Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis

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. The common occurrence of periodontal dysbiosis in RA suggests that oral pathogens may trigger the production of disease-specific autoantibodies and arthritis in susceptible individuals. We used mass spectrometry to define the microbial composition and antigenic repertoire of gingival crevicular fluid in patients with periodontal disease and healthy controls. Periodontitis was characterized by the presence of citrullinated autoantigens that are primary immune targets in RA. The citrullinome in periodontitis mirrored patterns of 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, Aggregatibacter actinomycetemcomitans (Aa), but not other candidate pathogens, induced hypercitrullination in host neutrophils. We identified the pore-forming toxin leukotoxin-A (LtxA) as the molecular mechanism by which Aa triggers dysregulated activation of citrullinating enzymes in neutrophils, mimicking membranolytic pathways that sustain autoantigen citrullination in the RA joint. Moreover, LtxA induced changes in neutrophil morphology mimicking extracellular trap formation, thereby releasing the hypercitrullinated cargo. Exposure to leukotoxic Aa strains was confirmed in patients with RA and was associated with both anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF). The effect of HLA-DRB1 shared epitope alleles on autoantibody positivity was limited to RA patients that were exposed to Aa. These studies identify the periodontal pathogen Aa as a candidate bacterial trigger of autoimmunity in RA

Synthons for carbide complex chemistry

The sterically accessible carbide complex, (Cy3P)Cl3Ru?C-PtCl(py)(2), acts as a synthon for terminal and bridging carbide fragments that relocate to pincer and A-frame scaffolds upon ligand addition. This concept, benefitting from coordination sphere selection as the concluding step, confronts traditional synthetic strategies and broadens the scope for carbide complexes

Weakening of Carbide–Platinum Bonds as a Probe for Ligand Donor Strengths

We report the observation of the weakening of the RuC–Pt single bond in (Cy₃P)₂Cl₂RuC–PtCl₂–L (<b>RuC–Pt–L</b>) complexes, leading to the incipient formation of the terminal ruthenium carbide complex, (Cy₃P)₂Cl₂Ru<b></b>C (<b>RuC</b>). In the solid state, elongation of RuC–Pt bonds illustrates the degree of weakening, and in solution, decreasing platinum–carbide coupling constants and increasing carbide chemical shifts reveal weaker interaction through the carbide bridge, as the electron donating ability of L becomes progressively stronger. For the bridging carbide ligands, the chemical shifts and coupling constants to platinum are linearly dependent, and NMR data for parent <b>RuC</b> conform to this relationship, providing a spectroscopic means of determining the strength of the RuC–Pt linkages relative to dissociated <b>RuC</b>. The pliancy of the <b>RuC–Pt–L</b> fragment with regard to the identity of L establishes the carbide-bridged complexes as remarkably wide-ranging and sensitive probes for ligand donor abilities