The detection of anti-citrullinated protein antibody (ACPA) has become part of the diagnostic criteria for rheumatoid arthritis (RA). Its appearance is associated with HLA-DR susceptibility alleles, predicts a more aggressive disease course and is frequently detected in patient sera before the onset of RA. Previous studies suggest that ACPA is induced through interactions between genetic risk factors and the environment, possibly playing a part in triggering the development of RA.
To better understand the possible origin of ACPA in RA, Reina Tsuda, MD, of the Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan, and her colleagues investigated ACPA’s reactivity to human autoantigens and plant and microbial proteins by determining its antigenic epitope. Their findings and methodology were published in Arthritis & Rheumatology, August 2015.
Human monoclonal ACPA (CCP-Ab1) from peripherial blood B cells was generated, using a monoclonal antibody-secreting cell screening system, from 31 patients with RA who possessed cfc1-cyc-specific antibodies in their sera. After the epitope for CCP-Ab1 was mapped, researchers used a computational methodology to identify proteins that share the same essential epitope. The researchers then produced selected autoantigens and proteins in vitro and examine their reactivity to CCP-Ab1.
On close examination, CCP-Ab1 did not react with the citrullinated recombinant vimentin, α-enolase or fibrinogen proteins, which do not share its essential epitope. However it did weakly, yet significantly, react with the citrullinated fibrinogen peptide, but not with the other peptides, demonstrating that CCP-Ab1 binds to many human citrullinated autoantigens.
To investigate if ACPA is induced by molecular mimicry, for instance by exposure to environmental risk factors, researchers searched for proteins with 100% sequence identity to the essential epitope sequence of 11 proteins that bound to CCP-Ab1. More than 3,000 proteins (56 from viruses, 1,383 from fungi, 547 from bacteria and 1,072 from plants) contained such sequences. These data suggest that more than 3,000 environmental proteins, such as plant proteins commonly found in a daily diet, may be candidate CCP-Ab1 antigens.
With these results, the researchers propose that countless environmental factors, including microbes and diet, play a role in generating ACPA, which then cross-reacts molecularly with autoantigens to induce RA.
Tsuda R, Ozawa T, Kobayashi E, et al. Monoclonal antibody to citrullinated-peptides obtained from rheumatoid arthritis patients reacts with numerous citrullinated microbial and food-proteins. Arthritis Rheumatol. 2015 Aug;67(8):2020–2031.
