title: Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.
abstract: Leukocyte adhesion deficiency type I (LAD-I), a disease syndrome associated with frequent microbial infections, is caused by mutations on the CD18 subunit of β₂ integrins. LAD-I is invariably associated with severe periodontal bone loss, which historically has been attributed to the lack of neutrophil surveillance of the periodontal infection. We provide an alternative mechanism by showing that the cytokine interleukin-17 (IL-17) plays a major role in the oral pathology of LAD-I. Defective neutrophil recruitment in LAD-I patients or in LFA-1 (CD11a/CD18)-deficient mice--which exhibit the LAD-I periodontal phenotype--was associated with excessive production of predominantly T cell-derived IL-17 in the periodontal tissue, although innate lymphoid cells also contributed to pathological IL-17 elevation in the LFA-1-deficient mice. Local treatment with antibodies to IL-17 or IL-23 in LFA-1-deficient mice not only blocked inflammatory periodontal bone loss but also caused a reduction in the total bacterial burden, suggesting that the IL-17-driven pathogenesis of LAD-I periodontitis leads to dysbiosis. Therefore, our findings support an IL-17-targeted therapy for periodontitis in LAD-I patients.
authors.affiliation: National Institute of Dental and Craniofacial Research, Oral Immunity and Infection Unit, Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Niki M
authors.initials: NM
authors.lastname: Moutsopoulos
authors.forename: Joanne
authors.initials: J
authors.lastname: Konkel
authors.forename: Mojgan
authors.initials: M
authors.lastname: Sarmadi
authors.forename: Mehmet A
authors.initials: MA
authors.lastname: Eskan
authors.forename: Teresa
authors.initials: T
authors.lastname: Wild
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dutzan
authors.forename: Loreto
authors.initials: L
authors.lastname: Abusleme
authors.forename: Camille
authors.initials: C
authors.lastname: Zenobia
authors.forename: Kavita B
authors.initials: KB
authors.lastname: Hosur
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Abe
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.forename: Wanjun
authors.initials: W
authors.lastname: Chen
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: George
authors.initials: G
authors.lastname: Hajishengallis
mesh_terms: D000293:Adolescent; D000818:Animals; D001862:Bone Resorption / Q000150:complications* / Q000473:pathology*; D002448:Cell Adhesion; D002648:Child; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000473:pathology*; D020381:Interleukin-17 / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000150:complications / Q000235:genetics / Q000473:pathology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D010518:Periodontitis / Q000150:complications / Q000235:genetics / Q000382:microbiology / Q000473:pathology
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23; D016169:Lymphocyte Function-Associated Antigen-1