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  • 1
    Online Resource
    Online Resource
    American Society for Clinical Investigation ; 2013
    In:  Journal of Clinical Investigation Vol. 123, No. 7 ( 2013-7-1), p. 2778-2780
    In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 123, No. 7 ( 2013-7-1), p. 2778-2780
    Type of Medium: Online Resource
    ISSN: 0021-9738
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2013
    detail.hit.zdb_id: 2018375-6
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  • 2
    Online Resource
    Online Resource
    Rockefeller University Press ; 2012
    In:  Journal of Experimental Medicine Vol. 209, No. 10 ( 2012-09-24), p. 1825-1840
    In: Journal of Experimental Medicine, Rockefeller University Press, Vol. 209, No. 10 ( 2012-09-24), p. 1825-1840
    Abstract: Dendritic cells (DCs) are best known for their ability to activate naive T cells, and emerging evidence suggests that distinct DC subsets induce specialized T cell responses. However, little is known concerning the role of DC subsets in the initiation of B cell responses. We report that antigen (Ag) delivery to DC-inhibitory receptor 2 (DCIR2) found on marginal zone (MZ)–associated CD8α− DCs in mice leads to robust class-switched antibody (Ab) responses to a T cell–dependent (TD) Ag. DCIR2+ DCs induced rapid up-regulation of multiple B cell activation markers and changes in chemokine receptor expression, resulting in accumulation of Ag-specific B cells within extrafollicular splenic bridging channels as early as 24 h after immunization. Ag-specific B cells primed by DCIR2+ DCs were remarkably efficient at driving naive CD4 T cell proliferation, yet DCIR2-induced responses failed to form germinal centers or undergo affinity maturation of serum Ab unless toll-like receptor (TLR) 7 or TLR9 agonists were included at the time of immunization. These results demonstrate DCIR2+ DCs have a unique capacity to initiate extrafollicular B cell responses to TD Ag, and thus define a novel division of labor among splenic DC subsets for B cell activation during humoral immune responses.
    Type of Medium: Online Resource
    ISSN: 1540-9538 , 0022-1007
    RVK:
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2012
    detail.hit.zdb_id: 1477240-1
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  • 3
    In: Immunity, Elsevier BV, Vol. 37, No. 2 ( 2012-08), p. 235-248
    Type of Medium: Online Resource
    ISSN: 1074-7613
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2012
    detail.hit.zdb_id: 2001966-X
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  • 4
    Online Resource
    Online Resource
    The American Association of Immunologists ; 2012
    In:  The Journal of Immunology Vol. 189, No. 6 ( 2012-09-15), p. 2758-2767
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 189, No. 6 ( 2012-09-15), p. 2758-2767
    Abstract: The interaction of CD28, which is constitutively expressed on T cells, with B7.1/B7.2 expressed on APCs is critical for T cell activation. CD28 is also expressed on murine and human plasma cells but its function on these cells remains unclear. There are two types of plasma cells: short-lived ones that appear in the secondary lymphoid tissue shortly after Ag exposure, and long-lived plasma cells that mainly reside in the bone marrow. We demonstrate that CD28-deficient murine short- and long-lived plasma cells produce significantly higher levels of Abs than do their wild-type counterparts. This was owing to both increased frequencies of plasma cells as well as increased Ab production per plasma cell. Plasma cells also express the ligand for CD28, B7.1, and B7.2. Surprisingly, deficiency of B7.1 and B7.2 in B cells also led to higher Ab levels, analogous to Cd28−/− plasma cells. Collectively, our results suggest that the CD28–B7 interaction operates as a key modulator of plasma cell function.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    RVK:
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    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2012
    detail.hit.zdb_id: 1475085-5
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  • 5
    Online Resource
    Online Resource
    The American Association of Immunologists ; 2010
    In:  The Journal of Immunology Vol. 184, No. 11 ( 2010-06-01), p. 6293-6298
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 184, No. 11 ( 2010-06-01), p. 6293-6298
    Abstract: Immunologic memory is a hallmark of the vertebrate immune system. The first antigenic exposure leads to a slow and modest immune response, whereas repeated exposure, even many years later, leads to a rapid and exaggerated response that is two to three orders of magnitude greater than the primary. In the case of humoral immunity, the increased efficacy of recall responses is due to the production of amplified levels of Ag-specific Ab, as well as the accelerated kinetics of their production. Current thinking suggests that this is due to selective activation of long-lived, Ag-specific memory B cells. A downside of restricting secondary responses solely to memory cells is that the repertoire of the memory B cell pool remains static while pathogens continue to evolve. In this study, we propose that during secondary responses, naive Ag-specific B cells participate alongside memory cells. We show that immune complexes formed in vivo between the Ag and pre-existing Abs from the primary response activate these naive B cells, inducing them to respond with accelerated kinetics and increased magnitude. Thus, the continued recruitment of new B cell clones after each antigenic exposure enables the immune system to stay abreast of rapidly changing pathogens.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    RVK:
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    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2010
    detail.hit.zdb_id: 1475085-5
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  • 6
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2012
    In:  Arthritis Research & Therapy Vol. 14, No. Suppl 4 ( 2012), p. S1-
    In: Arthritis Research & Therapy, Springer Science and Business Media LLC, Vol. 14, No. Suppl 4 ( 2012), p. S1-
    Type of Medium: Online Resource
    ISSN: 1478-6354
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2012
    detail.hit.zdb_id: 2041668-4
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  • 7
    Online Resource
    Online Resource
    Rockefeller University Press ; 2013
    In:  Journal of Experimental Medicine Vol. 210, No. 10 ( 2013-09-23), p. 2135-2146
    In: Journal of Experimental Medicine, Rockefeller University Press, Vol. 210, No. 10 ( 2013-09-23), p. 2135-2146
    Abstract: Antigen (Ag) targeting is an efficient way to induce immune responses. Ag is usually coupled to an antibody (Ab) specific for a receptor expressed on dendritic cells (DCs), and then the Ag–anti-receptor is inoculated with an adjuvant. Here we report that targeting Ag to a receptor expressed on both B cells and DCs, the TLR orphan receptor CD180, in the absence of adjuvant rapidly induced IgG responses that were stronger than those induced by Ag in alum. Ag conjugated to anti-CD180 (Ag-αCD180) induced affinity maturation and Ab responses that were partially T cell independent, as Ag-specific IgGs were generated in CD40- and T cell–deficient mice. After preimmunization with Ag-αCD180 and boosting with soluble Ag, both WT and CD40 knockout (KO) mice rapidly produced Ag-specific IgG-forming cells, demonstrating that Ag–anti-CD180 induces immunological memory. The potent adjuvant effect of Ag-αCD180 required Ag to be coupled to anti-CD180 and the responsive B cells to express both CD180 and an Ag-specific B cell receptor. Surprisingly, CD180 Ag targeting also induced IgG Abs in BAFF-R KO mice lacking mature B cells and in mice deficient in interferon signaling. Targeting Ag to CD180 may be useful for therapeutic vaccination and for vaccinating the immune compromised.
    Type of Medium: Online Resource
    ISSN: 1540-9538 , 0022-1007
    RVK:
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2013
    detail.hit.zdb_id: 1477240-1
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  • 8
    In: Journal of Experimental Medicine, Rockefeller University Press, Vol. 210, No. 12 ( 2013-11-18), p. 2773-2789
    Abstract: Toll-like receptor (TLR), a ligand for single-stranded RNA, has been implicated in the development of pathogenic anti-RNA autoantibodies both in systemic lupus erythematous (SLE) patients and in murine models of lupus. It is still unclear, however, where and how TLR7-mediated interactions affect the development of autoreactive B cells. We found that overexpression of TLR7 in transgenic mice (TLR7.1Tg) leads to marked alterations of transitional (T1) B cells, associated with their expansion and proliferation within the splenic red pulp (RP). This phenotype was intrinsic to the T1 subset of B cells and occurred independently of type 1 IFN signals. Overexpression of RNase in TLR7.1Tg mice significantly limited the expansion and proliferation of T1 cells, indicating that endogenous RNA complexes are driving their activation. TLR7.1Tg T1 cells were hyper-responsive to anti-IgM and TLR7 ligand stimulation in vitro and produced high concentrations of class-switched IgG2b and IgG2c, including anti-RNA antibodies. Our results demonstrate that initial TLR7 stimulation of B cells occurs at the T1 stage of differentiation in the splenic RP and suggest that dysregulation of TLR7 expression in T1 cells can result in production of autoantibodies.
    Type of Medium: Online Resource
    ISSN: 1540-9538 , 0022-1007
    RVK:
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2013
    detail.hit.zdb_id: 1477240-1
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  • 9
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 192, No. 12 ( 2014-06-15), p. 5789-5801
    Abstract: The C-type lectin receptor blood dendritic cell Ag 2 (BDCA2) is expressed exclusively on human plasmacytoid DCs (pDCs) and plays a role in Ag capture, internalization, and presentation to T cells. We used transgenic mice that express human BDCA2 and anti-BDCA2 mAbs to deliver Ags directly to BDCA2 on pDCs in vivo. Targeting Ag to pDCs in this manner resulted in significant suppression of Ag-specific CD4+ T cell and Ab responses upon secondary exposure to Ag in the presence of adjuvant. Suppression of Ab responses required both a decrease in effector CD4+ T cells and preservation of Foxp3+ regulatory T cells (Tregs). Reduction in Treg numbers following Ag delivery to BDCA2 restored both CD4+ T cell activation and Ab responses, demonstrating that Tregs were required for the observed tolerance. Our results demonstrate that Ag delivery to pDCs through BDCA2 is an effective method to induce immunological tolerance, which may be useful for treating autoimmune diseases or to inhibit unwanted Ab responses.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    RVK:
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    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2014
    detail.hit.zdb_id: 1475085-5
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  • 10
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2014
    In:  International Immunology Vol. 26, No. 1 ( 2014-01-01), p. 3-11
    In: International Immunology, Oxford University Press (OUP), Vol. 26, No. 1 ( 2014-01-01), p. 3-11
    Abstract: Delivering antigens in vivo by coupling them to mAbs specific for unique receptors on antigen-presenting cells (APCs) is a promising approach for modulating immune responses. Antigen delivery to receptors found on myeloid dendritic cell (DC) subsets, plasmacytoid DCs and B cells has shown them all to be viable targets to stimulate either the cellular or humoral arms of the immune system. It is now evident that antigen-targeting approaches can also be used to invoke antigen-specific inhibition of immune responses. The outcome of activation versus inhibition is determined by a combination of factors that include the choice of APC, the receptor that is targeted, whether to include an adjuvant and, if so, which adjuvant to employ. In addition to their use as a means to modulate immune responses, antigen-targeting systems are also a useful method to investigate the function of DC subsets and the early mechanistic events that underlie the initiation of both cellular and humoral immune responses. In this review, we focus on the literature surrounding the control of B-cell responses when antigen is delivered to various APC subsets.
    Type of Medium: Online Resource
    ISSN: 1460-2377 , 0953-8178
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2014
    detail.hit.zdb_id: 1467474-9
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