Mechanism Of Action Of Thymic Stromal Lymphopoietin In Bullous Pemphigoid

Background:Bullous pemphigoid(BP)is a classical autoimmune dermatosis.Autoantibodies and type 2 helper T cells(Th)play important roles in the pathogenesis of BP.Thymic stromal lymphopoietin(TSLP),as an epithelium-derived cytokine,could activate dendritic cells(DC),promote proliferation of B cells and production of antibodies,as well as promote Th2 immune response.TSLP was involved in many autoimmune diseases and.inflammatory diseases.Thus far,the relationship between BP and TSLP was reported,whereas the specific mechanism is still unclear.Additionally,there have been no general research about TSLP and inflammatory dermatoses.This study aims to investigate the relationship between TSLP and inflammatory dermatoses with different immune patterns,and explore the pathogenesis of TSLP and DC in BP,to uncover specific function of TSLP in the mechanism of BP.Objectives:1.To investigate the expression of TSLP in lichen planus(LP),discoid lupus erythematosus(DLE),eczema,BP,psoriasis vulgaris(PsV),sarcoidosis and mycosis fungoid(MF),and to analyze the relationship between TSLP and those dermatoses.2.To investigate the relationship of TSLP and BP,and further investigate the role of DC in this relationship.3.To confirm that TSLP promote Th2 immune response by DC in pathogenesis of BP.Method:1.The paraffin sections of LP,DLE,eczema,BP,PsV,sarcoidosis and MF were acquired from the Department of Dermatology in Peking Union Medical Collage Hospital.The immunochemistry was applied to detect the level of TSLP in those sections.2.Subsequently,patients with BP who had visited the Department of Dermatology in Peking Union Medical Collage Hospital were enrolled.Their sera,blisters fluids and lesional skin were collected.The ELISA,immunochemistry and immunofluorescence were conducted to evaluate the protein of TSLP and DC,Langerhans cells.3.Finally,the human DC deriving from peripheral blood mononuclear cells were cultured and treated with blister fluids from patients with BP or other blister dermatoses and the blister fluids were neutralized by anti-TSLP antibodies or isotype antibodies.After the culture,the protein and mRNA of CCL-17 and CCL-22 were detected.The protein of CCL-17 and CCL-22 in blister fluids of patients of BP and controls were also detected.Results:1.TSLP was distinctly expressed in the epidermis of LP,BP,PsV,sarcoidosis,and MF specimens,and was also expressed in the dermis of PsV and sarcoidosis.2.Expression of TSLP were upregulated in sera,blisters fluids and lesional skin of BP.Expression of TSLP in BP lesional skin was associated with the amount of DC-SIGN-positive DC,but not associated with Langerhans cells.The DC-SIGN-positive DCs were also positive for TSLPR expression,whereas langerin-positive Langerhans cells did not express TSLPR.3.Once the TSLP in blister fluids were neutralized,expression of CCL-17 by human DC was decreased,but the difference of expression of CCL-22 between two groups was not significant.As compared with non-dermatitis patients,the levels of CCL-17 and CCL-22 in blister fluids of BP were elevated.Whereas the difference of levels of CCL-22 between BP patients' group and dermatitis patients' group.In fluids of BP,the levels of TSLP were correlated with the levels of CCL-17.Conclusions:1.TSLP is related to inflammatory dermatoses with various immune patterns,and may be involved in the pathogenesis of different inflammatory dermatoses widely.2.TSLP may activates DC-SIGN-positive DCs directly,which may be involved in the pathogenesis of BP.3.TSLP may promote Th2 immune response in the pathogenesis of BP by activating DC and promoting production of CCL-17.