Background: Programmed cell death protein-1 (PD-1) maintains peripheral immune tolerance by preventing T-cell continuous activation.[1] However, little is known about the expression of PD-1 on immune cells other than T-cells in inflammatory arthritis.[2,3]

Objectives: To assess the possible role of PD-1 beyond T-cell response regulation in inflammatory arthritis.

Methods: PD-1 expression at single-cell level, using a 31-antibody panel and a 3 ^rd generation mass cytometer (CyTOF), Helios, was evaluated in the peripheral blood of biologic agent-naïve patients with active seropositive and seronegative RA (n=9 and n=8, respectively), active psoriatic arthritis (PsA; n=9) and age- and sex-matched healthy controls (HC; n=13). Patients were re-evaluated after 3 months of anti-rheumatic treatment. The levels of PD-1 ⁺ -expressing immune cells were correlated with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).

Results: PD-1 was expressed in all leukocyte subpopulations, with the highest PD-1 ⁺ cell frequencies in eosinophils (59-73%) and T-cells (50–60%), and the lowest in natural-killer cells (1–3%). PD-1 ⁺ cell frequencies and PD-1 median expression were comparable between patient subgroups and HC, in the majority of cell subsets. Exceptions included increases in certain T-cell/B-cell subsets of seropositive RA and specific monocyte subsets and dendritic cells of PsA; an expanded PD-1 ⁺ CD4 ⁺ CD45RA ⁺ CD27 ⁺ CD28 ⁺ Τ subset, denoting exhausted T-cells, was common across patient subgroups. Strikingly, significant inverse correlations between individual biomarkers of systemic inflammation (ESR and/or serum CRP) and PD-1 ⁺ cell frequencies and/or median expression were evident in several innate and adaptive immunity cell subsets of RA and PsA patients. Furthermore, all inverse correlations noted in individuals with active arthritis were no longer discernible in those who attained remission/low disease activity post-treatment.

Conclusion: PD-1 expression may be insufficient, relative to the magnitude of the concomitant systemic inflammatory response on distinct leukocyte subsets, varying between RA and PsA. Our results point to the potential therapeutic benefits of pharmacological PD-1 activation, in order to rebalance the autoimmune response and reduce inflammation.

REFERENCES: [1] L.M. Francisco, P.T. Sage, A.H. Sharpe, The PD-1 pathway in tolerance and autoimmunity, Immunol Rev 236 (2010) 219–242.

[2] J. Bartosińska, E. Zakrzewska, A. Król, et al., Differential expression of programmed death 1 (PD-1) on CD4 + and CD8 + T cells in rheumatoid arthritis and psoriatic arthritis, Pol Arch Intern Med 127 (2017) 815–822.

[3] K. Lowe, A. Small, Q. Song, L.Y. et al., Transcriptomic profiling of programmed cell death 1 (PD-1) expressing T cells in early rheumatoid arthritis identifies a decreased CD4 ⁺ PD-1 ⁺ signature post-treatment, Scientific Reports 13 (2023) 1–10.

Acknowledgements: We acknowledge the support of this work by the project “The Greek Research Infrastructure for Personalised Medicine (pMedGR)” (MIS 5002802) which is implemented under the Action “Reinforcement of the Research and Innovation Infrastructure”, funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014-2020) and co-financed by Greece and the European Union (European Regional Development Fund).

Disclosure of Interests: Eleni-Kyriaki Vetsika: None declared, George E. Fragoulis PFIZER, GENESIS, MSD, UCB, BOEHRINGER INGELHEIM, ENORASIS, FARMASERV-LILLY, ABBVIE, NOVARTIS, ROCHE, FARAN, AMGEN, JANNSEN, Maria Kyriakidi: None declared, Kleio Verrou: None declared, Maria G. Tektonidou ACTELION, PFIZER, GENESIS, MSD, UCB, BOEHRINGER INGELHEIM, ENORASIS, FARMASERV-LILLY, GILEAD, ABBVIE, NOVARTIS, ROCHE, FARAN, AMGEN, JANNSEN, Themis Alissafi: None declared, Petros P. Sfikakis ACTELION, PFIZER, GENESIS, MSD, UCB, BOEHRINGER INGELHEIM, ENORASIS, FARMASERV-LILLY, GILEAD, ABBVIE, NOVARTIS, ROCHE, FARAN, AMGEN, JANNSEN, ACTELION, PFIZER, GENESIS, MSD, UCB, BOEHRINGER INGELHEIM, ENORASIS, FARMASERV-LILLY, GILEAD, ABBVIE, NOVARTIS, ROCHE, FARAN, AMGEN, JANNSEN.