title: TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss.
abstract: The antiphospholipid syndrome (APS) is characterized by recurrent fetal loss, intrauterine growth restriction, and vascular thrombosis in the presence of antiphospholipid (aPL) Abs. Our studies in a murine model of APS induced by passive transfer of human aPL Abs have shown that activation of complement and recruitment of neutrophils into decidua are required for fetal loss, and emphasize the importance of inflammation in aPL Ab-induced pregnancy loss. In this study, we examine the role of TNF-alpha in pregnancy complications associated with aPL Abs in a murine model of APS. We show that aPL Abs are specifically targeted to decidual tissue and cause a rapid increase in decidual and systemic TNF-alpha levels. We identify the release of TNF-alpha as a critical intermediate that acts downstream of C5 activation, based on the fetal protective effects of TNF-alpha deficiency and TNF blockade and on the absence of increased TNF-alpha levels in C5-deficient mice treated with aPL Abs. Our results suggest that TNF-alpha links pathogenic aPL Abs to fetal damage and identify TNF blockade as a potential therapy for the pregnancy complications of APS.
authors.affiliation: Department of Medicine, Hospital for Special Surgery-Weill Medical College of Cornell University, 535 East 70th Street, New York, NY 10021, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Berman
authors.forename: Guillermina
authors.initials: G
authors.lastname: Girardi
authors.forename: Jane E
authors.initials: JE
authors.lastname: Salmon
mesh_terms: D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000097:blood / Q000276:immunology*; D016736:Antiphospholipid Syndrome / Q000276:immunology*; D003167:Complement Activation / Q000276:immunology; D003656:Decidua / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D011247:Pregnancy; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis* / Q000276:immunology
chemical_list: D017152:Antibodies, Antiphospholipid; D014409:Tumor Necrosis Factor-alpha