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  • The American Association of Immunologists  (7)
  • 1
    Online Resource
    Online Resource
    Mcl-1-Mediated Impairment of the Intrinsic Apoptosis Pathway in Circulating Neutrophils from Critically Ill Patients Can Be Overcome by Fas Stimulation
    The American Association of Immunologists ; 2009
    In:  The Journal of Immunology Vol. 183, No. 10 ( 2009-11-15), p. 6198-6206
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 183, No. 10 ( 2009-11-15), p. 6198-6206
    Abstract: The systemic inflammatory response syndrome and subsequent organ failure are mainly driven by activated neutrophils with prolonged life span, which is believed to be due to apoptosis resistance. However, detailed underlying mechanisms leading to neutrophil apoptosis resistance are largely unknown, and possible therapeutic options to overcome this resistance do not exist. Here we report that activated neutrophils from severely injured patients exhibit cell death resistance due to impaired activation of the intrinsic apoptosis pathway, as evidenced by limited staurosporine-induced mitochondrial membrane depolarization and decreased caspase-9 activity. Moreover, we found that these neutrophils express high levels of antiapoptotic Mcl-1 and low levels of proapoptotic Bax protein. Mcl-1 up-regulation was dependent on elevated concentrations of GM-CSF in patient serum. Accordingly, increased Mcl-1 protein stability and GM-CSF serum concentrations were shown to correlate with staurosporine-induced apoptosis resistance. However, cross-linking of neutrophil Fas by immobilized agonistic anti-Fas IgM resulted in caspase-dependent mitochondrial membrane depolarization and apoptosis induction. In conclusion, the observed impairment of the intrinsic pathway and the resulting apoptosis resistance may be overcome by immobilized agonistic anti-Fas IgM. Targeting of neutrophil Fas by immobilized agonistic effector molecules may represent a new therapeutic tool to limit neutrophil hyperactivation and its sequelae in patients with severe immune disorders.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.0901264
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2009
    detail.hit.zdb_id: 1475085-5
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  • 2
    Online Resource
    Online Resource
    Potentially neutralizing B cell clonotypes are eliminated at peripheral selection checkpoints (LYM6P.768)
    The American Association of Immunologists ; 2014
    In:  The Journal of Immunology Vol. 192, No. 1_Supplement ( 2014-05-01), p. 131.5-131.5
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 192, No. 1_Supplement ( 2014-05-01), p. 131.5-131.5
    Abstract: B lymphocyte stimulator (BLyS) signals via BR3 mediate selection and survival in the transitional, mature, and germinal center B cell pools. We have previously shown that treatment of mice with exogenous BLyS prior to immunization with HIV-1 envelope (Env) trimers improves neutralizing antibody breadth and potency. We are therefore investigating the hypothesis that broadly neutralizing B cell clonotypes are rare because of counter-selection at the transitional or germinal center checkpoints. Here we show that Env-specific murine B cells in pre-immune, germinal center, and memory B cell subsets can be visualized and tracked by flow cytometry using a biotinylated Env probe. Initial results indicate loss of Env+ B cells at both the transitional developmental stage and in the germinal center following immunization. As a first step in testing the feasibility of a BLyS pre-immunization treatment approach in nonhuman primates, we show that BLyS enhances survival of quiescent and dividing rhesus macaque B cells in vitro.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.192.Supp.131.5
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2014
    detail.hit.zdb_id: 1475085-5
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  • 3
    Online Resource
    Online Resource
    Age-Associated B Cells Express a Diverse Repertoire of VH and Vκ Genes with Somatic Hypermutation
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 198, No. 5 ( 2017-03-01), p. 1921-1927
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 5 ( 2017-03-01), p. 1921-1927
    Abstract: The origin and nature of age-associated B cells (ABCs) in mice are poorly understood. In this article, we show that their emergence required MHC class II and CD40/CD40L interactions. Young donor B cells were adoptively transferred into congenic recipients and allowed to remain for 1 mo in the absence of external Ag. B cells expressing the T-bet transcription factor, a marker for ABCs, were generated after multiple cell divisions from C57BL/6 donors but not from MHC class II– or CD40-deficient donors. Furthermore, old CD154 (CD40L)-deficient mice did not accrue ABCs, confirming that they arise primarily through T-dependent interactions. To determine what Igs ABCs express, we sequenced VH and Vκ rearranged genes from unimmunized 22-mo-old C57BL/6 mice and showed that they had a heterogeneous repertoire, which was comparable to that seen in old follicular and marginal zone B cell subsets. However, in contrast to the follicular and marginal zone cells, ABCs displayed significant somatic hypermutation. The mutation frequency was lower than found in germinal center cells after deliberate immunization, suggesting that ABCs have undergone mild stimulation from endogenous Ags over time. These observations show that quiescent ABCs are Ag-experienced cells that accumulate during T cell–dependent responses to diverse Ags during the life of an individual.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1601106
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
    detail.hit.zdb_id: 1475085-5
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  • 4
    Online Resource
    Online Resource
    NF-κB Links CO2 Sensing to Innate Immunity and Inflammation in Mammalian Cells
    The American Association of Immunologists ; 2010
    In:  The Journal of Immunology Vol. 185, No. 7 ( 2010-10-01), p. 4439-4445
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 185, No. 7 ( 2010-10-01), p. 4439-4445
    Abstract: Molecular O2 and CO2 are the primary substrate and product of aerobic metabolism, respectively. Levels of these physiologic gases in the cell microenvironment vary dramatically both in health and in diseases, such as chronic inflammation, ischemia, and cancer, in which metabolism is significantly altered. The identification of the hypoxia-inducible factor led to the discovery of an ancient and direct link between tissue O2 and gene transcription. In this study, we demonstrate that mammalian cells (mouse embryonic fibroblasts and others) also sense changes in local CO2 levels, leading to altered gene expression via the NF-κB pathway. IKKα, a central regulatory component of NF-κB, rapidly and reversibly translocates to the nucleus in response to elevated CO2. This response is independent of hypoxia-inducible factor hydroxylases, extracellular and intracellular pH, and pathways that mediate acute CO2-sensing in nematodes and flies and leads to attenuation of bacterial LPS-induced gene expression. These results suggest the existence of a molecular CO2 sensor in mammalian cells that is linked to the regulation of genes involved in innate immunity and inflammation.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1000701
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2010
    detail.hit.zdb_id: 1475085-5
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  • 5
    Online Resource
    Online Resource
    Decreased Neutrophil Adhesion to Human Cytomegalovirus-Infected Retinal Pigment Epithelial Cells Is Mediated by Virus-Induced Up-Regulation of Fas Ligand Independent of Neutrophil Apoptosis
    The American Association of Immunologists ; 2000
    In:  The Journal of Immunology Vol. 165, No. 8 ( 2000-10-15), p. 4405-4413
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 165, No. 8 ( 2000-10-15), p. 4405-4413
    Abstract: Human CMV (HCMV) retinitis frequently leads to blindness in iatrogenically immunosuppressed patients and in the end stage of AIDS. Despite the general proinflammatory potential of HCMV, virus infection is associated with a rather mild cellular inflammatory response in the retina. To investigate this phenomenon, the influence of HCMV (strains AD169 or Hi91) infection on C-X-C chemokine secretion, ICAM-1 expression, and neutrophil recruitment in cultured human retinal pigment epithelial (RPE) cells was studied. Supernatants from infected cultures contained enhanced levels of IL-8 and melanoma growth-stimulating activity/Gro α and induced neutrophil chemotaxis compared with supernatants from uninfected RPE cells. Despite HCMV-induced ICAM-1 expression on RPE cells, binding of activated neutrophils to HCMV-infected RPE cells and subsequent transepithelial penetration were significantly reduced. Reduced neutrophil adhesion to infected RPE cells correlated with HCMV-induced up-regulation of constitutive Fas ligand (FasL) expression. Functional blocking of FasL on RPE cells with the neutralizing mAbs NOK-1 and NOK-2 or of the Fas receptor on neutrophils with mAbB-D29 prevented the HCMV-induced impairment of neutrophil/RPE interactions. Fas-FasL-dependent impairment of neutrophil binding had occurred by 10 min after neutrophil/RPE coculture without apoptotic signs. Neutrophil apoptosis was first detected after 4 h. Treatment of neutrophils with a specific inhibitor of caspase-8 suppressed apoptosis, whereas it did not prevent impaired neutrophil binding to infected RPE. The current results suggest a novel role for FasL in the RPE regulation of neutrophil binding. This may be an important feature of virus escape mechanisms and for sustaining the immune-privileged character of the retina during HCMV ocular infection.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.165.8.4405
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2000
    detail.hit.zdb_id: 1475085-5
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  • 6
    Online Resource
    Online Resource
    A B cell subset uniquely responsive to innate stimuli accumulates in aged mice (45.7)
    The American Association of Immunologists ; 2011
    In:  The Journal of Immunology Vol. 186, No. 1_Supplement ( 2011-04-01), p. 45.7-45.7
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 186, No. 1_Supplement ( 2011-04-01), p. 45.7-45.7
    Abstract: We have discovered a functionally distinct mature B cell subset that accumulates with age, comprising up to 30% of all mature B cells by 22 months. Despite sharing some features with other mature B cell subsets, these cells are refractory to BCR and CD40 stimulation. Instead, they respond to TLR-9 stimulation and divide maximally upon combined BCR and TLR ligation. Although similar to follicular B cells in both BLyS receptor expression and BLyS binding capacity, these cells do not rely upon BLyS for survival. Further, they are not the result of intrinsically altered B lymphopoiesis in aged bone marrow, but instead appear to be gradually generated from a small subset of mature B cells that exhaustively expand throughout the individual’s lifetime. Thus, while the magnitude of the mature primary B cell niche is maintained with age, it is increasingly populated by cells refractory to BCR-driven activation yet responsive to innate receptor stimulation. This shift may contribute to the diminished capacity for adaptive humoral responses and increased propensity for autoimmunity associated with aging.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.186.Supp.45.7
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2011
    detail.hit.zdb_id: 1475085-5
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  • 7
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    Online Resource
    Human Cytomegalovirus Circumvents NF-κB Dependence in Retinal Pigment Epithelial Cells
    The American Association of Immunologists ; 2001
    In:  The Journal of Immunology Vol. 167, No. 4 ( 2001-08-15), p. 1900-1908
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 167, No. 4 ( 2001-08-15), p. 1900-1908
    Abstract: The human CMV (HCMV) is a persistent virus that may cause severe inflammatory responses especially in immunocompromised hosts. In different cell types, HCMV infection leads to the activation of the pleiotropic transcription factor, NF-κB, which triggers virus replication but also propagates cell-mediated inflammatory mechanisms that largely depend on PG synthesis. We investigated the interactions of HCMV and the NF-κB-dependent PG synthesis pathway in cultures of retinal pigment epithelial (RPE) cells that are known to be infected in HCMV retinitis patients. Unlike in other cell types, HCMV increased neither NF-κB activity nor p65 and p105/50 mRNA levels in RPE cells. Both TNF-α and phorbol ester 12,0-tetradecanoylphorbol 13-acetate (TPA) enhanced NF-κB activity but only TPA increased HCMV replication. Cyclooxygenase-2 expression and PGE2 release was increased by TPA and TNF-α but not by HCMV infection. Stimulatory activity of TPA on HCMV replication was suppressed by protein kinase C inhibitors and inhibitors of p42/44 and p38 mitogen-activated protein kinases but not by NF-κB inhibitors. In conclusion, HCMV circumvents the NF-κB route in favor of the protein kinase C-dependent mitogen-activated protein kinase pathway in RPE cells. This virus/host cell interaction might be a mechanism that promotes HCMV persistence in immune-privileged organs such as the eye.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.167.4.1900
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2001
    detail.hit.zdb_id: 1475085-5
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