Autoantibody Epitope Spreading in the Pre-Clinical Phase Predicts Progression to Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability. Though prior studies have demonstrated the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear. To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA. To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1–12 years prior to disease onset. We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines. We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing). We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes. At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA. Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-α, IL-6, IL-12p70, and IFN-γ. Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread. Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis.

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

“…The ability of abatacept to modify the interaction between naive CD41 T cells and APCs may have very important clinical consequences. Generation of neoantigens through citrullination or other posttranslational modifications and epitope spreading are critical for the progression of RA and have been reported to happen very early in disease development (59,60). Modification of the function of APCs and their ability to induce responses against these antigens early in disease development could halt these processes and thus ameliorate disease progression.…”

Fine specificity of anti-citrullinated peptide antibodies discloses a heterogeneous antibody population in rheumatoid arthritis

“…However, it is noteworthy that the repertoire of citrullinated peptides recognized by the ACPA seems to have been already developed before disease onset, while recognition of citrullinated peptides does not change as disease evolves [36]. Furthermore, this expansion of ACPA response has been correlated closely with an elevation of specific inflammatory cytokines such as tumour necrosis factor (TNF)-α and interferon (IFN)-γ that precedes the appearance of arthritis [37]. Thus, the breakdown of peripheral immune tolerance is centred probably in the preclinical phase of the disease, when citrullination is taking place and citrullinated autoantigens are being presented and recognized by the immune system, eliciting an autoimmune response [38].…”

A Contra Capture Protein Array Platform for Studying Post-translationally Modified (PTM) Auto-antigenomes

“…In addition, some samples showed responses to other citrullinated proteins, including moderate reactivity to Histone H2A type 1 (H2A) and ENO1. The fractions of samples reactive to other citrullinated autoantigens such as VIM and Histone H2B (H2B) were lower than those reported in the literature (47). Sampling bias due to our small sample size and over-representation of rheumatoid factor negative (RF-) RA subtypes in our samples (50% versus ϳ25% in the typical RA population (48)) may have contributed to the difference.…”