Background: Studies in infectious, cardiovascular, and neurodegenerative diseases have demonstrated the presence of memory in innate immune cells. This phenomenon, known as “trained immunity” (TI), leads to an enhanced response to subsequent challenges [1]. This concept was then validated in both in vitro and in vivo models in which microbial stimuli, vaccines or lipoproteins were found to induce TI. Ankylosing spondylitis (AS), a common form of inflammatory arthritis, is characterized by excessive monocyte and T-cell inflammation. However, whether TI plays a role in AS pathology remains unknown.

Objectives: This study aimed to explore whether trained immunity (TI) contributes to the pathology of AS.

Methods: Single-cell RNA sequencing (scRNA-seq) was employed to identify the monocyte subset exhibiting trained immunity features in peripheral blood mononuclear cells (PBMCs) from patients with ankylosing spondylitis (AS), healthy controls, and COVID-vaccinated individuals. Flow cytometry and enzyme-linked immunosorbent assays (ELISA) were used to assess the function of monocytes and T cells in vitro. β-glucan and activated T cells were utilized to train monocyte-derived macrophages in vitro. siRNA targeting genes enriched in TI monocytes was employed to screen for regulators of T-cell-induced monocyte activation.

Results: We identify a monocyte subset that is expanded in patients with ankylosing spondylitis (AS), increases following COVID vaccination, and displays transcriptional and functional features characteristic of trained immunity (TI), including hyper-responsiveness to LPS stimulation. We find that both trained monocytes in AS and β-glucan-trained monocyte-derived macrophages from healthy donors are hyper-responsive to T-cell-induced activation. Moreover, T-cell-stimulated monocytes can reciprocally influence T cells, promoting Th17 responses, which are central to AS pathology. Finally, through siRNA screening of AS risk genes, we identify ZC3H12C, ERN1, and IL1R1 as key regulators of T-cell-induced monocyte activation.

Conclusion: Our data demonstrate for the first time an increased presence of trained immunity (TI) in monocytes from patients with ankylosing spondylitis (AS) and highlight the pivotal role of monocyte-T cell interactions in AS pathology. We also identify three AS risk genes that contribute to T-cell-induced monocyte activation. These findings open new avenues for potential therapeutic interventions.

REFERENCES: [1] Defining trained immunity and its role in health and disease. Neteae M.G. Nat Rev Immunol. 2020.

Acknowledgements: L.C. is funded by a Versus Arthritis (22053 and 23206). P.B. is funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. P.B. is funded by a Versus Arthritis award grant number 22252. We thank the patients and the research nurses Alexandra Queiros and Shristi Lama for their contributions.

Disclosure of Interests: Jinyi Zhao: None declared , Feng Liu: None declared , Paul Bowness PB has received research support from Regeneron, Benevolent AI, Novartis and GSK, liye Chen This work has been partially funded by J&J to the Cartography Consortium. LC has received research support from Novartis.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.