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Autoantibody-induced arthritis pain caused by a sustained type I interferon signaling

ABSTRACT: Pain in rheumatoid arthritis is highly debilitating, impacts quality of life and lacks adequate treatment options. Although the presence of pathogenic autoantibodies and systemic and joint inflammation are distinctive features of the disease, the molecular and neuronal basis of pain remains unclear. Here, we identify the molecular mechanism and causative neurons for autoantibody-induced pain in mice. Single-cell RNA sequencing analysis during arthritis pain revealed interferon-stimulated genes, with a persistent nociceptor neuron sensitization, local inflammation and a causative role of interferons acting on polymodal GFRa3-positive C-fiber-nociceptors, as the origin of pain. Consistently, interferon inhibition blocked gene expression alterations and prevented onset as well as reversed established and residual arthritis pain. The discovered pain-causative mechanism may represent a novel therapeutic approach for treatment of pain in rheumatoid arthritis.

ORGANISM(S): Mus musculus

PROVIDER: GSE218634 | GEO | 2025/12/10

REPOSITORIES: GEO

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Project description:Rheumatoid arthritis 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. A total of 559 human sera were profiled using a custom made panel of putative rheumatoid arthritis associated autoantigens. The cohort was comprised of 79 patients with clinical RA for whom stored serum was available from 1-10 years prior to disease onset and 80 control subjects without RA that were matched to cases based on age, gender, race, region of assignment, and time of serum sampling.

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Autoantibody-induced arthritis pain caused by a sustained type I interferon signaling

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