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      Survival, Retention, and Selective Proliferation of Lymphocytes Is Mediated by Gingival Fibroblasts

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          Abstract

          Periodontitis, a chronic inflammatory disease of the periodontium, is characterized by osteoclast-mediated alveolar bone destruction. Gingival fibroblasts (GFs) present in the bone-lining mucosa have the capacity to activate the formation of osteoclasts, but little is known about which local immune cells (co-)mediate this process. The aim of this study was to investigate the cellular interactions of GFs with immune cells, including the contribution of GFs to osteoclast formation and their possible role in the proliferation of these immune cells. In addition, we investigated the expression of adhesion molecules and the inflammatory cytokines that are evoked by this interaction. GFs were cocultured with peripheral blood mononuclear cells (PBMCs), CD14+ monocytes or peripheral blood lymphocytes (PBLs) for 7, 14, and 21 days. After 21 days, comparable numbers of multinucleated cells (osteoclasts) were found in gingival fibroblast (GF)-PBMC and GF-monocyte cocultures. No osteoclasts were formed in GF-PBL cocultures, indicating that the PBLs present in GF-PBMC cocultures do not contribute to osteoclastogenesis. Persisting mononuclear cells were interacting with osteoclasts in GF-PBMC cocultures. Remarkably, a predominance of CD3+ T cells was immunohistochemically detected in GF cocultures with PBLs and PBMCs for 21 days that frequently interacted with osteoclasts. Significantly more T, B (CD19+), and NK (CD56+CD3−) cells were identified with multicolor flow cytometry in both GF-PBMC and GF-PBL cocultures compared to monocultures without GFs at all time points. GFs retained PBLs independently of the presence of monocytes or osteoclasts over time, showing a stable population of T, B, and NK cells between 7 and 21 days. T helper and cytotoxic T cell subsets remained stable over time in GF cocultures, while the number of Th17 cells fluctuated. Lymphocyte retention is likely mediated by lymphocyte-function-associated antigen-1 (LFA-1) expression, which was significantly higher in GF-PBL cultures compared to GF-monocyte cultures. When assessing inflammatory cytokine expression, high tumor necrosis alpha expression was only observed in the GF-PBMC cultures, indicating that this tripartite presence of GFs, monocytes, and lymphocytes is required for such an induction. Carboxyfluorescein succinimidyl ester-labeling showed that only the CD3+ cells proliferated in presence of GFs. This study demonstrates a novel role for GFs in the survival, retention, and selective proliferation of lymphocytes.

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          Mechanisms of Bone Resorption in Periodontitis

          Alveolar bone loss is a hallmark of periodontitis progression and its prevention is a key clinical challenge in periodontal disease treatment. Bone destruction is mediated by the host immune and inflammatory response to the microbial challenge. However, the mechanisms by which the local immune response against periodontopathic bacteria disturbs the homeostatic balance of bone formation and resorption in favour of bone loss remain to be established. The osteoclast, the principal bone resorptive cell, differentiates from monocyte/macrophage precursors under the regulation of the critical cytokines macrophage colony-stimulating factor, RANK ligand, and osteoprotegerin. TNF-α, IL-1, and PGE2 also promote osteoclast activity, particularly in states of inflammatory osteolysis such as those found in periodontitis. The pathogenic processes of destructive inflammatory periodontal diseases are instigated by subgingival plaque microflora and factors such as lipopolysaccharides derived from specific pathogens. These are propagated by host inflammatory and immune cell influences, and the activation of T and B cells initiates the adaptive immune response via regulation of the Th1-Th2-Th17 regulatory axis. In summary, Th1-type T lymphocytes, B cell macrophages, and neutrophils promote bone loss through upregulated production of proinflammatory mediators and activation of the RANK-L expression pathways.
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            Destructive and protective roles of cytokines in periodontitis: a re-appraisal from host defense and tissue destruction viewpoints.

            G Garlet (2010)
            Periodontal diseases (PD) are chronic infectious inflammatory diseases characterized by the destruction of tooth-supporting structures, being the presence of periodontopathogens required, but not sufficient, for disease development. As a general rule, host inflammatory mediators have been associated with tissue destruction, while anti-inflammatory mediators counteract and attenuate disease progression. With the discovery of several T-cell subsets bearing distinct immunoregulatory properties, this pro- vs. anti-inflammatory scenario became more complex, and a series of studies has hypothesized protective or destructive roles for Th1, Th2, Th17, and Treg subpopulations of polarized lymphocytes. Interestingly, the "protective vs. destructive" archetype is usually considered in a framework related to tissue destruction and disease progression. However, it is important to remember that periodontal diseases are infectious inflammatory conditions, and recent studies have demonstrated that cytokines (TNF-α and IFN-γ) considered harmful in the context of tissue destruction play important roles in the control of periodontal infection. Therefore, in this review, the state-of-the-art knowledge concerning the protective and destructive roles of host inflammatory immune response will be critically evaluated and discussed from the tissue destruction and control-of-infection viewpoints.
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              Cytokines that promote periodontal tissue destruction.

              Although periodontal diseases are initiated by bacteria that colonize the tooth surface and gingival sulcus, the host response is believed to play an essential role in the breakdown of connective tissue and bone, key features of the disease process. An intermediate mechanism that lies between bacterial stimulation and tissue destruction is the production of cytokines, which stimulates inflammatory events that activate effector mechanisms. These cytokines can be organized as chemokines, innate immune cytokines, and acquired immune cytokines. Although they were historically identified as leukocyte products, many are also produced by a number of cell types, including keratinocytes, resident mesenchymal cells (such as fibroblasts and osteoblasts) or their precursors, dendritic cells, and endothelial cells. Chemokines are chemotactic cytokines that play an important role in leukocyte recruitment and may directly or indirectly modulate osteoclast formation. This article focuses on aspects of osteoimmunology that affect periodontal diseases by examining the role of cytokines, chemokines, and immune cell mediators. It summarizes some of the key findings that attempt to delineate the mechanisms by which immune factors can lead to the loss of connective tissue attachment and alveolar bone. In addition, a discussion is presented on the importance of clarifying the process of uncoupling, a process whereby insufficient bone formation occurs following resorption, which is likely to contribute to net bone loss in periodontal disease.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                25 July 2018
                2018
                : 9
                : 1725
                Affiliations
                [1] 1Department of Periodontology, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit , Amsterdam, Netherlands
                [2] 2Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit , Amsterdam, Netherlands
                [3] 3Department of Clinical Chemistry, Medical Immunology, Vrije Universiteit Medical Center (VUMC) , Amsterdam, Netherlands
                [4] 4Opris Dent SRL , Sibiu, Romania
                Author notes

                Edited by: Heiko Mühl, Goethe-Universität Frankfurt am Main, Germany

                Reviewed by: Ulvi Kahraman Gürsoy, University of Turku, Finland; Koji Naruishi, Tokushima University, Japan; Eija Könönen, University of Turku, Finland

                *Correspondence: Teun J. de Vries, teun.devries@ 123456acta.nl

                Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2018.01725
                6094995
                ab5f4ee4-6733-48a1-9786-01a670c08f9d
                Copyright © 2018 Moonen, Alders, Bontkes, Schoenmaker, Nicu, Loos and de Vries.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 17 May 2018
                : 12 July 2018
                Page count
                Figures: 8, Tables: 2, Equations: 0, References: 51, Pages: 18, Words: 10979
                Categories
                Immunology
                Original Research

                Immunology
                osteoclast formation,osteoimmunology,gingival fibroblast,peripheral blood cells,cell–cell interaction,leukocytes

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