Allergen Immunotherapy Plays A Therapeutic Effect By Regulating The Function Of Tfh And Tfr Cells In Patients With Allergic Rhinitis

?Background?Allergic rhinitis(AR)is an IgE-mediated type I hypersensitivity reaction to airborne allergens.Despite the central role of IgE in the development of AR has been demonstrated by numerous studies,the mechanisms underlying the aberrant IgE production in AR remain elusive.Type 2 helper T(Th2)and regulatory T(Treg)cells had long been considered to regulate IgE production from B cells until follicular helper T(Tfh)and follicular regulatory T(Tfr)cells were identified as the major T helper(Th)cell subset type that control B cell response based on their localization in B-cell follicles and germinal center.However,the function of Tfh and Tfr cells in allergic diseases,especially in regulating IgE production,is poorly understood.Moreover,the relevance of Tfh and Tfr cells in allergen immunotherapy(AIT)remains to be defined.?Objective?(1)To establish the correlation between circulating Tfr cells and tonsil Tfr cells;(2)To investigate the frequency and phenotype of circulating Tfh subsets in patients with AR;(3)To explore the function of Tfh cells,especially in IgE production in patients with AR;(4)To examine the associations between Tfh and Tfr cell frequencies with antigen-specific IgE levels in patients with AR;(5)To examine the associations between Tfh and Tfr cells with disease severity in patients with AR;(6)To investigate the involvement of Tfh and Tfr cells in AIT in patients with AR.?Methods?(1)The number and localization of Tfr cells in human tonsils were analyzed by immunohistochemistry;(2)The phenotype and frequency of tonsillar and/or circulating Tfh and Tfr cells were characterized by flow cytometry;(3)The function of Tfh was examined in an assay by co-culturing with B cells,and the function of Tfr cells was examined in an assay by co-culturing with Tfh and B cells;(4)The disease severity and the antgen-specific IgE levels were recorded,and their relationship with T cell subsets in patients with AR were analyzed;(5)The combined symptom and medication score(CSMS),T cell subsets frequencies,and immunoglobulin levels were assessed before treatment(baseline)and at 3-,6-and12-month after treatment;(6)The associations between the changes of T cell subsets before and after AIT and AIT efficacy were analyzed.?Results?(1)Peripheral type 2 Tfh(Tfh2)cells,but not a counterpart type 2 non-Tfh cells,were increased in AR patients compared with controls;(2)Tfh2 cells secrete IL-4 to promote isotype switching to IgE in AR patients;(3)Dermatophagoides pteronyssinus(Der p)-specific IgE levels in patients with house dust mite induced AR positively correlated with the frequency of Dermatophagoides pteronyssinus group 1(Der p 1)-specific IL-4~+Tfh cells,but not non-Tfh cells;(4)AIT reduced the frequency of Der p 1-specific IL-4~+Tfh cells,and the reduction of Der p 1-specific IL-4~+Tfh cells correlated with the improvement of CSMS in AR patients;(5)Tfr cells were detected in germinal centers of tonsils but,compared to non-AR subjects,the frequencies declined in AR patients allergic to house dust mites;(6)Circulating Tfr cells in blood were phenotypically and numerically correlated with tonsillar Tfr cells;(7)A reduction of circulating Tfr cells,but not total or CXCR5~-Treg cells,was noted in AR patients compared to healthy controls;(8)Circulating Tfr cells in AR patients showed a specific defect in suppressing IgE production but were capable to suppress the production of other immunoglobulin types;(9)Associations of circulating Tfr cell frequencies and function with antigen-specific IgE levels or disease severity were identified in patients with AR;(10)The frequencies and function of circulating Tfr cells were improved after AIT;(11)The change of Tfr cells before and after AIT positively associated with disease remission.?Conclusion?(1)Allergen-specific IL-4~+Tfh cells may contribute to allergen-specific IgE production in patients with AR;(2)The changes of allergen-specific IL-4~+Tfh cells correlate with clinical efficacy of AIT in patients with AR;(3)The impairment of Tfr cells may contribute to aberrant IgE production in patients with AR;(4)AIT improves defective Tfr cell function in patients with AR;(5)Tfh and Tfr cells may serve as a potential biomarker to monitor clinical response to AIT.