title: Cytoplasmic microvesicular form of Fas ligand in human early placenta: switching the tissue immune privilege hypothesis from cellular to vesicular level.
abstract: The local immune privilege of the fetus is created by the placenta. Fas ligand (FasL) expression in trophoblast has been implied as one of the mechanisms of fetal tolerance. However, the expression of membranal FasL by trophoblast has failed to explain this role of FasL. Two objections can be raised: (1) there have been contradictions considering which trophoblast cells, syncytiotrophoblast (ST) or cytotrophoblast, express FasL; (2) in vivo and in vitro studies have shown that the membranal form of FasL evokes inflammatory response and thus may promote fetal rejection. Using different assays and the FasL-specific antibody G247-4 we demonstrate beyond doubt that in vivo, (1) FasL is produced by and stored in the first trimester human ST only and (2) the human ST lacks surface membranal FasL. Instead, FasL, loaded in microvesicles, is stored in cytoplasmic granules. These results complement the recent in vitro studies of the microvesicular form of FasL secretion by cultured trophoblast cells, and suggest that placental FasL is synthesized by villous ST, stored in microvesicular form and secreted as exosomes. Secretion of the exosome-associated form of FasL may be one mechanism by which the placenta promotes a state of immune privilege. Additionally, FasL expression in Hofbauer cells is also demonstrated.
authors.affiliation: Department of Clinical Immunology, Umeå University, S-90185 Umeå, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Frängsmyr
authors.forename: V
authors.initials: V
authors.lastname: Baranov
authors.forename: O
authors.initials: O
authors.lastname: Nagaeva
authors.forename: U
authors.initials: U
authors.lastname: Stendahl
authors.forename: L
authors.initials: L
authors.lastname: Kjellberg
authors.forename: L
authors.initials: L
authors.lastname: Mincheva-Nilsson
mesh_terms: D000906:Antibodies / Q000276:immunology; D002824:Chorionic Villi / Q000737:chemistry / Q000648:ultrastructure; D003594:Cytoplasmic Granules / Q000378:metabolism*; D053222:Fas Ligand Protein; D005260:Female; D005333:Fetus / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000276:immunology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D014327:Trophoblasts / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000906:Antibodies; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D012333:RNA, Messenger