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.
Highlights
Rheumatoid arthritis (RA) is a systemic inflammatory disease mainly manifested with peripheral polyarthritis
The discovery of HLA-DRB1 shared epitope (SE, HLADRB1SE), a hypervariable DRβ chain sequence shared by all alleles associated with RA, reinforced this concept (Gregersen et al, 1987; Wordsworth et al, 1989)
anti-citrullinated protein autoantibodies (ACPAs) in RA recognize many citrullinated autoantigens (Table 1) and are associated with HLA-DRB1SE (Snir et al, 2009), and HLADRB1SE appears to be a risk factor for ACPA production in RA rather than an independent risk factor for RA development. These findings and the fact that ACPAs are of IgG and IgA class suggest that T cells provide help to B cells for the subsequent ACPA production
Summary
Rheumatoid arthritis (RA) is a systemic inflammatory disease mainly manifested with peripheral polyarthritis. ACPAs in RA recognize many citrullinated autoantigens (Table 1) and are associated with HLA-DRB1SE (Snir et al, 2009), and HLADRB1SE appears to be a risk factor for ACPA production in RA rather than an independent risk factor for RA development (van der Helm-van Mil et al, 2006). These findings and the fact that ACPAs are of IgG and IgA class suggest that T cells provide help to B cells for the subsequent ACPA production. Smoking is a risk factor for RA (van der Helm-van Mil et al, 2007; Lundberg et al, 2013; Hensvold et al, 2015), and increases citrullination in bronchial tissues (Makrygiannakis et al, 2008), other environmental factors, in addition to smoking, appear to play a predominant role in the development of ACPA+RA (Lee et al, 2007; Hensvold et al, 2015) and infections are likely candidates (Bogdanos and Sakkas, 2017)
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