Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis

Maximilian F. Konig, Loreto Abusleme, Jesper Reinholdt, Robert J. Palmer, Ricardo P. Teles, Kevon Sampson, Antony Rosen, Peter A. Nigrovic, Jeremy Sokolove, Jon T. Giles, Niki M. Moutsopoulos, Felipe Andrade

Research output: Research - peer-reviewArticle

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.

LanguageEnglish (US)
Article number369ra176
JournalScience Translational Medicine
Volume8
Issue number369
DOIs
StatePublished - Dec 14 2016

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Aggregatibacter actinomycetemcomitans
Autoimmunity
Rheumatoid Arthritis
Infection
Periodontitis
Neutrophils
Autoantigens
Autoantibodies
Joints
leukotoxin
Dysbiosis
Gingival Crevicular Fluid
Enzyme Activation
Rheumatoid Factor
Periodontal Diseases
Proteomics
Arthritis
Epitopes
Mass Spectrometry
Alleles

ASJC Scopus subject areas

  • Medicine(all)

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Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. / Konig, Maximilian F.; Abusleme, Loreto; Reinholdt, Jesper; Palmer, Robert J.; Teles, Ricardo P.; Sampson, Kevon; Rosen, Antony; Nigrovic, Peter A.; Sokolove, Jeremy; Giles, Jon T.; Moutsopoulos, Niki M.; Andrade, Felipe.

In: Science Translational Medicine, Vol. 8, No. 369, 369ra176, 14.12.2016.

Research output: Research - peer-reviewArticle

Konig, MF, Abusleme, L, Reinholdt, J, Palmer, RJ, Teles, RP, Sampson, K, Rosen, A, Nigrovic, PA, Sokolove, J, Giles, JT, Moutsopoulos, NM & Andrade, F 2016, 'Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis' Science Translational Medicine, vol 8, no. 369, 369ra176. DOI: 10.1126/scitranslmed.aaj1921
Konig MF, Abusleme L, Reinholdt J, Palmer RJ, Teles RP, Sampson K et al. Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Science Translational Medicine. 2016 Dec 14;8(369). 369ra176. Available from, DOI: 10.1126/scitranslmed.aaj1921
Konig, Maximilian F. ; Abusleme, Loreto ; Reinholdt, Jesper ; Palmer, Robert J. ; Teles, Ricardo P. ; Sampson, Kevon ; Rosen, Antony ; Nigrovic, Peter A. ; Sokolove, Jeremy ; Giles, Jon T. ; Moutsopoulos, Niki M. ; Andrade, Felipe. / Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. In: Science Translational Medicine. 2016 ; Vol. 8, No. 369.
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