Rheumatoid Arthritis-Associated Autoimmunity Due to Aggregatibacter actinomycetemcomitans and Its Resolution With Antibiotic Therapy

Abstract

Background: Aggregatibacter actinomycetemcomitans (Aa) is a Gram-negative coccobacillus recognized as a pathogen in periodontitis and infective endocarditis. By producing a toxin (leukotoxin A, LtxA) that triggers global hypercitrullination in neutrophils, Aa has been recently linked to rheumatoid arthritis (RA) pathogenesis. Although mechanistic and clinical association studies implicate Aa infection in the initiation of autoimmunity in RA, direct evidence in humans is lacking.Case:We describe a 59-year-old man with anti-citrullinated protein antibody (ACPA)-positive RA who presented for evaluation of refractory disease. He was found to have Aa endocarditis. Following antibiotic treatment, joint symptoms resolved and ACPAs normalized. Given the implications for RA immunopathogenesis, we further investigated the bacterial, genetic and immune factors that may have contributed to the patient's clinical and autoimmune phenotypes.Methods:DNA was extracted from serum and used to amplify the Aa leukotoxin (ltx) promoter region by PCR, which was further analyzed by Sanger sequencing. High-resolution identification of HLA alleles was performed by sequenced based typing (SBT). TNF-α, IFN-γ, GM-CSF, IL-1β, IL-6, IL-8, IL-17A, IL-18, IL-21, and IL-22 were quantified in serum by a multiplex immunoassay. IgG and IgA antibodies to Aa LtxA were assayed by ELISA.Results:Aa genotyping confirmed infection with a highly leukotoxic strain carrying a 530-bp ltx promoter deletion, shown to result in 10- to 20-fold higher bacterial expression of LtxA. Immuno-phenotyping showed high anti-LtxA antibodies, elevated cytokines implicated in RA pathogenesis (Th1/Th17), and specific host susceptibility conferred by three HLA alleles strongly linked to ACPAs and RA (DRB1*04:04, DRB1*15:01, and DPB1*04:01). One year after eradication of Aa, the patient remained free of arthritis and anti-CCP antibodies.Conclusion: In the context of genetic risk for RA, systemic subacute infection with a leukotoxic strain of Aa can drive ACPA production and a clinical phenotype similar to RA.

Anti-Citrullinated Protein Antibodies in Patients with Rheumatoid Arthritis: Biological Effects and Mechanisms of Immunopathogenesis

“…The infection by periodontitis-causing bacteria, such as Porphyromomas gingivalis (P. gingivalis) and Aggregatibacter actinomycetemcomitans (Aa), as well as intestinal microbiota, likely contributes to ACPA-associated RA pathogenesis [91][92][93][94][95]. The bacterial pore-forming virulence and calcium ionophores, such as ionomycin and calcimycin from Streptomyces species and leukotoxin A from Aa, are important in triggering calcium influx and generating non-tolerized neo-citrullinated epitopes [27][28][29]. Citrullination in P. gingivalis-related periodontitis works through different mechanisms.…”

“…The revolutionary model for RA development stated that a 'second hit' may be required beyond the presence of ACPAs in disease induction [25]. As cigarette smoking and mucosal pathogens are both capable of activating peptidyl arginine deiminase (PAD) and generating citrullinated neoantigens [26][27][28][29], the accumulation of citrullinated antigens and strong immune triggers provided by the virulent agents within the smoke or microbe can possibly attract and activate dendritic cells and B cells for sequential antibody production [25]. With the help of human leukocyte antigen (HLA) molecules, interactions among antigen-specific B cells, T cells and antigen presenting cells (APCs) in the secondary lymphoid organs further promote the maturation of ACPAs [25].…”

The importance of differences; On environment and its interactions with genes and immunity in the causation of rheumatoid arthritis

“…ACPAs from ACPA-positive RA patients have been shown to cross-react with these bacterium-derived citrullinated molecules [131], and it has been suggested that the presence of these bacteria in an immunogenic context in the gums might be responsible for the triggering of some of the ACPAs in RA patients [130]. However, the relationships between periodontitis and RA are complex, and available data suggest that periodontitis and the presence of P. gingivalis per se may not be responsible for triggering of ACPA production in RA, but that immune activation rather occurs in a context of inflammation and genetics, where P. gingivalis and other bacteria including Aggregatibacter actinomycetemcomitans may be involved [133].…”

Immune System Sex Differences May Bridge the Gap Between Sex and Gender in Fibromyalgia

“…Aforementioned process probably plays a role in many autoimmune diseases but have been recognized for only a few. The clinical importance is high because antimicrobial treatment may resolve the initial infection, once the autoimmune disease has developed it may be too late (Mukherjee et al, 2018). Alternatively, it explains why steroid anti-inflammatory treatment worsens (Clark et al, 1985) rather than improves the symptoms.…”