The Correlation Of T Follicular Cells (Tfh) And Antoimmune Bullous Diseases

Autoimmune bullous diseases (ABD) are a group of classic autoimmunediseases characterized by clinical erythema, blister, bulla and erosion. Commonlyseen in elderly individuals, they are famous of intractable and being tend torecurrent attacks. ABD is generally classified in two broad categories:intraepidermal and subepidermal bullous diseases. Pemphigus is most common inthe former group, and bullous pemphigoid is the typical representation of the latergroup[1].The immunological pathogenesis of ABD mediated by autoantibodies isgenerally accepted. It is confirmed that the binding of autoantibody to antigeninitiates a series of immune inflammatory events including activation ofcomplement, accumulation of inflammatory cell, release of proteinase andlysosomal enzyme that disrupts the critical adhesion molecules of epidermis orbasement membrane zone or affects the function of adhesion molecules directly,then leads to clinical blister or bulla[2].Recently advances were showed about thepathogenesis of ABD. It is clear that Dsg3and Dsg1are the major antigens ofpemphigus vulgaris and pemphigus foliaceus respectively and BPAG1(BP230)and BPAG2(BP180) are the antigen of bullous pemphigoid[3], but the source and emerging mechanism of autoantibody is not clear yet.Previous studies have shown that CD4+Th cells are required for B cellsprimed by T cell-denpendent antigen during the process of antibody production.Antibody secreting cells produced in germinal center (GC) where somatichypermutation, class switching of Ig and the choice of high affinity occurred. Thcells play a critical role in formation of GC, choice of high affinity B cellsdifferentiate into memory cells or plasma cells and maintain a prolonged humoralimmune response[4]. From recent studies it is believed that T follicular helpercells (Tfh) are responsible for helping B cells during antibody response. Tfhlocalize to the follicles, the transcription factor of them is Bcl-6, Tfh cellsexpressed high levels of CXCR5, ICOS, CD40L, OX40, PD-1, SAP, and so on,the combination of them with corresponding receptors or ligands on B cellssurface ensures Tfh help B cells produce high affinity antibodies. Tfh cellsproduce high levels of IL-21, by which they regulate the GC reactionappropriately[5].Recent studies support the involvement of Tfh cells in autoimmune diseases.Abnormal levels of Tfh cells were observed participating in GC formation andthe production of autoantibodies in many mice or patients with autoimmunediseases, including SLE, RA, MG and so on. Blocking the function of importantmolecules such as ICOS, CD40L and IL-21in Tfh resulted in reduced productionof antibodies[6-10]. Due to the source and mechanism of autoantibodies with ABDis not yet clear, and the major function of Tfh cells is help B cells to produceantibodies, by detecting the populations of Tfh cells in peripheral blood ofpatients with pemphigus and bullous pemphigoid, we explore preliminarywhether Tfh is involved in the incidence of ABD, seek further complement in thepathogenesis of ABD and find new ideas for the therapy of ABD. Objective: To explore the correlation of Tfh cells to ABD which representedby pemphigus and bullous pemphigoid.Methods: Peripheral blood was collected from pemphigus and BP patientsand normal controls. PBMC was extracted and serum was separated, doubleantibody sandwich ELISA was performed to measure the levels of serum IL-21,flow cytometry was performed to detect the level of Tfh in PBMCs, by which weexplore the correlation of Tfh cells to ABD.Results: The increase of Tfh cells in the peripheral blood of BP patients wasobserved compared with healthy controls (median11.25%versus4.95%,P<0.001). The populations of Tfh cells were positively correlated to the titer ofanti-BP180-NC16A in BP patients (R=0.712, P<0.01). Compared with healthycontrols, serum level of interleukin21(IL-21) was higher in the peripheral bloodof BP patients (103.98pg/ml versus46.77pg/ml, P<0.001). The levels of IL-21were positively correlated to the titer of anti-BP180-NC16A in BP patients(R=0.578, P=0.030). After therapy, accompanied by the remission of diseasesand decrease of titers of autoantibodies, the populations of Tfh cells weredescended compared with themselves before therapy (median10.50%versus4.10%, P=0.003). And the IL-21levels were declined too (median99.98pg/mlversus64.08pg/ml, P=0.012).Similarly, The increase of Tfh cells in the peripheral blood of pemphiguspatients was observed compared with healthy controls (median10.00%versus4.80%, P=0.001). Compared with healthy controls, serum level of IL-21washigher in the peripheral blood of pemphigus patients (median72.84pg/ml versus60.34pg/ml, P=0.011). After therapy, accompanied by the remission of diseasesand decrease of titers of autoantibodies, the populations of Tfh cells weredescended compared with themselves before therapy (median9.90%versus 5.00%，P=0.018); The IL-21levels were declined compared with themselvesbefore therapy too (median84.46pg/ml versus69.58pg/ml, P=0.028).Conclusion: Significant increase of Tfh cells populations were observed inpatients with pemphigus and BP, and IL-21, the major cytokine secteted by Tfhwas also increased compared with normal controls. Especially, Both of the Tfhpopulations and the IL-21levels show positive correlations with the titer ofanti-BP18NC16A autoantibodies in BP patients. After therapy, with the relief ofthe diseases, both of the levels of Tfh and IL-21were decreased compared withthemselves before therapy. These results suggest that Tfh cells play a critical rolein the autoantibody production of ABD and positively correlated with the diseaseseverity and activity. Our results provide new cues for searching of the source ofautoantibodies in ABD, add more mechanisms of ABD, and supply new ideasabout the therapy of ABD.