title: 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.
abstract: B-lineage cells (B lymphocytes and plasma cells) predominate in the inflammatory infiltrate of human chronic periodontitis. However, their role in disease pathogenesis and the factors responsible for their persistence in chronic lesions are poorly understood. In 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 κ L chain-expressing B-lineage cells at the epithelial-connective tissue interface. Ligature-induced periodontitis resulted in significantly 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.
authors.affiliation: Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Abe
authors.affiliation: Department of Periodontics, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Mohammed
authors.initials: M
authors.lastname: AlSarhan
authors.affiliation: Department of Periodontics, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Manjunatha R
authors.initials: MR
authors.lastname: Benakanakere
authors.affiliation: Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Tomoki
authors.initials: T
authors.lastname: Maekawa
authors.affiliation: Department of Periodontics, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Denis F
authors.initials: DF
authors.lastname: Kinane
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cancro
authors.affiliation: Department of Periodontics, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104; and geoh@upenn.edu jkorosto@upenn.edu.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Korostoff
authors.affiliation: Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104; geoh@upenn.edu jkorosto@upenn.edu.
authors.forename: George
authors.identifier: http://orcid.org/0000-0001-7392-8852
authors.initials: G
authors.lastname: Hajishengallis
mesh_terms: D000328:Adult; D000368:Aged; D016301:Alveolar Bone Loss / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D007145:Immunoglobulin kappa-Chains / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010518:Periodontitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000378:metabolism*
chemical_list: D053264:B-Cell Activating Factor; D007145:Immunoglobulin kappa-Chains; D012333:RNA, Messenger; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13