The Experts below are selected from a list of 321 Experts worldwide ranked by ideXlab platform

Michael C Carroll - One of the best experts on this subject based on the ideXlab platform.

  • Follicular Dendritic Cells modulate germinal center b cell diversity through fcγriib
    Cell Reports, 2019
    Co-Authors: Cees E Van Der Poel, Goran Bajic, Charles Macaulay, Theo Van Den Broek, Christian Ellson, Gerben Bouma, Gabriel D Victora, Soren E Degn, Michael C Carroll
    Abstract:

    Follicular Dendritic Cells (FDCs), a rare and enigmatic stromal cell type in the B cell follicles of secondary lymphoid organs, store and present antigen to B Cells. While essential for germinal center (GC) responses, their exact role during GC B cell selection remains unknown. FDCs upregulate the inhibitory IgG Fc receptor FcγRIIB during GC formation. We show that the stromal deficiency of FcγRIIB does not affect GC B cell frequencies compared to wild-type mice. However, in the absence of FcγRIIB on FDCs, GCs show aberrant B cell selection during autoreactive and selective foreign antigen responses. These GCs are more diverse as measured by the AidCreERT2 -confetti system and show the persistence of IgM+ clones with decreased numbers of IgH mutations. Our results show that FDCs can modulate GC B cell diversity by the upregulation of FcγRIIB. Permissive clonal selection and subsequent increased GC diversity may affect epitope spreading during autoimmunity and foreign responses.

  • the role of Dendritic Cells in s pneumoniae transport to Follicular Dendritic Cells
    Cell Reports, 2016
    Co-Authors: Balthasar A. Heesters, Michael C Carroll
    Abstract:

    Summary Affinity-mature B Cells require cognate antigen, retained by Follicular Dendritic Cells (FDCs), for clonal selection within germinal centers. Studies on how FDCs in lymphoid tissues acquire antigen have relied primarily on model protein antigens. To examine delivery of intact bacteria to FDCs, we used inactivated Streptococcus pneumonia (SP). We found that both medullary macrophages and a subset of SIGN-R1-positive Dendritic Cells (DCs) in the lymph node capture SP from the draining afferent lymphatics. The presence of DCs is required for initial complement activation, opsonization of the bacteria, and efficient transport of SP to FDCs. Moreover, we observed a major role for transport of bacteria to FDCs by naive B Cells via a CD21-dependent pathway. We propose a mechanism by which efficient transport of SP to FDCs is dependent on DCs for initial binding and activation of complement and either direct transport to FDCs or transfer to naive B Cells.

  • Follicular Dendritic Cells Retain Infectious HIV in Cycling Endosomes
    PLOS Pathogens, 2015
    Co-Authors: Balthasar A. Heesters, Marcus Altfeld, Parsia A. Vagefi, Eileen P. Scully, Frank A. Schildberg, Daniel Kaufmann, Madelene Lindqvist, Bruce D. Walker, Michael C Carroll
    Abstract:

    Despite the success of antiretroviral therapy (ART), it does not cure Human Immunodeficiency Virus (HIV) and discontinuation results in viral rebound. Follicular Dendritic Cells (FDC) are in direct contact with CD4+ T Cells and they retain intact antigen for prolonged periods. We found that human FDC isolated from patients on ART retain infectious HIV within a non-degradative cycling compartment and transmit infectious virus to uninfected CD4 T Cells in vitro. Importantly, treatment of the HIV+ FDC with a soluble complement receptor 2 purges the FDC of HIV virions and prevents viral transmission in vitro. Our results provide an explanation for how FDC can retain infectious HIV for extended periods and suggest a therapeutic strategy to achieve cure in HIV-infected humans.

  • do Follicular Dendritic Cells regulate lupus specific b Cells
    Molecular Immunology, 2014
    Co-Authors: Balthasar A. Heesters, Michael C Carroll, Abhishek Das, Priyadarshini Chatterjee
    Abstract:

    The factors that allow self-reactive B Cells to escape negative selection and become activated remain poorly defined. In this review we describe recently published results in which a B cell receptor-knock-in mouse strain specific for nucleolar self-antigens was bred with mice deficient in complement C4 and discuss the implications for the lupus field. Absence of C4 leads to a breakdown in the elimination of autoreactive B cell clones at the transitional stage. This is characterized by a relative increase in their response to a range of stimuli, entrance into follicles and a greater propensity to form self-reactive germinal centers. In this review, a model is proposed in which, in the absence of complement C4, inappropriate clearance of apoptotic debris promotes chronic activation of myeloid Cells and Follicular Dendritic Cells, resulting in secretion of Type I interferon. This allows for the maturation and activation of self-reactive B cell clones leading to increased spontaneous formation of germinal centers and subsequent generation of autoantibodies.

  • Follicular Dendritic Cells: dynamic antigen libraries
    Nature Reviews Immunology, 2014
    Co-Authors: Balthasar A. Heesters, Riley C. Myers, Michael C Carroll
    Abstract:

    Follicular Dendritic Cells (FDCs) are essential for high-affinity antibody production and for the development of B cell memory. Historically, FDCs have been characterized as 'accessory' Cells that passively support germinal centre (GC) responses. However, recent observations suggest that FDCs actively shape humoral immunity. In this Review, we discuss recent findings concerning the antigen acquisition and retention functions of FDCs, and relevant implications for protective immunity. Furthermore, we describe the roles of FDCs within GCs in secondary lymphoid organs and discuss FDC development within this dynamic environment. Finally, we discuss how a better understanding of FDCs could facilitate the design of next-generation vaccines. Follicular Dendritic Cells (FDCs) in lymph nodes support the development of high-affinity antibody responses by retaining antigens at their cell surface for long periods of time. Although FDCs are generally regarded as 'accessory Cells' in the germinal centre, recent data suggest that they have more active roles in the development of humoral immune responses. This Review focuses on our current understanding of FDCs. Follicular Dendritic Cells (FDCs) are non-haematopoietic Cells that are of stromal origin. They are integrated into the continuous stromal network within lymphoid organs. FDCs can acquire antigen through multiple pathways; small antigens flow through conduits directly to the FDCs, whereas larger antigens are transported to FDCs by B Cells in a complement-dependent manner. Acquired antigens are retained in their native form by FDCs for long periods of time. The antigens are protected from damage by storage in non-degradative endosomal vesicles that periodically cycle to the cell surface. Retention and concentration of antigen by FDCs is important for an efficient germinal centre reaction, especially under conditions of limited antigen availability. Toll-like receptor signalling in FDCs may affect their functions, such as their retention and cycling of antigen. HIV might hijack the cycling mechanism of FDCs in order to evade the immune system, which makes FDCs unique as a non-infected cell that is also an infectious reservoir of the virus.

Adriano Aguzzi - One of the best experts on this subject based on the ideXlab platform.

  • Follicular Dendritic Cells: origin, phenotype, and function in health and disease
    Trends in immunology, 2013
    Co-Authors: Adriano Aguzzi, Jan Kranich, Nike J. Krautler
    Abstract:

    Follicular Dendritic Cells (FDCs) were originally identified by their specific morphology and by their ability to trap immune-complexed antigen in B cell follicles. By virtue of the latter as well as the provision of chemokines, adhesion molecules, and trophic factors, FDCs participate in the shaping of B cell responses. Importantly, FDCs also supply tingible body macrophages (TBMs) with the eat-me-signaling molecule milk fat globule-EGF factor 8 (Mfge8), thereby enabling the disposal of apoptotic B Cells. Recent studies have provided fundamental insights into the multiple functions of FDCs in both physiological and pathophysiological contexts and into their origin. Here we review these findings, and discuss current concepts related to FDC histogenesis both in lymphoid organs and in inflammatory lymphoneogenesis.

  • positioning of Follicular Dendritic Cells within the spleen controls prion neuroinvasion
    Nature, 2003
    Co-Authors: Marco Prinz, Petra Schwarz, Markus Glatzel, Mathias Heikenwalder, Tobias Junt, Frank L Heppner, Martin Lipp, Adriano Aguzzi
    Abstract:

    Peripheral infection is the natural route of transmission in most prion diseases. Peripheral prion infection is followed by rapid prion replication in lymphoid organs, neuroinvasion and progressive neurological disease. Both immune Cells and nerves are involved in pathogenesis, but the mechanisms of prion transfer from the immune to the nervous system are unknown. Here we show that ablation of the chemokine receptor CXCR5 juxtaposes Follicular Dendritic Cells (FDCs) to major splenic nerves, and accelerates the transfer of intraperitoneally administered prions into the spinal cord. Neuroinvasion velocity correlated exclusively with the relative locations of FDCs and nerves: transfer of CXCR5-/- bone marrow to wild-type mice induced perineural FDCs and enhanced neuroinvasion, whereas reciprocal transfer to CXCR5-/- mice abolished them and restored normal efficiency of neuroinvasion. Suppression of lymphotoxin signalling depleted FDCs, abolished splenic infectivity, and suppressed acceleration of pathogenesis in CXCR5-/- mice. This suggests that prion neuroimmune transition occurs between FDCs and sympathetic nerves, and relative positioning of FDCs and nerves controls the efficiency of peripheral prion infection.

  • lymph nodal prion replication and neuroinvasion in mice devoid of Follicular Dendritic Cells
    Proceedings of the National Academy of Sciences of the United States of America, 2002
    Co-Authors: Marco Prinz, Fabio Montrasio, Michael A Klein, Petra Schwarz, Josef Priller, Bernhard Odermatt, Klaus Pfeffer, Adriano Aguzzi
    Abstract:

    Variant Creutzfeldt–Jakob disease and scrapie are typically initiated by extracerebral exposure to prions, and exhibit early prion accumulation in germinal centers. Follicular Dendritic Cells (FDCs), whose development and maintenance in germinal centers depends on tumor necrosis factor (TNF) and lymphotoxin (LT) signaling, are thought to be indispensable for extraneural prion pathogenesis. Here, we administered prions intraperitoneally to mice deficient for TNF and LT signaling components. LTα−/−, LTβ−/−, LTβR−/−, and LTα−/− × TNFα−/− mice resisted infection and contained no infectivity in spleens and lymph nodes (when present). However, TNFR1−/−, TNFR2−/−, and some TNFα−/− mice developed scrapie similarly to wild-type mice. High prion titers were detected in lymph nodes, but not spleens, of TNFR1−/− and TNFα−/− mice despite absence of FDCs and germinal centers. Transfer of TNFR1−/− fetal liver Cells into lethally irradiated Prnp0/0 mice restored infectivity mainly in lymph nodes. Prion protein (PrP) colocalized with a minority of macrophages in tumor necrosis factor receptor (TNFR) 1−/− lymph nodes. Therefore, prion pathogenesis can be restricted to lymphoreticular subcompartments, and mature Follicular Dendritic Cells are dispensable for this process. Macrophage subsets are plausible candidates for lymphoreticular prion pathogenesis and neuroinvasion in the absence of FDCs, and may represent a novel target for postexposure prophylaxis.

  • impaired prion replication in spleens of mice lacking functional Follicular Dendritic Cells
    Science, 2000
    Co-Authors: Fabio Montrasio, Fabienne Mackay, Michael A Klein, Adriano Aguzzi, Rico Frigg, Markus Glatzel, Charles Weissmann
    Abstract:

    In scrapie-infected mice, prions are found associated with splenic but not circulating B and T lymphocytes and in the stroma, which contains Follicular Dendritic Cells (FDCs). Formation and maintenance of mature FDCs require the presence of B Cells expressing membrane-bound lymphotoxin-alpha/beta. Treatment of mice with soluble lymphotoxin-beta receptor results in the disappearance of mature FDCs from the spleen. We show that this treatment abolishes splenic prion accumulation and retards neuroinvasion after intraperitoneal scrapie inoculation. These data provide evidence that FDCs are the principal sites for prion replication in the spleen.

Nike J. Krautler - One of the best experts on this subject based on the ideXlab platform.

  • How Follicular Dendritic Cells shape the B-cell antigenome
    Frontiers in Immunology, 2016
    Co-Authors: Jan Kranich, Nike J. Krautler
    Abstract:

    Follicular Dendritic Cells (FDCs) are stromal Cells residing in primary follicles and in germinal centers of secondary and tertiary lymphoid organs (SLOs and TLOs). There, they play a crucial role in B-cell activation and affinity maturation of antibodies. FDCs have the unique capacity to bind and retain native antigen in B-cell follicles for long periods of time. Therefore, FDCs shape the B-cell antigenome (the sum of all B-cell antigens) in SLOs and TLOs. In this review we discuss recent findings that explain, how this stromal cell type can arise in almost any tissue during TLO formation and, furthermore focus on the mechanisms of antigen capture and retention involved in the generation of long-lasting antigen depots displayed on FDCs.

  • Follicular Dendritic Cells: origin, phenotype, and function in health and disease
    Trends in immunology, 2013
    Co-Authors: Adriano Aguzzi, Jan Kranich, Nike J. Krautler
    Abstract:

    Follicular Dendritic Cells (FDCs) were originally identified by their specific morphology and by their ability to trap immune-complexed antigen in B cell follicles. By virtue of the latter as well as the provision of chemokines, adhesion molecules, and trophic factors, FDCs participate in the shaping of B cell responses. Importantly, FDCs also supply tingible body macrophages (TBMs) with the eat-me-signaling molecule milk fat globule-EGF factor 8 (Mfge8), thereby enabling the disposal of apoptotic B Cells. Recent studies have provided fundamental insights into the multiple functions of FDCs in both physiological and pathophysiological contexts and into their origin. Here we review these findings, and discuss current concepts related to FDC histogenesis both in lymphoid organs and in inflammatory lymphoneogenesis.

  • Follicular Dendritic Cells emerge from ubiquitous perivascular precursors
    Cell, 2012
    Co-Authors: Nike J. Krautler, Jan Kranich, Jeffrey L Browning, Petra Schwarz, Veronika Kana, Yinghua Tian, Dushan Perera, Doreen Lemm, Annika Armulik, Michelle D Tallquist
    Abstract:

    The differentiation of Follicular Dendritic Cells (FDC) is essential to the remarkable microanatomic plasticity of lymphoid follicles. Here we show that FDC arise from ubiquitous perivascular precursors (preFDC) expressing platelet-derived growth factor receptor β (PDGFRβ). PDGFRβ-Cre-driven reporter gene recombination resulted in FDC labeling, whereas conditional ablation of PDGFRβ(+)-derived Cells abolished FDC, indicating that FDC originate from PDGFRβ(+) Cells. Lymphotoxin-α-overexpressing prion protein (PrP)(+) kidneys developed PrP(+) FDC after transplantation into PrP(-) mice, confirming that preFDC exist outside lymphoid organs. Adipose tissue-derived PDGFRβ(+) stromal-vascular Cells responded to FDC maturation factors and, when transplanted into lymphotoxin β receptor (LTβR)(-) kidney capsules, differentiated into Mfge8(+)CD21/35(+)FcγRIIβ(+)PrP(+) FDC capable of trapping immune complexes and recruiting B Cells. Spleens of lymphocyte-deficient mice contained perivascular PDGFRβ(+) FDC precursors whose expansion required both lymphoid tissue inducer (LTi) Cells and lymphotoxin. The ubiquity of preFDC and their strategic location at blood vessels may explain the de novo generation of organized lymphoid tissue at sites of lymphocytic inflammation.

  • Characterizing Follicular Dendritic Cells: A progress report
    European Journal of Immunology, 2010
    Co-Authors: Adriatic Aguzzi, Nike J. Krautler
    Abstract:

    In 1965, Mitchell and Abbot (Mitchell, J. and Abbot A, Nature 1965. 30: 500-502) discovered peculiar Cells with filiform processes, which were capable of capturing and retaining antigens within secondary lymphoid organs. Yet half a century since the first description of Follicular Dendritic Cells (FDC), their function and their histogenesis remain largely mysterious. FDC are thought to help with organization of the lymphoid follicles, to facilitate the germinal center reaction by presenting antigen to B Cells, and to legislate the engulfment of apoptotic bodies, but it has proved difficult to stringently verify any of these functions. One reason for such slow progress is a dearth of markers specific to FDC and their precursors, which limits our ability to isolate, target, and follow FDC. Here we review the current state of FDC science with specific reference to a study in this issue of the European Journal of Immunology and its efforts in discovering new FDC markers.

John G. Tew - One of the best experts on this subject based on the ideXlab platform.

  • activation of b Cells by antigens on Follicular Dendritic Cells
    Trends in Immunology, 2010
    Co-Authors: Mohey Eldin El M Shikh, Andras K. Szakal, Rania El M Sayed, Selvakumar Sukumar, John G. Tew
    Abstract:

    A need for antigen-processing and presentation to B Cells is not widely appreciated. However, cross-linking of multiple B cell receptors (BCRs) by T-independent antigens delivers a potent signal that induces antibody responses. Such BCR cross-linking also occurs in germinal centers where Follicular Dendritic Cells (FDCs) present multimerized antigens as periodically arranged antigen-antibody complexes (ICs). Unlike T Cells that recognize antigens as peptide-MHC complexes, optimal B cell-responses are induced by multimerized FDC-ICs that simultaneously engage multiple BCRs. FDC-FcgammaRIIB mediates IC-periodicity and FDC-BAFF, FDC-IL-6 and FDC-C4bBP are co-stimulators. Remarkably, specific antibody responses can be induced by FDC-ICs in the absence of T Cells, opening up the exciting possibility that people with T cell insufficiencies may be immunized with T-dependent vaccines via FDC-ICs.

  • Follicular Dendritic Cells beyond the necessity of t cell help
    Trends in Immunology, 2001
    Co-Authors: John G. Tew, Andras K. Szakal, Mohamed Fakher, Dahui Qin
    Abstract:

    Follicular Dendritic Cells (FDCs) are potent accessory Cells for B Cells, but the molecular basis of their activity is not understood. Several important molecules involved in FDC-B-cell interactions are indicated by blocking the ligands and receptors on FDCs and/or B Cells. The engagement of CD21 in the B-cell coreceptor complex by complement-derived CD21 ligand on FDCs delivers a crucial signal that dramatically augments the stimulation delivered by the binding of antigen to the B-cell receptor (BCR). The engagement of Fc gamma receptor IIB (FcgammaRIIB) by the Ig crystallizable fragment (Fc) in antigen-antibody complexes held on FDCs decreases the activation of immunoreceptor tyrosine-based inhibition motifs (ITIMs), mediated by the crosslinking of BCR and FcgammaRIIB. Thus, FDCs minimize a negative B-cell signal. In short, these ligand-receptor interactions help to signal to B Cells and meet a requirement for B-cell stimulation that goes beyond the necessity of T-cell help.

  • persistence of infectious hiv on Follicular Dendritic Cells
    Journal of Immunology, 2001
    Co-Authors: Beverly A Smith, Andras K. Szakal, Alan S Perelson, Suzanne Gartner, Yiling Liu, Nikolaos I Stilianakis, Brandon F Keele, Thomas M Kerkering, Andrea Ferreiragonzalez, John G. Tew
    Abstract:

    Follicular Dendritic Cells (FDCs) trap Ags and retain them in their native state for many months. Shortly after infection, HIV particles are trapped on FDCs and can be observed until the Follicular network is destroyed. We sought to determine whether FDCs could maintain trapped virus in an infectious state for long periods of time. Because virus replication would replenish the HIV reservoir and thus falsely prolong recovery of infectious virus, we used a nonpermissive murine model to examine maintenance of HIV infectivity in vivo. We also examined human FDCs in vitro to determine whether they could maintain HIV infectivity. FDC-trapped virus remained infectious in vivo at all time points examined over a 9-mo period. Remarkably, as few as 100 FDCs were sufficient to transmit infection throughout the 9-mo period. Human FDCs maintained HIV infectivity for at least 25 days in vitro, whereas virus without FDCs lost infectivity after only a few days. These data indicate that HIV retained on FDCs can be long lived even in the absence of viral replication and suggest that FDCs stabilize and protect HIV, thus providing a long-term reservoir of infectious virus. These trapped stores of HIV may be replenished with replicating virus that persists even under highly active antiretroviral therapy and would likely be capable of causing infection on cessation of drug therapy.

  • fcγ receptor iib on Follicular Dendritic Cells regulates the b cell recall response
    Journal of Immunology, 2000
    Co-Authors: Dahui Qin, Andras K. Szakal, Kalpit A Vora, Jeffrey V Ravetch, Tim Manser, John G. Tew
    Abstract:

    Generation of the B cell recall response appears to involve interaction of Ag, in the form of an immune complex (IC) trapped on Follicular Dendritic Cells (FDCs), with germinal center (GC) B Cells. Thus, the expression of receptors on FDC and B Cells that interact with ICs could be critical to the induction of an optimal recall response. FDCs in GCs, but not in primary follicles, express high levels of the IgG Fc receptor Fc gamma RIIB. This regulated expression of Fc gamma RIIB on FDC and its relation to recall Ab responses were examined both in vitro and in vivo. Trapping of IC in spleen and lymph nodes of Fc gamma RII-/- mice was significantly reduced compared with that in wild-type controls. Addition of ICs to cultures of Ag-specific T and B Cells elicited pronounced Ab responses only in the presence of FDCs. However, FDCs derived from Fc gamma RIIB-/- mice supported only low level Ab production in this situation. Similarly, when Fc gamma RIIB-/- mice were transplanted with wild-type Ag-specific T and B Cells and challenged with specific Ag, the recall responses were significantly depressed compared with those of controls with wild-type FDC. These results substantiate the hypothesis that FcgammaRIIB expression on FDCs in GCs is important for FDCs to retain ICs and to mediate the conversion of ICs to a highly immunogenic form and for the generation of strong recall responses.

  • Destruction of Follicular Dendritic Cells in Murine Acquired Immunodeficiency Syndrome (Maids)
    Advances in experimental medicine and biology, 1993
    Co-Authors: Akihiro Masuda, Gregory F. Burton, Bruse A. Fuchs, Andras K. Szakal, John G. Tew
    Abstract:

    Follicular Dendritic Cells (FDCs) degenerate in individuals manifesting persistent generalized lymphadenopathy after infection with HIV. At the light microscopic level, this degeneration of FDC is noted by the destruction of the FDC network in lymph node follicles1-3, and it is called “follicle lysis”1. Ultimately, FDC are depleted as indicated by a lack of labeling with FDC specific monoclonal antibodies3. At the electronmicroscopic level, it has been reported that HIV, observed as viral particles, were attached to the processes of FDC2,4. These findings support the concept that HIV infection leads to destruction of FDC and loss of FDC functions.

Moira E. Bruce - One of the best experts on this subject based on the ideXlab platform.

  • Follicular Dendritic Cells as targets for intervention in transmissible spongiform encephalopathies.
    Seminars in immunology, 2002
    Co-Authors: Neil A. Mabbott, Moira E. Bruce
    Abstract:

    Transmissible spongiform encephalopathies (TSEs) are often acquired peripherally, for example by ingestion or iatrogenic exposure. After entry, TSE agents, as identified by disease-specific protein accumulation, usually accumulate on Follicular Dendritic Cells (FDCs) in lymphoid tissues long before infection spreads to the brain. Neuroinvasion of TSE agents is significantly impaired in the absence of mature FDCs. Treatments that interfere with the integrity or function of FDCs extend survival time by blocking replication in lymphoid tissues and spread to the brain. The identification of FDCs as critical for TSE pathogenesis provides a cellular target to which therapies can be specifically directed.

  • temporary inactivation of Follicular Dendritic Cells delays neuroinvasion of scrapie
    Nature Medicine, 2000
    Co-Authors: Neil A. Mabbott, Fabienne Mackay, Fiona Minns, Moira E. Bruce
    Abstract:

    Although the transmissible spongiform encephalopathies (TSEs) are neurological diseases, TSE agents usually replicate in lymphoid tissues long before infection spreads to the brain. Studies of a mouse scrapie TSE model have demonstrated that mature Follicular Dendritic Cells (FDCs) expressing the host prion protein (PrPc) are essential for replication of infection in lymphoid tissues1 and subsequent spread of infection to the nervous system2. Abnormal forms of PrP (PrPSc) accumulate on FDCs in scrapie-infected mice2, 3, and in patients with variant Creutzfeldt-Jakob disease (ref. 4). Here we confirm that, as predicted, treatment that interferes with the integrity of FDCs also interferes with TSE pathogenesis.

  • Follicular Dendritic Cells in scrapie pathogenesis.
    Archives of virology. Supplementum, 2000
    Co-Authors: K. L. Brown, H Fraser, K. Stewart, D. L. Ritchie, W. I. Morrison, Moira E. Bruce
    Abstract:

    Scrapie pathogenesis was studied in chimaeric mice that carried the prion protein (PrP) gene only in particular Cells of the immune system. These mice were produced by grafting bone marrow from PrP expressing donors into PrP deficient recipients and vice versa. As Follicular Dendritic Cells are not replaced significantly from the bone marrow in adult mice, this procedure resulted in a mismatch in PrP genotype between these Cells and bone marrow derived Cells such as lymphocytes. Using these models we obtained strong evidence that Follicular Dendritic Cells produced high levels of the normal form of PrP in uninfected mice. Furthermore, the replication of a mouse-passaged scrapie strain in the spleen depended only on the presence of PrP expressing Follicular Dendritic Cells. PrP expression by lymphocytes or other bone marrow derived Cells had no influence on replication in spleen or on neuroinvasion in these models. These results indicate that the Follicular Dendritic cell is a potential target for prophylactic or therapeutic intervention in transmissible spongiform encephalopathies.

  • Follicular Dendritic Cells in TSE pathogenesis
    Immunology today, 2000
    Co-Authors: Moira E. Bruce, Neil A. Mabbott, Karen Brown, Christine Farquhar, Martin Jeffrey
    Abstract:

    The pathogenesis of transmissible spongiform encephalopathies (TSEs) often includes a replication phase in lymphoid tissues before infection spreads to the central nervous system. Recent studies show that the Follicular Dendritic Cells of the germinal centres are critical for this replication. These Cells are therefore potential targets for therapy or prophylaxis in natural TSEs, such as variant Creutzfeldt-Jakob disease.

  • scrapie replication in lymphoid tissues depends on prion protein expressing Follicular Dendritic Cells
    Nature Medicine, 1999
    Co-Authors: Karen Brown, Neil A. Mabbott, H Fraser, K. Stewart, W. I. Morrison, D Ritchie, Alun Williams, Moira E. Bruce
    Abstract:

    The immune system is central in the pathogenesis of scrapie and other transmissible spongiform encephalopathies (TSEs) or 'prion' diseases1. After infecting by peripheral (intraperitoneal or oral) routes, most TSE agents replicate in spleen and lymph nodes before neuroinvasion2. Characterization of the Cells supporting replication in these tissues is essential to understanding early pathogenesis and may indicate potential targets for therapy, for example, in 'new variant' Creutzfeldt-Jakob disease. The host 'prion' protein (PrP) is required for TSE agent replication3,4 and accumulates in modified forms in infected tissues. Abnormal PrP is detected readily on Follicular Dendritic Cells (FDCs) in lymphoid tissues of patients with 'new variant' Creutzfeldt-Jakob disease5, sheep with natural scrapie6 and mice experimentally infected with scrapie7. The normal protein is present on FDCs in uninfected mice7 and, at lower levels, on lymphocytes8. Studies using severe combined immunodeficiency (SCID) mice, with and without bone marrow (BM) grafts, have indicated involvement of FDCs and/or lymphocytes in scrapie pathogenesis9. To clarify the separate roles of FDCs and lymphocytes, we produced chimeric mice with a mismatch in PrP status between FDCs and other Cells of the immune system, by grafting bone marrow from PrP-deficient knockout mice4 into PrP-expressing mice and vice versa. Using these chimeric models, we obtained strong evidence that FDCs themselves produce PrP and that replication of a mouse-passaged scrapie strain in spleen depends on PrP-expressing FDCs rather than on lymphocytes or other bone marrow-derived Cells.