Multifaceted immune dysregulation characterizes individuals at-risk for rheumatoid arthritis

Eddie A. James, V. Michael Holers (), Radhika Iyer, E. Barton Prideaux, Navin L. Rao, Cliff Rims, Virginia S. Muir, Sylvia E. Posso, Michelle S. Bloom, Amin Zia, Serra E. Elliott, Julia Z. Adamska, Rizi Ai, R. Camille Brewer, Jennifer A. Seifert, LauraKay Moss, Saman Barzideh, M. Kristen Demoruelle, Christopher C. Striebich, Yuko Okamoto, Enkhtsogt Sainbayar, Alexandra A. Crook, Ryan A. Peterson, Lauren A. Vanderlinden, Wei Wang, David L. Boyle, William H. Robinson, Jane H. Buckner, Gary S. Firestein and Kevin D. Deane
Additional contact information
Eddie A. James: Benaroya Research Institute
V. Michael Holers: University of Colorado Anschutz Medical Campus
Radhika Iyer: Stanford University
E. Barton Prideaux: University of California, San Diego
Navin L. Rao: Janssen Research and Development
Cliff Rims: Benaroya Research Institute
Virginia S. Muir: Benaroya Research Institute
Sylvia E. Posso: Benaroya Research Institute
Michelle S. Bloom: Stanford University
Amin Zia: Stanford University
Serra E. Elliott: Stanford University
Julia Z. Adamska: Stanford University
Rizi Ai: University of California, San Diego
R. Camille Brewer: Stanford University
Jennifer A. Seifert: University of Colorado Anschutz Medical Campus
LauraKay Moss: University of Colorado Anschutz Medical Campus
Saman Barzideh: University of Colorado Anschutz Medical Campus
M. Kristen Demoruelle: University of Colorado Anschutz Medical Campus
Christopher C. Striebich: University of Colorado Anschutz Medical Campus
Yuko Okamoto: University of Colorado Anschutz Medical Campus
Enkhtsogt Sainbayar: University of Colorado Anschutz Medical Campus
Alexandra A. Crook: University of Colorado Anschutz Medical Campus
Ryan A. Peterson: University of Colorado Anschutz Medical Campus
Lauren A. Vanderlinden: University of Colorado Anschutz Medical Campus
Wei Wang: University of California, San Diego
David L. Boyle: Allergy and Immunology, University of California, San Diego
William H. Robinson: Stanford University
Jane H. Buckner: Benaroya Research Institute
Gary S. Firestein: Allergy and Immunology, University of California, San Diego
Kevin D. Deane: University of Colorado Anschutz Medical Campus

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Molecular markers of autoimmunity, such as antibodies to citrullinated protein antigens (ACPA), are detectable prior to inflammatory arthritis (IA) in rheumatoid arthritis (RA) and may define a state that is ‘at-risk’ for future RA. Here we present a cross-sectional comparative analysis among three groups that include ACPA positive individuals without IA (At-Risk), ACPA negative individuals and individuals with early, ACPA positive clinical RA (Early RA). Differential methylation analysis among the groups identifies non-specific dysregulation in peripheral B, memory and naïve T cells in At-Risk participants, with more specific immunological pathway abnormalities in Early RA. Tetramer studies show increased abundance of T cells recognizing citrullinated (cit) epitopes in At-Risk participants, including expansion of T cells reactive to citrullinated cartilage intermediate layer protein I (cit-CILP); these T cells have Th1, Th17, and T stem cell memory-like phenotypes. Antibody-antigen array analyses show that antibodies targeting cit-clusterin, cit-fibrinogen and cit-histone H4 are elevated in At-Risk and Early RA participants, with the highest levels of antibodies detected in those with Early RA. These findings indicate that an ACPA positive at-risk state is associated with multifaceted immune dysregulation that may represent a potential opportunity for targeted intervention.

Date: 2023
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DOI: 10.1038/s41467-023-43091-8

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