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Periodontitis Bone Loss in Experimental Murine Dependent The B Cell−Stimulatory Cytokines BLyS and APRIL Are Elevated in Human Periodontitis and Are Required for B Cell−Dependent Bone Loss in Experimental Murine This information is current as Periodontitis of September 28, 2021. Toshiharu Abe, Mohammed AlSarhan, Manjunatha R. Benakanakere, Tomoki Maekawa, Denis F. Kinane, Michael P. Cancro, Jonathan M. Korostoff and George Hajishengallis J Immunol 2015; 195:1427-1435; Prepublished online 6 July Downloaded from 2015; doi: 10.4049/jimmunol.1500496 http://www.jimmunol.org/content/195/4/1427 http://www.jimmunol.org/ References This article cites 52 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/195/4/1427.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 28, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The B Cell–Stimulatory Cytokines BLyS and APRIL Are Elevated in Human Periodontitis and Are Required for B Cell–Dependent Bone Loss in Experimental Murine Periodontitis Toshiharu Abe,*,1 Mohammed AlSarhan,†,1,2 Manjunatha R. Benakanakere,† Tomoki Maekawa,* Denis F. Kinane,† Michael P. Cancro,‡ Jonathan M. Korostoff,† and George Hajishengallis* B-lineage cells (B lymphocytes and plasma cells) predominate in the inflammatory infiltrate of human chronic periodontitis. How- ever, their role in disease pathogenesis and the factors responsible for their persistence in chronic lesions are poorly understood. In Downloaded from this regard, two cytokines of the TNF ligand superfamily, a proliferation-inducing ligand (APRIL) and B-lymphocyte stimulator (BLyS), are important for the survival, proliferation, and maturation of B cells. Thus, we hypothesized that APRIL and/or BLyS are upregulated in periodontitis and contribute to induction of periodontal bone loss. This hypothesis was addressed in both human and mouse experimental systems. We show that, relative to healthy controls, the expression of APRIL and BLyS mRNA and protein was upregulated in natural and experimental periodontitis in humans and mice, respectively. The elevated expression of these cytokines correlated with increased numbers of B cells/plasma cells in both species. Moreover, APRIL and BLyS partially colocalized with k L http://www.jimmunol.org/ chain-expressing B-lineage cells at the epithelial–connective tissue interface. Ligature-induced periodontitis resulted in signifi- cantly less bone loss in B cell–deficient mice compared with wild-type controls. Ab-mediated neutralization of APRIL or BLyS diminished the number of B cells in the gingival tissue and inhibited bone loss in wild-type, but not in B cell-deficient, mice. In conclusion, B cells and specific cytokines involved in their growth and differentiation contribute to periodontal bone loss. Moreover, APRIL and BLyS have been identified as potential therapeutic targets in periodontitis. The Journal of Immunology, 2015, 195: 1427–1435. eriodontitis is a prevalent chronic inflammatory disease typ- sufficient to cause disease; it is actually the host inflammatory re- by guest on September 28, 2021 ified by destruction of the tooth-supporting tissues (gingiva, sponse to this polymicrobial challenge that ultimately induces tissue P periodontal ligament, and alveolar bone) and is associated damage and bone loss, the hallmark of periodontitis (2). A number of with increased risk for certain systemic disorders (e.g., atherosclerosis inflammatory and stromal cell types have been implicated in this and rheumatoid arthritis) (1). Although the pathogenesis of peri- destructive process (3–6). However, the role of plasma cells and their odontitis involves polymicrobial synergy and dysbiosis, the bacterial precursors, B lymphocytes, remains quite enigmatic, despite their communities of the tooth-associated biofilm (dental plaque) are not high abundance in advanced periodontal lesions (7–9). Indeed, plasma and B cells together make up ∼60% of the total leukocytes *Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, present in periodontal lesions associated with bone loss (8). Philadelphia, PA 19104; †Department of Periodontics, Penn Dental Medicine, Uni- Through their role in humoral immunity, B cells/plasma cells versity of Pennsylvania, Philadelphia, PA 19104; and ‡Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, could, in principle, have a protective function in periodontitis. For Philadelphia, PA 19104 instance, the Ab response could contribute to the control of the 1T.A. and M.A. contributed equally to this work. dysbiotic microbiota in periodontal pockets and prevent bacterial 2Current address: Department of Periodontics and Community Dentistry, College of invasion into the gingival connective tissue, thereby limiting Dentistry at King Saud University, Riyadh, Saudi Arabia. inflammation and disease. However, it is well established that ORCID: 0000-0001-7392-8852 (G.H.). periodontitis progresses, despite the induction of specific Ab Received for publication March 2, 2015. Accepted for publication June 12, 2015. responses to periodontal bacteria in affected individuals. This is This work was supported by National Institutes of Health Grants DE015254, likely due to the low affinity of the Abs and/or their unfavorable DE017138, DE021685, DE024716, AI068730 (all to G.H.), and DE023836 (to functional characteristics (e.g., poor opsonophagocytic capacity) D.F.K.). M.A. was supported by funds (Grant 4/52/146299) from the College of Dentistry Research Center and Deanship of Scientific Research at King Saud University. (5, 10, 11). In fact, it is thought that the B cell–mediated immune response, and specifically an IgG-dominant response, might Address correspondence and reprint requests to Dr. George Hajishengallis or Dr. Jonathan M. Korostoff, School of Dental Medicine, University of Pennsylvania, contribute to the pathogenesis of periodontitis. In this regard, 240 South 40th Street, Philadelphia, PA 19104-6030 (G.H.) or Department of Peri- advanced periodontitis is associated with increased deposition odontics, Penn Dental Medicine, University of Pennsylvania, 240 South 40th Street, Philadelphia, PA 19104 (J.M.K.). E-mail addresses: [email protected] (G.H.) or of IgG immune complexes along with complement activation [email protected] (J.M.K.) fragments (12, 13). Most importantly, B cells constitute a major Abbreviations used in this article: ABC, alveolar bone crest; APRIL, a proliferation- source of membrane-bound and secreted receptor activator of inducing ligand; BLyS, B-lymphocyte stimulator; CEJ, cementoenamel junction; KO, NF-kB ligand (RANKL) in the bone resorptive lesions of hu- knockout; RANKL, receptor activator of NF-kB ligand; WT, wild-type. man periodontitis (14). In this regard, it was shown that .90% Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 of B cells in periodontitis lesions express RANKL, whereas the www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500496 1428 BLyS AND APRIL IN ALVEOLAR BONE LOSS percentage of RANKL+ B cells in healthy gingiva is negligible Materials and Methods (14). Given that RANKL plays a key role in osteoclast differ- Human subjects and gingival tissue specimens entiation and activation (15), it is plausible that B cells partici- Research was performed under an Institutional Review Board–approved pate in the induction of pathological bone loss in periodontitis. protocol. Signed informed consent was obtained to procure normally dis- The notion that B cells mediate destructive effects in peri- carded gingival tissue from individuals treated in the postgraduate clinic of odontitis is consistent with findings from previous studies in the Department of Periodontics, University of Pennsylvania School of Dental animal models. Adoptive transfer of bacterial Ag-specific B cells Medicine. All subjects were 18 y of age or older with no serious medical into rats, followed by local oral exposure to the same bacterium illness contraindicative of surgical treatment. Diseased tissue was obtained from 14 patients undergoing pocket-reduction surgery to treat chronic peri- (Aggregatibacter actinomycetemcomitans), leads to RANKL- odontitis. Control tissue specimens were obtained from 14 clinically healthy dependent periodontal bone loss (16, 17). Despite the artificial subjects who required crown-lengthening surgery. The mean demographic priming approach involved, these studies indicated that specific and clinical parameters of the two groups are shown in Table I. The inclusion Ag-triggered B cells can potentially provoke bone resorption. criteria for chronic periodontitis were diseased sites with probing pocket depth $ 5 mm associated with clinical attachment loss $ 4 mm, presence of The role of B cells in periodontitis
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