<i>Aggregatibacter actinomycetemcomitans</i> virulence factors and systemic inflammation: linking periodontitis to rheumatoid arthritis

Growing evidence supports an association between oral microbiota, periodontitis (PD) and systemic diseases. Periodontal pathobionts can trigger immune responses that extend beyond the oral mucosa, promoting inflammatory and autoimmune conditions. In this context, Aggregatibacter actinomycetemcomitans (Aa), a Gram-negative coccobacillus and one of the causal agents of PD, has gained attention for its potential contribution to the pathogenesis of rheumatoid arthritis (RA). PD is a known risk factor for RA, and both pathologies share common T helper (Th)1 and Th17 cell-driven inflammatory pathways. Aa stimulates these responses locally, promoting alveolar bone resorption, and could also contribute to systemic autoimmunity through molecular mimicry, post-translational modifications, and sustained inflammation. Aa produces various virulence factors, including leukotoxin A (LtxA), lipopolysaccharide (LPS), and cytolethal distending toxin (CDT), enabling tissue invasion, inflammation, as well as modulation and evasion of immune responses. Many of these factors are released in association with outer-membrane vesicles (OMVs), facilitating their transport to distal tissues, including synovial joints, to induce systemic effects. This review summarizes current knowledge on Aa virulence mechanisms and their potential contribution to systemic inflammation and autoimmunity. We propose Aa OMVs as possible link between PD and RA and offer new perspectives on therapeutic targeting of both diseases.