Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction

Abstract

Individuals at high risk of developing seropositive rheumatoid arthritis (RA) can be identified for translational research and disease prevention studies through the presence of highly informative and predictive patterns of RA-related autoantibodies, especially anti-citrullinated protein antibodies (ACPAs), in the serum. In serologically positive individuals without arthritis, designated ACPA positive at risk, the presence of mucosal inflammatory processes associated with the presence of local ACPA production has been demonstrated. In other at-risk populations, local RA-related autoantibody production is present even in the absence of serum autoantibodies. Additionally, a proportion of at-risk individuals exhibit local mucosal ACPA production in the lung, as well as radiographic small-airway disease, sputum hypercellularity and increased neutrophil extracellular trap formation. Other mucosal sites in at-risk individuals also exhibit autoantibody production, inflammation and/or evidence of dysbiosis. As the proportion of individuals who exhibit such localized inflammation-associated ACPA production is substantially higher than the likelihood of an individual developing future RA, this finding raises the hypothesis that mucosal ACPAs have biologically relevant protective roles. Identifying the mechanisms that drive both the generation and loss of externally focused mucosal ACPA production and promote systemic autoantibody expression and ultimately arthritis development should provide insights into new therapeutic approaches to prevent RA.Preclinical rheumatoid arthritis (RA) is characterized by the presence of RA-related autoantibodies in the serum in the absence of clinical symptoms. This Review discusses the relationships during this period between mucosal alterations and the initiation of local and systemic anti-citrullinated protein antibody production.Key pointsPatients who eventually develop seropositive rheumatoid arthritis (RA) pass through a period of RA-related autoantibody positivity that is associated with increased levels of cytokines and chemokines.Various mucosal processes can influence the development of systemic immunity and autoimmunity.Individuals who are at high risk of the future development of RA demonstrate evidence of chronic systemic and mucosal inflammation.Rather than reflecting a loss of citrullinated antigen tolerance, immunoglobulin A (IgA) anti-citrullinated protein antibodies (ACPAs) are normally produced locally; a systemic IgG response likely results from loss of externally focused compartmentalization.Ongoing studies are linking the development of mucosal dysbiosis, inflammation and autoantibody production to the next stages of development of systemic autoimmunity.Novel autoimmune-promoting processes are likely to be identified that function primarily, or exclusively, in the preclinical period of RA and could be the targets for new prevention strategies.