The Infectious Basis of ACPA-Positive Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is associated with HLA-DRB1 shared epitope (HLA-DRB1SE) and anti-citrullinated protein autoantibodies (ACPAs). ACPAs precedes the onset of clinical and subclinical RA. There are strong data for three infectious agents as autoimmunity triggers in RA, namely Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans causes of periodontal disease (PD), and Epstein-Barr virus (EBV). P. gingivalis expresses arginine gingipains, that cleave proteins at the arginine residues, and peptidyl arginine deiminase (PPAD), which citrullinates arginine residues of proteins, thus forming neoantigens that lead to ACPA production. Peripheral blood plasmablasts from ACPA+RA patients produce ACPAs the majority of which react against P. gingivalis. A. actinocycetemcomitans produces leukotoxin A, a toxin that forms pores in the neutrophil membranes and leads to citrullination and release of citrullinated autoantigens in the gums. EBV can infect B cells and epithelial cells and resides as latent infection in resting B cells. Abs against citrullinated peptides derived from EBV nuclear antigen appear years before RA and cross-react with human citrullinated fibrin. Citrullinated proteins are potential arthritogenic autoantigens in RA. The conversion of arginine to citrulline increases the peptide binding affinity to HLA-DRB1SE. Also, citrullinated fibrinogen induces arthritis in HLA-DRB1*0401 transgenic mice, and transfer of their splenic T cells causes arthritis to recipient mice.

HLA associations in inflammatory arthritis: emerging mechanisms and clinical implications

“…[H3] Gene-environment interactions involving the shared epitope Epidemiologic studies of ACPA-positive RA have provided striking evidence for a gene-environment interaction: two environmental factors, smoking and gingivitis, increase the risk of RA, but only in carriers of SE-containing HLA-DRB1 alleles [57][58][59][60][61] . Both smoking and gingivitis induce protein citrullination, a post-translational modification of positively charged arginine residues to citrulline, which is catalyzed by peptidylarginine deiminases (PAD) (Fig.…”

“…Smoking-induced inflammation upregulates host PAD enzymes in the lungs 57 . Porphyromonas gingivalis, a bacterium associated with gingivitis, has its own PAD enzyme; another gingivitis-associated pathogen, Aggregatibacter actinomycetemcomitans, produces a toxin that induces hypercitrullination of proteins in neutrophils and promotes their extracellular release 60 . This evidence suggests a model in which the SE confers risk of autoreactivity directed against citrullinated self-proteins, which are generated at sites of neutrophilic inflammation.…”

“…This suggested that self peptides with arginine residues at position P4 (the residue that binds the P4 pocket) may not be presented under non-inflammatory conditions, when PAD is unavailable, and thus fail to induce tolerance. Citrullination of such arginyl side chains, which neutralizes their positive charges, occurs in inflammatory states when PAD is released by neutrophils 57,60 . At least some of the resulting P4-citrullinated self peptides acquire the ability to bind HLA-DR0401 molecules 66,67 .…”

“…Smoking [57][58][59] and gingivitis 60,61 are environmental risk factors for RA, but only in individuals who carry SE-containing HLA-DRB1 alleles. In principle, this knowledge enables the identification of at-risk individuals so that preventative approaches, such as smoking cessation and oral hygiene, can be personalized.…”

Herpesvirus‐bacteria synergistic interaction in periodontitis

“…During the last 20 years, periodontitis has been linked statistically to more than 50 seemingly unrelated systemic diseases and conditions, such as adverse pregnancy outcome, rheumatic fever, cardiovascular disease and stroke, dementia, and cancer . Herpesviruses, however, can infect any organ system of the body and, arguably, periodontal herpesviruses comprise the most likely linkage between periodontitis and various systemic diseases .…”