Session Type: ACR Plenary Session
Session Time: 11:00AM-12:30PM
Background/Purpose: 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, particularly the gingiva, the gut and the lungs. The common occurrence of periodontal dysbiosis in RA suggests that oral pathogens may trigger the production of anti-citrullinated protein antibodies (ACPAs) and arthritis in susceptible individuals. Here, we studied the periodontal microenvironment in health and disease to define mechanisms underlying mucosal inflammation and autoimmunity in RA.
Methods: Gingival crevicular fluid (GCF) from patients with periodontitis and healthy subjects without periodontitis was analyzed by immunoblotting to detect citrullinated proteins (AMC). Mass spectrometry (MS) was employed to define the microbial composition and antigenic repertoire of GCF in periodontal disease and oral health. Isolated human neutrophils were analyzed by AMC immunoblotting and MS after incubation with periodontal pathogens (Aggregatibacter actinomycetemcomitans [Aa], P gingivalis, T forsythia, T denticola, F nucleatum, P micra, P intermedia, S intermedius) and purified Aa leukotoxin A (LtxA). Neutrophils incubated alone or with LtxA were stained with SYTOX Green, anti-citH3, and ACPA-positive RA serum. Antibodies against Aa and LtxA were quantified in patients with RA (n=196) and healthy controls without periodontitis (n=37) by ELISA.
Results: Periodontitis was characterized by the presence of citrullinated autoantigens that are primary immune targets in RA. The citrullinome in periodontitis mirrored patterns of cellular 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, Aa, but not other candidate pathogens or commensals, induced hypercitrullination in host neutrophils. We identified the pore-forming toxin LtxA as the molecular mechanism by which Aa triggers dysregulated activation of citrullinating enzymes in neutrophils, mimicking membranolytic pathways known to sustain autoantigen citrullination in the RA joint. Moreover, LtxA induced changes in neutrophil morphology suggestive of extracellular trap formation, thereby releasing the hypercitrullinated cargo. Exposure to Aa was confirmed in RA patients (43% vs 8% of controls without periodontitis; p<0.0001) and significantly associated with both ACPAs and rheumatoid factor (RF). The effect of RA susceptibility alleles (the HLA-DRB1 shared epitope) on ACPA and RF positivity was surprisingly conditioned on patient exposure to LtxA (Table 1), suggesting a two-hit model of RA pathogenesis.
Conclusion: These studies identify the periodontal pathogen Aa as a candidate bacterial trigger of autoimmunity in RA.
|Anti-LtxA negative RA (n=112)||Anti-LtxA positive RA (n=82)||
|SE negative||SE positive||P||SE negative||SE positive||P||P-|
|Anti-CCP positivity, n (%)||20 (61)||62 (78)||0.051||14 (56)||54 (95)||*<0.001||*0.035|
|ACPA positivity, n (%)||21 (64)||54 (68)||0.63||16 (64)||52 (93)||*0.002||*0.025|
|RF positivity, n (%)||22 (67)||57 (72)||0.56||17 (68)||55 (96)||*<0.001||*0.015|
Table 1: The association of ACPAs and RF with shared epitope alleles is conditioned on Aggregatibacter actinomycetemcomitans LtxA exposure in patients with RA.
To cite this abstract in AMA style:Konig MF, Abusleme L, Reinholdt J, Palmer RJ, Sampson K, Teles RP, Nigrovic PA, Rosen A, Sokolove J, Giles JT, Moutsopoulos NM, Andrade F. Aggregatibacter Actinomycetemcomitans-Induced Hypercitrullination Links Periodontal Infection to Autoimmunity in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/aggregatibacter-actinomycetemcomitans-induced-hypercitrullination-links-periodontal-infection-to-autoimmunity-in-rheumatoid-arthritis/. Accessed November 25, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/aggregatibacter-actinomycetemcomitans-induced-hypercitrullination-links-periodontal-infection-to-autoimmunity-in-rheumatoid-arthritis/