Expression And Significance Of Programmed Death-1(PD-1)and Its Ligand PD-L1 In Endometriosis

Background and ObjectiveEndometriosis(EM)is one of the most common diseases among reproductive age women and the major reason that causes infertility.Increased chronic pelvic pain,dysmenorrhea,and dyspareunia are the typical symptoms of EM.These symptoms can have a serious impact on a patient's physical and mental health.A number of hypotheses have been proposed to explain its origin,and Sampson's theory of"retrograde menstrual reflux" is one such hypothesis that is widely accepted.However,Sampson's theory dose not explain all the phenomenon observed in EM.Thus,Lang and his team make supplement to it with theory of "eutopic endometria determined".They believe that the situation and microenvironment of eutopic endometriosis are the key to EM,while retrograde menstrual reflux is an incentive.Studies have shown that dysfunctions of immune cells in the uterine and abdominal cavity's microenvironment enhance the ability of endometrial cells to adhere and invade and are responsible for the increased proliferation and angiogenesis in as well as the poor clearance of ectopic endometrium.Therefore,the immune system is thought to play a vital role in the initiation and progression of EM.Patients with EM usually suffer from dysfunctions of immune system.Programmed death-1(PD-1;also known as CD279)is a negative regulator of T cells.Programmed death-L1(PD-L1,also known as CD274)is a ligand of PD-1.And PD-L1 is expressed on not only a variety of immune cells but also a wide range of non-immunologic cells.Under physiological conditions,the PD-1/PD-L1 pathway has emerged as a powerful immune regulatory system that can attenuate immune responses and limit immune-mediated tissue damage.However,under pathological conditions,including cancers and chronic infections,this pathway can suppress protective T cell responses and induce disorders of the immune system as a result of the abnormal expression of PD-1/PD-L1.The expression and functions of members of the PD-1/PD-L1 pathway have been intensively studied in many cancers and infected diseases.Moreover the PD-1/PD-L1 pathway has been used as a molecular marker and its antibodies used as immune therapies in clinical trials.We therefore hypothesized that PD-1 and PD-L1 are abnormally expressed in EM,and potentially regulated by IFN-?,TNF-? and 17-? estrogen(17-?E2).MethodsTo test these hypotheses,we examined the expression of PD-1/PD-L1 in endometrial tissues and blood that were collected from pre-menopausal women with EM(n=15)as well as control group(n=15)using immunohistochemistry,western blot and flow cytometry analysis.We also explored their expression patterns in endometrial cells,including glands and stroma,that were treated with or without IFN-?,TNF-? and 17-?E2.Results1.PD-1 and PD-L1 were expressed at higher levels in the eutopic/ectopic endometrium of women with EM than in controls;2.PD-1/PD-L1 expressed at high levels in CD4+/CD8+T leukomonocyte.3.PD-L1 expression was upregulated by E2 in eutopic epithelial cells in EM.Conclusion1.PD-1/PD-L1 pathway may be involved in immune dysfunctions in EM;2.The role of PD-1/PD-L1 pathway in EM was regulated by estrogen,;3.Providing a potential method for detecting and therapeutic target for immune therapy for EM.