title: Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis.
abstract: A bacterial etiology of rheumatoid arthritis (RA) has been suspected since the beginnings of modern germ theory. Recent studies implicate mucosal surfaces as sites of disease initiation. The common occurrence of periodontal dysbiosis in RA suggests that oral pathogens may trigger the production of disease-specific autoantibodies and arthritis in susceptible individuals. We used mass spectrometry to define the microbial composition and antigenic repertoire of gingival crevicular fluid in patients with periodontal disease and healthy controls. Periodontitis was characterized by the presence of citrullinated autoantigens that are primary immune targets in RA. The citrullinome in periodontitis mirrored patterns of hypercitrullination observed in the rheumatoid joint, implicating this mucosal site in RA pathogenesis. Proteomic signatures of several microbial species were detected in hypercitrullinated periodontitis samples. Among these, Aggregatibacter actinomycetemcomitans (Aa), but not other candidate pathogens, induced hypercitrullination in host neutrophils. We identified the pore-forming toxin leukotoxin A (LtxA) as the molecular mechanism by which Aa triggers dysregulated activation of citrullinating enzymes in neutrophils, mimicking membranolytic pathways that sustain autoantigen citrullination in the RA joint. Moreover, LtxA induced changes in neutrophil morphology mimicking extracellular trap formation, thereby releasing the hypercitrullinated cargo. Exposure to leukotoxic Aa strains was confirmed in patients with RA and was associated with both anticitrullinated protein antibodies and rheumatoid factor. The effect of human lymphocyte antigen-DRB1 shared epitope alleles on autoantibody positivity was limited to RA patients who were exposed to Aa These studies identify the periodontal pathogen Aa as a candidate bacterial trigger of autoimmunity in RA.
authors.affiliation: Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors.forename: Maximilian F
authors.initials: MF
authors.lastname: Konig
authors.affiliation: National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Loreto
authors.initials: L
authors.lastname: Abusleme
authors.affiliation: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Reinholdt
authors.affiliation: National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Palmer
authors.affiliation: Department of Periodontology, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Department of Applied Oral Sciences, Forsyth Institute, Cambridge, MA 02142, USA.
authors.forename: Ricardo P
authors.initials: RP
authors.lastname: Teles
authors.affiliation: Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors.forename: Kevon
authors.initials: K
authors.lastname: Sampson
authors.affiliation: Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors.forename: Antony
authors.initials: A
authors.lastname: Rosen
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA.|Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Nigrovic
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sokolove
authors.affiliation: Division of Rheumatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Jon T
authors.initials: JT
authors.lastname: Giles
authors.affiliation: National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Niki M
authors.initials: NM
authors.lastname: Moutsopoulos
authors.affiliation: Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA. andrade@jhmi.edu.
authors.forename: Felipe
authors.initials: F
authors.lastname: Andrade
mesh_terms: D000328:Adult; D016976:Aggregatibacter actinomycetemcomitans; D000075422:Anti-Citrullinated Protein Antibodies / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000382:microbiology; D001324:Autoantigens / Q000737:chemistry; D016022:Case-Control Studies; D002908:Chronic Disease; D002956:Citrulline / Q000737:chemistry*; D002986:Clinical Trials as Topic; D005260:Female; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology; D016871:Pasteurellaceae Infections / Q000276:immunology*; D010518:Periodontitis / Q000276:immunology / Q000382:microbiology*; D011446:Prospective Studies
chemical_list: D000075422:Anti-Citrullinated Protein Antibodies; D001324:Autoantigens; D059811:HLA-DRB1 Chains; D002956:Citrulline