Sirolimus therapy restores the PD-1+ICOS+Tfh:CD45RA-Foxp3high activated Tfr cell balance in primary Sjögren’s syndrome

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作者：Yanlin Wang, Hui Guo, Zhaojun Liang, Min Feng, Yanyao Wu, Yan Qin, Xiangcong Zhao, Chong Gao, Guangying Liu, Jing Luo
期刊：MOLECULAR IMMUNOLOGY
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Background:Primary Sjögren's syndrome (pSS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands. The current study was performed to investigate the roles of follicular helper T (Tfh) and follicular regulatory T (Tfr) subsets in patients with pSS, and to evaluate the effects of sirolimus on these cells.

Methods:Levels of circulating Tfh and Tfr subsets in 58 pSS patients and 26 healthy controls (HC) were determined by flow cytometry. These T cell subsets were also analyzed in 12 patients before and after treatment with sirolimus. Clinical features and correlations with follicular T cells were analyzed systematically. The discriminative ability of the cells and ratios was evaluated based on the area under the receiver operating characteristic curves.

Results:Patients with pSS had higher percentage and absolute number of PD-1+ICOS+Tfh cells, while lower percentage and absolute number of Tfr, activated regulatory T (aTreg) cells, and CD45RA-Foxp3^high activated Tfr cells. Furthermore, increased number of PD-1+ICOS+Tfh cells was associated with B cells, while decreased numbers of Tfr and their subsets was strongly associated with aTreg cells in pSS patients. Also, the higher proportion of PD-1+ICOS+Tfh cells was positively correlated with higher level of autoantibodies, ESR, IgG, cytokines (IL-2, IL-4, IL-10, IL-17, IFN-γ, TNF-α, IL-21 and sIL-2αR), and disease activity. Unexpectedly, the elevated PD-1+ICOS+Tfh:CD45RA-Foxp3^high activated Tfr ratio had the greatest ability to discriminate between pSS and HC, and sirolimus therapy restored the PD-1+ICOS+Tfh cells:CD45RA-Foxp3^high activated Tfr ratio, and controlled disease activity.

Conclusion:The novel ratio of PD-1+ICOS+Tfh to CD45RA-Foxp3^high activated Tfr cells can effectively discriminate the pSS patients from controls, and Tfr cell subsets may resemble Treg cell lineages. Furthermore, the PD-1+ICOS+Tfh cells can be used as a biomarker of disease activity and to verify the therapeutic effects of sirolimus in pSS.