The oral microbiome in rheumatoid arthritis

In collaboration with the Andrade Lab at Johns Hopkins, we study the role of periodontal inflammation in the immunopathogenesis of rheumatoid arthritis (RA).

Our studies identified the periodontal pathogen Aggregatibacter actinomycetemcomitans (Aa) as a driver of dysregulated protein citrullination in immune cells and as a possible etiologic factor in RA. We showed that periodontal disease was characterized by the presence of citrullinated autoantigens in gingival crevicular fluid and identified the bacterial pore-forming toxin leukotoxin A (LtxA) as the unique mechanism by which Aa triggers protein arginine deiminase (PAD) activity and abnormal citrullination. We further found that exposure to Aa and LtxA was highly enriched in patients with RA, and that combined exposure to LtxA and presence of HLA-DRB1 genetic risk alleles was associated with the development of anti-citrullinated protein antibodies (ACPAs), an immune hallmark of RA. Our studies proposed a new model of RA disease pathogenesis by which chronic infection with a specific pathogen (i.e., Aa) may lead to the promotion of autoimmunity directed against citrullinated proteins and RA.

In subsequent studies, we identified an association of Aa and LtxA with accelerated cardiovascular disease in patients with RA, showed exposure to Aa in individuals with preclinical RA, and described the resolution of inflammatory arthritis and ACPAs in a patient with Aa endocarditis following antibiotic treatment. Our studies also delineated a form of neutrophil cell death distinct from NETosis (i.e., leukotoxic hypercitrullination), which is uniquely associated with abnormal protein citrullination.

Collaborators

Felipe Andrade, MD, PhD; Johns Hopkins University School of Medicine

Niki Moutsopoulos, DDS, PhD; National Institutes of Health

Jesper Reinholdt, PhD; Aarhus University

Jon T. Giles, MD; Columbia University

Joan M, Bathon, MD; Columbia University

Clifton O. Bingham III, M.D., Johns Hopkins University School of Medicine

Publications

• Gómez-Bañuelos E, Konig MF, Andrade F. Microbial pathways to subvert host immunity generate citrullinated neoantigens targeted in rheumatoid arthritis. Curr Opin Struct Biol. 2022 Jul 11;75:102423.

• Giles JT, Reinholdt J, Andrade F, Konig MF. Associations of Antibodies Targeting Periodontal Pathogens With Subclinical Coronary, Carotid, and Peripheral Arterial Atherosclerosis in Rheumatoid Arthritis. Arthritis Rheumatol. 2021 Apr;73(4):568-575.

• Gomez-Bañuelos E, Johansson L, Konig MF, Lundquist A, Paz M, Buhlin K, Johansson A, Rantapää-Dahlqvist S, Andrade F. Exposure to Aggregatibacter actinomycetemcomitans before Symptom Onset and the Risk of Evolving to Rheumatoid Arthritis. J Clin Med. 2020 Jun 18;9(6):1906.

• Konig MF. The microbiome in autoimmune rheumatic disease. Best Pract Res Clin Rheumatol. 2020 Feb;34(1):101473. Review.

• Konig MF, Giles JT, Teles RP, Moutsopoulos NM, Andrade F. Response to comment on "Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis". Sci Transl Med. 2018 Mar 21;10(433):eaao3031.

• Mukherjee A, Jantsch V, Khan R, Hartung W, Fischer R, Jantsch J, Ehrenstein B*, Konig MF*, Andrade F*. Rheumatoid Arthritis-Associated Autoimmunity Due to Aggregatibacter actinomycetemcomitans and Its Resolution With Antibiotic Therapy. Front Immunol. 2018 Oct 16;9:2352.

• Konig MF, Andrade F. A Critical Reappraisal of Neutrophil Extracellular Traps and NETosis Mimics Based on Differential Requirements for Protein Citrullination. Front Immunol. 2016 Nov 4;7:461. doi: 10.3389/fimmu.2016.00461.

• Konig MF, Abusleme L, Reinholdt J, Palmer RJ, Teles RP, Sampson K, Rosen A, Nigrovic PA, Sokolove J, Giles JT, Moutsopoulos NM, Andrade F. Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Sci Transl Med. 2016 Dec 14;8(369):369ra176.

• Konig MF, Bingham CO 3rd, Andrade F. PPAD is not targeted as a citrullinated protein in rheumatoid arthritis, but remains a candidate for inducing autoimmunity. Ann Rheum Dis. 2015 Jan;74(1):e8.

• Konig MF, Paracha AS, Moni M, Bingham CO 3rd, Andrade F. Defining the role of Porphyromonas gingivalis peptidylarginine deiminase (PPAD) in rheumatoid arthritis through the study of PPAD biology. Ann Rheum Dis. 2015 Nov;74(11):2054-61.

Read more: How RA Begins. LEAP Magazine.