Circulating Follicular Helper T Cells: Evaluating Potential Clinical Biomarkers in Patients with Autoimmunity

Abstract

Background Circulating T follicular helper (cTfh) cells are pivotal in facilitating high-affinity antibody generation and autoimmunity. Variations in the distribution of CD4(+)T cells expressing the C-X-C chemokine receptor type 5 (CXCR5) and their subsets (cTfh1, cTfh17, cTfh1/17, cTfh2) have been documented in various autoimmune diseases. Despite the prominent role of TSH receptor autoantibody (TRAb) production and lymphocytic infiltration in Graves disease (GD), the involvement of cTfh cells in its pathogenesis remains incompletely understood. This study investigated the clinical utility of measuring cTfh subsets in managing patients with GD.

Methods We conducted an observational study of cTfh cell profiles in pediatric patients diagnosed with GD. Our objective was to delineate potential clinical correlates, including disease activity and TRAb positivity, associated with patterns of cTfh skewing. We identified protein biomarkers potentially implicated in GD using the 7k SomaScan Assay v4.1, principal component analysis and pathway enrichment analysis with Enrichr. To validate the SomaScan findings, we performed enzyme-linked immunosorbent assays (ELISAs) for von Willebrand Factor (vWF) and actinin-alpha-2, selected based on their potential relevance to GD across the entire GD cohort.

Results We enrolled a cohort of 38 patients with GD and 50 controls without any history of autoimmunity or immunologic disorders. Among the GD cohort, 89% were female, with a median age of 18 years. At the time of enrollment, 50% of the patients had active disease, 21% were in remission, and 29% had undergone definitive therapy. The most frequent comorbidities were obesity and Trisomy 21. Overall, CD4(+)CXCR5+ cTfh cell percentages were normal, with 15% exhibiting CD4(+)CXCR5+CXCR3+CCR6+ cTfh1/17 skewing. Levels of vWF, a marker of endothelial dysfunction or inflammation, were elevated in patients with active GD and significantly higher in those with Trisomy 21.

Conclusions Increased percentages of cTfh1/17 cells and the presence of platelet dysfunction markers showed significant correlations with active GD, particularly evident in patients with Trisomy 21. cTfh cells and vWF levels could be potentially relevant biomarkers in patients with Trisomy 21. Targeting T cell activation pathways may offer therapeutic benefits in certain subgroups of patients with GD.