Abstract
Leukotoxin A (LtxA) is the major virulence factor of an oral bacterium known as Aggregatibacter actinomycetemcomitans (Aa). LtxA is associated with elevated levels of anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients. LtxA targets leukocytes and triggers an influx of extracellular calcium into cytosol. The current proposed model of LtxA-mediated hypercitrullination involves the dysregulated activation of peptidylarginine deiminase (PAD) enzymes to citrullinate proteins, the release of hypercitrullinated proteins through cell death, and the production of autoantigens recognized by ACPA. Although model-based evidence is yet to be established, its interaction with the host’s immune system sparked interest in the role of LtxA in RA. The first part of this review summarizes the current knowledge of Aa and LtxA. The next part highlights the findings of previous studies on the association of Aa or LtxA with RA aetiology. Finally, we discuss the unresolved aspects of the proposed link between LtxA of Aa and RA.
Highlights
While previous studies attributed the release of citrullinated autoantigens to NETosis, this study found that Leukotoxin A (LtxA)-induced hypercitrullination was unaffected by neutrophil extracellular trap (NET) formation inhibitors
Anti-LtxA positivity in rheumatoid arthritis (RA) subjects was significantly associated with anti-citrullinated protein antibodies (ACPA) and rheumatoid factors (RF) levels, whereby ACPA of RA subjects positive for anti-LtxA antibodies primarily recognized the citrullinated autoantigens resulting from LtxA-induced hypercitrullination
Studies have shown that there is a link between periodontitis and RA, which is established by the activity of periodontopathogens
Summary
Aggregatibacter actinomycetemcomitans (Aa) is a bacterium isolated from actinomycotic lesions of men and was termed more than a century ago by Klinger as ‘Bacterium actinomycetem comitans’ [1]. At the time of its debut as a novel bacterial species, co-isolated with the ray-shaped fungi Actinomyces spp, responsible for actinomycosis, which is a rare chronic fungal infection. It was given the terms ‘actinomycetem’ and ‘comitans’, which can be literally translated as ‘ray-fungus– accompanying’. In 1985, Aa was reclassified under the genus Haemophilus based on the DNA–DNA hybridization results of a study that attempted to identify potential relationships between strains of Actinobacillus and Haemophilus genera [3] This was objected to by Norskov-Lauritsen and Kilian [4] who assigned this bacterium to a novel genus called “Aggregatibacter”, an evolutionarily distinct branch of the Pasteurellaceae family, after citing their 16S RNA sequencing results.
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