The Role Of Th Subsets In RA And Exploration Of Differentiated Treg From Tfh As A New RA Treatment Strategy

Rheumatoid arthritis(RA)is a chronic autoimmune inflammatory disease,accompanied by progressive destruction of joint cartilage and bone,ultimately leading to functional impairment and disability.Numerous studies have demonstrated that the abundance of T cells within the mononuclear infiltrates of the hyperplastic synovial membrane,taken together with the local production of T cell-derived cytokines are responsible in the autoimmune response in RA.Experimental animals immunized with collagen can be induced arthritis and the symptom is similar to RA patients.This kind of animal model is called collagen-induced arthritis(CIA).And it is commonly used for the RA research.T cell subsets include: Th1,Th2,Th9,Th17,Th22,Treg and Tfh.At the early studying stage,Th1 was considered dominately cause of the pathogenesis in RA.However,recent evidence indicates an important role for Th17 in RA development.Tfh locates in the germinal center,Tfh expresses high levels of CXCR5,ICOS,PD-1 but low levels of CCR7 and secretes IL-21.Bcl6 is a key transcription factor of Tfh.Moreover,Tfh contributes to B cells survival,proliferation and maturation.It has demonstrated that Tfh dysregulation is involved in the development of autoimmune pathologies.Treg is essential for the maintenance of peripheral tolerance and to control the immune response.We aim at finding a new cellular therapy for RA.It's dependent on the changes of Th subsets in RA patients.However,they still have disputes,especially the changes of Th17 and Treg.So,we firstly investigated percentages of Th1,Th17,Tfh and Treg in RA peripheral blood and within lymph node,spleen at CIA onset and peak.We found that all of them increased in RA patients and CIA mouse compared with that in healthy controls.Secondly,our study showed that igratimod can improve RA clinical symptoms by simultaneously reducing Th1,Th17,Tfh and increasing Treg.Besides,we got that Tfh dysregulation was positively correlated with RA and CIA severity and the imbalance among Th subsets and the functional impairment of Treg were responsible for CIA.Therefore,we proposed hypothesis that whether Tfh can be induced to diffenentiate into Treg to recover the balance among Th subsets.What's more,the induced Treg will work well for taking place of damaged Treg,ultimately leading to RA remission.Our results showed that it is possible to induce Tfh transdifferentiation to Treg.The finding riches the Tfh plasticity,and provides a theoretical possibility for differentiated Treg from Tfh in vivo as a new RA treatment strategy.