Follicular Helper and Follicular Regulatory T Cell Subsets Imbalance is Associated with higher activated B cells and Abnormal Auto-antibody Production in Primary Anti-phospholipid Syndrome Patients.

Long, Yan; Li, Wenyi; Feng, Jinghong; Ma, Yingting; Sun, Yuanyuan; Xu, Lijuan; Song, Ying; Liu, Chen

Primary anti-phospholipid antibody syndrome (pAPS) is a multi-organs autoimmune disease, and autoantibodies were involved in its pathogenesis. Follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr) are critical for B cells maturation and antibodies production, but their roles in pAPS remain unknown. We enrolled Thirty-two pAPS patients and twenty-three healthy controls (HCs) and comprehensively analyzed circulating Tfh and Tfr, as well as their subsets, using flow cytometry. Clinical data including autoantibody levels were collected and their correlations with Tfh and Tfr subsets were analyzed. In addition, correlations between B cell functional subsets and Tfh, Tfr were also performed. Changes and potential effects of serum cytokines on Tfr and Tfh were further explored. We found the circulating Tfr was significantly decreased while Tfh and Tfh/Tfr ratios were increased in pAPS patients. Tfh2, ICOS+PD-1+Tfh and Ki-67+Tfh percentages were elevated while CD45RA-FoxP3hi, Helios+, TIGIT+ and Ki-67+ Tfr percentages were decreased in pAPS patients. New memory B cells and plasmablasts were increased and altered B cell subsets and serum autoantibodies were positively correlated with Tfh, Tfh2, ICOS+PD-1+Tfh cells, and negatively associated with Tfr, CD45RA-FoxP3hiTfr and Helios+ Tfr cells. In addition, pAPS with LA/aCL/β2GPI autoantibodies showed lower functional Tfr subsets and higher activated Tfh subsets. Serum IL-4, IL-21, IL-12 and TGF-β1 were up-regulated and associated with Tfh and Tfr subset changes. Our study demonstrated that imbalance of circulating Tfr and Tfh, as well as their functional subsets, is associated with abnormal autoantibody levels in pAPS, which may contribute to the pathogenesis of pAPS.