Regulation and targeting of T follicular helper cell response in primary Sjögren's syndrome

Abstract

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder that primarily affects the exocrine glands, leading to dry eyes and dry mouth symptoms. However, the underlying mechanisms of pSS remain poorly understood, and thus effective therapies are lacking. Current medication mainly includes biologics (mostly in the clinical trials) and immunosuppresants, such as methotrexate (MTX). MTX is a commonly used drug in the clinical treatment of pSS, associated with various side effects and drug resistance. In the context of pSS, T follicular helper (Tfh) cells, which display heightened activation, play a crucial role in facilitating autoreactive B cell response, in particular pathogenic autoantibodies production. Therefore, understanding and targeting Tfh cell responses in pSS are urgently warranted.

Caveolin-1 (Cav-1) is a protein involved in the formation of caveolae and lipid domains and has been implicated in various diseases. However, the precise role of Cav-1 in the development of autoimmune diseases remains uncertain. Recent studies have suggested its involvement in TCR and BCR signaling, while mice deficient for Cav-1 showed ameliorated disease pathology of experimental multiple sclerosis. In this study, we demonstrated that Cav-1 deficiency exacerbated Tfh cell responses and the pathology of experimental Sjögren's syndrome (ESS) in mice. Further investigations revealed positive correlations between Cav-1 and PPARα levels in Tfh cells derived from ESS mice and pSS patients. PPARα was found to bind to the Icos promoter, repressing Icos transcription in Tfh cells independently of lipid metabolism. Thus, Cav-1 deficiency or PPARα antagonism resulted in enhanced ICOS-dependent Tfh cell migration. FDA-approved PPARα agonist, fenofibrate, suppressed human Tfh cells and ameliorated disease pathology in ESS mice, suggesting PPARα as a potential therapeutic target for regulating Tfh cell dysregulation in autoimmune conditions.

In recent years, alternative medicine, including ethnopharmacology, has received increasing attention for drug development. Through an analysis of frequently prescribed Traditional Chinese Medicine (TCM) formulas in clinical practice, we noticed that Astragali Radix (AR) is among the most frequently used. Calycosin (Caly) is a major flavonoid in AR, which is derived from its glycoside form calycosin-7-glucoside (Cal7, a standardized component for the quality control of AR in China Pharmacopoeia). Our studies have identified that Caly intervened IL-6-induced Tfh differentiation through the BATF/c-Maf axis. Caly rapidly binds to BATF protein, leading to the inhibition of c-Maf transcription both in human and in mice. Thus, Caly suppressed the proliferation and differentiation of Tfh cells, as well as the production of IL-21 and alleviated the symptoms of ESS.

Despite MTX being the current first-line treatment for pSS, it has been found to enhance Tfh responses instead of suppressing them. Currently, there are no drugs available that specifically target Tfh cells. We took advantages of our finding of Caly, and observed a superb therapy effect when Caly and MTX treatment were combined, in particular at chronic stage. This innovative therapy, which combines a Chinese herb with first-line immunosuppressants, not only reduces the dosage of MTX, but also provides additional treatment options for the clinical management of autoimmune disorders.