.1. Many NK1.1+CD8+ T cells had also acquired expression of Ly-49 receptors and other NK cell-associated molecules. The acquisition of NK1.1 expression on CD8+ T cells was a particular property of the IL-2Rβ+ subpopulation of the CD8+ T cells. Efficient NK1.1 expression on CD8+ T cells required Lck but not Fyn. The induction of NK1.1 on CD8+ T cells was not just an in vitro phenomenon as we observed a 5-fold increase of NK1.1+CD8+ T cells in the lungs of influenza virus-infected mice. These data suggest that CD8+ T cells can acquire NK1.1 and other NK cell-associated molecules upon appropriate stimulation in vitro and in vivo.
  •  
32.
  • Assarsson, E, et al. (författare)
  • NK cells stimulate proliferation of T and NK cells through 2B4/CD48 interactions
  • 2004
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 173:1, s. 174-180
  • Tidskriftsartikel (refereegranskat)abstract
    • Few studies have addressed the consequences of physical interactions between NK and T cells, as well as physical interactions among NK cells themselves. We show in this study that NK cells can enhance T cell activation and proliferation in response to CD3 cross-linking and specific Ag through interactions between 2B4 (CD244) on NK cells and CD48 on T cells. Furthermore, 2B4/CD48 interactions between NK cells also enhanced proliferation of NK cells in response to IL-2. Overall, these results suggest that NK cells augment the proliferation of neighboring T and NK cells through direct cell-cell contact. These results provide new insights into NK cell-mediated control of innate and adaptive immunity and demonstrate that receptor/ligand-specific cross talk between lymphocytes may occur in settings other than T-B cell or T-T cell interactions.
  •  
33.
  • Assarsson, Erika, et al. (författare)
  • Severe defect in thymic development in an insertional mutant mouse model.
  • 2007
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 178:8, s. 5018-5027
  • Tidskriftsartikel (refereegranskat)abstract
    • Transgenic mice were generated expressing NK1.1, an NK cell-associated receptor, under control of the human CD2 promoter. Unexpectedly, one of the founder lines, Tg66, showed a marked defect in thymic development characterized by disorganized architecture and small size. Mapping of the transgene insertion by fluorescence in situ hybridization revealed integration in chromosome 2, band G. Already from postnatal day 3, the thymic architecture was disturbed with a preferential loss of cortical thymic epithelial cells, a feature that became more pronounced over time. Compared with wild-type mice, total thymic cell numbers decreased dramatically between 10 and 20 days of age. Thymocytes isolated from adult Tg66 mice were predominantly immature double-negative cells, indicating a block in thymic development at an early stage of differentiation. Consequently, Tg66 mice had reduced numbers of peripheral CD4(+) and CD8(+) T cells. Bone marrow from Tg66 mice readily reconstituted thymi of irradiated wild-type as well as RAG-deficient mice. This indicates that the primary defect in Tg66 mice resided in nonhemopoietic stromal cells of the thymus. The phenotype is observed in mice heterozygous for the insertion and does not resemble any known mutations affecting thymic development. Preliminary studies in mice homozygous for transgene insertion reveal a more accelerated and pronounced phenotype suggesting a semidominant effect. The Tg66 mice may serve as a useful model to identify genes regulating thymic epithelial cell differentiation, thymic development, and function.
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34.
  • Astori, Audrey, et al. (författare)
  • ARID1a Associates with Lymphoid-Restricted Transcription Factors and Has an Essential Role in T Cell Development
  • 2020
  • Ingår i: Journal of Immunology. - : AMER ASSOC IMMUNOLOGISTS. - 0022-1767 .- 1550-6606. ; 205:5, s. 1419-1432
  • Tidskriftsartikel (refereegranskat)abstract
    • Maturation of lymphoid cells is controlled by the action of stage and lineage-restricted transcription factors working in concert with the general transcription and chromatin remodeling machinery to regulate gene expression. To better understand this functional interplay, we used Biotin Identification in human embryonic kidney cells to identify proximity interaction partners for GATA3, TCF7 (TCF1), SPI1, HLF, IKZF1, PAX5, ID1, and ID2. The proximity interaction partners shared among the lineagerestricted transcription factors included ARID1a, a BRG1-associated factor complex component. CUT&RUN analysis revealed that ARID1a shared binding with TCF7 and GATA3 at a substantial number of putative regulatory elements in mouse T cell progenitors. In support of an important function for ARID1a in lymphocyte development, deletion of Aridla in early lymphoid progenitors in mice resulted in a pronounced developmental arrest in early T cell development with a reduction of CD4(+)CD8(+) cells and a 20-fold reduction in thymic cellularity. Exploring gene expression patterns in DN3 cells from Wt and Aridla-deficient mice suggested that the developmental block resided in the DN3a to DN3b transition, indicating a deficiency in beta-selection. Our work highlights the critical importance of functional interactions between stage and lineage-restricted factors and the basic transcription machinery during lymphocyte differentiation.
  •  
35.
  • Avirutnan, Panisadee, et al. (författare)
  • Binding of Flavivirus Nonstructural Protein NS1 to C4b Binding Protein Modulates Complement Activation
  • 2011
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 187:1, s. 424-433
  • Tidskriftsartikel (refereegranskat)abstract
    • The complement system plays a pivotal protective role in the innate immune response to many pathogens including flaviviruses. Flavivirus nonstructural protein 1 (NS1) is a secreted nonstructural glycoprotein that accumulates in plasma to high levels and is displayed on the surface of infected cells but absent from viral particles. Previous work has defined an immune evasion role of flavivirus NS1 in limiting complement activation by forming a complex with C1s and C4 to promote cleavage of C4 to C4b. In this study, we demonstrate a second mechanism, also involving C4 and its active fragment C4b, by which NS1 antagonizes complement activation. Dengue, West Nile, or yellow fever virus NS1 directly associated with C4b binding protein (C4BP), a complement regulatory plasma protein that attenuates the classical and lectin pathways. Soluble NS1 recruited C4BP to inactivate C4b in solution and on the plasma membrane. Mapping studies revealed that the interaction sites of NS1 on C4BP partially overlap with the C4b binding sites. Together, these studies further define the immune evasion potential of NS1 in reducing the functional capacity of C4 in complement activation and control of flavivirus infection. The Journal of Immunology, 2011, 187: 424-433.
  •  
36.
  • Babbin, Brian A., et al. (författare)
  • Annexin A1 regulates intestinal mucosal injury, inflammation, and repair
  • 2008
  • Ingår i: Journal of Immunology. - Bethesda, United States : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 181:7, s. 5035-5044
  • Tidskriftsartikel (refereegranskat)abstract
    • During mucosal inflammation, a complex array of proinflammatory and protective mechanisms regulates inflammation and severity of injury. Secretion of anti-inflammatory mediators is a mechanism that is critical in controlling inflammatory responses and promoting epithelial restitution and barrier recovery. AnxA1 is a potent anti-inflammatory protein that has been implicated to play a critical immune regulatory role in models of inflammation. Although AnxA1 has been shown to be secreted in intestinal mucosal tissues during inflammation, its potential role in modulating the injury/inflammatory response is not understood. In this study, we demonstrate that AnxA1-deficient animals exhibit increased susceptibility to dextran sulfate sodium (DSS)-induced colitis with greater clinical morbidity and histopathologic mucosal injury. Furthermore, impaired recovery following withdrawal of DSS administration was observed in AnxA1 (-/-) animals compared with wild-type (WT) control mice that was independent of inflammatory cell infiltration. Since AnxA1 exerts its anti-inflammatory properties through stimulation of ALX/FPRL-1, we explored the role of this receptor-ligand interaction in regulating DSS-induced colitis. Interestingly, treatment with an ALX/FPRL-1 agonist, 15-epi-lipoxin A4 reversed the enhanced sensitivity of AnxA1 (-/-) mice to DSS colitis. In contrast, 15-epi-lipoxin A4 did not significantly improve the severity of disease in WT animals. Additionally, differential expression of ALX/FPLR-1 in control and DSS-treated WT and AnxA1-deficient animals suggested a potential role for AnxA1 in regulating ALX/FPRL-1 expression under pathophysiological conditions. Together, these results support a role of endogenous AnxA1 in the protective and reparative properties of the intestinal mucosal epithelium.
  •  
37.
  • Backstrom, E, et al. (författare)
  • Direct NK cell-mediated lysis of syngenic dorsal root ganglia neurons in vitro
  • 2000
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 165:9, s. 4895-4900
  • Tidskriftsartikel (refereegranskat)abstract
    • In contrast to extensive studies on the role of T and B lymphocytes in the pathogenesis of autoimmune diseases of the nervous system, little is known about NK cells and their potential role in the destruction of neural tissue. NK cells have been implicated in the selective death of sympathetic neurons resident in the superior cervical ganglia of rats after exposure to the drug guanethidine. This observation suggests that NK cells may function as principle effectors in immunological diseases of the nervous system. However, the direct mechanism of action of NK cells in this model is not known. In particular, it is not known whether NK cells can kill autologous neurons directly. The aim of the present study was to examine whether NK cells can kill directly dorsal root ganglia neurons cultured in vitro. We demonstrate that C57BL/6 (B6)-derived dorsal root ganglia neurons can be killed directly by syngenic IL-2-activated NK cells, and that this nerve cell lysis is dependent on the expression of perforin in the NK cells. NK cells were less effective in destroying neurons grown in the presence of glial cells. These observations indicate a potential role for NK cells in nerve cell degeneration in inflammatory diseases of the nervous system.
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38.
  • Baharom, Faezzah, et al. (författare)
  • Dendritic Cells and Monocytes with Distinct Inflammatory Responses Reside in Lung Mucosa of Healthy Humans
  • 2016
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 196:11, s. 4498-4509
  • Tidskriftsartikel (refereegranskat)abstract
    • Every breath we take contains potentially harmful pathogens or allergens. Dendritic cells (DCs), monocytes, and macrophages are essential in maintaining a delicate balance of initiating immunity without causing collateral damage to the lungs because of an exaggerated inflammatory response. To document the diversity of lung mononuclear phagocytes at steady-state, we performed bronchoscopies on 20 healthy subjects, sampling the proximal and distal airways (bronchial wash and bronchoalveolar lavage, respectively), as well as mucosal tissue (endobronchial biopsies). In addition to a substantial population of alveolar macrophages, we identified subpopulations of monocytes, myeloid DCs (MDCs), and plasmacytoid DCs in the lung mucosa. Intermediate monocytes and MDCs were highly frequent in the airways compared with peripheral blood. Strikingly, the density of mononuclear phagocytes increased upon descending the airways. Monocytes from blood and airways produced 10-fold more proinflammatory cytokines than MDCs upon ex vivo stimulation. However, airway monocytes were less inflammatory than blood monocytes, suggesting a more tolerant nature. The findings of this study establish how to identify human lung mononuclear phagocytes and how they function in normal conditions, so that dysregulations in patients with respiratory diseases can be detected to elucidate their contribution to immunity or pathogenesis.
  •  
39.
  • Baharom, F, et al. (författare)
  • Protection of human myeloid dendritic cell subsets against influenza A virus infection is differentially regulated upon TLR stimulation
  • 2015
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 194:9, s. 4422-4430
  • Tidskriftsartikel (refereegranskat)abstract
    • The proinflammatory microenvironment in the respiratory airway induces maturation of both resident and infiltrating dendritic cells (DCs) upon influenza A virus (IAV) infection. This results in upregulation of antiviral pathways as well as modulation of endocytic processes, which affect the susceptibility of DCs to IAV infection. Therefore, it is highly relevant to understand how IAV interacts with and infects mature DCs. To investigate how different subsets of human myeloid DCs (MDCs) involved in tissue inflammation are affected by inflammatory stimulation during IAV infection, we stimulated primary blood MDCs and inflammatory monocyte-derived DCs (MDDCs) with TLR ligands, resulting in maturation. Interestingly, MDDCs but not MDCs were protected against IAV infection after LPS (TLR4) stimulation. In contrast, stimulation with TLR7/8 ligand protected MDCs but not MDDCs from IAV infection. The reduced susceptibility to IAV infection correlated with induction of type I IFNs. We found that differential expression of TLR4, TRIF, and MyD88 in the two MDC subsets regulated the ability of the cells to enter an antiviral state upon maturation. This difference was functionally confirmed using small interfering RNA and inhibitors. Our data show that different human MDC subsets may play distinct roles during IAV infection, as their capacity to induce type I IFNs is dependent on TLR-specific maturation, resulting in differential susceptibility to IAV infection.
  •  
40.
  • Baldan, A, et al. (författare)
  • ABCG1 is required for pulmonary B-1 B cell and natural antibody homeostasis
  • 2014
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 193:11, s. 5637-5648
  • Tidskriftsartikel (refereegranskat)abstract
    • Many metabolic diseases, including atherosclerosis, type 2 diabetes, pulmonary alveolar proteinosis, and obesity, have a chronic inflammatory component involving both innate and adaptive immunity. Mice lacking the ATP-binding cassette transporter G1 (ABCG1) develop chronic inflammation in the lungs, which is associated with the lipid accumulation (cholesterol, cholesterol ester, and phospholipid) and cholesterol crystal deposition that are characteristic of atherosclerotic lesions and pulmonary alveolar proteinosis. In this article, we demonstrate that specific lipids, likely oxidized phospholipids and/or sterols, elicit a lung-specific immune response in Abcg1−/− mice. Loss of ABCG1 results in increased levels of specific oxysterols, phosphatidylcholines, and oxidized phospholipids, including 1-palmitoyl-2-(5′-oxovaleroyl)-sn-glycero-3-phosphocholine, in the lungs. Further, we identify a niche-specific increase in natural Ab (NAb)-secreting B-1 B cells in response to this lipid accumulation that is paralleled by increased titers of IgM, IgA, and IgG against oxidation-specific epitopes, such as those on oxidized low-density lipoprotein and malondialdehyde-modified low-density lipoprotein. Finally, we identify a cytokine/chemokine signature that is reflective of increased B cell activation, Ab secretion, and homing. Collectively, these data demonstrate that the accumulation of lipids in Abcg1−/− mice induces the specific expansion and localization of B-1 B cells, which secrete NAbs that may help to protect against the development of atherosclerosis. Indeed, despite chronic lipid accumulation and inflammation, hyperlipidemic mice lacking ABCG1 develop smaller atherosclerotic lesions compared with controls. These data also suggest that Abcg1−/− mice may represent a new model in which to study the protective functions of B-1 B cells/NAbs and suggest novel targets for pharmacologic intervention and treatment of disease.
  •  
41.
  • Ballan, WM, et al. (författare)
  • Natural killer cells in perinatally HIV-1-infected children exhibit less degranulation compared to HIV-1-exposed uninfected children and their expression of KIR2DL3, NKG2C, and NKp46 correlates with disease severity
  • 2007
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 179:5, s. 3362-3370
  • Tidskriftsartikel (refereegranskat)abstract
    • NK cells play an integral role in the innate immune response by targeting virally infected and transformed cells with direct killing and providing help to adaptive responses through cytokine secretion. Whereas recent studies have focused on NK cells in HIV-1-infected adults, the role of NK cells in perinatally HIV-1-infected children is less studied. Using multiparametric flow cytometric analysis, we assessed the number, phenotype, and function of NK cell subsets in the peripheral blood of perinatally HIV-1-infected children on highly active antiretroviral therapy and compared them to perinatally exposed but uninfected children. We observed an increased frequency of NK cells expressing inhibitory killer Ig-like receptors in infected children. This difference existed despite comparable levels of total NK cells and NK cell subpopulations between the two groups. Additionally, NK cell subsets from infected children expressed, with and without stimulation, significantly lower levels of the degranulation marker CD107, which correlates with NK cell cytotoxicity. Lastly, increased expression of KIR2DL3, NKG2C, and NKp46 on NK cells correlated with decreased CD4+ T-lymphocyte percentage, an indicator of disease severity in HIV-1- infected children. Taken together, these results show that HIV-1-infected children retain a large population of cytotoxically dysfunctional NK cells relative to perinatally exposed uninfected children. This reduced function appears concurrently with distinct NK cell surface receptor expression and is associated with a loss of CD4+ T cells. This finding suggests that NK cells may have an important role in HIV-1 disease pathogenesis in HIV-1-infected children.
  •  
42.
  • Barthel, Diana, et al. (författare)
  • Haemophilus influenzae Uses the Surface Protein E To Acquire Human Plasminogen and To Evade Innate Immunity
  • 2012
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 188:1, s. 379-385
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Pathogenic microbes acquire the human plasma protein plasminogen to their surface. In this article, we characterize binding of this important coagulation regulator to the respiratory pathogen nontypeable Haemophilus influenzae and identify the Haemophilus surface protein E (PE) as a new plasminogen-binding protein. Plasminogen binds dose dependently to intact bacteria and to purified PE. The plasminogen-PE interaction is mediated by lysine residues and is also affected by ionic strength. The H. influenzae PE knockout strain (nontypeable H. influenzae 3655 Delta pe) bound plasminogen with similar to 65% lower intensity as compared with the wild-type, PE-expressing strain. In addition, PE expressed ectopically on the surface of Escherichia coli also bound plasminogen. Plasminogen, either attached to intact H. influenzae or bound to PE, was accessible for urokinase plasminogen activator. The converted active plasmin cleaved the synthetic substrate S-2251, and the natural substrates fibrinogen and C3b. Using synthetic peptides that cover the complete sequence of the PE protein, the major plasminogen-binding region was localized to a linear 28-aa-long N-terminal peptide, which represents aa 41-68. PE binds plasminogen and also vitronectin, and the two human plasma proteins compete for PE binding. Thus, PE is a major plasminogen-binding protein of the Gram-negative bacterium H. influenzae, and when converted to plasmin, PE-bound plasmin aids in immune evasion and contributes to bacterial virulence. The Journal of Immunology, 2012, 188: 379-385.
  •  
43.
  • Bas, Anna, et al. (författare)
  • Extrathymic TCR gene rearrangement in human small intestine : identification of new splice forms of recombination activating gene-1 mRNA with selective tissue expression.
  • 2003
  • Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 171:7, s. 3359-71
  • Tidskriftsartikel (refereegranskat)abstract
    • Two new 5'-untranslated region (5'UTR) exons were identified in the human gene for the lymphocyte-specific endonuclease recombination activating gene-1 (RAG1) required for the somatic recombination yielding functional Ag receptors. These 5'UTR exons were used in three different splice forms by jejunal lymphocytes of the T cell lineage. RAG1 mRNA containing the previously described 5'UTR exon was not expressed in these cells. Conversely, one of the new 5'UTR exons was not expressed in thymus. The new RAG1 mRNA splice forms were all expressed in immature T cells (CD2(+)CD7(+)CD3(-)). This cell population also expressed high levels of mRNA for the pre-T alpha-chain. In situ hybridization demonstrated jejunal cells expressing the new splice forms of RAG1 mRNA, both intraepithelially and in lamina propria. Pre-T alpha-chain mRNA-expressing cells were detected at the same sites. These results strongly suggest ongoing TCR gene rearrangement in human small intestinal mucosa, yielding T cells specially adapted for this environment. This seems to be achieved by two parallel processes, extrathymic T cell development and peripheral Ag-driven TCR editing.
  •  
44.
  • Batsalova, T, et al. (författare)
  • Mice producing less reactive oxygen species are relatively resistant to collagen glycopeptide vaccination against arthritis
  • 2010
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 185:5, s. 2701-2709
  • Tidskriftsartikel (refereegranskat)abstract
    • The bottleneck for the induction of collagen-induced arthritis in mice is the recognition of immunodominant type II collagen (CII) peptide (CII259-273) bound to the MHC class II molecule Aq. We have shown previously that the posttranslationally glycosylated lysine at position 264 in this epitope is of great importance for T cell recognition and tolerance induction to CII as well as for arthritis development. The Ncf1 gene, controlling oxidative burst, has been shown to play an important role for immune tolerance to CII. To investigate the effect of oxidation on the efficiency of immune-specific vaccination with MHC class II/glycosylated–CII peptide complexes, we used Ncf1 mutated mice. We demonstrate that normal reactive oxygen species (ROS) levels contribute to the establishment of tolerance and arthritis protection, because only mice with a functional oxidative burst were completely protected from arthritis after administration of the glycosylated CII259–273 peptide in complex with MHC class II. Transfer of T cells from vaccinated mice with functional Ncf1 protein resulted in strong suppression of clinical signs of arthritis in B10.Q mice, whereas the Ncf1 mutated mice as recipients had a weaker suppressive effect, suggesting that ROS modified the secondary rather than the primary immune response. A milder but still significant effect was also observed in ROS deficient mice. During the primary vaccination response, regulatory T cells, upregulation of negative costimulatory molecules, and increased production of anti-inflammatory versus proinflammatory cytokines in both Ncf1 mutated and wild type B10.Q mice was observed, which could explain the vaccination effect independent of ROS.
  •  
45.
  • Becanovic, K, et al. (författare)
  • Advanced intercross line mapping of Eae5 reveals Ncf-1 and CLDN4 as candidate genes for experimental autoimmune encephalomyelitis
  • 2006
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 176:10, s. 6055-6064
  • Tidskriftsartikel (refereegranskat)abstract
    • Eae5 in rats was originally identified in two F-2 intercrosses, (DA x BN) and (E3 X DA), displaying linkage to CNS inflammation and disease severity in experimental autoimmune encephalomyelitis (EAE), respectively. This region overlaps with an arthritis locus, Pia4, which was also identified in the (E3 X DA) cross. Two congenic strains, BN.DA-Eae5 and BN.DA-Eae5.R1, encompassing the previously described Eae5 and Pia4, were established. DA alleles within the chromosome 12 fragment conferred an increase in disease susceptibility as well as increased inflammation and demyelination in the CNS as compared with BN alleles. To enable a more precise fine mapping of EAE regulatory genes, we used a rat advanced intercross line between the EAE-susceptible DA strain and the EAE-resistant PVG.1AV1 strain. Linkage analysis performed in the advanced intercross line considerably narrowed down the myelin oligodendrocyte glycoprotein-EAE regulatory locus (Eae5) to a similar to 1.3-megabase region with a defined number of candidate genes. In this study we demonstrate a regulatory effect of Eae5 on MOG-EAE by using both congenic strains as well as fine mapping these effects to a region containing Ncf-1, a gene associated with arthritis. In addition to structural polymorphisms in Ncf-1, both sequence polymorphisms and expression differences were identified in CLDN4. CLDN4 is a tight junction protein involved in blood-brain barrier integrity. In conclusion, our data strongly suggests Ncf-1 to be a gene shared between two organ-specific inflammatory diseases with a possible contribution by CLDN4 in encephalomyelitis.
  •  
46.
  • Becanovic, K, et al. (författare)
  • New loci regulating rat myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis
  • 2003
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 170:2, s. 1062-1069
  • Tidskriftsartikel (refereegranskat)abstract
    • Myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease in rats that closely mimics many clinical and histopathological aspects of multiple sclerosis. Non-MHC quantitative trait loci regulating myelin oligodendrocyte glycoprotein-induced EAE have previously been identified in the EAE-permissive strain, DA, on rat chromosomes 4,10,15, and 18. To find any additional gene loci in another well-known EAE-permissive strain and thereby to assess any genetic heterogeneity in the regulation of the disease, we have performed a genome-wide linkage analysis in a reciprocal (LEW.1AV1 x PVG.1AV1) male/female F-2 population (n = 185). We examined reciprocal crosses, but no parent-of-origin effect was detected. The parental rat strains share the RT1(av1) MHC haplotype; thus, non-MHC genes control differences in EAE susceptibility. We identified Eae(16) on chromosome 8 and Eae17 on chromosome 13, significantly linked to EAE phenotypes. Two loci, on chromosomes 1 and 17, respectively showed suggestive linkage to clinical and histopathological EAE phenotypes. Eae16 and Eae17 differ from those found in previously studied strain combinations, thus demonstrating genetic heterogeneity of EAE. Furthermore, we detected a locus-specific parent-of-origin effect with suggestive linkage in Eae17. Further genetic and functional dissection of these loci may disclose critical disease-regulating molecular mechanisms.
  •  
47.
  • Bellner, Lars, 1973, et al. (författare)
  • A proinflammatory peptide from herpes simplex virus type 2 glycoprotein G affects neutrophil, monocyte, and NK cell functions
  • 2005
  • Ingår i: J Immunol. - : American Association of Immunologists. ; 174:4, s. 2235-2241
  • Tidskriftsartikel (refereegranskat)abstract
    • We have identified a synthetic peptide derived from the secreted portion of HSV type 2 glycoprotein G, denoted gG-2p20, which has proinflammatory properties in vitro. The gG-2p20 peptide, corresponding to aa 190-205 of glycoprotein G-2, was a chemoattractant for both monocytes and neutrophils in a dose-dependent fashion, and also induced the release of reactive oxygen from these cells. The receptor mediating the responses was identified as the formyl peptide receptor. The gG-2p20-induced activation of phagocytes had a profound impact on NK cell functions. The reactive oxygen species produced by gG-2p20-activated phagocytes both inhibited NK cell cytotoxicity and accelerated the apoptotic cell death in NK cell-enriched lymphocyte populations. Hence, we have for the first time been able to identify a potential function of the secreted portion of HSV-2 glycoprotein G. We propose that the proinflammatory gG-2p20 peptide identified could contribute to a reduced function and viability of NK cells during HSV-2 infection due to its ability to recruit and activate phagocytic cells.
  •  
48.
  • Bemark, Mats, 1967, et al. (författare)
  • A Unique Role of the Cholera Toxin A1-DD Adjuvant for Long-Term Plasma and Memory B Cell Development
  • 2011
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 186:3, s. 1399-1410
  • Tidskriftsartikel (refereegranskat)abstract
    • Adjuvants have traditionally been appreciated for their immunoenhancing effects, whereas their impact on immunological memory has largely been neglected. In this paper, we have compared three mechanistically distinct adjuvants: aluminum salts (Alum), Ribi (monophosphoryl lipid A), and the cholera toxin A1 fusion protein CTA1-DD. Their influence on long-term memory development was dramatically different. Whereas a single immunization i.p. with 4-hydroxy-3-nitrophenyl acetyl (NP)-chicken γ-globulin and adjuvant stimulated serum anti-NP IgG titers that were comparable at 5 wk, CTA1-DD–adjuvanted responses were maintained for >16 mo with a half-life of anti-NP IgG ∼36 wk, but <15 wk after Ribi or Alum. A CTA1-DD dose-dependent increase in germinal center (GC) size and numbers was found, with >60% of splenic B cell follicles hosting GC at an optimal CTA1-DD dose. Roughly 7% of these GC were NP specific. This GC-promoting effect correlated well with the persistence of long-term plasma cells in the bone marrow and memory B cells in the spleen. CTA1-DD also facilitated increased somatic hypermutation and affinity maturation of NP-specific IgG Abs in a dose-dependent fashion, hence arguing that large GC not only promotes higher Ab titers but also high-quality Ab production. Adoptive transfer of splenic CD80+, but not CD80−, B cells, at 1 y after immunization demonstrated functional long-term anti-NP IgG and IgM memory cells. To our knowledge, this is the first report to specifically compare and document that adjuvants can differ considerably in their support of long-term immune responses. Differential effects on the GC reaction appear to be the basis for these differences.
  •  
49.
  • Bendrik, Christina, et al. (författare)
  • Estradiol Increases IL-8 Secretion of Normal Human Breast Tissue and Breast Cancer In Vivo
  • 2009
  • Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 182:1, s. 371-378
  • Tidskriftsartikel (refereegranskat)abstract
    • IL-8 or CXCL8 has been associated with tumor angiogenesis, metastasis, and poor prognosis in breast cancer. Estrogen is crucial in breast carcinogenesis and tumor progression. Whether sex steroids affect IL-8 secretion of normal breast tissue or breast cancer is not known. Several cell types in a tissue secrete IL-8. Hence, regulatory mechanisms of IL-8 need to be investigated in whole tissue. We used microdialysis to sample IL-8 in normal human breast tissue in situ in pre- and postmenopausal women, preoperatively in breast cancers of women, and in experimental breast cancer in mice. We found a significant positive correlation between IL-8 and estradiol in normal breast tissue and hormone-dependent breast cancer in vivo. Ex vivo, estradiol exposure increased the IL-8 secretion of normal whole breast tissue in culture. In experimental breast cancer, estradiol increased IL-8 whereas the anti-estrogen tamoxifen inhibited the secretion of IL-8 both in vitro and extracellularly in vivo in tumors of nude mice. An anti-IL-8 Ab inhibited endothelial cell proliferation induced by cancer cell produced IL-8 and tumors with low IL-8 levels exhibited decreased angiogenesis. Our results strongly suggest that estradiol has a critical role in the regulation of IL-8 in normal human breast tissue and human breast cancer. IL-8 may present a novel therapeutic target for estrogen driven breast carcinogenesis and tumor progression.
  •  
50.
  • Bengtson, Per, et al. (författare)
  • Polymorphonuclear Leukocytes from Individuals Carrying the G329A Mutation in the α1,3-Fucosyltransferase VII Gene (FUT7) Roll on E- and P-Selectins
  • 2002
  • Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 169:7, s. 3940-3946
  • Tidskriftsartikel (refereegranskat)abstract
    • We recently identified several individuals carrying a missense mutation (G329A; Arg110-Gln) in the FUT7 gene encoding fucosyltransferase VII. This enzyme is involved in the biosynthesis of the sialyl Lewis x (Lex) epitope on human leukocytes, which has been identified as an important component of leukocyte ligands for E- and P-selectin. No enzyme activity was measurable in expression studies in COS-7 cells using the mutated FUT7 construct. One of the identified individuals carried this mutation homozygously. Flow cytometry analysis of polymorphonuclear leukocytes (PMN) from this individual showed a nearly complete absence of staining with mAbs directed against sialyl Lex and a diminished staining with an E-selectin IgG chimera. However, staining with P-selectin IgG chimera and Abs directed against P-selectin glycoprotein ligand-1 was not affected by the mutation. PMN from the homozygously mutated individual was further analyzed in an in vitro flow chamber assay. The number of rolling PMN and the rolling velocities on both E- and P-selectin were in the range of PMN from nonmutated individuals. FUT4 and FUT7 mRNA was quantified in PMN isolated from individuals carrying the FUT7 mutation. It was found that PMN from both FUT7 homozygously and heterozygously mutated individuals exhibited an elevated expression of FUT4 mRNA compared with PMN from FUT7 nonmutated individuals. The elevated expression of fucosyltransferase IV was reflected as an increased expression of the Lex and CD65s Ags on PMN from these individuals. The significance of the mutation was supported by transfection of BJAB cells.
  •  
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