The Ratio of Blood T Follicular Regulatory Cells to T Follicular Helper Cells Marks Ectopic Lymphoid Structure Formation While Activated Follicular Helper T Cells Indicate Disease Activity in Primary Sjögren's Syndrome

Objective To investigate whether the balance of blood follicular helper T (Tfh) cells and T follicular regulatory (Tfr) cells can provide information about ectopic lymphoid neogenesis and disease activity in primary Sjögren's syndrome ( SS ). Methods We prospectively recruited 56 patients clinically suspected of having SS . Sixteen of these patients subsequently fulfilled the American–European Consensus Group criteria for SS and were compared to 16 patients with non‐ SS sicca syndrome. Paired blood and minor salivary gland ( MSG ) biopsy samples were analyzed to study Tfr cells and subsets of Tfh cells in both compartments. Results Patients with primary SS had normal Tfh cell counts in peripheral blood; however, activated programmed death 1–positive ( PD ‐1+) inducible costimulator–positive ( ICOS +) Tfh cells in peripheral blood were strongly associated with disease activity assessed by the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (r = 0.8547, P = 0.0008). Conversely, the blood Tfr cell:Tfh cell ratio indicated ectopic lymphoid structure formation in MSG s, being strongly associated with B cell, CD 4+ T cell, and PD ‐1+ ICOS + T cell infiltration in MSG s, and was especially increased in patients with focal sialadenitis. Further analysis showed that the blood Tfr cell:Tfh cell ratio allowed discrimination between SS patients and healthy donors with excellent accuracy and was a strong predictor of SS diagnosis (odds ratio [ OR ] 12.96, P = 0.028) and the presence of focal sialadenitis ( OR 10, P = 0.022) in patients investigated for sicca symptoms, thus highlighting the potential clinical value of this marker. Conclusion The blood Tfr cell:Tfh cell ratio and PD ‐1+ ICOS + Tfh cells constitute potential novel biomarkers for different features of primary SS . While the blood Tfr cell:Tfh cell ratio is associated with ectopic lymphoid neogenesis, activated Tfh cells indicate disease activity.