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  • Review Article
  • Published:

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

Nature Reviews Rheumatology volume 14, pages 542–557 (2018)Cite this article

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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.

Key points

  • Patients 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.

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Fig. 1: Factors relevant to preclinical RA pathogenesis.
Fig. 2: Local immune system and microbial factors that interact in the mucosal environment.
Fig. 3: Immune alterations in at-risk individuals.
Fig. 4: Loss of the mucosal barrier allows systemic spread of ACPA response.

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Acknowledgements

The work of the authors is supported by U01 AI101981 (V.M.H.), T32 AR07534 (V.M.H.), UH2 AR067681 (V.M.H.), UM1 AI110503 (V.M.H.), the Rheumatology Research Foundation (V.M.H. and K.D.), R01 AR051394 (V.M.H.), U19 AI50864 (V.M.H.), K08 DK107905 and Pfizer ASPIRE (K.A.K.). The authors appreciate the early input by R. Thomas to the conception of this Review.

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Authors and Affiliations

  1. Division of Rheumatology, University of Colorado–Denver, Aurora, CO, USA

    V. Michael Holers, M. Kristen Demoruelle, Kristine A. Kuhn, Yuko Okamoto & Kevin D. Deane

  2. Benaroya Research Institute, Seattle, WA, USA

    Jane H. Buckner

  3. Division of Immunology and Rheumatology, Stanford University, Stanford, CA, USA

    William H. Robinson

  4. Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA

    Jill M. Norris

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Contributions

V.M.H. researched data, contributed to discussion of content, wrote, reviewed and edited the manuscript before submission. M.K.D., K.A.K., Y.O., J.M.N. and K.D.D. contributed to discussion of content, and reviewed and edited the manuscript before submission. J.H.B. and W.H.R. reviewed and edited the manuscript before submission.

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Glossary

Dysbiosis

A general term used to indicate a change in the normal bacterial ecology, usually with a potential for association with a disease state.

Shared epitope

A set of HLA antigens that are preferentially found in patients with RA and that are characterized by conserved amino acids within the peptide-binding groove.

Epitope spreading

A process in which the epitopes (target antigen shapes or sequences recognized by B and T cell receptors) that are distinct from and non-cross-reactive with the initial target epitope become major targets of an ongoing immune response.

Avidity maturation

A process in which the accumulated strength of multiple affinities of individual non-covalent binding interactions between antigens and antibodies increases over time.

NETosis

A unique form of neutrophil extracellular trap (NET)-associated cell death characterized by nuclear condensation and extrusion of chromatic and granular contents in a manner especially conducive to capturing pathogens.

Molecular mimicry

The development of autoreactivity commonly considered to be through the recognition of a microbial or other foreign pathogen peptide that is structurally similar to self-antigen.

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Holers, V.M., Demoruelle, M.K., Kuhn, K.A. et al. Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction. Nat Rev Rheumatol 14, 542–557 (2018). https://doi.org/10.1038/s41584-018-0070-0

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