title: Possible pathogenic engagement of soluble Semaphorin 4D produced by γδT cells in medication-related osteonecrosis of the jaw (MRONJ).
abstract: Prior consensus held that medication-related osteonecrosis of the jaw (MRONJ) lesion was composed of necrotic bone; however, more recent studies have identified inflammatory infiltrates in the lesion. Herein, we report that remarkably elevated infiltrating γδT cells (90% of lymphocytes) express Semaphorin 4D (Sema4D) in human patient with MRONJ lesion, whereas γδT cells only account for 2-5% of lymphocytes in blood. Importantly, Sema4D is implicated in the pathogenesis of T cell-mediated inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. Indeed, in a mouse model of MRONJ, an elevated number of γδT, but not αβT, cells infiltrating in the MRONJ-like lesion was observed. Both elevated soluble Sema4D (sSema4D) production accompanied by pro-inflammatory cytokines, including TNF-α IFN-γ and IL-1β, and Sema4D-expressing γδT cells were detected in mouse MRONJ-like lesion. Activated γδT cells produced sSema4D in vitro, which could promote TNF-α production from macrophages. Meanwhile, γδT cell-KO mice were resistant to the induction of MRONJ and, hence, showed no elevation of local productions of Sema4D and TNF-α. Finally, systemic administration of anti-Sema4D neutralizing mAb suppressed the onset of MRONJ in wild-type mice in conjunction with diminished level of TNF-α. These results suggested a critical pathogenic engagement of Sema4D produced by γδT cells in the development of MRONJ.
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Movila
authors.affiliation: Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Hani
authors.initials: H
authors.lastname: Mawardi
authors.affiliation: Maxillo-oral Disorders, Tohoku University Hospital, Sendai, Japan; Division of Oral Dysfunction of Science, Tohoku University Graduate School of Density, Sendai, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Division of Oral Molecular Regulation, Tohoku University, Sendai, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kiyama
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA; Research and Development Headquarters, LION Corporation, Kanagawa, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Egashira
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA; Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Boston, MA, USA; Harvard School of Dental Medicine, Department of Oral Medicine, Infection and Immunity, Boston, MA, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Villa
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA; Harvard School of Dental Medicine, Department of Oral Medicine, Infection and Immunity, Boston, MA, USA.
authors.forename: Hajime
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Boston, MA, USA; Harvard School of Dental Medicine, Department of Oral Medicine, Infection and Immunity, Boston, MA, USA.
authors.forename: Sook-Bin
authors.initials: SB
authors.lastname: Woo
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA; Harvard School of Dental Medicine, Department of Oral Medicine, Infection and Immunity, Boston, MA, USA. Electronic address: tkawai@forsyth.org.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Kawai
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D004164:Diphosphonates / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D000077268:Pamidronate; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D039961:Semaphorins / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000077211:Zoledronic Acid
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C093224:CD100 antigen; D004164:Diphosphonates; D007093:Imidazoles; D016692:Receptors, Antigen, T-Cell, gamma-delta; D039961:Semaphorins; D000077211:Zoledronic Acid; D000077268:Pamidronate
keywords: Inflammation; Medication-related osteonecrosis of jaw; Monoclonal antibody; Semaphorin 4D; TNF-α; γδT cells