Multifaceted immune dysregulation characterizes individuals at-risk for rheumatoid arthritis
Year: 2023
Type: article
Study design: Observational Study
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.
Source: Nature Communications
Authors: 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, Kevin D. Deane
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,290
Awards: G2800195642, G4119534169, G5850682332, IN-DEPTH ANALYSIS OF CITRULLINE-SPECIFIC CD4T CELL IN RHEUMATOID ARTHRITIS, Prevention Center U01: Early Targets for Antigen-Specific Tolerance Induction in Preclinical Rheumatoid Arthritis, Identification of key regulators in rheumatoid arthritis, Rheumatic Diseases Research Training Grant
OpenAlex ID: W4388912002