title: Oxidized beta2-glycoprotein I induces human dendritic cell maturation and promotes a T helper type 1 response.
abstract: The human plasma protein beta2-glycoprotein I (beta2-GPI) is the most common target for antiphospholipid antibodies associated with thrombotic events in chronic disorders related to endothelial cell dysfunction. Crucial information is needed to clarify why this self-abundant protein is targeted by autoimmune responses. In this study, we investigated whether oxidative modification of beta2-GPI, either spontaneous in culture wells or induced by treatment with H2O2, renders this self-protein able to activate immature monocyte-derived dendritic cells (DCs) from healthy human donors. Oxidized beta2-GPI caused DCs to mature so that CD83 appeared and CD80, CD86, human leukocyte antigen-D region related (HLA-DR), and CD40 increased. The interaction between oxidized beta2-GPI and DCs specifically stimulated these cells to secrete interleukin 12 (IL-12), IL-1beta, IL-6, IL-8, tumor necrosis factor alpha (TNF-alpha), and IL-10. Oxidized beta2-GPI-stimulated DCs had increased allostimulatory ability and primed naive T lymphocytes, thus inducing T helper 1 (Th1) polarization. The interaction between oxidized beta2-GPI and DCs involved interleukin-1 receptor associated kinase (IRAK) phosphorylation and nuclear factor kappaB (NFkappaB) activation. Pretreatment of beta2-GPI with the antioxidant alpha-tocopherol prevented DC maturation. These findings show that human oxidized beta2-GPI, probably by interacting with a member of the Toll-like receptor (TLR) family, causes DCs to mature. Because this key beta2-GPI function requires oxidative modification, in several chronic disorders related to endothelial cell dysfunction oxidative stress might trigger the "autoimmune spiral."
authors.affiliation: Dipartimento di Malattie Infettive, Parassitarie ed Immunomediate, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Brigitta
authors.initials: B
authors.lastname: Buttari
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Profumo
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mattei
authors.forename: Alessandra
authors.initials: A
authors.lastname: Siracusano
authors.forename: Elena
authors.initials: E
authors.lastname: Ortona
authors.forename: Paola
authors.initials: P
authors.lastname: Margutti
authors.forename: Bruno
authors.initials: B
authors.lastname: Salvati
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sorice
authors.forename: Rachele
authors.initials: R
authors.lastname: Riganò
mesh_terms: D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006023:Glycoproteins / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D053482:beta 2-Glycoprotein I
chemical_list: D006023:Glycoproteins; D007378:Interleukins; D053482:beta 2-Glycoprotein I