title: Potential new mechanisms of placental damage in celiac disease: anti-transglutaminase antibodies impair human endometrial angiogenesis.
abstract: Celiac disease (CD) is an autoimmune enteropathy triggered by gluten ingestion and characterized by circulating anti-transglutaminase type 2 (anti-TG2) autoantibodies. An epidemiological link between maternal CD and increased risk of pregnancy failure has been established; however, the mechanism underlying this association is still poorly understood. Because proper endometrial angiogenesis and decidualization are prerequisites for placental development, we investigated the effect of anti-TG2 antibodies on the process of endometrial angiogenesis. Binding of anti-TG2 antibodies to human endometrial endothelial cells (HEECs) was evaluated by ELISA. Angiogenesis was studied in vitro on HEECs and in vivo in a murine model. In particular, we investigated the effect of anti-TG2 antibodies on HEEC matrix metalloprotease-2 (MMP-2) activity by gelatin zymography, cytoskeletal organization and membrane properties by confocal microscopy, and activation of extracellular signal-regulated kinases (ERKs) and focal adhesion kinase (FAK) by Western blot analysis. Anti-TG2 antibodies bound to HEECs and decreased newly formed vessels both in vitro and in vivo. Anti-TG2 antibodies impaired angiogenesis by inhibiting the activation of MMP-2, disarranging cytoskeleton fibers, changing the physical and mechanical properties of cell membranes, and inhibiting the intracellular phosphorylation of FAK and ERK. Anti-TG2 antibodies inhibit endometrial angiogenesis affecting the TG2-dependent migration of HEECs and extracellular matrix degradation, which are necessary to form new vessels. Our results identify pathogenic mechanisms of placental damage in CD.
authors: Department of Obstetrics and Gynecology, Policlinico A. Gemelli, Università Cattolica Del Sacro Cuore, Rome, Italy.
authors: Nicoletta
authors: N
authors: Di Simone
authors: Marco
authors: M
authors: De Spirito
authors: Fiorella
authors: F
authors: Di Nicuolo
authors: Chiara
authors: C
authors: Tersigni
authors: Roberta
authors: R
authors: Castellani
authors: Marco
authors: M
authors: Silano
authors: Giuseppe
authors: G
authors: Maulucci
authors: Massimiliano
authors: M
authors: Papi
authors: Riccardo
authors: R
authors: Marana
authors: Giovanni
authors: G
authors: Scambia
authors: Antonio
authors: A
authors: Gasbarrini
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000032:analysis / Q000378:metabolism*; D002446:Celiac Disease / Q000097:blood / Q000276:immunology / Q000503:physiopathology*; D002465:Cell Movement; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D004717:Endometrium / Q000098:blood supply* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000737:chemistry / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011247:Pregnancy; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011499:Protein Processing, Post-Translational; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014591:Uterine Diseases / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D001323:Autoantibodies; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D019204:GTP-Binding Proteins
keywords: angiogenesis; celiac disease; cytoskeleton; endometrium; reproductive immunology