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.

Background. KRAS mutations are highly prevalent in pancreatic, lung, and colorectal carcinomas with G12V point substitution being one of the most prevalent mutations. While developments of peptide vaccines for KRAS(+) cancers are usually associated with poor immunogenicity, coupling mutant K-ras vaccines with universal CD4+ carrier molecules may enhance its outcome. Additionally, recent immunotherapeutic advances also suggest the possibility of inducing mucosal immunity against cancers using Lactococcus lactis as a live gastrointestinal delivery vehicle. Methods. A region of wild-type K-ras peptide was previously modified with a V7D substitution flanking the G12V mutation, generating a K-ras peptide (termed 68-V) with improved predicted antigenicity. This peptide was fused with a diphtheria toxoid sequence, and cloned into pNZ8048 vector within Lactococcus lactis NZ9000. BALB/c mice were then immunized orally, and then subjected to T/B cells immunophenotyping, as well as IgG and IgA detection. Results. Modified 68-V K-ras peptide and controls were successfully cloned and detection of His-tagged proteins expressed following induction by nisin was observed. Populations of CD3-CD19+ immune cells increased following immunization of 68-V, while K-ras specific-IgG and -IgA sera titers were elevated compared to wild-type and G12V K-ras controls. Conclusion. 68-V K-ras mimotope was shown to induce humoral-mediated immunity, highlighting the ability of an additional mutation flanking the G12V KRAS mutation to induce B cell activation and production of K-ras specific antibodies, while diphtheria toxoid was unable to stimulate an enhanced response when fused to 68-V. Nevertheless, these findings showed that further assessments are required to understand the role of K-ras specific antibodies within a KRAS(+) environment.