Type-1 interferon-driven innate and <i>GZMK</i> + CD8 T cell activation precedes subclinical joint inflammation when rheumatoid arthritis is imminent

This study identifies immune signatures that may precede subclinical joint inflammation in individuals at high risk for rheumatoid arthritis, highlighting the role of type-1 interferon activation.

Summary and findings

This study investigated immune signatures associated with the transition to subclinical joint inflammation in anti-citrullinated protein antibodies (ACPA+)-positive individuals. It involved single-cell transcriptomic and proteomic profiling of blood samples from high-risk ACPA+ imminent progressors. The findings indicate type-1 interferon activation in specific immune cells prior to the onset of subclinical joint inflammation.

Abstract

Rheumatoid arthritis is a prototypical autoimmune disease, characterised by prolonged systemic autoimmunity prior to organ-specific tissue inflammation. To achieve the contemporary goal of autoimmune disease prevention, a nuanced understanding of the transition from systemic autoimmunity to tissue-specific inflammation is critical. Here, we sought to identify immune signatures associated with the transition to subclinical joint inflammation detected by multi-joint ultrasound in anti-citrullinated protein antibodies (ACPA+)-positive individuals who imminently progress to RA. To achieve this, we performed single-cell transcriptomic and proteomic profiling on prospectively collected blood samples from high-risk ACPA+ imminent progressors, who were further stratified by the presence or absence of ultrasound (US)-detectable subclinical synovitis and compared them with ACPA+ non-progressors. We found type-1 interferon (IFN-I) activation in circulating CD14+ classical monocyte and GZMK + CD8+ T cells preceding subclinical joint inflammation in ultrasound-negative (USneg) future progressors. In contrast, US-positive (USpos) future progressors exhibited a phenotypic shift in CD14+ classical monocytes towards IL1ß+ expression and clonal expansion of GZMB + cytotoxic CD8+ T cells at the onset of subclinical synovitis. Plasma proteomics also revealed a shift from Toll-like receptor–associated innate pathways in USneg future progressors toward effector and tissue-remodeling signatures in USpos future progressors. These findings suggest IFN-I-driven immune priming in specific immune subsets precedes the onset of subclinical joint inflammation, whereas tissue-directed inflammatory and cytotoxic programmes emerge at the onset of joint inflammation when clinical RA is imminent.

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