What is RA’s connection with citrullination and anticitrullinated protein (ACPA) antibodies? The fundamental role of ACPAs and RA is now accepted, with considerable attention now to investigating their role in pathogenesis of disease (which is mostly beyond the scope of this discussion). ACPAs precede RA, are predictive of RA, and have been found in serum and synovial immune deposits in patients with early and established disease.18-26 Antibodies to human citrullinated alpha enolase and P. gingivalis enolase cross react, suggesting important linkage and/or molecular mimicry in disease pathogenesis.27 Studies of the repertoires of ACPAs in RA patients with and without periodontal disease showed distinct ACPA reactivities compatible with the possibility that uncitrullinated peptide breaks tolerance in periodontal disease with epitope spreading to citrullinated epitopes. This, in some patients, might eventuate in or contribute to RA.28
Further, patients with RA had antibodies to P. gingivalis more frequently than controls, although less frequently than patients with periodontal disease, and with correlations to RA-related autoantibody and CRP levels.29 And, in patients with RA, both patients and their relatives had antibodies to P. gingivalis, which were associated with ACPA.30 These observations are consistent with a role for P. gingivalis in RA, but do not themselves represent proof, as other explanations for these data are possible.
Finally, are there experimental studies examining these putative associations? These were interesting. In one study, mice (DR4-IE transgenic, C57BL/6, and control) were immunized with recombinant human alpha enolase and P. gingivalis enolase, citrullinated or uncitrullinated; DR4-IE subjects developed arthritis and antibodies to citrullinated and unmodified human alpha enolase and arginine-bearing control peptide. These data support a possible role for P. gingivalis enolase in RA.31 In other experiments, using a model of chronic antigen-induced arthritis, it was found that the model mimicked several features of RA and periodontal disease, with associated manifestations of both disorders.32
Whether or not importation of sugar from the Americas led to emergence of RA in Europe may never be known. But, certainly, RA and periodontal disease share common clinical, immunopathologic, serologic, and epidemiologic features. Several lines of evidence intersect at P. gingivalis and its peptidyl arginine deiminase, suggesting a role in the immunopathogenesis of RA.
Dr. Panush is professor of medicine, division of rheumatology, department of medicine, Keck School of Medicine, University of Southern California in Los Angeles.
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- De Smit M, Westra A, Vissink A, Doornbos-van der Meer B, van Winkelhoff AJ, Brouwer E. Patients with rheumatoid arthritis and periodontitis have higher disease activity and a more pronounced antibody response against Porphyromonas gingivalis. Ann Rheum Dis. 2012;71:A26-A27.
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- Darrah E, Rosen A, Giles JT, Andrade F. Peptidylarginine deiminase 2, 3 and 4 have distinct specificities against cellular substrates: Novel insights into autoantigen selection in rheumatoid arthritis. Ann Rheum Dis. 2012;71:92-98.
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