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.

Figure 1.. Biomarker studies relevant to pre-clinical RA pathogenesis.

Shown in the middle are EULAR recommendations for definition of disease stages (a – f) in the natural history of RA, with the pre-clinical stages bracketed. Boxes above and below the natural history stages include experimental approaches that are discussed herein and utilized through the pre-clinical period to understand the causal drivers of pre-clinical disease. Study populations include retrospective serum samples in addition to analyses of biomarkers in At-Risk populations.

Figure 2.. Local immune system and microbial factors that interact in the mucosal environment.

Illustrated are components of the bi-directional regulation between the luminal microbiome and the cells within the mucosa itself, with several cell types contributing individually to produce local cytokines. Specific examples are described in the text, but for example MAIT cells produce IL-17 while ILC3 are responsible for elaborating IL-22. PMN: polymorphonuclear neutrophils.

Figure 3.. Representations of immune alterations in At-Risk individuals.

Studies of At-Risk individuals demonstrate immune alterations, both systemically and within local mucosal sites, consistent with the presence of chronic mucosal inflammation. Shown are findings found in these At-Risk populations. Not included are findings from patients with classified RA, as it is unknown as to whether those factors play a role in pre-clinical RA.

Figure 4.. Loss of the mucosal firewall allows systemic spread of ACPA response.

Hypothetical model for RA initiation as chronic mucosal inflammation and then transition to systemic autoimmune disease, focusing on the potential roles for normal and dysregulated local mucosal ACPA generation. Depicted at left is the reversible production of IgA ACPA in individuals as part of normal surveillance or who have transient mild inflammation. This process is common and part of normal homeostasis at the mucosal surface. At right is the postulated status of individuals in the pre-clinical RA state where persistent inflammation leads to increased ACPA production and systemic spread of an autoimmune process through multiple potential processes described herein. The drivers of this local and then systemic process could include cytokines, metabolomic changes, cross-reactive ACPA with bacterial antigens, or the presence of other antigen-specific cells that are expanded. Regardless of the mechanisms involved, these antibodies and cells begin to circulate as a reflection of the chronic inflammation and are detectable through serologic and other biomarker studies.