Research ArticleAutoimmunity

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

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Science Translational Medicine  14 Dec 2016:
Vol. 8, Issue 369, pp. 369ra176
DOI: 10.1126/scitranslmed.aaj1921

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A joint effect of bacteria and genetics

Although rheumatoid arthritis is an autoimmune disease, scientists have long suspected that bacterial infections (and in particular, periodontal infections) may play a role in its pathogenesis. Konig et al. now demonstrate that a particular periodontal pathogen called Aggregatibacter actinomycetemcomitans (Aa) induces changes in neutrophil function, including hypercitrullination of host proteins, an abnormality that is also observed in the joints of patients with rheumatoid arthritis. Moreover, the effect of HLA-DRB1, an allele associated with increased risk of rheumatoid arthritis, was only observed in patients exposed to Aa, suggesting the possibility of eventually using these results to identify and possibly even treat high-risk patients.


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.

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